![CHAPTER 1 INTRODUCTION TO NORMAL VALUES (REFERENCE RANGES)
Interpretation of Diagnostic Tests
CHAPTER 1 INTRODUCTION TO NORMAL VALUES (REFERENCE RANGES)
General Principles
References Values
GENERAL PRINCIPLES
The purpose of all testing (laboratory, radiologic, electrocardiographic [ECG], etc.) is to reduce clinical uncertainty. The degree of reduction varies with the test
characteristics and clinical situation. Modern medicine has superseded Voltaire's dictum that “the art of medicine consists of amusing the patient while nature cures
the disease.”
Many clinicians are still largely unaware of the reasoning process that they pursue in seeking a diagnosis and tend to follow an empirical path that was previously
successful or was learned during early training periods by observing their mentors during clinical rounds without appreciating the rationale for selecting, ordering, and
interpreting laboratory tests; this is often absorbed in a subliminal, informal, or rote fashion. The need to control health care costs and many recent studies on
laboratory test utilization have emphasized the need for a selective approach.
Some important principles in utilizing laboratory (and all other) tests are as follows:
1. Under the best of circumstances, no test is perfect (e.g., 100% sensitivity, specificity, predictive value). In any specific case, the results may be misleading. The
most sensitive tests are best used to rule out a suspected disease so that the number of false-negative tests is minimal; thus a negative test tends to exclude the
disease. The most specific tests are best used to confirm or exclude a suspected disease and minimize the number of false-positive results. Sensitivity and
specificity may be markedly altered by the coexistence of other disorders or by complications or sequelae of the primary disease.
2. Choice of tests should be based on the prior probability of the diagnosis being sought, which affects the predictive value of the test. This prior probability is
determined by the history, physical examination, and prevalence of the suspected disorder (in that community at that time), which is why history and physical
examination should precede ordering of tests. The clinician need not know the exact prior probability of the disease. Estimating this as high, intermediate, or low
is usually sufficient. Moderate errors in estimating prior probability have only relatively limited effects on interpretation of the tests. If the prior prevalence is high,
a positive result tends to confirm the presence of the disease, but an unexpected negative result is not very useful in ruling out the disease. Conversely, when
the prior prevalence is low, a normal result tends to rule out the disease, but an unexpected positive result is not very useful in confirming the disease. (See
Table 1-1 and Table 1-2.)
Table 1-1. Assuming a Low Prior Probability (10%) (in 1000 Tests, Disease is Present in 100 and Absent in 900)
Table 1-2. Assuming a High Prior Probability (90%) (in 1000 Cases Tested, Disease is Present in 900 and Absent in 100)
3. In the majority of laboratory measurements, the combination of short-term physiologic variation and analytic error is sufficient to render the interpretation of
single determinations difficult when the concentrations are in the borderline range. Any particular laboratory result may be incorrect for a large variety of
reasons, regardless of the high quality of the laboratory; such results should be rechecked. If indicated, a new specimen sample should be submitted with
careful confirmation of patient identification, prompt delivery to the laboratory, and immediate processing; in some circumstances, confirmation of test results at
another laboratory may be appropriate.
4. Reference ranges vary from one laboratory to another; the user should know what these ranges are for each laboratory used and should also be aware of
variations due to age, sex, race, size, physiologic status (e.g., pregnancy, lactation) that apply to the particular patient. These “normal” ranges represent
collected statistical data rather than classification of patients as having disease or being healthy and are based on the statistical definition of normal as 95%
range of values, whereby 5% of independent tests will be outside this normal range in the absence of disease. This is best illustrated in the use of multitest
chemical profiles for screening persons known to be free of disease. The probability of any given test being abnormal is approximately 2% to 5% and the
probability of disease if a screening test is abnormal is generally low (0% to 15%). The frequency of abnormal single tests is 1.5% (albumin) to 5.9% (glucose)
and up to 16.6% for sodium. Based on statistical expectations, when a panel of 8 tests is performed in a multiphasic health program, 25% of the patients have
one or more abnormal results and when the panel includes 20 tests, 55% have one or more test abnormalities. 1
5. Tables of reference values represent statistical data for 95% of the population; values outside of these ranges do not necessarily represent disease. Results
may still be within the reference range but be elevated above the patient's baseline, which is why serial testing is important in a number of conditions. For
example, in acute myocardial infarction, the increase in serum total creatine kinase (CK) may be abnormal for that patient although the value may be within
“normal” range.
6. An individual's test values when measured by a good laboratory tend to remain fairly consistent over a period of years when performed with comparable
technology; comparison of results with previous values obtained when the patient was not ill (if available) are often a better reference value than “normal”
ranges.
7. Multiple test abnormalities are more likely to be significant than single test abnormalities. When two or more tests for the same disorder are positive, the results
reinforce the diagnosis, but when only one test is positive and the other is not positive, the strength of the interpretation is diluted.
8. The greater the degree of abnormality of a test result, the more likely that a confirmed value is clinically significant or represents a real disorder. Thus, an
increase ten times the upper reference range is much more likely to be significant compared to a result that is only slightly increased. Most slightly abnormal
results are due to preanalytic factors.
9. Characteristic laboratory test profiles that are described in the literature and in this book represent the full-blown picture of the well-developed or far-advanced
case, but all abnormal tests may be present simultaneously in only a small fraction (e.g., one-third) of patients with that condition. Even when a test profile](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-8-320.jpg)
![Table 1-6. Pediatric Reference Ranges for Lymphocyte Counts
Carboxyhemoglobin <5% of total
Delta-aminolevulinic acid 1.5–7.5 mg/24-hr urine
Erythrocyte sedimentation rate (ESR)
Westergren
Males 0–13 mm in 1 hr
Females 0–20 mm in 1 hr
Wintrobe
Males 0–10 mm in 1 hr
Females 0–15 mm in 1 hr
Children 0–13 mm in 1 hr
Newborns 0–2 mm in 1 hr
Erythropoietin (radioimmunoassay [RIA])
Males 17.2 mU/mL (mean)
Females 18.8 mU/mL (mean)
Ferritin
Newborns 25–200 ng/mL
1 mo 200–600 ng/mL
2–5 mos 50–200 ng/mL
6 mos–15 yrs 7–142 ng/mL
Adult males 20–300 ng/mL
Adult females 15–120 ng/mL
Borderline (males or females) 10–20 ng/mL
Iron excess >400 ng/mL
Folate, erythrocyte
<1 yr 74–995 ng/mL
1–11 yrs 96–362 ng/mL
³12 yrs 180–600 ng/mL
Folate, serum ³3.5 µg/L
Free erythrocyte protoporphyrin (FEP) <100 µg/dL packed red blood cells (RBCs)
Glucose-6-phosphate dehydrogenase (G-6-PD) erythrocyte
2–17 yrs 6.4–15.6 U/gm hemoglobin (Hb)
³18 yrs 8.6–18.6 U/gm Hb
Haptoglobins Genetic absence in 1% of population
Newborns Absent in 90%; 10 mg/dL in 10%
Age 1–6 mos Gradual increase to 30 mg/dL
6 mos–17 yrs 40–180 mg/dL
Adults 40–270 mg/dL
Hemoglobin, plasma
³18 yrs old <15 mg/dL
Infants and newborns May be higher
Hemoglobin electrophoresis
HbA
0–30 days 10–40%
6 mos to adult >95%
HbA2
0–30 days <1%
1 yr to adult 1.5–3.0%
3–3.5% (borderline)
HbF <2%
No abnormal Hb variants
Hemoglobin F, RBC HbF remaining in <1% of RBCs
Hemosiderin, urine Negative
Iron, liver tissue 530–900 µg/gm dry weight
Iron, serum
Newborns 100–250 µg/dL
Infants 40–100 µg/dL
Children 50–120 µg/dL
Adults
Males 65–175 µg/dL
Females 50–170 µg/dL
Iron, urine 100–300 ng/24 hrs
Iron-binding capacity 250–450 µg/dL
% saturation 14–50%
Leukocyte alkaline phosphatase score 40–100
Lysozyme (muramidase), plasma 0.2–15.8 µg/mL
Lysozyme (muramidase), urine <3 mg/24 hrs
Marrow sideroblasts ³30% of normoblasts
Methemoglobin <3% of total
Myoglobin, serum £90 ng/mL
Myoglobin, urine 0–2 mg/mL
Osmotic fragility of RBC Increased if hemolysis occurs in >0.5% NaCl
Decreased if incomplete in 0.30% NaCl
Phosphofructokinase, erythrocyte 3.0–6.0 U/gm Hb
Plasma iron turnover rate 38 mg/24 hrs (0.47 mg/kg)
Pyruvate kinase, erythrocyte 2.0–8.8 U/gm Hb
Red blood cell survival time (sodium chromate [51
Cr]) Half-life: 25–35 days
Reticulocyte count
% 0.5–1.85% of erythrocytes
Absolute 29–87 × 109
/L
Ringed sideroblasts None
Transferrin 240–480 mg/dL
Unsaturated vitamin B12–binding capacity 870–1800 pg/mL
Urobilinogen, stool 50–300 mg/24 hrs
Urobilinogen, urine <4 mg/24 hrs
Vitamin B12, serum 190–900 ng/L
By seventh decade Decrease to 60–80%
Higher in black than in white populations](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-10-320.jpg)
![Volume (mL/kg body weight) MalesFemales
Blood 75 67
RBC 30 24
Plasma 44 43
Blood Coagulation Tests—Reference Values
Antithrombin III, plasma
Immunologic 17–30 mg/dL
Functional 80–120%
Bleeding time (Simplate) 3–9.5 mins
Clot retraction, qualitative Begins in 30–60 mins; complete within 24 hrs, usually within 6 hrs
Coagulation factor assay3
Activity Plasma Levels
I (fibrinogen)
Males 180–340 mg/dL
Females 190–420 mg/dL
II (prothrombin) 70–140%* 100 µg/mL
V (accelerator globulin) 70–160%* † 10 µg/mL
VII (proconvertin-Stuart) 65–170%* † 0.5 µg/mL
VIII (anti-hemophilic globulin) 55–145%* 0.1 µg/mL
IX 70–140%* † 5 µg/mL
X (Stuart factor) 70–140%* † 10 µg/mL
XI 65–145%* 5 µg/mL
XII (Hageman factor) 60–160%* 30 µg/mL
XIII 50–200%* 10 µg/mL
Factor VIII–related antigen 45–185%
Coagulation factor VIII inhibitor Negative
Coagulation time (Lee-White) 6–17 mins (glass tubes)
19–60 mins (siliconized tubes)
Euglobulin lysis No lysis in 2 hrs
Fibrinogen
Males 180–340 mg/dL
Females 190–420 mg/dL
Fibrinogen split products Negative at >1:4 dilution
Positive at >1:8 dilution
Fibrinolysins No clot lysis in 24 hrs
Lupus anticoagulant (dilute Russell viper venom time [dRVVT]) (plasma [P]) Negative
Partial thromboplastin time, activated (aPTT) 25–38 secs
Platelet aggregation Full response to adenosine diphosphate, epinephrine, and collagen
Platelet antibody, serum Negative
Platelet count 140,000–340,000/cu mm (Rees-Ecker)
150,000–350,000/cu mm (Coulter counter)
Protein C activity (P) 70–130%
Protein C antigen (P) 60–125%
Protein S activity, total or free (P)
Males 60–130%
Females 50–120%
Prothrombin time (PT), one stage ±2 secs of control (control should be 11–16 secs)
Ristocetin cofactor (P) 45–140%
Ristocetin-von Willebrand's factor (vWF) 45–140%
Thrombin time (TT) ±5 secs of control
vWF antigen, plasma 45–165%
Whole blood clot lysis No clot lysis in 24 hrs
*
Infants may not reach adult level until age 6 mos.
†
Increased with age in elderly.
Blood Chemistries—Reference Values
These values will vary, depending on the individual laboratory as well as the methods and instruments used. Each clinician should compare the applicability of these
data to his or her own situation.
Acetone 0.3–2.0 mg/dL
Aldolase
0–2 yrs 3.4–11.8 U/L
2–16 yrs 1.2–8.8 U/L
Adults (³17 yrs) 1.7–4.9 U/L
Ammonia 9–33 U/L
Newborns at term or premature <50 U/L
Amylase (total)
<18 yrs 0–260 U/L
Adults (³18 yrs) 35–115 U/L
Apolipoprotein A-I
Males 90–155 mg/dL
Females 94–172 mg/dL
Apolipoprotein B
Males 55–100 mg/dL
Females 45–110 mg/dL
Base, excess
Newborns –10 to –2 mEq/L
Infants –7 to –1 mEq/L
Children –4 to +2 mEq/L
Adults –3 to +3 mEq/L
Bicarbonate
Males Females
1–2 yrs 1–3 yrs 17–25 mEq/L](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-11-320.jpg)
![12–13 yrs 0.6–1.0 mg/dL
14–15 yrs 0.7–1.1 mg/dL
³16 yrs (adult values) 0.8–1.2 mg/dL
Cryoglobulins 0
Gamma-glutamyl transferase (GGT)
1–3 yrs 6–19 U/L
4–6 yrs 10–22 U/L
7–9 yrs 13–25 U/L
Males Females
10–11 yrs 17–30 U/L 17–28 U/L
12–13 yrs 17–44 U/L 14–25 U/L
14–15 yrs 12–33 U/L 14–26 U/L
16–19 yrs 11–34 U/L 11–28 U/L
Glucose (fasting) 60–100 mg/dL (depends on method)
Homocysteine, total 5–15 µmol/L
Desirable <10 µmol/L
Optimal <12 µmol/L
Borderline 12–15 µmol/L
Moderate hyperhomocystinemia >15–30 µmol/L
Intermediate hyperhomocystinemia >30–100 µmol/L
Severe hyperhomocystinemia >100 µmol/L
Isocitrate dehydrogenase (ICD) 3–85 U/L
Lactate 6.3–18.9 mg/dL
Lactate dehydrogenase (LD)
Newborn 160–1500 U/L
Infant 150–360 U/L
Child 150–300 U/L
Adult 100–250 U/L
LD isoenzymes
LD-1 17–28%
LD-2 30–36%
LD-3 19–25%
LD-4 10–16%
LD-5 6–13%
Lead
Adults <20 µg/dL
£15 yrs <10 µg/dL
Leptin
<15% body fat in men and <25% in women 1–16 µg/L
Leucine aminopeptidase (LAP) Depends on method
Lipase 56–239 U/L
Lipid fractionation (see Table 1-7 and Table 1-8)
Table 1-8. Lipid Fractionation: Desirable Levels for HDL Cholesterol and LDL Cholesterol a
Cholesterol esters 60–75% of total
Phospholipids 180–320 mg/dL
Magnesium 1.7–2.3 mg/dL
Myoglobin (serum [S]) £90 ng/mL
Osmolality 275–295 mOsm/kg
Oxygen
Saturation, arterial 96–100% of capacity
Tension, partial pressure of oxygen (pO 2), arterial while breathing room air
Newborns 60–75 mm Hg
<60 yrs >85 mm Hg
60 yrs >80 mm Hg
70 yrs >70 mm Hg
80 yrs >60 mm Hg
90 yrs >50 mm Hg
While breathing 100% oxygen >500 mm Hg
Oxygen dissociation, P50
(RBCs) 26–30 mm Hg
pH, arterial 7.36–7.44
pH, venous 7.32–7.38
Phenylalanine
£1 wk 42–124 µmol/L
<16 yrs 26–86 µmol/L
³16 yrs 41–68 µmol/L
Phosphatase, prostatic acid (PAP) <3.7 ng/mL
Phosphatase, alkaline (ALP)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-13-320.jpg)
![4–5 yrs 0.3–25.0 U/mL
5–6 yrs 0.2–17.6 U/mL
6–7 yrs 0.2–13.1 U/mL
7–8 yrs 0.3–46.1 U/mL
8–9 yrs 1.8–60.1 U/mL
9–10 yrs 3.6–81.0 U/mL
10–11 yrs 8.0–95.0 U/mL
11–12 yrs 1.5–99.7 U/mL
12–13 yrs 3.9–83.5 U/mL
13–16 yrs 3.3–188.0 U/mL
IgD 0–14 mg/dL
Sodium 135–145 mEq/L
Transaminase
Aspartate aminotransferase (AST; serum glutamic oxaloacetic transaminase [SGOT])
1–3 yrs 20–60 U/L
4–6 yrs 15–50 U/L
7–9 yrs 15–40 U/L
10–11 yrs 10–60 U/L
Males Females
12–15 yrs 15–40 U/L 10–30 U/L
16–19 yrs 15–45 U/L 5–30 U/L
Alanine aminotransferase (ALT; serum glutamic pyruvic transaminase [SGPT])
1–3 yrs 5–45 U/L
4–6 yrs 10–25 U/L
7–9 yrs 10–35 U/L
Males Females
10–11 yrs 10–35 U/L 10–30 U/L
12–13 yrs 10–55 U/L 10–30 U/L
14–15 yrs 10–45 U/L 5–30 U/L
16–19 yrs 10–40 U/L 5–35 U/L
Troponin I <1.6 ng/mL
Troponin T <0.1 ng/mL
Urea nitrogen, blood (BUN)
1–3 yrs 5–17 mg/dL
4–13 yrs 7–17 mg/dL
14–19 yrs 8–21 mg/dL
Uric acid
1–3 yrs 1.8–5.0 mg/dL
4–6 yrs 2.2–4.7 mg/dL
7–9 yrs 2.0–5.0 mg/dL
Males Females
10–11 yrs 2.3–5.4 mg/dL 3.0–4.7 mg/dL
12–13 yrs 2.7–6.7 mg/dL 3.0–5.8 mg/dL
14–15 yrs 2.4–7.8 mg/dL 3.0–5.8 mg/dL
16–19 yrs 4.0–8.6 mg/dL 3.0–5.9 mg/dL
Viscosity (correlates with fibrinogen, high-density lipoprotein [HDL] cholesterol) (viscosimeter)
Plasma 1.38±0.08 relative units
Serum 1.26±0.08 relative units
See Table 1-9.
Table 1-9. Reference Blood Values for Fetal Umbilical Blood at 18–40 Wks of Pregnancy (Hitachi 717 Analyzer)
Normal Blood and Urine Hormone Levels
Adrenocorticotropic hormone (ACTH), plasma £60 pg/mL
Aldosterone, serum
0–3 wks 16.5–154 ng/dL
1–11 mos 6.5–86 ng/dL
1–10 yrs (supine) 3.0–39.5 ng/dL
1–10 yrs (upright) 3.5–124 ng/dL
³11 yrs (morning specimen, peripheral vein) 1–21 ng/dL
Aldosterone, urine
0–30 days 0.7–11 µg/24 hrs
1–11 mos 0.7–22 µg/24 hrs
³1 yr 2–16 µg/24 hrs
Androstenedione, serum Males Females
0–7 yrs 0.1–0.2 ng/mL 0.1–0.3 ng/mL
8–9 yrs 0.1–0.3 ng/mL 0.2–0.5 ng/mL](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-15-320.jpg)
![CHAPTER 2 CRITICAL VALUES
Interpretation of Diagnostic Tests
CHAPTER 2 CRITICAL VALUES
Hematology
Blood Chemistry
Cerebrospinal Fluid
Microbiology
Urinalysis
Serology
Therapeutic Drugs
These values may indicate the need for prompt clinical intervention. Any sudden changes may also be critical. Also called action values or automatic call back values.
Values will vary according to the laboratory performing the tests as well as patient age and other factors.
HEMATOLOGY
Low High
Hct (packed cell volume) <20 vol% >60 vol%
Hb <7 gm/dL >20 gm/dL
Platelet count (adult) <40,000/cu mm >1,000,000/cu mm
Platelet count (pediatric) <20,000/cu mm >1,000,000/cu mm
aPTT None >78 secs
PT None >30 secs or >3× control level
Positive test for fibrin split products, protamine sulfate, high heparin level
Fibrinogen <100 mg/dL >700 mg/dL
WBC <2000/cu mm >30,000/cu mm
Presence of blast cells, sickle cells
New diagnosis of leukemia, sickle cell anemia, aplastic crisis
BLOOD CHEMISTRY
Low High
Ammonia None >40 µmol/L
Amylase None >200 U/L
Arterial pCO2 <20 mm Hg >70 mm Hg
Arterial pH <7.2 U >7.6 U
Arterial pO2 (adults) <40 mm Hg None
Arterial pO2 (newborns) <37 mm Hg (standard deviation [SD] = 7) 92 mm Hg (SD = 12)
Bicarbonate <10 mEq/L >40 mEq/L
Bilirubin, total (newborns) None >15 mg/dL
Calcium <6 mg/dL >13 mg/dL
Carbon dioxide <10 mEq/L >40 mEq/L
Cardiac troponin (cTn)
Cardiac troponin T (cTnT) None >0.1 µg/L
Cardiac troponin I (cTnI) None >1.6 µg/L
Chloride <80 mEq/L >115 mEq/L
CK None >3–5× upper limit of normal (ULN)
CK-MB None >5% or ³10 µg/L
Creatinine (except dialysis patients) None >5.0 mg/dL
Glucose <40 mg/dL >450 mg/dL
Glucose (newborns) <30 mg/dL >300 mg/dL
Magnesium <1.0 mg/dL >4.7 mg/dL
Phosphorus <1 mg/dL None
Potassium <2.8 mEq/L >6.2 mEq/L
Potassium (newborns) <2.5 mEq/L >8.0 mEq/L
Sodium <120 mEq/L >160 mEq/L
BUN (except dialysis patients) 2 mg/dL >80 mg/dL
CEREBROSPINAL FLUID
Low High
Glucose <80% of blood level
Protein, total None >45 mg/dL
Positive bacterial stain (e.g., Gram, acid-fast), antigen detection, culture, or India ink preparation
WBC in CSF None >10/cu mm
Presence of malignant cells or blasts or any other body fluid
MICROBIOLOGY
Positive blood culture
Positive Gram stain or culture from any body fluid (e.g., pleural, peritoneal, joint)
Positive acid-fast stain or culture from any site
Positive culture or isolate for Corynebacterium diphtheriae, Cryptococcus neoformans, Bordetella pertussis, Neisseria gonorrhoeae (only nongenital sites), dimorphic
fungi (Histoplasma, Coccidioides, Blastomyces, Paracoccidioides)
Presence of blood parasites (e.g., malaria organisms, Babesia, microfilaria)
Positive antigen detection (e.g., Cryptococcus, group B streptococci, Haemophilus influenzae type B, Neisseria meningitidis, Streptococcus pneumoniae)
Stool culture positive for Salmonella, Shigella, Campylobacter, Vibrio, or Yersinia](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-22-320.jpg)
![CHAPTER 3 CORE BLOOD ANALYTES: ALTERATIONS BY DISEASES
Interpretation of Diagnostic Tests
CHAPTER 3 CORE BLOOD ANALYTES: ALTERATIONS BY DISEASES
Alanine Aminotransferase (ALT; Serum Glutamic-Pyruvic Transaminase [SGPT])
Alkaline Phosphatase (ALP)
Ammonia
Antistreptococcal Antibody Titers (ASOT)
Apolipoproteins
Aspartate Aminotransferase (AST; Serum Glutamic-Oxaloacetic Transaminase [SGOT])
AST/ALT (SGOT/SGPT) Ratio
Autohemagglutination, Cold
Bilirubin
Blood Urea Nitrogen (BUN)/Creatinine Ratio
Calcium, Ionized
Calcium, Total
Chloride
Cholesterol, High-Density Lipoprotein (HDL) Cholesterol, Low-Density Lipoprotein (LDL) Cholesterol, Triglycerides
Complement
C-Reactive Protein (CRP)
Creatine
Creatine Kinase (CK), Total
Creatine Kinase (CK) Isoenzymes
Creatinine
Erythrocyte Sedimentation Rate (ESR)
5'-Nucleotidase (5'-N)
Gamma-Glutamyl Transferase (GGT)
Glucose
Immunoglobulin A (IgA)
Immunoglobulin D (IgD)
Immunoglobulin E (IgE)
Immunoglobulin G (IgG)
Immunoglobulin M (IgM)
Immunologic Tests
Inflammatory Reactants, Acute
Lactate Dehydrogenase (LD)
Lactate Dehydrogenase Isoenzymes
Leucine Aminopeptidase (LAP)
Magnesium (Mg)
Osmolality
Osmolal Gap >10 Due to
Phosphorus
Plasma, Discolored
Potassium
Pregnancy Test
Protein Gammopathies
Protein, Total
Protein Separation (Immunodiffusion, Immunofixation, Electrophoresis)
Sodium
Urea Nitrogen (BUN)
Uric Acid
Vitamin D
ALANINE AMINOTRANSFERASE (ALT; SERUM GLUTAMIC-PYRUVIC TRANSAMINASE [SGPT])
Use
Differential diagnosis of diseases of hepatobiliary system and pancreas
Repeat testing to establish chronicity of viral hepatitis
Generally parallels but lower than AST in alcohol-related diseases
Increased In
See serum AST
Obesity (not AST; modest increase to 1–3× ULN)
Severe preeclampsia (both)
Rapidly progressing acute lymphoblastic leukemia (both)
Levels in females ~75% of those in males
Decreased In
GU tract infection
Malignancy
Pyridoxal phosphate deficiency states (e.g., malnutrition, pregnancy, alcoholic liver disease)
Others
Albumin
(Generally parallels total protein except when total protein changes are due to gamma globulins)
Use
Marker of disorders of protein metabolism (e.g., nutritional, decreased synthesis, increased loss)
Increased In
Dehydration (relative increase)
Intravenous (IV) albumin infusions
Decreased In
Inadequate intake (e.g., malnutrition)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-24-320.jpg)
![Decreased absorption (e.g., malabsorption syndromes)
Increased need (e.g., hyperthyroidism, pregnancy)
Impaired synthesis (e.g., liver diseases, chronic infection, hereditary analbuminemia)
Increased breakdown (e.g., neoplasms, infection, trauma)
Increased loss (e.g., edema, ascites, burns, hemorrhage, nephrotic syndrome, protein-losing enteropathy)
Dilutional states (e.g., IV fluids, SIADH, psychogenic diabetes/water intoxication)
Congenital deficiency
ALKALINE PHOSPHATASE (ALP)
(See also Table 13-7.)
Use
Diagnosis of causes and monitoring of course of cholestasis (e.g., neoplasm, drugs)
Diagnosis of various bone disorders (e.g., Paget's disease, osteogenic sarcoma)
Interferences
Intravenous injection of albumin; sometimes marked increase (e.g., 10× normal level) lasting for several days (placental origin); total parenteral nutrition (TPN)
Decreased by collection of blood in EDTA, fluoride, or oxalate anticoagulant
Increased (£30%) by standing at room or refrigerator temperature
Increased In
Bone origin—increased deposition of calcium
Hyperparathyroidism.
Paget's disease (osteitis deformans) (highest reported values 10–20× normal). Marked elevation in absence of liver disease is most suggestive of Paget's
disease of bone or metastatic carcinoma from prostate.
Increase in cases of metastases to bone is marked only in prostate carcinoma.
Osteoblastic bone tumors (osteogenic sarcoma, metastatic carcinoma).
Osteogenesis imperfecta (due to healing fractures).
Familial osteoectasia.
Osteomalacia, rickets.
Polyostotic fibrous dysplasia.
Osteomyelitis.
Late pregnancy; reverts to normal level by 20th day postpartum.
Children.
Administration of ergosterol.
Hyperthyroidism.
Transient hyperphosphatasemia of infancy.
Hodgkin's disease.
Healing of extensive fractures (slightly).
Liver disease—any obstruction of biliary system (e.g., stone, carcinoma, primary biliary cirrhosis); is a sensitive indicator of intra- or extrahepatic cholestasis.
Whenever the ALP is elevated, a simultaneous elevation of 5'-NT establishes biliary disease as the cause of the elevated ALP. If the 5'-NT is not increased, the cause
of the elevated ALP must be found elsewhere, e.g., bone disease.
Nodules in liver (metastatic or primary tumor, abscess, cyst, parasite, tuberculosis [TB], sarcoid); is a sensitive indicator of a hepatic infiltrate. Increase >2×
upper limit of normal in patients with primary breast or lung tumor with osteolytic metastases is more likely due to liver than bone metastases.
Liver infiltrates (e.g., amyloid or leukemia).
Cholangiolar obstruction in hepatitis (e.g., infectious, toxic).
Hepatic congestion due to heart disease.
Adverse reaction to therapeutic drug (e.g., chlorpropamide) (progressive elevation of serum ALP may be first indication that drug therapy should be halted); may
be 2–20× normal.
Increased synthesis of ALP in liver.
Diabetes mellitus—44% of diabetic patients have 40% increase of ALP.
Parenteral hyperalimentation of glucose.
Liver diseases with increased ALP.
<3–4× increase lacks specificity and may be present in all forms of liver disease.
2× increase: acute hepatitis (viral, toxic, alcoholic), acute fatty liver, cirrhosis.
5× increase: infectious mononucleosis, postnecrotic cirrhosis.
10× increase: carcinoma of head of pancreas, choledocholithiasis, drug chole-static hepatitis.
15–20× increase: primary biliary cirrhosis, primary or metastatic carcinoma.
Chronic therapeutic use of anticonvulsant drugs (e.g., phenobarbital, phenytoin)
Hodgkin's disease.
Placental origin—appears 16th–20th wk of normal pregnancy, increases progressively to 2× normal up to onset of labor, disappears 3–6 days after delivery of
placenta. May be increased during complications of pregnancy (e.g., hypertension, preeclampsia, eclampsia, threatened abortion) but difficult to interpret without
serial determinations. Lower in diabetic than in nondiabetic pregnancy.
Intestinal origin—is a component in ~25% of normal sera; increases 2 hrs after eating in persons with blood type B or O who are secretors of H blood group. Has been
reported to be increased in cirrhosis, various ulcerative diseases of GI tract, severe malabsorption, chronic hemodialysis, acute infarction of intestine.
Benign familial hyperphosphatasemia.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-25-320.jpg)
![Multiple sclerosis in remission
Drugs (e.g., dexamethasone)
Decreased In
Drugs (e.g., ACTH)
ASPARTATE AMINOTRANSFERASE (AST; SERUM GLUTAMIC-OXALOACETIC TRANSAMINASE [SGOT])
Use
Differential diagnosis of diseases of hepatobiliary system and pancreas
Formerly surrogate test for screening blood donors for hepatitis
Interferences
Increase due to hemolysis, lipemia
Increase due to calcium dust in air (e.g., due to construction in laboratory)
Increased due to enzyme activation during test
Therapy with oxacillin, ampicillin, opiates, erythromycin
Decreased (because of increased serum lactate–consuming enzyme during test)
Diabetic ketoacidosis
Beriberi
Severe liver disease
Chronic hemodialysis (reason unknown)
Uremia—proportional to BUN level (reason unknown)
Increased In
Liver diseases (see Chapter 8)
Active necrosis of parenchymal cells is suggested by extremely high levels.
Acute viral hepatitis shows greatest increases; may be 20× to 100×.
Rapid rise and decline suggests extrahepatic biliary disease.
Administration of opiates to patients with diseased biliary tract or previous cholecystectomy causes increase in LD and especially AST. AST increases by 2–4
hrs, peaks in 5–8 hrs; increase may persist for 24 hrs; elevation may be 2.5–65× normal.
Congestion, e.g., heart failure, cirrhosis, biliary obstruction, primary or metastatic cancer, granulomas, hepatic ischemia.
Eclampsia.
Hepatotoxic drugs and chemicals (e.g., carbon tetrachloride).
Musculoskeletal disorders (see Chapter 10), including trauma, surgery, and IM injections
Myoglobinuria
Acute myocardial infarction
Others
Acute pancreatitis
Intestinal injury (e.g., surgery, infarction)
Local irradiation injury
Pulmonary infarction (relatively slight increase)
Cerebral infarction (increased in following week in 50% of patients)
Cerebral neoplasms (occasionally)
Renal infarction (occasionally)
Drugs (e.g., heparin therapy, salicylates, opiates, tetracycline, chlorpromazine [Thorazine], isoniazid)
Burns
Heat exhaustion
Mushroom poisoning
Lead poisoning (not useful for screening)
Hemolytic anemia
Marked Increase (>3000 U/L) In
Acute hypotension (e.g., AMI, sepsis, post–cardiac surgery)
Toxic liver injury (e.g., drugs)
Viral hepatitis
Liver trauma
Liver metastases
Rhabdomyolysis
Decreased In
Azotemia](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-30-320.jpg)
![See Chapter 8, Hepatobiliary Diseases and Diseases of the Pancreas.
Use
Differential diagnosis of diseases of hepatobiliary system and pancreas and other causes of jaundice.
Jaundice becomes apparent clinically at ³2.5 mg/dL.
Interferences
Exposure to either white or ultraviolet light decreases total and indirect bilirubin 2% to >20%.
Fasting for 48 hrs produces a mean increase of 240% in healthy persons and 194% in those with hepatic dysfunction.
Increased Direct (Conjugated) Bilirubin In
Hereditary disorders (e.g., Dubin-Johnson syndrome, Rotor's syndrome)
Hepatic cellular damage. Increased conjugated bilirubin may be associated with normal total bilirubin in up to one-third of patients with liver diseases.
Viral
Toxic
Alcohol related
Drug related
Methodologic interference
Evelyn-Malloy (dextran, novobiocin)
Diazo reaction (ethoxazene, histidine, indican, phenazopyridine, rifampin, theophylline, tyrosine)
SMA 12/60 (aminophenol, ascorbic acid, epinephrine, isoproterenol, levodopa, methyldopa, phenelzine)
Spectrophotometric methods (drugs that cause lipemia)
Other effects (e.g., toxic, cholestasis)
Biliary duct obstruction
Extrahepatic
Intrahepatic
Infiltrations, space-occupying lesions, e.g.,
Metastatic tumor
Abscess
Granulomas
Amyloidosis
Direct bilirubin
20–40% of total: more suggestive of hepatic than posthepatic jaundice
40–60% of total: occurs in either hepatic or posthepatic jaundice
>50% of total: more suggestive of posthepatic than hepatic jaundice
Total serum bilirubin >40 mg/dL indicates hepatocellular rather than extrahepatic obstruction.
Increased Unconjugated (Indirect) Bilirubin (Conjugated <20% of Total)
Increased bilirubin production
Hemolytic diseases (e.g., hemoglobinopathies, RBC enzyme deficiencies, disseminated intravascular coagulation [DIC], autoimmune hemolysis)
Ineffective erythropoiesis (e.g., PA)
Blood transfusions
Hematomas
Hereditary disorders (e.g., Gilbert's disease, Crigler-Najjar syndrome)
Drugs (e.g., causing hemolysis)
Decreased In
Drugs (e.g., barbiturates)
Interferences
Presence of hemoglobin
Exposure to sunlight or fluorescent light
Decreased In
Ingestion of certain drugs (e.g., barbiturates)
BLOOD UREA NITROGEN (BUN)/CREATININE RATIO
(See also Table 15-3.)
Normal range for healthy person on normal diet = 12–20; ratio for most individuals is 12–16. Because of considerable variability, should be used only as a rough](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-32-320.jpg)
![Malignant tumors (especially breast, lung, kidney; 2% of patients with Hodgkin's or non-Hodgkin's lymphoma)
Direct bone metastases (up to 30% of these patients) (e.g., breast cancer, Hodgkin's and non-Hodgkin's lymphoma, leukemia, pancreatic cancer, lung cancer)
Osteoclastic activating factor (e.g., multiple myeloma, Burkitt's lymphoma; may be markedly increased in adult T-cell [HTLV] lymphoma)
Humoral hypercalcemia of malignancy (parathyroid hormone–related protein [PTHrP])
Ectopic production of 1,25-dihydroxyvitamin D3 (e.g., Hodgkin's and non-Hodgkin's lymphoma)
Effect of drugs
Vitamin D intoxication
Milk-alkali (Burnett's) syndrome
Diuretic use (thiazide and chlorthalidone rarely increase serum calcium >1.0 mg/dL)
Use of therapeutic agents (estrogens, androgens, progestins, tamoxifen, lithium)
Others (e.g., vitamin A intoxication, thyroid hormone use, parenteral nutrition)
Chronic renal failure
Other endocrine conditions
Hyperthyroidism (in 20–40% of patients; usually <14 mg/dL)
Hypothyroidism in some patients, Cushing's syndrome, adrenal insufficiency acromegaly, pheochromocytoma, vasoactive intestinal polypeptide
hormone–producing tumor
Multiple endocrine neoplasia (MEN) syndrome
Granulomatous disease (1,25-dihydroxyvitamin D excess) (e.g., sarcoidosis, TB, leprosy, mycoses, berylliosis, silicone granulomas)
Acute osteoporosis (e.g., immobilization of young patients or in Paget's disease)
Polyuric phase of acute renal failure
Miscellaneous
Familial hypocalciuric hypercalcemia
Rhabdomyolysis causing acute renal failure
Porphyria
Dehydration with hyperproteinemia
Hypophosphatasia
Idiopathic hypercalcemia of infancy
Decreased In
Hypoparathyroidism
Surgical
Idiopathic
Infiltration of parathyroids (e.g., sarcoidosis, amyloidosis, hemochromatosis, tumor)
Congenital (DiGeorge syndrome)
Pseudohypoparathyroidism
Malabsorption of calcium and vitamin D
Obstructive jaundice
Chronic renal disease with uremia and phosphate retention; Fanconi's syndrome; renal tubular acidosis
Acute pancreatitis with extensive fat necrosis
Insufficient calcium, phosphorus, and vitamin D ingestion
Bone disease (osteomalacia, rickets)
Starvation
Late pregnancy
Use of certain drugs
Cancer chemotherapy drugs (e.g., cisplatin, mithramycin, cytosine arabinoside)
Fluoride intoxication
Antibiotics (e.g., gentamicin, pentamidine, ketoconazole)
Chronic therapeutic use of anticonvulsant drugs (e.g., phenobarbital, phenytoin)
Loop-active diuretics
Calcitonin
Multiple citrated blood transfusions
Neonates born of complicated pregnancies
Hyperbilirubinemia
Respiratory distress, asphyxia
Cerebral injuries
Infants of diabetic mothers
Prematurity
Maternal hypoparathyroidism
Hypomagnesemia
Malignant disease](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-35-320.jpg)
![Toxic shock syndrome
Rhabdomyolysis
Tumor lysis syndrome
Temporary hypocalcemia after subtotal thyroidectomy in >40% of patients; >20% are symptomatic.
Concomitant hypokalemia is not infrequent in hypercalcemia. Concomitant dehydration is almost always present because hypercalcemia causes nephrogenic diabetes
insipidus.
CHLORIDE
Use
With sodium, potassium, and carbon dioxide to assess electrolyte, acid-base, and water balance. Usually changes in same direction as sodium except in metabolic
acidosis with bicarbonate depletion and metabolic alkalosis with bicarbonate excess when serum sodium levels may be normal.
Interferences
Hyperlipidemia (artifactual change; see Sodium)
Increased In
Metabolic acidosis associated with prolonged diarrhea with loss of NaHCO 3
Renal tubular diseases with decreased excretion of H+
and decreased reabsorption of HCO3
– (“hyperchloremic metabolic acidosis”)
Respiratory alkalosis (e.g., hyperventilation, severe central nervous system [CNS] damage)
Drugs
Excessive administration of certain drugs (e.g., NH4Cl, IV saline, salicylate intoxication; acetazolamide therapy)
False (methodological) increase due to bromides or other halogens
Retention of salt and water (e.g., corticosteroids, guanethidine, phenylbutazone)
Some cases of hyperparathyroidism
Diabetes insipidus, dehydration
Sodium loss > chloride loss (e.g., diarrhea, intestinal fistulas)
Ureterosigmoidostomy
Decreased In
Prolonged vomiting or suction (loss of HCl)
Metabolic acidoses with accumulation of organic anions (see Anion Gap Classification)
Chronic respiratory acidosis
Salt-losing renal diseases
Adrenocortical insufficiency
Primary aldosteronism
Expansion of extracellular fluid (e.g., SIADH, hyponatremia, water intoxication, congestive heart failure)
Burns
Drugs
Alkalosis (e.g., bicarbonates, aldosterone, corticosteroids)
Diuretic effect (e.g., ethacrynic acid, furosemide, thiazides)
Other loss (e.g., chronic laxative abuse)
CHOLESTEROL, HIGH-DENSITY LIPOPROTEIN (HDL) CHOLESTEROL, LOW-DENSITY LIPOPROTEIN (LDL) CHOLESTEROL,
TRIGLYCERIDES
See Disorders of Lipid Metabolism.
COMPLEMENT
Use
Evaluate role of complement in immune disorders.
Determine if deficiency is acquired or genetic.
Normal In
Renal diseases
IgG-IgA nephropathy (Berger's disease)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-36-320.jpg)
![Highest levels are found in acute bacterial infections (>30 mg/dL) but <20 mg/dL in acute viral infections.
Lower in viral compared to bacterial infection but may be very high in both. CSF CRP has been reported specific to differentiate bacterial from viral meningitis.
Infections in various sites (e.g., newborns; GU, GI, and biliary tracts, pelvic inflammatory disease [PID], CNS) or due to other organisms (e.g., parasites, fungi).
In premature rupture of membranes, CRP >12.5 mg/dL in cord blood strongly suggests chorioamnionitis.
Increased CRP in seriously ill neonate is indication for immediate vigorous antibiotic therapy.
In children younger than 6 yrs with meningitis, CRP >20 mg/dL after 12 hrs (50 mg/dL in older patients) suggests bacterial rather than viral cause.
Not Increased In
Autoimmune diseases (e.g., SLE, mixed connective tissue disease, dermatomyositis, scleroderma): Little or no increase unless infection is present.
Pregnancy
Strenuous exercise
Angina
Cerebrovascular accident
Seizures
Asthma
Common cold
Rejection of heart transplant
CREATINE
Use
Is rarely used clinically.
Increased In
High dietary intake (meat)
Destruction of muscle
Hyperthyroidism (this diagnosis almost excluded by normal serum creatine)
Active RA
Testosterone therapy
Decreased In
Not clinically significant
Drugs (e.g., TMP/SMX, cimetidine, cefoxitin)
Interferences
Artifactual decrease in diabetic ketoacidosis
CREATINE KINASE (CK), TOTAL
Use
Marker for injury or diseases of cardiac with good specificity
Measurement of choice for striated muscle disorders (see Chapter 10)
Increased In
Necrosis or inflammation of cardiac muscle
Disorders listed under CK-MB (CK index usually >2.5%)
Necrosis, inflammation or acute atrophy of striated muscle (see Chapter 10)
Disorders listed under CK-MB (CK index usually <2.5%)
Muscular dystrophy
Myotonic dystrophy
Amyotrophic lateral sclerosis (>40% of cases)
Polymyositis (70% of cases; average 20× ULN)
Thermal and electrical burns (values usually higher than in AMI)
Rhabdomyolysis (especially with trauma and severe exertion); marked increase may be 1000× ULN
Severe or prolonged exercise as in marathon running (begins 3 hrs after start of exercise; peaks after 8–16 hrs; usually normal by 48 hrs); smaller increases in
well-conditioned athletes
Status epilepticus
Parturition and frequently the last few weeks of pregnancy
Malignant hyperthermia
Hypothermia
Familial hypokalemic periodic paralysis](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-39-320.jpg)
![McArdle's disease
Drugs and chemicals
Cocaine
Alcohol
Emetine (ipecac) (e.g., bulimia)
Toxic chemicals (benzene ring compounds [e.g., xylene] depolarize surface membrane and leach out low-molecular-weight enzymes, producing very high levels
of total CK [100% MM] with increased LD 3–5× normal)
Half of patients with extensive brain infarction. Maximum levels in 3 days; increase may not appear before 2 days; levels usually less than in AMI and remain
increased for longer time; return to normal within 14 days; high mortality associated with levels >300 IU. Elevated serum CK in brain infarction may obscure diagnosis
of concomitant AMI.
Some persons with large muscle mass (£2× normal) (e.g., football players)
Slight Increase Occasionally In
IM injections. Variable increase after IM injection to 2–6× normal level. Returns to normal 48 hrs after cessation of injections. Rarely affects CK-MB, LD-1, AST.
Muscle spasms or convulsions in children
Moderate hemolysis
Normal In
Pulmonary infarction
Renal infarction
Liver disease
Biliary obstruction
Some muscle disorders
Thyrotoxicosis myopathy
Steroid myopathy
Muscle atrophy of neurologic origin (e.g., old poliomyelitis, polyneuritis)
PA
Most malignancies
Scleroderma
Acrosclerosis
Discoid lupus erythematosus
Decreased In
Decreased muscle mass (e.g., old age, malnutrition, alcoholism)
RA (approximately two-thirds of patients)
Untreated hyperthyroidism
Cushing's disease
Connective tissue disease not associated with decreased physical activity
Pregnancy level (8th to 12th wk) is said to be ~75% of nonpregnancy level
Various drugs (e.g., phenothiazine, prednisone, estrogens, tamoxifen, ethanol), toxins, and insecticides (e.g., aldrin, dieldrin)
Metastatic tumor in liver
Multiple organ failure
Intensive care unit patients with severe infection or septicemia
CREATINE KINASE (CK) ISOENZYMES
Use
CK-MB is the most widely used early marker for myocardial injury.
CK-MB Increased In
Necrosis of cardiac muscle (CK index >2.5%; in all other causes, CK index usually <2.5%)
AMI.
Cardiac contusion.
After thoracic/open heart surgery, values return to baseline in 24–48 hrs. AMI is difficult to diagnose in first 24 postoperative hrs.
Resuscitation for cardiac arrest may increase CK and CK-MB in ~50% of patients with peak at 24 hrs due to defibrillation (>400 J) and chest compression but
CK-MB/CK total ratio may not be increased even with AMI.
Percutaneous transluminal coronary angioplasty.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-40-320.jpg)
![Myocarditis.
Prolonged supraventricular tachycardia.
Cardiomyopathies (e.g., hypothyroid, alcohol).
Collagen diseases involving the myocardium.
Coronary angiography (transient).
Necrosis, inflammation, or acute atrophy of striated muscle
Exercise myopathy; slight to significant increases in 14–100% of persons after extreme exercise (e.g., marathons); smaller increases in well-conditioned athletes
Skeletal muscle trauma with rhabdomyolysis, myoglobinuria
Skeletal muscle diseases (e.g., myositis, muscular dystrophies, polymyositis, collagen vascular diseases [especially SLE])
Familial hypokalemic periodic paralysis
Electrical and thermal burns and trauma (~50% of patients; but not supported by LD-1 > LD-2)
Drugs (e.g., alcohol, cocaine, halothane [malignant hyperthermia], ipecac)
Endocrine disorders (e.g., hypoparathyroidism, acromegaly, diabetic ketoacidosis; hypothyroidism—total CK 4–8× ULN in 60–80% of cases; becomes normal within 6
wks of initiating replacement therapy)
Some infections
Viral (e.g., HIV, Epstein-Barr virus [EBV], influenza, picornaviruses, coxsackievirus, echoviruses, adenoviruses)
Bacterial (e.g., Staphylococcus, Streptococcus, Clostridium, Borrelia)
Rocky Mountain spotted fever
Fungal
Parasitic (e.g., trichinosis, toxoplasmosis, schistosomiasis, cysticercosis)
Other conditions
Malignant hyperthermia; hypothermia
Reye's syndrome
Peripartum period for first day beginning within 30 mins
Acute cholecystitis
Hyperthyroidism and chronic renal failure may cause persistent increase, although the proportion of CK-MB remains low
Acute exacerbation of obstructive lung disease
Drugs (e.g., aspirin, tranquilizers)
Carbon monoxide poisoning
Some neoplasms (see Tumor Markers)
For example, prostate, breast.
Increase in 90% of patients after cryotherapy for prostate carcinoma with peak at 16 hrs to ~5× upper limit of normal value; similar increase in total CK.
% Activity Distribution of CK Isoenzymes in Tissue
CK-MM CK-MB CK-BB
Skeletal muscle 99 1 0
Myocardium 77 22 1
Brain 4 0 96
CK-MB >15–20% should raise the possibility of an atypical macro CK-MB.
CK-MB Not Increased In
Angina pectoris, coronary insufficiency, exercise testing for coronary artery disease, or pericarditis; an increase implies some necrosis of cardiac muscle even if a
discrete infarct is not identified.
After cardiopulmonary bypass, cardiac catheterization (including Swan-Ganz), cardiac pacemaker implantation, and coronary arteriography unless myocardium has
been injured by catheter
IM injections (total CK may be slightly increased)
Seizures (total CK may be markedly increased)
Brain infarction or injury (total CK may be increased)
CK-BB Isoenzyme
Use
Is rarely encountered clinically.
CK-BB May Be Increased In
Malignant hyperthermia, uremia, brain infarction or anoxia, Reye's syndrome, necrosis of intestine, various metastatic neoplasms (especially prostate), biliary atresia
Atypical Macro Isoenzyme
(High-molecular-mass complex of a CK isoenzyme and immunoglobulin, most often CK-BB and monoclonal IgG and a kappa light chain)
May cause falsely high or low CK-MB results (depending on type of assay), resulting in an incorrect diagnosis of myocardial infarction or delayed recognition of a real
myocardial infarction.
Discovered in <2% of all CK isoenzyme electrophoresis studies.
Type 1 Type 2
Electrophoretic location Between CK-MM and CK-MB Cathode side of CK-MM
Prevalence (%) 0.43 1.30
Associated disorders Myositis Malignancy
Autoimmune disease](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-41-320.jpg)
![CREATININE
Use
Diagnosis of renal insufficiency. Serum creatinine is a more specific and sensitive indicator of renal disease than BUN. Use of simultaneous BUN and creatinine
determinations provides more information in conditions listed in next section.
Increased In
Diet
Ingestion of creatinine (roast meat)
Muscle disease
Gigantism
Acromegaly
Prerenal azotemia (see BUN)
Postrenal azotemia (see BUN)
Impaired kidney function; 50% loss of renal function is needed to increase serum creatinine from 1.0 to 2.0 mg/dL; therefore not sensitive to mild to moderate renal
injury.
Decreased In
Pregnancy—normal value is 0.4–0.6 mg/dL. >0.8 mg/dL is abnormal and should alert clinician to further diagnostic evaluation.
Interferences
(Depending on methodology)
Artifactual decrease by
Marked increase of serum bilirubin
Enzymatic reaction (glucose >100 mg/dL)
Artifactual increase due to
Reducing alkaline picrate (e.g., glucose, ascorbate, uric acid). Ketoacidosis may substantially increase serum creatinine results with alkaline picrate reaction.
Formation of colored complexes (e.g., acetoacetate, pyruvate, other ketoacids, certain cephalosporins).
Enzymatic reaction (flucytosine [5-fluorocytosine] may increase serum creatinine £0.6 mg/dL).
Other methodologic interference (e.g., ascorbic acid, PSP, L-dopa, para-aminohippurate).
ERYTHROCYTE SEDIMENTATION RATE (ESR)
See Table 3-1.
Table 3-1. Changes in Erythrocyte Sedimentation Rate
Use
mIndicates presence and intensity of an inflammatory process; never diagnostic of a specific disease. Changes are more significant than a single abnormal
occurrence.
Detect occult disease (e.g., screening program), but a normal ESR does not exclude malignancy or other serious disease.
Monitor the course of or response to treatment of certain diseases (e.g., temporal arteritis, polymyalgia rheumatica, acute rheumatic fever, RA, SLE, Hodgkin's
disease, TB, bacterial endocarditis). ESR is normal in 5% of patients with RA or SLE.
wConfirm or exclude a diagnosis (a normal ESR virtually excludes diagnosis of temporal arteritis or polymyalgia rheumatica; >50 mm/hr in 90% of these patients).
Rarely may assist in differential diagnosis (e.g., acute myocardial infarction versus angina pectoris; early acute appendicitis versus ruptured ectopic pregnancy or
acute pelvic inflammatory disease; RA versus osteoarthritis; acute versus quiescent gout).
ESR is said to be useful to differentiate iron deficiency anemia (ESR normal) from anemia of acute or chronic disease alone or combined with iron deficiency, in which
ESR is almost always increased.
Rarely (6 in 10,000) useful for screening of asymptomatic persons after history and physical examination. Unexplained increase with no detectable disease occurs in
<3% of cases.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-42-320.jpg)
![mHyperviscosity syndrome should be suspected in patients with hyperproteinemia (e.g., multiple myeloma, Waldenström's macroglobulinemia) with rouleaux formation
but no increase of ESR.
mExtreme elevation of ESR is found particularly in association with malignancy (most frequently malignant lymphoma, carcinomas of colon and breast), hematologic
diseases (most frequently myeloma), collagen diseases (e.g., RA, SLE), renal diseases (especially with azotemia), drug fever, and other conditions (e.g., cirrhosis). In
patients with cancer, ESR >100 mm/hr indicates metastases. Other causes of ESR >100 mm/hr are severe infections (osteomyelitis, SBE), giant cell arteritis,
polymyalgia rheumatica, renal diseases.
Interferences That Increase ESR
Macrocytosis
Hypercholesterolemia
Increased fibrinogen, gamma or beta globulins
Technical factors (e.g., tilted ESR tube, high room temperature)
Drugs (e.g., dextran, methyldopa, methysergide, penicillamine, theophylline, trifluperidol, vitamin A)
Interferences That Decrease ESR
Polycythemia, vera or secondary
Abnormal RBCs, especially sickle cells; hereditary spherocytosis; acanthocytosis
Microcytosis (e.g., HbC disease)
Hypofibrinogenemia (e.g., DIC, massive hepatic necrosis)
High WBC count
Technical factors (e.g., short ESR tube, low room temperature, delay in test performance >2 hrs, clotted blood sample, excess anticoagulation)
Drugs (e.g., quinine [therapeutic], salicylates [therapeutic], drugs that cause a high glucose level, high doses of adrenal steroids)
Increased In
Chronic inflammatory diseases, especially collagen and vascular diseases
Postoperative (may be increased for up to 1 mo), postpartum
Decreased In
Congestive heart failure
Cachexia
High doses of adrenal steroids
Factors That Do Not Affect ESR
Body temperature
Recent meal
Aspirin
Nonsteroidal anti-inflammatory drugs
Formula for normal range Westergren ESR:
5'-NUCLEOTIDASE (5'-N)
Use
Is rarely used.
May aid in differential diagnosis of hepatobiliary disease during pregnancy.
Increased Only In
Obstructive type os hepatobiliary disease.
May be an early indication of liver metastases in the cancer patient, especially if jaundice is absent.
Normal In
Pregnancy and postpartum period (in contrast to serum LAP and ALP).](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-43-320.jpg)
![GAMMA-GLUTAMYL TRANSFERASE (GGT)
Use
In liver disease, generally parallels changes in serum ALP.
Sensitive indicator of occult alcoholism
Diagnosis of liver disease in presence of bone disease or pregnancy, or in childhood; serum ALP and LAP increased but not GGT.
Increased In
Liver disease—generally parallels changes in serum ALP, LAP, and 5'-nucleotidase but is more sensitive.
Acute hepatitis. Elevation is less marked than that of other liver enzymes, but it is the last to return to normal and therefore is useful to indicate recovery.
Chronic active hepatitis. Increased (average >7× ULN) more than in acute hepatitis. More elevated than AST and ALT. In dormant stage, may be the only
enzyme elevated.
In alcoholic hepatitis, average increase is >3.5× ULN.
Cirrhosis. In inactive cases, average values are lower (4× ULN) than in chronic hepatitis. Increase >10–20 times in cirrhotic patients suggests superimposed
primary carcinoma of the liver (average increase >21× ULN).
Primary biliary cirrhosis. Elevation is marked: average >13× ULN.
Fatty liver. Elevation parallels that of AST and ALT but is greater.
Obstructive jaundice. Increase is faster and greater than that of serum ALP and LAP. Average increase >5× ULN.
Liver metastases. Parallels ALP; elevation precedes positive liver scans. Average increase >14× ULN.
Cholestasis. In mechanical and viral cholestasis, GGT and LAP are about equally increased, but in drug-induced cholestasis, GGT is much more increased than
LAP. Average increase >6× ULN.
Children. Much more increased in biliary atresia than in neonatal hepatitis (300 U/L is useful differentiating level). Children with alpha 1-antitrypsin deficiency
have higher levels than other patients with biliary atresia.
Pancreatitis: Always elevated in acute pancreatitis. In chronic pancreatitis is increased when involvement of the biliary tract or active inflammation is present.
Acute myocardial infarction. Increased in 50% of patients. Elevation begins on fourth to fifth day, reaches maximum at 8–12 days. With shock or acute right heart
failure, may have early peak within 48 hrs, with rapid decline followed by later rise.
Heavy use of alcohol: Is the most sensitive indicator and a good screening test for alcoholism, because elevation exceeds that of other commonly assayed liver
enzymes.
Various drugs (e.g., barbiturates, phenytoin, tricyclic antidepressants, acetaminophen)
Some cases of carcinoma of prostate
Neoplasms, even in absence of liver metastases; especially malignant melanoma, carcinoma of breast and lung; highest levels in hypernephroma
Other conditions (e.g., gross obesity [slight increase], renal disease, cardiac disease, postoperative state)
Normal In
Pregnancy (in contrast to serum ALP, LAP) and children older than 3 mos; therefore may aid in differential diagnosis of hepatobiliary disease occurring during
pregnancy and childhood.
Patients with bone disease or with increased bone growth (children and adolescents); therefore useful in distinguishing bone disease from liver disease as a cause of
increased serum ALP.
Renal failure
Strenuous exercise
GLUCOSE
Use
Diagnosis of diabetes mellitus (defined by World Health Organization as unequivocal increase of fasting serum [or plasma] glucose ³126 mg/dL on more than one
occasion or any glucose level ³200 mg/dL)
Control of diabetes mellitus
Diagnosis of hypoglycemia
May Be Increased In
Diabetes mellitus, including
Hemochromatosis
Cushing's syndrome (with insulin-resistant diabetes)
Acromegaly and gigantism (with insulin-resistant diabetes in early stages; hypopituitarism later)
Increased circulating epinephrine
Adrenalin injection
Pheochromocytoma
Stress (e.g., emotion, burns, shock, anesthesia)
Acute pancreatitis
Chronic pancreatitis (some patients)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-44-320.jpg)
![Wernicke's encephalopathy (vitamin B 1 deficiency)
Some CNS lesions (subarachnoid hemorrhage, convulsive states)
Effect of drugs (e.g., corticosteroids, estrogens, alcohol, phenytoin, thiazides, propran olol, vitamin A [chronic hypervitaminosis])
May Be Decreased In
Pancreatic disorders
Islet cell tumor, hyperplasia
Pancreatitis
Glucagon deficiency
Extrapancreatic tumors
Carcinoma of adrenal gland
Carcinoma of stomach
Fibrosarcoma
Other
Hepatic disease
Diffuse severe disease (e.g., poisoning, hepatitis, cirrhosis, primary or metastatic tumor)
Endocrine disorders
Hypopituitarism*
Addison's disease
Hypothyroidism
Adrenal medulla unresponsiveness
Early diabetes mellitus
Functional disturbances
Postgastrectomy
Gastroenterostomy
Autonomic nervous system disorders
Pediatric anomalies
Prematurity*
Infant of diabetic mother*
Ketotic hypoglycemia
Zetterstrom's syndrome
Idiopathic leucine sensitivity
Spontaneous hypoglycemia in infants
Enzyme diseases
von Gierke's disease*
Galactosemia*
Fructose intolerance*
Amino acid and organic acid defects*
Methylmalonic acidemia*
Glutaric acidemia, type II*
Maple syrup urine disease*
3-hydroxy, 3-methyl glutaric acidemia*
Fatty acid metabolism defects*
Acyl coenzyme A dehydrogenase defects*
Carnitine deficiencies*
Other
Exogenous insulin (factitious)
Oral hypoglycemic medications (factitious)
Leucine sensitivity
Malnutrition
Hypothalamic lesions
Alcoholism
*
May cause neonatal hypoglycemia.
Interferences
Blood samples in which serum is not separated from blood cells will show glucose values decreasing at rate of 3–5%/hr at room temperature.
Most glucose strips and meters quantify whole blood glucose, whereas most laboratories use plasma or serum, which reads 10–15% higher.
Postprandial capillary glucose is £36 mg/dL higher than venous glucose at peak of 1 hr postprandial; usually returns to negligible difference with fasting level within 4
hrs but in ~15% of patients may still be >20 mg/dL difference.
Considerable imprecision is found between glucose meters from the same manufacturer and between different types of meters.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-45-320.jpg)
![CNS malignant neoplasms LD-5
Abnormally migrating macroenzymes (circulating complexes of LD with IgA or IgG immunoglobulins) may be found in some autoimmune conditions, cancer, and some
miscellaneous conditions but not useful for diagnosis.
Increased total LD with normal distribution of isoenzymes may be seen in AMI, arteriosclerotic heart disease with chronic heart failure, and various combinations of
acute and chronic diseases (this may represent a general stress reaction).
Approximately 50% of patients with malignant tumors have altered LD patterns. This change often is nonspecific and of no diagnostic value. Solid tumors, especially of
germ cell origin, may increase LD-1.
In megaloblastic anemia, hemolysis, renal cortical infarction, and cancer in some patients the isoenzyme pattern may mimic that of AMI, but the time to peak value and
the increase help to differentiate.
LEUCINE AMINOPEPTIDASE (LAP)
Use
Is rarely used.
Parallels serum ALP except that
LAP is usually normal in the presence of bone disease or malabsorption syndrome.
LAP is a more sensitive indicator of choledocholithiasis and of liver metastases in anicteric patients.
When serum LAP is increased, urine LAP is almost always increased; but when urine LAP is increased, serum LAP may have already returned to normal.
MAGNESIUM (Mg)
Use
Diagnose and monitor hypo- and hypermagnesemia, especially in renal failure or GI disorders
Increased In
Iatrogenic (usual cause, most often with acute or chronic renal failure)
Antacids containing magnesium
Enemas containing magnesium
Laxative and cathartic abuse
Parenteral nutrition
Magnesium for eclampsia or premature labor
Lithium carbonate intoxication
Renal failure (when glomerular filtration rate [GFR] approaches 30 mL/min); in chronic renal failure, hypermagnesemia is inversely related to residual renal function.
Increase is rarely observed with normal renal function.
Diabetic coma before treatment
Hypothyroidism
Addison's disease and after adrenalectomy
Controlled diabetes mellitus in older patients
Accidental ingestion of large amount of sea water
Signs Approximate Serum Levels in Adults
Neuromuscular depression, hypotension >4–6 mg/dL
Difficulty in urination >5 mg/dL
CNS depression 6–8 mg/dL
Nausea, vomiting, cutaneous flushing 6 mg/dL
Hyporeflexia, drowsiness 8 mg/dL
Coma 12–17 mg/dL
ECG changes >10 mg/dL
Complete heart block 30 mg/dL
Cardiac arrest 34–40 mg/dL
Decreased In
(Almost always due to GI or renal disturbance)
GI disease
Malabsorption (e.g., sprue, small bowel resection, biliary and intestinal fistulas, abdominal irradiation, celiac disease and other causes of steatorrhea; familial
magnesium malabsorption)
Abnormal loss of GI fluids (chronic ulcerative colitis, Crohn's disease, villous adenoma, carcinoma of colon, laxative abuse, prolonged aspiration of GI tract
contents, vomiting, etc.)
Renal disease (>2 mEq/day in urine during hypomagnesemia indicates excessive renal loss)
Chronic GN
Chronic pyelonephritis
Renal tubular acidosis
Diuretic phase of acute tubular necrosis
Postobstructive diuresis
Drug injury
Diuretics (e.g., furosemide, thiazides, ethacrynic acid)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-50-320.jpg)
![Osmotic diuresis—hyperglycemia, administration of urea or mannitol
Hypernatremia with normal hydration—due to hypothalamic disorders
Insensitivity of osmoreceptors (essential hypernatremia)—water loading does not return serum osmolality to normal; chlorpropamide may lower serum sodium
toward normal
Defect in thirst (hypodipsia)—forced water intake returns serum osmolality to normal
Hypernatremia with overhydration—iatrogenic or accidental (e.g., infants given feedings with high sodium concentrations or given NaHCO 3 for respiratory distress or
cardiopulmonary arrest)
Alcohol ingestion is the most common cause of hyperosmolar state and of coexisting coma and hyperosmolar state.
Decreased In (Equivalent to Hyponatremia)
Hyponatremia with hypovolemia (urine sodium is usually >20 mEq/L)
Adrenal insufficiency (e.g., salt-losing form of congenital adrenal hyperplasia, congenital adrenal hypoplasia, hemorrhage into adrenals, inadequate replacement
of corticosteroids, inappropriate tapering of steroids)
Renal losses (e.g., osmotic diuresis, proximal renal tubular acidosis, salt-losing nephropathies, usually tubulointerstitial diseases such as GU tract obstruction,
pyelonephritis, medullary cystic disease, polycystic kidneys)
GI tract loss (e.g., vomiting, diarrhea)
Other losses (e.g., burns, peritonitis, pancreatitis)
Hyponatremia with normal volume or hypervolemia (dilutional syndromes)
Congestive heart failure, cirrhosis, nephrotic syndrome
SIADH
Formulas for calculation or prediction of serum osmolality:
Osmolal Gap
Difference between measured and calculated values; <10 in healthy persons.
Use
Osmolal gap has been used to estimate the blood alcohol. Because serum osmolality increases 22 mOsm/kg for every 100 mg/dL of ethanol :
OSMOLAL GAP >10 DUE TO
Decreased serum water content
Hyperlipidemia (serum will appear lipemic)
Hyperproteinemia (total protein >10 gm/dL)
Additional low-molecular-weight substances are in serum (measured osmolality will be >300 mOsm/kg water):
Ethanol. (An especially large osmolal gap with a low or only moderately elevated ethanol level should raise the possibility of another low-molecular-weight toxin
[e.g., methanol].)
Methanol.
Isopropyl alcohol.
Mannitol. (Osmolal gap can be used to detect accumulation of infused mannitol in serum.)
Ethylene glycol, acetone, paraldehyde result in relatively small osmolal gaps even at lethal levels.
Severe illness, especially shock, acidosis (lactic, diabetic, alcoholic), renal failure
Laboratory analytic error
Random error from all measurements could add or subtract £15 mOsm/kg.
Use of incorrect blood collection tubes.
PHOSPHORUS
See Fig. 3-1.
Fig. 3-1. Algorithm for hyperphosphatemia. (PTH = parathyroid hormone.)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-52-320.jpg)
![Use
Diagnosis and monitoring of hyper- and hypokalemia in various conditions (e.g., treatment of diabetic coma, renal failure, severe fluid and electrolyte loss, effect of
certain drugs)
Diagnosis of familial hyperkalemic periodic paralysis and hypokalemic paralysis
Increased In
Potassium Retention
Glomerular filtration rate <3–5 mL/min
Oliguria due to any condition (e.g., renal failure)
Chronic nonoliguric renal failure associated with dehydration, obstruction, trauma, or excess potassium
Drugs
Renal toxicity (e.g., amphotericin B, methicillin, tetracycline)
Glomerular filtration rate >20 mL/min
Decreased (aldosterone) mineralocorticoid activity
Addison's disease
Hypofunction of renin-angiotensin-aldosterone system
Hyporeninemic hypoaldosteronism with renal insufficiency (GFR 25–75 mL/minute)
Various drugs (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], angio-tensin-converting enzyme inhibitors, cyclosporine, pentamidine)
Decreased aldosterone production
Pseudohypoaldosteronism
Aldosterone antagonist drugs (e.g., spironolactone, captopril, heparin)
Inhibition of tubular secretion of potassium
Drugs (e.g., spironolactone, triamterene, amiloride)
Hyperkalemic type of distal renal tubular acidosis (e.g., sickle cell disease, obstructive uropathy)
Mineralocorticoid-resistant syndromes (increased renin and aldosterone may be low in those marked with *
)
Primary tubular disorders
Hereditary
Acquired (e.g., SLE, amyloidosis, sickle cell nephropathy, *
obstructive uropathy,*
renal allograft transplant, chloride shift)
Potassium Redistribution
Familial hyperkalemic periodic paralysis (Gamstorp's disease, adynamia episodica hereditaria)
Acute acidosis (especially hyperchloremic metabolic acidosis; less with respiratory acidosis; little with metabolic acidosis due to organic acids) (e.g., diabetic
ketoacidosis, lactic acidosis, acute renal failure, acute respiratory acidosis)
Decreased insulin
Beta-adrenergic blockade
Drugs (e.g., succinylcholine, great excess of digitalis, arginine infusion)
Use of hypertonic solutions (e.g., saline, mannitol)
Intravascular hemolysis (e.g., transfusion reaction, hemolytic anemia), rhabdomyolysis
Rapid cellular release (e.g., crush injury, chemotherapy for leukemia or lymphoma, burns, major surgery)
Increased Supply of Potassium
Laboratory artifacts (e.g., hemolysis during venipuncture, conditions associated with thrombocytosis [>1,000,000/cu mm] or leukocytosis [>100,000/cu mm],
incomplete separation of serum and clot)
Potassium value can be elevated ~15% in slight hemolysis (Hb £50 mg/dL); elevated ~30–50% in moderate hemolysis (Hb >100 mg/dL). Thus potassium status can
be assessed with slight hemolysis but not with moderate hemolysis.
Prolonged tourniquet use and hand exercise when drawing blood
Excess dietary intake or rapid potassium infusion
Drugs (e.g., those with high potassium content [1 million U of penicillin G potassium contains 1.7 mEq of potassium])
Urinary Diversion
Ureteral implants into jejunum
In neonates—dehydration, hemolysis (e.g., cephalohematoma, intracranial hemorrhage, bruising, exchange transfusion), acute renal failure, congenital adrenal
hyperplasia, adrenocortical insufficiency
Decreased In
See Table 12-3 and Fig. 3-3.
(Each 1 mEq/L decrease of serum potassium reflects a total deficit of <200–400 mEq; serum potassium <2 mEq/L may reflect total deficit >1000 mEq.)
Excess Renal Excretion
Osmotic diuresis of hyperglycemia (e.g., uncontrolled diabetes)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-55-320.jpg)
![Nephropathies
Renal tubular acidosis (proximal and especially distal)
Bartter's syndrome
Liddle's syndrome
Magnesium depletion due to any cause
Renal vascular disease, malignant hypertension, vasculitis
Renin-secreting tumors
Endocrine
Hyperaldosteronism (primary, secondary)
Cushing's syndrome, especially due to ectopic ACTH production
Congenital adrenal hyperplasia
Hyperthyroidism (especially in Asian persons)
Drugs
Diuretics (e.g., thiazides, ethacrynic acid, furosemide)
Mineralocorticoids (e.g., fludrocortisone)
High-dose glucocorticoids
High-dose antibiotics (e.g., penicillin, nafcillin, ampicillin, carbenicillin)
Substances with mineralocorticoid effect (e.g., glycyrrhizic acid [ licorice], carbenoxolone, gossypol)
Drugs associated with magnesium depletion (e.g., aminoglycosides, cisplatin, amphotericin B, foscarnet)
Acute myelogenous, monomyeloblastic or lymphoblastic leukemia
Nonrenal Causes of Excess Potassium Loss
Gastrointestinal
Vomiting
Diarrhea (e.g., infections, malabsorption, radiation)
Drugs (e.g., laxatives [phenolphthalein], enemas, cancer therapy)
Neoplasms (e.g., villous adenoma of colon, pancreatic vipoma that produces vasoactive intestinal polypeptide >200 pg/mL, Zollinger-Ellison [Z-E] syndrome)
Excessive spitting (sustained expectoration of all saliva in neurotic persons and to induce weight loss in professional wrestlers)
Skin
Excessive sweating
Cystic fibrosis
Extensive burns
Draining wounds
Cellular shifts
Respiratory alkalosis
Classic periodic paralysis
Insulin use
Use of certain drugs (e.g., bronchodilators, decongestants)
Accidental ingestion of barium compounds
Treatment of severe megaloblastic anemia with vitamin B12 or folic acid
Physiologic causes (e.g., in highly trained athletes)
Diet
Severe eating disorders (e.g., anorexia nervosa, bulimia)
Dietary deficiency
Delirium tremens
In neonates—asphyxia, alkalosis, renal tubular acidosis, iatrogenic causes (glucose and insulin administration), diuretic use
Major causes of hypokalemia with hypertension:
Diuretic drugs (e.g., thiazides)
Primary aldosteronism
Secondary aldosteronism (renovascular disease, renin-producing tumors)
Cushing's syndrome
Malignant hypertension
Renal tubular acidosis
PREGNANCY TEST
(Immunoassay detection of human chorionic gonadotropin [hCG] in blood)
(See also Urinary Chorionic Gonadotropins, Serum Human Chorionic Gonadotropin)
Use (Positive In)
Pregnancy. Test becomes positive as early as 4 days after expected date of menstruation; it is >95% reliable by 10th–14th day.
Ectopic pregnancy.
Hydatidiform mole, choriocarcinoma. Test negative one or more times in >60% of these patients and negative at all times in >20% of patients, for whom more
sensitive methods (e.g., radioimmunoassay) should be used. Quantitative titers should be performed for diagnosis and for following the clinical course of patients with
these conditions.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-56-320.jpg)
![Due To
Obstruction of the lymphochylous system, usually filariasis. Microfilariae appear in the urine for 6 wks after acute infection then disappear, unless endemic.
Trauma to chest or abdomen
Abdominal tumors or lymph node enlargement
Milky urine is due to chylomicrons recognized as fat globules by microscopy (this is almost entirely neutral fat). Protein is normal or low. Hematuria is common.
Specific gravity is low, and reaction is acid.
A test meal of milk and cream may cause chyluria in 1–4 hrs.
Laboratory findings due to pyelonephritis that is often present.
COLOR, ABNORMAL1
Red (“red” often includes colors from pink to red-brown)
No specific test (chlorzoxazone, ethoxazene, oxamniquine, phenothiazines, rifampin)
Acid urine only (phenolphthalein)
Red-orange
No specific test (butazopyridine, chlorzoxazone, ethoxazene, mannose, oxamniquine, phenothiazines, rifampin)
Alkaline urine only (phenindione)
Acid urine only (phenolphthalein)
Red or pink
No specific test (aminopyrine, aniline dyes, antipyrine, doxorubicin, fuscin, ibuprofen, phenacetin, phenothiazines, phensuximide, phenytoin)
Acid urine only (beets, blackberries, anisindione)
Alkaline urine only (anthraquinone laxatives, rhubarb, santonin, phenolsulfonphthalein, sulfobromophthalein sodium [Bromsulphalein]; eosin produces green
fluorescence)
Darkens on standing (porphyrins)
Presence of urates and bile
On contact with hypochlorite bleach (toilet bowl cleaner) (aminosalicylic acid)
Centrifuged specimen shows RBC in base (blood)
Purple
Alkaline urine only (phenolphthalein)
Darkens on standing (porphyrins; fluoresces with ultraviolet light)
No specific test (chlorzoxazone)
Red-brown
Acid urine only (methemoglobin, metronidazole, anisindione) ( Fig. 4-1)
Fig. 4-1. Algorithm for red or brown urine. (GU = genitourinary; Hb = hemoglobin; RBC = red blood cell.)
Alkaline urine only (anthraquinone laxatives, levodopa, methyldopa, parahydroxyphenylpyruvic acid, phenazopyridine)
Positive o-toludine test for blood
Centrifuged urine shows RBC in base if blood; centrifuged blood shows pink supernatant plasma if Hb but clear plasma if myoglobin.
Green in reflected light (antipyrine)
Orange with addition of HCl (phenazopyridine)
No specific test (chloroquine, deferoxamine, ethoxazene, ibuprofen, iron sorbitex, pamaquine, phenacetin, phenothiazines, phensuximide, phenytoin,
trinitrophenol)
Brown-black
Darkens on standing (homogentisic acid, melanin, melanogen, nitrobenzene, parahydroxyphenylpyruvic acid [alkaline urine only], phenol, cresol, naphthol)
Does not darken on standing
Ferric chloride test
Color fades (Argyrol)
Blue-green (homogentisic acid)
Black (melanin or melanogen)
Nitroprusside test is red with melanin, black with melanogen.
Yellow-brown
Darkens on standing in acid urine (anthraquinone laxatives, rhubarb)
Positive test for bile (bilirubin, urobilin)
No specific test (niridazole, nitrofurantoin, pamaquine, primaquine, sulfamethoxazole)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-64-320.jpg)
![Yellow
Acid urine only (quinacrine, santonin)
Alkaline urine only (beets)
Positive test for bile (bilirubin, urobilin)
No specific test (fluorescein dye, phenacetin, riboflavin, trinitrophenol)
Yellow-orange
Alkaline urine only (anisindione, sulfasalazine)
Positive test for bile (bilirubin, urobilin)
Color increases with HCl (phenazopyridine)
Ether soluble (carrots, vitamin A)
High specific gravity (dehydration)
No specific test (aminopyrine, warfarin)
Yellow-green or brown-green
Darkens on standing (cresol, phenol [Chloraseptic], methocarbamol [Robaxin], resorcinol)
Positive test for bile (biliverdin)
Blue-green
Darkens on standing (methocarbamol, resorcinol)
Blue fluorescence in acid urine (triamterene)
Bacteriuria, pyuria (Pseudomonas infection [rare])
Decolorizes with alkali (indigo-carmine dye)
Positive Obermayer's test (indican)
No specific test (chlorophyll breath mints [Clorets], Evans blue dye, guaiacol, magnesium salicylate [Doan's Pills], methylene blue, thymol [Listerine])
Biliverdin due to oxidation of bilirubin in poorly preserved specimens.
Gives negative diazo tests for bilirubin (Ictotest), but oxidative tests (Harrison spot test) may still be positive.
Milky
Lipuria, chyluria (ether soluble)
Many polymorphonuclear neutrophils (PMNs) (microscopic examination)
White cloud is due to excessive oxalic acid and glycolic acid in urine; occurs in oxalosis (primary hyperoxaluria).
Colorless
Specific gravity
High (diabetes mellitus with glycosuria; positive test for glucose)
Low (diabetes insipidus, recent fluid intake)
Variable (diuretics, ethyl alcohol, hypercalcemia)
Clear to deep yellow
Normal (due to urochrome pigment)
Blue diaper syndrome results from indigo blue in urine due to familial metabolic defect in tryptophan absorption associated with idiopathic hypercalcemia and
nephrocalcinosis.
Red diaper syndrome is due to a nonpathogenic chromobacterium (Serratia marcescens) that produces a red pigment when grown aerobically at 25–30°C.
Darkening of urine on standing, alkalinization, or oxygenation is nonspecific and may be due to
Melanogen, Hb, indican, urobilinogen, porphyrins, phenols, salicylate metabolites (e.g., gentisic acid), homogentisic acid (due to alkaptonuria), administration of
metronidazole hydrochloride (Flagyl). In acid pH, urine may not darken for hours (e.g., tyrosinosis).
Sickle cell crises produce a characteristic dark-brown color independent of volume or specific gravity that becomes darker on standing or on exposure to
sunlight due to increase in porphyrins.
CREATINE
Increased In
Physiologic states
Childhood growth
Pregnancy
Puerperium (2 wks)
Starvation
Raw meat diet
Increased formation
Myopathy
Amyotonia congenita
Muscular dystrophy
Poliomyelitis
Myasthenia gravis
Crush injury
Acute paroxysmal myoglobinuria
Endocrine diseases
Hyperthyroidism
Addison's disease
Cushing's syndrome
Acromegaly
Diabetes mellitus](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-65-320.jpg)
![Routine screening of all adults is not recommended.
Interferences
False positive
Vaginal bleeding
Factitious
Bacteriuria (due to catalase production by gram-negative bacteria and Staphylococcus sp. whose action on dipsticks is similar to that of Hb peroxidase)
Red diaper syndrome
Drugs (e.g., rifampin, phenolphthalein, iodides, bromides, copper, oxidizing agents, permanganate)
Foods (e.g., beets, blackberries, rhubarb)
Pigmenturia (porphyria, hemoglobinuria, myoglobinuria)
Oxidizing contaminants (e.g., bacterial peroxidases, povidone, hypochlorite)
False negative
Reducing agents (e.g., high doses of ascorbic acid [vitamin C])
pH <5.1
Nonglomerular Hematuria Due To
Trauma
Hemoglobinopathies (especially sickle cell trait and Hb sickle cell disease)
Hypercalciuria
Polycystic disease
GU tract tumors, infections
Some Causes of Hematuria in Adults4
Gross (%) Microscopic (%)
GU tract cancer 22.5 5.1
Kidney 3.6 0.5
Prostate 2.4 0.5
Ureter 0.8 0.2
Bladder 15 4
Other lesions
GU tract infection 33 4.3
Calculi 11 5
Benign prostatic hypertrophy 13 13
Renal 2.2
Systemic (e.g., hemophilia, thrombocytopenia,
dicumarol overdose)
1
No source found 8.4 43
Hematuria in Children
Due To
Glomerular
Acute postinfectious GN
Membranoproliferative GN
IgG-IgA nephropathy (Berger's disease)
Hereditary nephritis
SLE
Henoch-Schönlein purpura
Benign familial hematuria
Benign recurrent hematuria
Nonglomerular
Polycystic kidneys
Renal tumors
Renal TB
Vascular abnormalities (e.g., renal hemangioma, essential hematuria)
Hematologic conditions (e.g., sickle cell trait, coagulation disorders)
Hydronephrosis](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-69-320.jpg)
![GU tract infection, foreign body, calculi, etc. (usually symptomatic)
HEMATURIA, BENIGN FAMILIAL OR RECURRENT
Asymptomatic hematuria without proteinuria
Other laboratory and clinical findings are normal.
Renal biopsy is normal on light microscopy, electron microscopy, and immunofluorescence.
Other family members may also have asymptomatic hematuria.
Should gradually clear spontaneously; annual screening for other abnormalities should be performed until condition clears.
HEMOGLOBINURIA
Renal threshold is 100–140 mg/dL plasma.
Use
Confirms hemolyzed blood in urine from either GU tract or intravascular cause.
Due To
Hematuria (due to any cause) with hemolysis in urine
Infarction of kidney
Intravascular hemolysis due to
Parasites (e.g., malaria, Oroya fever due to Bartonella bacilliformis)
Infection (e.g., Clostridia, Escherichia coli bacteremia due to transfused blood)
Antibodies (e.g., transfusion reactions, acquired hemolytic anemia, paroxysmal cold hemoglobinuria, paroxysmal nocturnal hemoglobinuria)
DIC
Inherited hemolytic disorders (e.g., sickle cell disease, thalassemias, G-6-PD deficiency, pyruvate kinase deficiency, hereditary spherocytosis)
Fava bean sensitivity
Mechanical causes (e.g., prosthetic heart valve)
Hypotonicity (e.g., transurethral prostatectomy with irrigation of bladder with water, hemodialysis accidents)
Chemicals (e.g., naphthalene, sulfonamides)
Thermal burns injuring RBCs
Strenuous exercise and march hemoglobinuria
Interferences
False-positive (Occultest) results may occur in the presence of pus, iodides, bromides.
Serum is pink due to free Hb but clear due to myoglobin.
HEMOSIDERINURIA
Centrifuged specimen of random urine incubated for 10 mins with Prussian blue stain shows blue granules. Granules are located in cells, but if these have
disintegrated, free granules may be predominant.
Normal—absent
Use
Present in intravascular hemolysis even when hemoglobinuria is absent (e.g., paroxysmal nocturnal hemoglobinuria).
KETONURIA
(Ketone bodies [acetone, beta-hydroxybutyric acid, acetoacetic acid] appear in urine.)
Use
Screen for ketoacidosis, especially in diabetes mellitus when blood is not immediately available
Confirm fasting in testing for insulinoma
Interferences (reagent strips)
False positive
Drugs (e.g., levodopa)
False negative
Volatilization of acetone
Breakdown of acetoacetic acid
Occurs In
Metabolic conditions](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-70-320.jpg)
![mg/day makes a diagnosis of renal parenchymal disease very likely. >2000 mg/day in adults or >40 mg/m 2
in children usually indicates glomerular etiology. >3500
mg/day or protein/creatinine ratio >3.5 points to a nephrotic syndrome.
When a 24-hr urine specimen cannot be reliably collected, a spot urine for urine protein/creatinine ratio (especially after first morning specimen and before bedtime
and if renal function is not severely impaired) often correlate well. Normal value is <0.2 for adults, 0.5 for age 6–24 months, 0.2–0.25 for child >24 months. Low-grade
proteinuria = 0.2–1.0. Moderate proteinuria = 1.0–5.0. Value >5 is typical of nephrosis.
Dipstick is sensitive to ~30 mg/dL of protein; 1+ = 100 mg/dL; 2+ = 300 mg/dL; 4+ = 1000 mg/dL; may be falsely negative with predominantly low-molecular-weight or
nonalbumin proteins. Positive dipstick should always be followed by sulfosalicylic acid test, which is sensitive to 5–10 mg/dL of protein; may be falsely negative with
very alkaline or dilute urine; may be falsely positive due to certain drugs (e.g., radiographic contrast media, high doses of penicillin, chlorpromazine, tolbutamide, sulfa
drugs). When sulfosalicylic acid test shows a significantly higher concentration than the dipstick in an adult, Bence Jones proteinuria should be ruled out. Association
with hematuria indicates high likelihood of disease. For detection of proteinuria, sensitivity and specificity = 95–99%; positive predictive value for renal disease =
0–1.4% (in young populations).
Urine electrophoresis
Glomerular
Selective: primarily albumin (>80%) and transferrin (mild renal injury due to dibetes mellitus, immune complex disease, minimal change disease)
Nonselective: pattern resembles serum. Primary and secondary glomerulonephropathies (diabetes mellitus, amyloidosis, collagen diseases, dysglobulinemia,
HUS).
Tubular: principally alpha1, alpha2, beta, and gamma globulins; albumin is not marked.
Most often seen in chronic pyelonephritis, interstitial tubular nephritis, congenital tubular nephropathies, polycystic kidneys, hypercalciuria, acute tubular
necrosis due to ischemia or drugs.
Mixed glomerular-tubular: advanced renal disease involving entire nephron (e.g., chronic renal failure, chronic pyelonephritis)
Dysglobulinemias (see Chapter 11; e.g., multiple myeloma, macroglobulinemia, heavy chain diseases)
Due To
Orthostatic (postural)
w First morning urine before arising shows high specific gravity but no protein (protein/creatinine ratio <0.1). Protein appears only after person
is upright; usually <1.5 gm/day (protein/creatinine ratio usually 0.1–1.3).
Urine microscopy is normal.
Is usually considered benign and slowly disappears with time but is still present in 50% of persons 10 yrs later.
Progressive renal insufficiency does not occur.
Occurs in 15% of apparently healthy young men and 3% of otherwise healthy persons and some patients with resolving acute pyelonephritis
or GN.
Renal biopsy, electron microscopy, and immunofluorescent stains show pathologic changes in some patients.
Transient
Commonly found in routine urinalysis of asymptomatic healthy children and young adults initially but not subsequently.
Progressive renal disease is not present.
Functional occurs in 10% of hospital medical patients; associated with high fever, congestive heart failure, hypertension, stress, exposure to cold, strenuous
exercise, seizures. Usually <2 gm/day; disappears with recovery from precipitating cause. Progressive renal disease is not present.
Persistent
Glomerular (composed of large proteins, e.g., albumin, alpha 1-antitrypsin, transferrin)
Idiopathic (e.g., membranoproliferative GN, membranous glomerulopathy, minimal change disease, focal segmental glomerulosclerosis, amyloidosis)
Secondary
Infection (e.g., poststreptococcal, hepatitis B, bacterial endocarditis, malaria, infectious mononucleosis, pyelonephritis, etc.)
Vascular (e.g., thrombosis of inferior vena cava or renal vein, renal artery stenosis)
Drugs (e.g., nonsteroidal antiinflammatory drugs, heroin, gold, captopril, penicillamine)
Autoimmune (e.g., SLE, RA, dermatomyositis, polyarteritis, Goodpasture's syndrome, Henoch-Schönlein purpura, ulcerative colitis)
Neoplasia
Hereditary and metabolic (e.g., polycystic kidney disease, diabetes mellitus, Fabry's disease, Alport's syndrome of progressive interstitial nephritis and
nerve deafness)
Decreased tubular reabsorption (composed of low-molecular-weight proteins [e.g., alpha and beta microglobulins, free Ig light chains, retinol-binding protein,
lysozyme; usually <1.5 gm/day])
Acquired
Drugs (e.g., phenacetin, aminoglycoside, cephalosporins, cyclosporine, high-dose analgesics, lithium, methicillin, etc.)
Heavy metals (e.g., lead, mercury, cadmium)
Sarcoidosis
Acute tubular necrosis
Interstitial nephritis
Renal tubular acidosis
Acute and chronic pyelonephritis
Renal graft rejection
Balkan nephropathy
Congenital (e.g., Fanconi's syndrome, oculo-cerebral-renal syndrome)
Hereditary (e.g., Wilson's disease, sickle cell disease, medullary cystic disease, oxalosis, cystinosis)
Increased plasma levels of normal or abnormal proteins (e.g., Bence Jones proteins, myoglobin, lysozyme in monocytic or myelocytic leukemias)
Common causes of low-grade proteinuria (<1 gm/24 hrs)
Kimmelstiel-Wilson syndrome
Idiopathic low-grade proteinuria–normal history and physical examination, renal function, and urine sediment with no hematuria.
Nephrosclerosis
Polycystic kidney disease
Medullary cystic disease
Chronic obstruction of urinary tract
Chronic interstitial nephritis (e.g., analgesic abuse, uric acid, oxalate, hypercalcemia, hypokalemia, lead, cadmium)
Interferences
False Positive
Dipstick Sulfosalicylic Acid](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-73-320.jpg)
![Now replaced by electrophoretic and immunologic procedures.
Globulin (Predominantly) Rather than Albumin
Multiple myeloma
Macroglobulinemia
Primary amyloidosis
Adult Fanconi's syndrome (some patients)
Postrenal Proteinuria
Primarily associated with epithelial tumors of bladder or renal pelvis
Degree of proteinuria related to size and invasiveness; generally <1 gm/day (similar to pyelonephritis) and includes IgM
Renal Diseases in Which Proteinuria May Be Absent
Congenital abnormalities
Renal artery stenosis
Obstruction of GU tract
Pyelonephritis
Stone
Tumor
Polycystic kidneys
Hypokalemic nephropathy
Hypercalcemic nephropathy
Prerenal azotemia
Retinol-Binding Protein
Use
Detection of various renal disorders
Increased In
Proximal tubular dysfunction. Correlates with beta 2-microglobulin excretion but not affected by acid urine. More sensitive than N-acetyl-beta-D-glucosaminidase
excretion. May show false negative due to low serum level in vitamin A deficiency.
REDUCING SUBSTANCES
Use
Screening for diabetes mellitus (not recommended as primary screening modality due to poor sensitivity)
Interferences (Reagent Strips)
False positive
Strips exposed to air (uncapped bottles) for a week or more
Peroxidase contamination
Oxidizing agents
False negative (found in >1% of routine urine analyses in hospital)
Ascorbic acid >25 mg/dL
Drugs (e.g., aspirin)
Specific gravity >1.020
High pH
Due To
Glycosuria
Hyperglycemia
Endocrine (e.g., diabetes mellitus, pituitary, adrenal, thyroid disease)
Nonendocrine (e.g., liver, CNS diseases)
Administration of hormones (e.g., ACTH, corticosteroids, thyroid, epinephrine) or drugs (e.g., morphine, anesthetic drugs, tranquilizers)
Renal
Tubular origin (serum glucose <180 mg/dL; oral and IV glucose tolerance test [GTT] are normal; ketosis is absent)
Fanconi's syndrome
Toxic renal tubular disease (e.g., due to lead, mercury, degraded tetracycline)
Inflammatory renal disease (e.g., acute GN, nephrosis)
Glomerular due to increased GFR without tubular damage](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-75-320.jpg)
![Idiopathic
Melituria (5% of cases of melituria in the general population are due to renal glycosuria [incidence = 1:100,000], pentosuria [incidence = 1:50,000], essential
fructosuria [incidence = 1:120,000])
Hereditary (e.g., galactose, fructose, pentose, lactose)
Galactose (classic and variant forms of galactosemia). Galactosuria (in galactosemia) shows a positive urine reaction with Clinitest but negative with Clinistix
and Tes-Tape.
Fructose (fructosemia, essential fructosuria, hereditary fructose intolerance)
Lactose (lactase deficiency, lactose intolerance)
Phenolic compounds (phenylketonuria, tyrosinosis)
Xylulose (pentosuria)
Neonatal (e.g., physiologic lactosuria, sepsis, gastroenteritis, hepatitis)
Lactosuria during lactation
Xylose (excessive ingestion of fruit)
Non–sugar-reducing substances (e.g., ascorbic acid, glucuronic acid, homogentisic acid, salicylates)
RENAL ANTIGENS EXCRETION
(Derived from proximal tubule brush borders)
Low levels in healthy persons
May Be Useful To
Distinguish cases of prerenal azotemia and glomerular disease (with low levels) from increased levels in acute renal failure due to proximal tubular disease
Follow course of renal transplant patients
Distinguish pyelonephritis from cystitis
RENAL ENZYME EXCRETION
Lactate Dehydrogenase (LD)
Increased In
Carcinoma of kidney, bladder, and prostate in a high proportion of cases; may be useful for detection of asymptomatic lesions or screening of susceptible population
groups and differential diagnosis of renal cysts
Other renal diseases
Active GN, SLE with nephritis, nephrotic syndrome, acute tubular necrosis, diabetic nephrosclerosis, malignant nephrosclerosis, renal infarction
Active pyelonephritis (25% of patients), cystitis, and other inflammations
Instrumentation of the GU tract (especially cystoscopy with retrograde pyelography); transient increase is <1 wk
AMI and other conditions with considerably increased serum levels
Normal In
Benign nephrosclerosis
Pyelonephritis (most patients)
Obstructive uropathy
Renal stones
Polycystic kidneys
Renal cysts
The test is not useful in routine screening for malignancy of kidney, renal pelvis, and bladder because increased levels suggest GU tract disease but do not indicate its
nature. Increased values usually precede clinical symptoms.
Precautions
8-hr overnight urine collection, clean voided to prevent bacterial and menstrual contamination. Refrigerate until analysis is begun. Specimen must be dialyzed to
remove inhibitors in urine. Urinalysis should be performed first, because false-positive LD may occur if there are >10 bacteria/HPF or if RBCs or hemolyzed blood is
present.
L-Alanine Aminopeptidase
(Derived from proximal tubule brush borders)
Normal is 1500–3700 mU/24 hrs in women and 2000–6000 mU/24 hrs in men. Affected by diuresis and circadian rhythm but not by proteinuria or bacteriuria.
Increased by all types of proximal tubular injury and other renal diseases (e.g., glomerular disease, tumors); consequently, test too sensitive and nonspecific.
N-Acetyl-Beta-D-glucosaminidase
(Derived from proximal tubule lysozymes)
Increased in many types of renal disease causing low specificity; therefore not clinically useful.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-76-320.jpg)
![CHAPTER 5 CARDIOVASCULAR DISEASES
Interpretation of Diagnostic Tests
CHAPTER 5 CARDIOVASCULAR DISEASES
Arrhythmias
Arteriovenous Fistulas, Angiomatous, Congenital
Behçet's Syndrome
Churg-Strauss Syndrome (Allergic Granulomatosis and Angiitis)
Cor Pulmonale
Coronary Heart Disease (CHD)
Endocarditis, Bacterial
Giant Cell Arteritis (GCA)
Heart Failure
Hypertension
Kawasaki Syndrome (Mucocutaneous Lymph Node Syndrome)
Löffler's Parietal Fibroplastic Endocarditis
Myocardial Contusion
Myocardial Infarction, Acute (AMI)
Myocarditis, Viral
Myxoma of Left Atrium
Pericardial Effusion, Chronic
Pericarditis, Acute
Phlebothrombosis
Polyarteritis Nodosa
Prosthetic Heart Valves
Rheumatic Fever, Acute
Shock
Systemic Capillary Leak Syndrome
Takayasu's Syndrome (Arteritis)
Thromboangiitis Obliterans (Buerger's Disease)
Thrombophlebitis, Septic
Transplant Rejection (Acute) of Heart
Valvular Heart Disease
Vasculitis, Classification
Wegener's Granulomatosis
ARRHYTHMIAS
Metabolic abnormalities should always be ruled out before performing Holter monitor studies or committing to long-term antiarrhythmic therapy (e.g., hypokalemia,
hypomagnesemia, anemia, hypoxemia, hypo- or hyperthyroidism).
ARTERIOVENOUS FISTULAS, ANGIOMATOUS, CONGENITAL
Platelet count may be decreased.
BEHÇET'S SYNDROME
(Systemic vasculitis involving arteries and veins characterized by triad of recurrent aphthous ulcers of mouth and genitalia, and relapsing panuveitis.)
No definitive laboratory tests
Laboratory findings due to involvement of various organ systems, e.g.,
Large vessel occlusion (e.g., aneurysms, arthritis, meningitis) Skin lesions
CHURG-STRAUSS SYNDROME (ALLERGIC GRANULOMATOSIS AND ANGIITIS)
w Biopsy showing granulocytes around an arteriole and venule establishes the diagnosis. 1
ESR is high.
WBC count is increased.
Eosinophilia is usual and seems to correlate with disease activity.
Serum IgE is often increased.
p-ANCA is found in £60% of patients. c-ANCA is rare.
COR PULMONALE
Secondary polycythemia
Increased blood CO2 when cor pulmonale is secondary to chest deformities or pulmonary emphysema
Laboratory findings of the primary lung disease (e.g., chronic bronchitis and emphysema, multiple small pulmonary emboli, pulmonary schistosomiasis)
CORONARY HEART DISEASE (CHD)
Increased risk factors
Increased serum total and LDL cholesterol, decreased HDL cholesterol and various ratios (see Chapter 12).
Recent reports suggest that apo A-I and apo B may be better discriminators of CHD than cholesterol, and low ratio of apo A-I to apo B may be best predictor.
(Variation in methodology and lack of interlaboratory standardization makes this difficult to evaluate at present.)
Atherogenic index (combination of ratio of LDL to HDL × apo B with ratio of apo B to apo A-I) =
Increased serum homocysteine >15.9 µmol/L (normal = 5–15 µmol/L) triples risk of AMI. Each increase of 5 µmol/L increases risk equivalent to increased
cholesterol of 20 mg/dL. Increase may be due to vitamin B deficiency or genetic deficiency of methylene-tetrahydrofolate reductase enzyme. Increased in
end-stage renal disease dialysis patients and in hypothyroidism, certain drug therapies (e.g., methotrexate [transient], phenytoin and carbamazepine [mild],
theophylline, nitrous oxide), cigarette smoking.
Low plasma vitamin B12 and folate levels are each independent risk factors for coronary artery disease.
Increased serum triglyceride level is a risk factor but may not be independent of other factors.
Clinical evidence of CHD or atherosclerosis in patient <age 40, family history of premature CHD, hypertension, male gender, smoking.
Syndrome X: insulin resistance, low HDL level, high level of very low density lipoproteins (VLDLs) and triglycerides.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-79-320.jpg)
![Table 5-1. Summary of Increased Serum Marker Levels After Acute Myocardial Infarction (AMI)
Table 5-2. Interpretation of Markers for Diagnosis of Acute Myocardial Infarction (AMI)
Table 5-3. Characteristics of Serum Markers for Myocardial Damage
Includes the whole spectrum of acute coronary syndromes, from silent ischemia, unstable angina, and “non–Q wave” infarction, to typical AMI.
w Diagnostic Criteria for AMI
Two of the following three findings:
History of ischemic chest discomfort for ³30 mins
Characteristic evolution of ECG changes
Typical rise and fall of cardiac enzymes. Blood should be drawn promptly after onset of symptoms. Repeat determinations should be made at appropriate
intervals (e.g., 4, 8, and 12 hrs) and also if symptoms recur or new signs or symptoms develop. Changes may indicate extension or additional myocardial
infarction (MI) or other complications (e.g., pulmonary infarction).
Use of Laboratory Determinations
For diagnosis when ECG changes are nondiagnostic (occurs in ~50% of AMI patients) on admission to emergency room (e.g., masked by bundle branch block
or Wolff-Parkinson-White syndrome) or may not reveal intramural or posterior or lateral infarcts. False-positive ECG occurs in >10–20% of cases.
For differential diagnosis of chest pain.
To follow the course of the patient with AMI.
To estimate prognosis (e.g., marked elevation of serum enzyme [4–5× normal] correlates with increased incidence of ventricular arrhythmia, shock, and heart
failure, and with higher mortality).
For noninvasive assessment of coronary reperfusion after thrombolytic therapy.
Utility of each enzyme depends on time of specimen's collection after onset of AMI.
Combination of markers (e.g., serum myoglobin, CK-MB, cTn) and (ratios of) serial changes are most effective because of uncertainty as to actual duration of
myocardial damage.
Serum Total Creatine Kinase (CK)
Use
Replaced by serum cTn, CK-MB, myoglobin in various combinations.
May allow early diagnosis because increased levels appear 3–6 hrs after onset and persist £48 hrs.
Sensitive indicator because of large amplitude of change (6–12× normal).
Interpretation
Serial total CK has sensitivity of 98% early in course of MI but false-positive rate of 15% due to many causes of increased CK.
Returns to normal by third day; a poorer prognosis is suggested if the increase lasts more than 3–4 days. Reinfarction is indicated by an elevated level after the
fifth day after previous return to normal.
Useful in differential diagnosis of chest pain due to diseases often associated with MI or difficult to distinguish from MI.
Serial Serum CK-MB Concentrations
Use
Present gold standard for diagnosis within 24 hrs of onset of symptoms.
Detect reinfarction or extension of MI after 72 hrs.
Document reperfusion after thrombolytic therapy.
Interpretation](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-84-320.jpg)
![WBC, as increase may occur before fever and persists after temperature and WBC have returned to normal. Degree of ESR increase does not correlate with severity
or prognosis.
CRP is usually normal in unstable angina patients who have a normal cTnT (<0.1 µg/L). Peak CRP correlates with peak CK-MB.
Blood lactate is increased; sensitivity = 55%, specificity = 96% in patients presenting with acute chest pain.
Glycosuria and hyperglycemia occur in £50% of patients.
Glucose tolerance is decreased.
Laboratory findings due to underlying coronary heart disease.
Laboratory findings due to sequelae (e.g., congestive heart failure).
MYOCARDITIS, VIRAL
(Routine autopsy incidence of 1.2–3.5%)
Due To
Coxsackievirus B (causes most cases in United States) and coxsackievirus A, echovirus, poliomyelitis, influenza A and B, cytomegalovirus (CMV), EBV, adenovirus,
rubeola, mumps, rubella, variola, vaccinia, varicella-zoster virus (VZV), rabies, lymphocytic choriomeningitis, chikungunya, dengue, yellow fever
w Serologic tests for viral antigen, IgM antibody, or changed titer using acute and convalescent paired sera
w Endomyocardial biopsy of right ventricular muscle showing >5 lymphocytes/HPF and degeneration of muscle fibers has become major diagnostic tool to establish
diagnosis of myocarditis and rules out other lesions (e.g., sarcoidosis).
Increased serum markers of myocardial damage is common only in early stages
cTn sensitivity = 53%, specificity = 93%
CK-MB and CK total <10% sensitivity
Increased acute phase reactants (e.g., ESR, CRP, mild to moderate leukocytosis)
MYXOMA OF LEFT ATRIUM
m Anemia that is hemolytic in type and mechanical in origin (due to local turbulence of blood) should be sought and may be severe. Bizarre poikilocytes may be
seen in blood smear. Reticulocyte count may be increased. Other findings may reflect effects of hemolysis or compensatory erythroid hyperplasia. The anemia is
recognized in ~50% of patients with this tumor. Increased serum LD reflects hemolysis.
Serum gamma globulin is increased in ~50% of patients. IgG may be increased.
Increased ESR is a reflection of abnormal serum proteins.
Platelet count may be decreased (possibly the cause here also is mechanical) with resultant findings due to thrombocytopenia.
Negative blood cultures differentiate this tumor from bacterial endocarditis.
Occasionally WBC is increased, and CRP may be positive.
Laboratory findings due to complications
Emboli to various organs (increased AST may reflect many small emboli to striated muscle)
Congestive heart failure
These findings are reported much less frequently in myxoma of the right atrium, which is more likely to be accompanied by secondary polycythemia than by anemia.
PERICARDIAL EFFUSION, CHRONIC
See Table 6-2 on body fluids.
Laboratory findings due to underlying disease (e.g., TB, myxedema, metastatic tumor, uremia, SLE). Rarely due to severe anemia, scleroderma, polyarteritis nodosa,
Wegener's granulomatosis, RA, irradiation therapy, mycotic or viral infections, primary tumor of heart, African endomyocardial fibrosis, idiopathic causes.
PERICARDITIS, ACUTE
Laboratory Findings Due to Primary Disease
Active rheumatic fever (40% of patients)
Bacterial infection (20% of patients)
Other infections (e.g., viral [especially coxsackievirus B], rickettsial, parasitic, mycobacterial, fungal)
Viruses are most common infectious causes.
Uremia (11% of patients)
Benign nonspecific pericarditis (10% of patients)
Neoplasms (3.5% of patients)
Collagen disease (e.g., SLE, polyarteritis nodosa) (2% of patients)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-87-320.jpg)
![Acute myocardial infarction, postcardiac injury syndrome
Trauma
Myxedema
Others (e.g., hypersensitivity, unknown origin or in association with various syndromes)
WBC is usually increased in proportion to fever; normal or low in viral disease and tuberculous pericarditis; markedly increased in suppurative bacterial pericarditis
Examination of aspirated pericardial fluid (see Table 6-1)
PHLEBOTHROMBOSIS
Tests indicate recent extensive clotting of any origin (e.g., postoperative status).
D-dimer test (see Pulmonary Embolism and Infarction).
Staphylococcal clumping test measures breakdown products of fibrin in serum; these indicate the presence of a clot that has begun to dissolve. Sensitivity =
88%, specificity = 66% using venography as gold standard.
Serial dilution protamine sulfate test measures the presence of a fibrin monomer that is one of the polymerization products of fibrinogen. It is less sensitive than
the staphylococcal clumping test but indicates clotting earlier.
Laboratory findings of pulmonary infarction should be sought as evidence of embolization.
POLYARTERITIS NODOSA
w Tissue biopsy is basis for diagnosis
Findings on biopsy of small or medium-sized artery.
Findings in random skin and muscle biopsy are confirmatory in 25% of patients; most useful when taken from area of tenderness; if no symptoms are present,
pectoralis major is the most useful site.
Testicular biopsy is useful when local symptoms are present.
Lymph node and liver biopsies are usually not helpful.
Renal biopsy is not specific; often shows glomerular disease.
Increased BUN or creatinine; uremia occurs in 15% of patients.
Hepatitis B surface antigen (HBsAg) is present in 20–40% of adult patients.
p-ANCA is positive in 70% of patients; rarely reflects disease activity.
Increased WBC (£40,000/cu mm) and PMNs. A rise in eosinophils takes place in 25% of patients and is sometimes very marked; it usually occurs in patients with
pulmonary manifestations.
ESR and CRP are increased.
Mild anemia is frequent; it may be hemolytic anemia with positive Coombs' test.
Urine is frequently abnormal.
Albuminuria (60% of patients)
Hematuria (40% of patients)
“Telescoping” of sediment (variety of cellular and noncellular casts)
Serum globulins are increased.
Abnormal serum proteins occasionally occur. Biological false-positive test for syphilis, circulating anticoagulants, cryoglobulins, macroglobulins, etc., occurs.
Laboratory findings due to organ involvement by arteritis may be present (e.g., GU, pulmonary, GI, neurologic in >75% of patients).
PROSTHETIC HEART VALVES
Complications
Hemolysis—increased serum LD, decreased haptoglobin, reticulocytosis are usual. Severe hemolytic anemia is uncommon and suggests leakage due to partial
dehiscence of valve or infection.
Prosthetic valve infection
Early (<60 days after valve replacement)—usually due to Staphylococcus epidermidis, S. aureus, gram-negative bacteria, diphtheroids, fungi; occasionally due
to Mycobacteria and Legionella. 30–80% mortality.
Late (>60 days postoperatively)—usually due to streptococci. S. epidermidis is common up to 12 mos after surgery. 20–40% mortality.
w· Blood culture positive in >90% of patients unless received antibiotic therapy, infection involves fastidious organism (e.g., HACEK
[Haemophilus-Actinobacillus-Cardiobacterium -Eikenella-Kingella]), or identification requires special technique (e.g., Rickettsia, fungi, mycobacteria, Legionella).
Surgery is indicated if blood culture is positive after 5 days of appropriate antimicrobial therapy or infection is recurrent. Infection with organisms other than
Streptococcus usually require valve replacement.
Complications of anticoagulant therapy
RHEUMATIC FEVER, ACUTE5
w Increased serum cTn implies some myocardial necrosis due to myocarditis.
w Laboratory confirmation of preceding group A streptococcal infection](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-88-320.jpg)
![Large vessel
Takayasu's arteritis
Giant cell (temporal) arteritis
Medium-sized vessel
Polyarteritis nodosa
Kawasaki's disease
Primary granulomatous CNS vasculitis
Small vessel
ANCA-associated vasculitis
Wegener's granulomatosis
Churg-Strauss syndrome
Drug induced
Microscopic polyangiitis
Immune complex–type vasculitis
Henoch-Schönlein purpura
Cryoglobulinemia
Rheumatoid vasculitis
SLE
Sjögren's syndrome
Goodpasture's syndrome
Behçet's disease
Drug induced
Serum sickness
Paraneoplastic vasculitis (lymphoproliferative, myeloproliferative, carcinoma)
Inflammatory bowel disease
WEGENER'S GRANULOMATOSIS7
(Necrotizing granulomatous vasculitis affecting respiratory tract; disseminated form shows renal involvement)
w Diagnosis is established by biopsy of affected tissue with cultures and special stains that exclude mycobacterial and fungal infection.
Antineutrophil Cytoplasmic Antibodies (ANCA)
Use
Aid in diagnosis and classification of various vasculitis-associated and autoimmune disorders.
Interpretation
w c-ANCA (anti-proteinase 3; coarse diffuse cytoplasmic pattern) is highly specific (>90%) for active Wegener's granulomatosis. Sensitivity >90% in systemic
vasculitic phase, ~65% in predominantly granulomatous disease of respiratory tract, ~30% during complete remission. Height of ELISA titer does not correlate with
disease activity; high titer may persist during remission for years. Also occasionally found in other vasculitides (polyarteritis nodosa, microscopic polyangiitis [e.g.,
lung, idiopathic crescentic and pauci-immune GN], Churg-Strauss vasculitis).
p-ANCA (against various proteins [e.g., myeloperoxidase, elastase, lysozyme], perinuclear pattern) occurs only with fixation in alcohol, not formalin. Positive result
should be confirmed by ELISA. Has poor specificity and 20–60% sensitivity in a variety of autoimmune diseases (microscopic polyangiitis, Churg-Strauss vasculitis,
SLE, inflammatory bowel disease, Goodpasture's syndrome, Sjögren's syndrome, idiopathic GN, chronic infection). However, pulmonary small vessel vasculitis is
strongly linked with myeloperoxidase antibodies.
Both p-ANCA and c-ANCA may be found in non–immune mediated polyarteritis and other vasculitides.
Atypical pattern (neither c-ANCA or p-ANCA; unknown target antigens) has poor specificity and unknown sensitivity in various conditions (e.g., HIV infection,
endocarditis, cystic fibrosis, Felty's syndrome, Kawasaki syndrome, ulcerative colitis, Crohn's disease).
Laboratory findings reflecting specific organ involvement
Kidneys—renal disease in ~80% of cases. Hematuria (>5 RBCs/HPF), proteinuria, azotemia. Nephrosis or chronic nephritis may occur. Most patients develop
renal insufficiency. Biopsy most frequently shows focal necrotizing GN with crescent formation; coarse granular pattern with immunofluorescent staining. Biopsy
is important to define extent of disease.
CNS.
Respiratory tract.
Heart.
Nonspecific laboratory findings
Normochromic anemia, thrombocytosis, and mild leukocytosis occur in 30–40% of patients; eosinophilia may occur but is not a feature. Leukopenia or
thrombocytopenia occur only during cytotoxic therapy.
ESR is increased in 90% of cases, often to very high levels; CRP level correlates with disease activity even better than ESR.
Serum globulins (IgG and IgA) are increased in up to 50% of cases.
Serum C3 and C4 complement levels may be increased.
RF may be present in low titer in two-thirds of cases.
ANA is negative.
Laboratory findings due to secondary infection (usually staphylococcal) of sinus, mucosal, pulmonary lesions.
Laboratory findings due to therapy (e.g., bladder cancer and sterility due to cyclophosphamide therapy).
1
Included in American College of Rheumatology 1990 criteria for classification of vasculitis. Arthritis Rheum 1990;33:1068.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-91-320.jpg)
![CHAPTER 6 RESPIRATORY DISEASES
Interpretation of Diagnostic Tests
CHAPTER 6 RESPIRATORY DISEASES
Bronchoscopy and Bronchoalveolar Lavage (BAL)
Gases, Blood
Lymph Node (Scalene) Biopsy
Pleural Needle Biopsy (Closed Chest)
Sputum
Thoracoscopy/Open Lung Biopsy
Abscess, Lung
Adult Respiratory Distress Syndrome (ARDS)
Asthma, Bronchial
Bronchiectasis
Bronchitis, Acute
Bronchitis, Chronic
Carcinoma, Bronchogenic
Croup (Epiglottitis, Laryngotracheitis)
Dysplasia, Bronchopulmonary
Emphysema, Obstructive
Goodpasture's Syndrome
Hantavirus Pulmonary Syndrome
Hernia, Diaphragmatic
Histiocytosis X
Interstitial Pneumonitis, Diffuse
Larynx Diseases
Legionnaires' Disease
Nasopharyngitis, Acute
Neonatal Respiratory Distress Syndrome (RDS)
Pleural Effusion
Pneumoconiosis
Pneumonia
Pneumonia, Lipid
Pulmonary Alveolar Proteinosis
Pulmonary Embolism and Infarction
Sinusitis, Acute
LABORATORY TESTS FOR RESPIRATORY SYSTEM DISEASE
BRONCHOSCOPY AND BRONCHOALVEOLAR LAVAGE (BAL)1
(Saline lavage of lung subsegment via fiberoptic bronchoscope)
Use
For biopsy of endobronchial tumor in which obstruction may cause secondary pneumonia with effusion but still a resectable tumor
To obtain bronchial washings for
Diagnosis of nonresectable tumors that may be treated with radiation (e.g., oat cell carcinoma, Hodgkin's disease), metastatic tumors, peripheral lesions that
cannot be reached by bronchoscope.
Diagnosis of pulmonary infection, especially when sputum examination is not diagnostic. Quantitative bacterial culture and cytocentrifugation for staining slides
provides overall diagnostic accuracy of 79% for pulmonary infection. Negative predictive value = 94%.
Giemsa stain
Healthy persons show <3% neutrophils, 8–18% lymphocytes, 80–89% alveolar macrophages.
>10% neutrophils: indicates acute inflammation (e.g., bacterial infection, including Legionella, acute respiratory distress syndrome [ARDS], drug reaction).
>1% squamous epithelial cells: indicates that a positive culture may reflect saliva contamination.
>80% macrophages: common in pulmonary hemorrhage. Aspergillosis is the only infection associated with significant alveolar hemorrhage, which may also be
found in >10% of patients with hematologic malignancies.
>30% lymphocytes: may indicate hypersensitivity pneumonitis (often up to 50—60% with more cytoplasm and large irregular nucleus).
>10% neutrophils and >3% eosinophils: characteristic of idiopathic pulmonary fibrosis; alveolar macrophages predominate. Lymphocyte percentage may be
increased.
>105
colony-forming bacteria/mL indicates bacterial infection if <1% squamous epithelial cells are present on Giemsa stain.
Gram stain
Many bacteria suggests bacterial infection if there are <1% squamous epithelial cells, especially if culture shows >10 4
bacteria/mL.
No bacteria suggests that bacterial infection is unlikely but Legionella should be ruled out with direct fluorescent antibody (DFA) test if Giemsa stain shows
increased neutrophils.
Combined with methenamine silver or Pap stain, 94% sensitivity for diagnosis of Pneumocystis infection; increased to 100% when BAL is combined with
transbronchial biopsy.
Acid-fast stain: positive result may indicate Mycobacterium tuberculosis or Mycobacterium avium-intracellulare infection.
Toluidine blue stain: may show Pneumocystis carinii cysts in Pneumocystis pneumonia or Aspergillus hyphae in immunocompromised host with invasive aspergillosis.
Prussian blue–nuclear red stain: strongly positive result indicates severe alveolar hemorrhage; moderately positive indicates some hemorrhage; absent indicates no
evidence of alveolar hemorrhage.
DFA stain for Legionella, herpes simplex virus (HSV) I and II (stains bronchial epithelial cells and macrophages), and CMV (stains mononuclear cells) may indicate
infection with corresponding organism.
Pap stain: atypical cytology may be due to cytotoxic drugs, radiation therapy, viral infection (intranuclear inclusions of herpesvirus or CMV), tumor.
Oil red O stain: shows many large intracellular fat droplets in one-third to two-thirds of cells in some patients with fat embolism due to bone fractures but in <3% of
patients without embolism.
GASES, BLOOD
See Chapter 12.
Decreased pO2 (Anoxemia)
Hypoventilation (e.g., chronic airflow obstruction): due to increased alveolar CO 2, which displaces O2](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-93-320.jpg)
![Alveolar hypoxia (e.g., high altitude, gaseous inhalation)
Pulmonary diffusion abnormalities (e.g., interstitial lung disease): supplemental O 2 usually improves pO2
Right-to-left shunt: supplemental O2 has no effect; requires positive end-expiratory pressure
Congenital anomalies of heart and great vessels
Acquired (e.g., ARDS)
Ventilation-perfusion mismatch: supplemental O2 usually improves pO2
Airflow obstruction (e.g., chronic obstructive pulmonary disease [COPD], asthma)
Interstitial inflammation (e.g., pneumonia, sarcoidosis)
Vascular obstruction (e.g., pulmonary embolism)
Decreased venous oxygenation (e.g., anemia)
Increased pCO2 (Hypercapnia)
Decreased ventilation
Airway obstruction
Drug overdose
Metabolic disorders (e.g., myxedema, hypokalemia)
Neurologic disorders (e.g., Guillain-Barré syndrome, multiple sclerosis)
Muscle disorders (e.g., muscular dystrophy, polymyositis)
Chest wall abnormalities (e.g., scoliosis)
Increased dead space in lungs (perfusion decreased more than ventilation decreased)
Lung diseases (e.g., COPD, asthma, pulmonary fibrosis, mucoviscidosis)
Chest wall changes affecting lung parenchyma (e.g., scoliosis)
Increased production (e.g., sepsis, fever, seizures, excess carbohydrate loads)
LYMPH NODE (SCALENE) BIOPSY
(Biopsy of scalene fat pad even without palpable lymph nodes)
Positive in 15% of bronchogenic carcinoma cases. May also be positive in various granulomatous diseases (e.g., TB, sarcoidosis, pneumoconiosis).
PLEURAL NEEDLE BIOPSY (CLOSED CHEST)
(Whenever cannot diagnose otherwise)
Positive for tumor in ~6% of malignant mesothelioma cases and ~60% of other cases of malignancy.
Positive for tubercles in two-thirds of cases on first biopsy with increased yield on second and third biopsies; therefore repeat biopsy if suspicious clinically. Can also
culture biopsy material for TB. Fluid culture alone establishes diagnosis of TB in 25% of cases.
SPUTUM
Color in various conditions
• Rusty Lobar pneumonia
• Anchovy paste (dark brown) Amebic liver abscess rupture into bronchus
• Red currant jelly Klebsiella pneumoniae
• Red (pigment, not blood) Serratia marcescens; rifampin overdose
• Black Bacteroides melaninogenicus pneumonia; anthracosilicosis
• Green (with WBCs, sweet odor) Pseudomonas infection
• Milky Bronchioalveolar carcinoma
• Yellow (without WBCs) Jaundice
Smears and cultures for infections (e.g., pneumonias, TB, fungi) must be adequate samples of sputum showing ciliated cells, macrophages; neutrophils (usually
>25/LPF in good specimen) if acute inflammation is present unless patient is neutropenic; monobacterial population if due to bacterial infection; acute inflammation
without a definite bacterial pattern may be due to Legionella or RSV or influenza viruses. Must be promptly refrigerated Saliva contamination may show squamous
epithelial cells (>19/LPF = poor specimen; 11–19/LPF = fair specimen; <10/LPF = good specimen), extracellular strands of streptococci, clumps of anaerobic
Actinomyces, candidal budding yeasts with pseudohyphae. For possible anaerobic aspiration, fine needle aspiration (FNA) or alveolar lavage is needed.
Cytology for carcinoma
Positive in 40% on first sample
Positive in 70% with three samples
Positive in 85% with five samples
False-positive in <1%
Cytology in bronchogenic carcinoma
Positive in 67–85% of squamous cell carcinoma
Positive in 64–70% of small-cell undifferentiated carcinoma
Positive in 55% of adenocarcinoma
THORACOSCOPY/OPEN LUNG BIOPSY
Use](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-94-320.jpg)
![Diagnosis of pleural malignancy
Accuracy = 96%; sensitivity = 91%, specificity = 100%; negative predictive value = 93% 2
Diagnosis of pulmonary infection or neoplasm when BAL is not diagnostic
RESPIRATORY DISEASES
ABSCESS, LUNG
w Sputum: marked increase; abundant, foul, purulent; may be bloody; contains elastic fibers.
Gram stain is diagnostic—sheets of PMNs with a bewildering variety of organisms.
Bacterial cultures (including tubercle bacilli)—anaerobic as well as aerobic; rule out amebas, parasites.
Cytologic examination for malignant cells.
Blood culture: may be positive in acute stage.
Increased WBC in acute stages (15,000–30,000/cu mm)
Increased ESR
Normochromic normocytic anemia in chronic stage
Albuminuria is frequent.
Findings of underlying disease—especially bronchogenic carcinoma; also drug addiction, postabortion state, coccidioidomycosis, amebic abscess, TB, alcoholism
ADULT RESPIRATORY DISTRESS SYNDROME (ARDS)
Defined As3
Ratio of pO2 (partial pressure arterial O 2)/FiO2 (fraction inspired O2 concentration) £ 200 regardless of positive end-expiratory pressure. This ratio correlates with
patient's outcome. In acute lung injury (change in lung function) this ratio is £ 300.
Bilateral pulmonary infiltrates on frontal radiography
Pulmonary wedge pressure £ 18 mm Hg or no evidence of increased left atrial pressure
Preceding or associated event (e.g., sepsis [most common], aspiration, infection, pneumonia, pancreatitis, shock, fat emboli, trauma, DIC, etc.; more than one cause
is often present). Infection is more likely due to gram-negative than gram-positive organisms. Occurs in 23% of cases of gram-negative bacteremia.
Static pulmonary compliance <50 mL/cm H2O that markedly reduces vital capacity, total lung capacity, functional residual capacity.
Initially there is respiratory alkalosis and varying degrees of hypoxemia resistant to supplementary O 2; then profound anoxemia with pO2 <50 mm Hg on room air.
BAL shows increased PMNs (£ 80%). Eosinophilia occurs occasionally. Opportunistic organisms may be found if presents as ARDS.
ASTHMA, BRONCHIAL
Earliest change is decreased pCO2 with respiratory alkalosis with normal pO2. Then pO2 decreases before pCO2 increases.
With severe episode
Hyperventilation causes decreased pCO2 in early stages (may be <35 mm Hg).
Rapid deterioration of patient's condition may be associated with precipitous fall in pO2 and rise in pCO 2 (>40 mm Hg).
pO2 <60 mm Hg may indicate severe attack or presence of complication.
Normal pCO2 suggests that the patient is tiring.
Acidemia and increased pCO2 suggest impending respiratory failure.
Mixed metabolic and respiratory acidosis occurs.
When patient requires hospitalization, arterial blood gases should be measured frequently to assess status.
Eosinophilia may be present.
Sputum is white and mucoid without blood or pus (unless infection is present).
Eosinophils, crystals (Curschmann's spirals), and mucus casts of bronchioles may be found.
Laboratory findings due to underlying diseases that may be primary and that should be ruled out, especially polyarteritis nodosa, parasitic infestation, bronchial
carcinoid, drug reaction (especially to aspirin), poisoning (especially by cholinergic drugs and pesticides), hypogammaglobulinemia.
BRONCHIECTASIS
WBC usually normal unless pneumonitis is present.
Mild to moderate normocytic normochromic anemia with chronic severe infection
Sputum abundant and mucopurulent (often contains blood); sweetish smell
Sputum bacterial smears and cultures](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-95-320.jpg)
![CROUP (EPIGLOTTITIS, LARYNGOTRACHEITIS)
Group B H. influenzae causes >90% of cases of epiglottitis; other bacteria include beta-hemolytic streptococci and pneumococci.
Cultures, smears, and tests for specific causative agents
Blood cultures should be taken at the same time as throat cultures.
Neutrophilic leukocytosis is present.
Clinical picture in infectious mononucleosis or diphtheria may resemble epiglottitis.
Laryngotracheitis is usually viral (especially parainfluenza) but rarely bacterial in origin.
DYSPLASIA, BRONCHOPULMONARY
Usually seen in infants recovering from respiratory distress syndrome (RDS) in whom endotracheal tube and intermittent positive pressure ventilation have been used
for >24 hrs.
Stage I (first days of life)—severe RDS is present.
Stage II (late in first week)—clinical improvement but not asymptomatic
Stage III (second week of life)—clinical deterioration, increasing hypoxemia, hypercapnia, acidosis, diffuse radiographic changes in lungs
Stage IV (after 1 mo of age)—chronic healing phase with further radiographic changes. 25% die, usually due to pneumonia. Symptoms usually resolve by 2 yrs but
abnormal pulmonary function tests and right ventricular hypertrophy may persist for several years.
EMPHYSEMA, OBSTRUCTIVE
Laboratory findings of underlying disease that may be primary (e.g., pneumoconiosis, TB, sarcoidosis, kyphoscoliosis, marked obesity, fibrocystic disease of
pancreas, alpha-1-antitrypsin deficiency)
Laboratory findings of associated conditions, especially duodenal ulcer
Laboratory findings due to decreased lung ventilation
pO2 decreased and pCO2 increased
Ultimate development of respiratory acidosis
Secondary polycythemia
Cor pulmonale
GOODPASTURE'S SYNDROME
(Alveolar hemorrhage and GN [usually rapidly progressive] associated with antibody against pulmonary alveolar and glomerular basement membranes)
Proteinuria and RBCs and RBC casts in urine
Renal function may deteriorate rapidly or renal manifestations may be mild.
w Renal biopsy may show characteristic linear immunofluorescent deposits of IgG and often complement and focal or diffuse proliferative GN.
w Serum may show antiglomerular basement membrane IgG antibodies by enzyme immunoassay (EIA). Titer may not correlate with severity of pulmonary or renal
disease.
Eosinophilia absent and iron-deficiency anemia more marked than in idiopathic pulmonary hemosiderosis
Sputum or BAL showing hemosiderin-laden macrophages may be a clue to occult pulmonary hemorrhage.
Other causes of combined pulmonary hemorrhage and GN are
Wegener's granulomatosis
Hypersensitivity vasculitis
SLE
Polyarteritis nodosa
Endocarditis
Mixed cryoglobulinemia
Allergic angiitis and granulomatosis (Churg-Strauss syndrome)
Behçet's syndrome
Henoch-Schönlein purpura
Pulmonary-renal reactions due to drugs (e.g., penicillamine)
HANTAVIRUS PULMONARY SYNDROME
HERNIA, DIAPHRAGMATIC
Microcytic anemia (due to blood loss) may be present.
Stool may be positive for blood.
HISTIOCYTOSIS X
w Diagnosis is established by open lung biopsy.
Pulmonary disorder is the major manifestation of this disease; bone involvement in minority of cases with lung disease. Pleural effusion is rare.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-97-320.jpg)
![BAL shows increase in total number of cells; 2–20% Langerhans' cells, small numbers of eosinophils, neutrophils, and lymphocytes, and 70% macrophages.
Most adults do not have positive gallium citrate 67 ( 67
Ga) scans.
Mild decrease in pO2, which falls with exercise
INTERSTITIAL PNEUMONITIS, DIFFUSE
Serum LD is increased.
LARYNX DISEASES
w Culture and smears for specific organisms (e.g., tubercle bacilli, fungi)
w Biopsy for diagnosis of visible lesions (e.g., leukoplakia, carcinoma)
May be due to any respiratory viruses.
LEGIONNAIRES' DISEASE
See Chapter 15.
NASOPHARYNGITIS, ACUTE
Due To
Bacteria (e.g., Group A beta-hemolytic streptococci [causes 10–30% of cases seen by doctors], H. influenzae, M. pneumoniae, etc.). (Mere presence of staphylococci,
pneumococci, alpha- and beta-hemolytic streptococci [other than groups A, C, and G] in throat culture does not establish them as cause of pharyngitis and does not
warrant antibiotic treatment.)
Virus (e.g., EBV, CMV, adenovirus, RSV, HSV, coxsackievirus)
M. pneumoniae
C. pneumoniae (formerly TWAR agent)
Fungus, allergy, foreign body, trauma, neoplasm
Idiopathic (no cause is identified in ~50% of cases)
Microscopic Examination of Stained Nasal Smear
m Large numbers of eosinophils suggest allergy. Does not correlate with blood eosinophilia.
Eosinophils and neutrophils suggest chronic allergy with superimposed infection.
m Large numbers of neutrophils suggest infection.
m Gram stain and culture of pharyngeal exudate may show significant pathogen.
NEONATAL RESPIRATORY DISTRESS SYNDROME (RDS)
Hypoxemia
Hypercapnia and acidosis in severe cases
pO2 is maintained between 50–70 mm Hg to minimize retinal damage.
Laboratory findings due to complications (e.g., hypoglycemia, hypocalcemia, acidosis, anemia)
PLEURAL EFFUSION
See Fig. 6-1, Table 6-1, Table 6-2 and Table 6-3.
Fig. 6-1. Algorithm for pleural effusion.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-98-320.jpg)
![w Cholesterol <55 mg/dL is said to be found in transudates and >55 mg/dL in exudates.
w CEA >10 ng/mL has specificity of >95% and sensitivity of 54–100% for lung cancer, 83% for breast cancer, 100% for GI tract cancers. May also be increased in
empyema and parapneumonic effusions.
w C125 tumor antigen (CA-125;) has sensitivity of 71% and specificity of 99% for non-mucinous epithelial ovarian carcinoma.
Combined CEA and CA-125 have sensitivity for detection of malignant effusions due to carcinomas of lung, breast, GI tract, and ovary of 75–100% and specificity of
98%. May indicate primary site when the source is unknown or cytology is negative ( Table 6-3).
Other tumor markers have been suggested for diagnosis of cancer, but value not established (e.g., acid phosphatase in prostatic cancer, hyaluronic acid in
mesothelioma, beta 2-microglobulin, etc.)
Acid mucopolysaccharides (especially hyaluronic acid) may be increased (>120 µg/mL) in mesotheliomas.
Immune complexes (measured by Raji cell, C1q component of C, RIA, etc.) are often found in exudates due to collagen vascular diseases (SLE, RA). RA latex
agglutination tests show frequent false-positives and should not be ordered.
Occasionally latex agglutination for bacterial antigens is useful. Gas-liquid chromatography has been reported to show butyric, isobutyric, propionic, and isovaleric
acids in anaerobic acute bacterial infection and increased lactic and acetic acid levels in aerobic infections.
Cell Count
Total WBC count is almost never diagnostic.
>10,000/cu mm indicates inflammation, most commonly with pneumonia, pulmonary infarct, pancreatitis, postcardiotomy syndrome.
>50,000/cu mm is typical only in parapneumonic effusions, usually empyema.
Chronic exudates (e.g., malignancy and TB) are usually <5000/cu mm.
Transudates are usually <1000/cu mm.
5000–6000 RBCs/cu mm needed to give red appearance to pleural fluid
Can be caused by needle trauma producing 2 mL of blood in 1000 mL of pleural fluid.
>100,000 RBCs/cu mm is grossly hemorrhagic and suggests malignancy, pulmonary infarct, or trauma but occasionally seen in congestive heart failure alone.
Hemothorax (pleural fluid to venous Hct ratio >2) suggests trauma, bleeding from a vessel, bleeding disorder, or malignancy but may be seen in same conditions as
above.
Smears
Wright's stain differentiates PMNs from mononuclear cells; cannot differentiate lymphocytes from monocytes.
Mononuclear cells predominate in transudates and chronic exudates (lymphoma, carcinoma, TB, rheumatoid conditions, uremia). >50% is seen in two-thirds of cases
due to cancer. >85–90% suggests TB, lymphoma, sarcoidosis, rheumatoid causes.
PMNs predominate in early inflammatory effusions (e.g., pneumonia, pulmonary infarct, pancreatitis, subphrenic abscess).
After several days, mesothelial cells, macrophages, lymphocytes may predominate.
Large mesothelial cells >5% are said to rule out TB (must differentiate from macrophages).
Lymphocytes
>85% suggests TB, lymphoma, sarcoidosis, chronic rheumatoid pleurisy, yellow nail syndrome, chylothorax.
50–75% in >50% of cases of carcinoma.
Eosinophils in pleural fluid (>10% of total WBCs) is not diagnostically significant.
May mean blood or air in pleural space (e.g., pneumothorax [most common], repeated thoracenteses, traumatic hemothorax).
It also is said to be associated with asbestosis, pulmonary infarction, polyarteritis nodosa.
Parasitic disease (e.g., paragonimiasis, hydatid disease, amebiasis, ascariasis).
Fungal disease (e.g., histoplasmosis, coccidioidomycosis).
Drug-related (e.g., nitrofurantoin, bromocriptine, dantrolene).
Idiopathic effusion (in approximately one-third of cases; may be due to occult pulmonary embolism or asbestosis).
Uncommon with malignant effusions.
Rare with TB.
Not usually accompanied by striking blood eosinophilia. Many diseases associated with blood eosinophilia infrequently cause pleural effusion eosinophilia.
Basophils >10% only in leukemic involvement of pleura.
Occasionally lupus erythematosus (LE) cells make the diagnosis of SLE.
Gram stain for early diagnosis of bacterial infection.
Acid-fast smears are positive in 20% of tuberculous pleurisy.
Culture is often positive in empyema but not in parapneumonic effusions.
w Bacterial antigens may detect H. influenzae type b, Streptococcus pneumoniae, several types of Neisseria meningitidis. Useful when viable organisms cannot be
recovered (e.g., due to prior antibiotic therapy).
w Cytology
Positive in 60% of malignancies on first tap, 80% by third tap. Therefore should repeat taps with cytologic examinations if cancer is suspected. Is more sensitive than
needle biopsy. Combined with needle biopsy, increases sensitivity by <10%. 4
(See Carcinoma, Bronchogenic.) High yield with adenocarcinoma, low yield with
Hodgkin's disease.
Rheumatoid effusions: cytologic triad of slender elongated and round giant multinucleated macrophages and necrotic background material with characteristically low](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-102-320.jpg)
![See Table 6-5.
Table 6-5. Opportunistic Pulmonary Infections
Due To
Bacteria
S. pneumoniae causes 60–70% of bacterial pneumonia in patients requiring hospitalization. May cause ~25% of hospital-acquired cases of pneumonia. Blood culture
positive in 25% of untreated cases during first 3–4 days.
Staphylococcus causes <1% of all acute bacterial pneumonia with onset outside the hospital but more frequent after outbreaks of influenza; may be secondary to
measles, mucoviscidosis, prolonged antibiotic therapy, debilitating diseases (e.g., leukemia, collagen diseases). Frequent cause of nosocomial pneumonia.
Bacteremia in <20% of patients.
H. influenzae is important in 6- to 24-mo age group; rare in adults except for middle-aged men with chronic lung disease and/or alcoholism and patients with
immunodeficiency (HIV, multiple myeloma, chronic lymphocytic leukemia [CLL]). Can mimic pneumococcal pneumonia; may be isolated with S. pneumoniae.
Gram-negative bacilli (e.g., K. pneumoniae, enterobacteria, E. coli, P. mirabilis, Pseudomonas aeruginosa) are common causes of hospital-acquired pneumonia but
unlikely outside the hospital. K. pneumoniae causes 1% of primary bacterial pneumonias, especially in alcoholic patients and patients with upper lobe pneumonia;
tenacious red-brown sputum is typical.
Tubercle bacilli
Legionella pneumophila
M. pneumoniae—most common in young adult male population (e.g., armed forces camps)
C. pneumoniae, Chlamydia psittaci
Others (e.g., streptococcosis, tularemia, plague)
See Table 6-5.
Viruses
Influenza, parainfluenza, adenoviruses, RSV, echovirus, coxsackievirus, reovirus, CMV, viruses of exanthems, herpes simplex, hantavirus
Rickettsiae
Q fever is most common in endemic areas; typhus.
Fungi
P. carinii, Histoplasma, and Coccidioides in particular; Blastomyces, Aspergillus.
Protozoans
Toxoplasma
Underlying
Condition
Organism
Obstructive
cancer
S. pneumoniae, H. influenzae, M. catarrhalis, anaerobes
Alcoholism S. pneumoniae, H. influenzae, Klebsiella spp., Legionella spp., anaerobes, M. tuberculosis
HIV infection S. pneumoniae, H. influenzae, S. aureus, gram-negative bacilli, P. carinii, M. tuberculosis and MAI (mycobacterium avium-intracellulare), Toxoplasma
gondii, Cryptococcus, Nocardia, CMV, histoplasmosis, Coccidioides immitis, Legionella, M. catarrhalis, Rhodococcus equi
Atypical
pneumonia
M. pneumoniae, C. psittaci, C. pneumoniae, Coxiella bur-netii, Francisella tularensis, many viruses
Laboratory Findings
WBC is frequently normal or slightly increased in nonbacterial pneumonias; considerable increase in WBC is more common in bacterial pneumonia. In severe
bacterial pneumonia, WBC may be very high or low or normal. Because individual variation is considerable, it has limited value in distinguishing bacterial and
nonbacterial pneumonia.
Urine protein, WBCs, hyaline and granular casts in small amounts are common. Ketones may occur with severe infection. Check for glucose to rule out underlying
diabetes mellitus.
w Sputum reveals abundant WBCs in bacterial pneumonias. Gram stain shows abundant organisms in bacterial pneumonias (e.g., Pneumococcus, Staphylococcus).
Culture sputum for appropriate bacteria. Sputum that contains many organisms and WBCs on smear but no pathogens on aerobic culture may indicate aspiration
pneumonia. Sputum is not appropriate for anaerobic culture.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-105-320.jpg)
![w In all cases of pneumonia, blood culture and sputum culture and smear for Gram stain should be performed before antibiotic therapy is started. Optimum specimen
of sputum shows >25 PMNs and £5 squamous epithelial cells/LPF (10× magnification), but >10 PMNs and <25 epithelial cells may be considered acceptable
sputum specimen. >25 epithelial cells indicate unsatisfactory specimen from oropharynx which should not be submitted for culture. If good sputum specimen is
obtained, further diagnostic microbiological tests are usually not performed.
Nasopharyngeal aspirate may identify S. pneumoniae with few false positives but S. aureus and gram-negative bacilli often represent false-positive findings.
In H. influenzae pneumonia, sputum culture is negative in >50% of patients with positive cultures from blood, pleural fluid, or lung tissue, and may be present in the
sputum in the absence of disease.
w Transtracheal aspiration (puncture of cricothyroid membrane) generally yields a faster, more accurate diagnosis.
w Protected brush bronchoscopy and BAL have high sensitivity.
w Diagnostic lung puncture to determine specific causative agent as a guide to antibiotic therapy may be indicated in critically ill children.
w Open lung biopsy is gold standard with 97% accuracy but 10% complication rate.
For pleural effusions that are aspirated, Gram stain and culture should also be performed.
w Respiratory pathogens isolated from blood, pleural fluid, or transtracheal aspirate (except in patients with chronic bronchitis) or identified by bacterial
polysaccharide antigen in urine may be considered the definite causal agent.
w Urine testing for capsular antigen from S. pneumoniae or type B H. influenzae by latex agglutination may be helpful. Positive in ~90% of bacteremic pneumococcal
pneumonias and 40% of nonbacteremic pneumonias. May be particularly useful when antibiotic therapy has already begun.
Acute phase serum should be stored at onset. If causal diagnosis is not established, a convalescent phase serum should be taken. A 4× increase in antibody titer
establishes the causal diagnosis (e.g., L. pneumophila, Chlamydia spp., respiratory viruses [including influenza and RSV]), M. pneumoniae. Serologic tests to
determine whether pneumonia is due to Histoplasma, Coccidioides, etc.
PNEUMONIA, LIPID
m Sputum shows fat-containing macrophages that stain with Sudan. They may be present only intermittently; therefore, examine sputum more than once.
PULMONARY ALVEOLAR PROTEINOSIS
(Rare disease characterized by amorphous, lipid-rich, proteinaceous material in alveoli)
m PAS–positive material appears in sputum.
m PSP dye injected intravenously is excreted in sputum for long periods of time.
BAL fluid contains increased total protein, albumin, phospholipids, and CEA.
w Recently antibodies to surfactant protein A (ELISA assay) in sputum and BAL have been reported to be highly specific.
m Serum CEA is increased and correlates with BAL findings. Reflects severity of disease and decreases with response to treatment.
m Routine laboratory test findings are nonspecific.
Serum LD increases when protein accumulates in lungs and becomes normal when infiltrate resolves; correlates with serum CEA.
Decreased arterial O2.
Secondary polycythemia may occur.
w Diagnosis usually requires open lung biopsy. Electron microscopy shows many lamellar bodies.
Laboratory findings due to superinfection.
PULMONARY EMBOLISM AND INFARCTION
No laboratory test is diagnostic.
<10% of emboli lead to infarction
Measurement of arterial blood gases (obtained when patient is breathing room air) is the most sensitive and specific laboratory test.
m • pO2 <80 mm Hg in 88% of cases but normal pO2 does not rule out pulmonary embolus. In appropriate clinical setting, pO 2 <88 mm Hg (even with a normal chest
radiograph) is indication for lung scans and search for deep vein thromboses. pO 2 >90 mm Hg with a normal chest radiograph suggests a different diagnosis.
Normal complete lung scans exclude the diagnosis.
• Hypocapnia and slightly elevated pH.
Increased WBC in 50% of patients but is rarely >15,000/cu mm (whereas in acute bacterial pneumonia is often >20,000/cu mm).
Increased ESR
Triad of increased LD and bilirubin with normal AST is found in only 15% of cases.
Serum enzymes differ from those in acute myocardial infarction.
Increased serum LD (due to isoenzymes LD-2 and LD-3) in 80% of patients rises on first day, peaks on second, normal by tenth day.
Serum AST is usually normal or only slightly increased.
cTn not increased.
Serum indirect bilirubin is increased (as early as fourth day) to ~5 mg/dL in 20% of cases.
Pleural effusion may occur.
w Plasma D-dimer (ELISA or Latex Agglutination Kits)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-106-320.jpg)
![Vomiting
Dehydration
Drugs (e.g., NSAIDs)
Normal In
Steatorrhea due to pancreatic disease
Postgastrectomy state
Malnutrition
GASTRIC ANALYSIS
Use
Determine status of acid secretion in hypergastrinemia patients being treated for gastrinoma.
Determine if patients who have undergone surgery for ulcer disease and who have complications are secreting acid.
Interpretation
1-hr basal acid
<2 mEq Normal, gastric ulcer, or carcinoma
2–5 mEq Normal, gastric or duodenal ulcer
>5 mEq Duodenal ulcer
>20 mEq Z-E (Zollinger-Ellison) syndrome
1 hr after stimulation by pentagastrin
0 mEq Achlorhydria, gastritis, gastric carcinoma
1–20 mEq Normal, gastric ulcer, or carcinoma
20–35 mEq Duodenal ulcer
35–60 mEq Duodenal ulcer, high normal, Z-E syndrome
>60 mEq Z-E syndrome
Ratio of basal acid to poststimulation outputs
20% Normal, gastric ulcer, or carcinoma
20–40% Gastric or duodenal ulcer
40–60% Duodenal ulcer, Z-E syndrome
>60% Z-E syndrome
Achlorhydria1
Chronic atrophic gastritis (serum gastrin is frequently increased)
PA 100% of patients
Vitiligo 20–25%
Alopecia areata 6%
RA 10–20%
Thyrotoxicosis 10%
Gastric carcinoma (50% of patients) even after pentagastrin stimulation. Hypochlorhydria occurs in 25%, hydrochloric acid is normal in 25%, hyperchlorhydria is rare
in patients with gastric carcinoma.
Gastric ulcer Common
Adenomatous polyps of stomach 85% of patients
Ménétrier's disease 75%
Chronic renal failure 13% (usually normal; occasionally increased)
Iatrogenic
Postvagotomy, postantrectomy >90%
Measure acid output after IV insulin to demonstrate adequacy of vagotomy (see Insulin Test Meal).
Medical (e.g., potent H2 receptor
antagonists, substituted benzimidazoles)
>80%
Occurs in normal persons: 4% of children, increasing to 30% of adults older than age 60 years.
True achlorhydria excludes duodenal ulcer.
Hyperchlorhydria and Hypersecretion2
Duodenal ulcer 40–45%
Z-E syndrome 100%
Twelve-hour night secretion shows acid of >100 mEq/L and volume >1500 mL.
Basal secretion is >60% of secretion caused by histamine or betazole stimulation.
Hyperplasia/hyperfunction of antral gastrin cells >90% (unusual condition with marked hyperchlorhydria, severe peptic ulceration, moderately increased fasting serum
gastrin with exaggerated postprandial increase [>200% above fasting levels], no gastrin-secreting tumors)
Hypertrophic hypersecretory gastropathy 100%
Massive resection of small intestine (transient) 50%
Systemic mastocytosis Rare
When basal serum gastrin level is equivocal, serum gastrin level should be measured after stimulation with infusion of secretin or calcium.
GASTRIN, SERUM](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-110-320.jpg)
![Salicylates Due to bleeding
Santonin Yellow
Senna Yellow to brown
Tetracyclines in syrup (due to glucosamine) Red
Occult Blood
Use
Screening for asymptomatic ulcerated lesions of GI tract, especially carcinoma of the colon and large adenomas, is generally recommended now.
Interpretation
Kits (e.g., Hemoccult cards) use guaiac; detect blood losses of ~20 mL/day; "normal" amount of blood lost in stool daily is <2 mL/day or 2 mg Hb/gm of stool, but
sensitivity is only 20% at this level and 90% at Hb concentration >25 mg/gram of stool. ~50% of colon cancers shed enough blood to produce a positive test.
Hemoccult gives 1—3% false-positives even with strict protocol for stool collection. Sensitivity of Hemoccult and HemoQuant is only ~20—30% for colorectal cancer
and ~13% for polyps; most of these lesions are missed.4
Benzidine reaction is too sensitive; yields too many false-positive results. Guaiac test yields too many false-negative results.
In various screening programs, 2—6% of participants have positive tests; of these, carcinoma is found in 5—10% and adenoma in 20—40%. Sensitivity = 81% for left
colon cancer, 47% for colon and cecum cancer, 45% for rectal cancer. ~90% of positives are false-positives.
Adenomas <2 cm in size are less likely to bleed. Upper GI tract bleeding is less likely than lower GI tract bleeding to cause a positive test.
Long-distance running is associated with positive guaiac test in up to 23% of runners.
Recommendations for testing
Test two areas from each of three consecutive stool samples.
Test all samples within 7 days of collection.
Rehydration of slide before development is controversial.
Use of fecal sample obtained during digital rectal examination is not recommended.
For 3 days before test, avoid large doses of aspirin (>325 mg/day) and other NSAIDs, ascorbic acid (false-negative may occur with >500 mg/day), oral iron, red
meat, poultry, fish, and certain fruits and vegetables that contain catalases and peroxidases (e.g., cucumbers, horseradish, cauliflower), especially if slides are
rehydrated.
Even one positive result is considered a positive test even without dietary restriction. 5,6
Other tests for occult blood
Quantitative HemoQuant test kit (uses fluorescence to assay stool-derived porphyrins) doubles sensitivity of guaiac tests; may be affected by red meat and
aspirin (for up to 4 days) but not by other substances mentioned above. Manual test performed in a laboratory requires 90 mins (<2 mg/gm is normal; >4 mg/gm
is increased; 2–4 mg/gm is borderline).
Immunochemical tests (e.g., HemeSelect) specifically detect human hemoglobin, do not require diet or chemical restrictions (do not react with animal heme or
foods), are stable for up to 30 days, detect ~0.3 mg Hb/gm of stool whereas 5–10× this amount is required to cause a positive guaiac test.
Samples from upper GI tract should not be tested for blood using urine dipsticks or stool occult blood test kits (low pH may cause false-negative and oral drug
use false-positive results).7,8
51
CR TEST FOR BLEEDING
Tag 10 mL of the patient's blood with 200 µCi of 51
Cr, and administer it IV.
Collect daily stool specimens for radioactivity measurement and also measure simultaneous blood samples.
Use
Measure GI blood loss in ulcerative diseases (e.g., ulcerative colitis, regional enteritis, peptic ulcer).
Interpretation
Radioactivity in the stool establishes GI blood loss. Comparison with radioactivity measurements of 1 mL of blood indicates the amount of blood loss.
Electrolytes
Sodium Chloride Potassium
(mEq/24 hrs) (mEq/24 hrs) (mEq/24 hrs)
Normal* 7.8±2.0 3.2±0.7 18.2±2.5
Idiopathic proctocolitis 22.3 19.8 Normal
Ileostomy 30 19.0 4.1
Cholera Increased Increased
*Average values for eight healthy individuals. Variable but considerably lower than simultaneous concentrations in serum.
Normal calcium »170;0.6 gm/24 hrs
Fat
See Malabsorption.
Osmotic Gap
(Osmotic gap = measured osmolality minus 2 × [Na + K] or 290 mOsm/kg H2O minus 2 × [Na + K])
Increased In
Osmotic diarrhea
See Factitious Disorders.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-113-320.jpg)
![Fig. 7-2. Algorithm for spontaneous bacterial peritonitis.
w· Infection: Peritonitis is defined as WBC >100/cu mm, usually with >50% PMNs (normal value is <50 WBC/cu mm, usually mononuclear cells), or positive Gram
stain or culture (most prevalent: coagulase-negative staphylococci, Staphylococcus aureus, Streptococcus spp.; multiple organisms, especially mixed aerobes and
anaerobes, occur with bowel perforation). Successful therapy causes fall in WBC within first 2 days and return to <100/cu mm in 4–5 days; differential returns to
predominance of monocytes in 4–7 days with increased eosinophils in 10% of cases. Patients check outflow bags for turbidity. Turbid dialysate can occasionally
occur without peritonitis during first few months of placing catheter (due to catheter hypersensitivity) with WBC 100–8000/cu mm and 10–95% eosinophils,
sometimes increased PMNs, and negative cultures. Occasional RBCs may be seen during menstruation or with ovulation at midcycle. Because of low WBC
decision level, manual hemocytometer count rather than an automated instrument must be used.
Metabolic change: Assay dialysate for creatinine and glucose; calculate ultrafiltrate volume by weighing dialysate fluid after 4-hr dwell time and subtracting it
from preinfusion weight using specific gravity of 1.0.
w Pancreatic disease: Ascitic fluid amylase greater than serum amylase is virtually specific for pancreatic disease, but both levels are normal in 10% of cases.
Methemalbumin in serum or ascitic fluid and total protein >4.5 gm/dL indicate poor prognosis.
Chylous ascites: Triglyceride is 2–8× serum level. Protein is 2–3 gm/dL. Due to lymphatic obstruction (e.g., lymphoma or carcinoma [60% of cases]), inflammation or
obstruction of small intestine, trauma to chest or abdomen, filariasis; in pediatric patients, is often due to congenital lymphatic defects.
w Malignant ascites: Increased fluid cholesterol (>45 mg/dL) and fibronectin (>10 mg/dL) have sensitivity of 90% and specificity of 82%. Positive cytology has
sensitivity of 70% and specificity of 100%. Increased ascitic fluid CEA (>2.5 mg/dL) has sensitivity of 45% and specificity of 100%.
w Criteria to diagnose penetrating abdominal wounds by peritoneal lavage
>10,000 RBC/cu mm (>5000 RBC/cu mm for gunshot wounds).
>500 WBC/cu mm or
Bacteria, fecal, or vegetable matter on Gram stain or bile (Ictotest) or
Detection of endotoxin by limulus amoebocyte lysate assay for ileocolic perforation or
Amylase or ALP level has been used to detect small bowel or pancreatic injury.
Increases in WBC, amylase, and ALP are often delayed >3 hrs.
RBC and WBC counts of lavage fluid have most clinical utility.
w Criteria to diagnose blunt abdominal trauma by peritoneal lavage with 10,000 mL of normal saline; falsely low RBC count if <600–800 mL of fluid is recovered.
Grossly bloody fluid or
>100,000 RBC/cu mm (newspaper print is unreadable through lavage tubing if RBC count is this high); negative test = <50,000 RBC/cu mm; equivocal results =
50,000–100,000; or
>500 WBC/cu mm or
Amylase >2.5× normal
w Criteria to diagnose intestinal injury in blunt abdominal trauma by peritoneal lavage with 10,000 mL of normal saline, especially 3–18 hrs after injury
If bloody ascites is not present, may signal solid organ injury
>10,000 WBC/cu mm and
WBC/cu mm ³(RBC/cu mm divided by 150)
w To differentiate urine from ascitic or pleural fluid (in cases of possible GU tract fistula or accidental aspiration of bladder)
Urine creatinine is >2× serum level.
Uncontaminated ascitic or pleural fluid creatinine is usually same as serum level but always <2× serum level.
Urea nitrogen also greater in urine.
Increased serum inorganic phosphate in 25% of cases of ischemic bowel disease; >5.5 mg/dL indicates extensive bowel injury, acute renal failure, metabolic acidosis,
and poorer prognosis.
Peritoneal fluid bicarbonate value to differentiate site of penetrating wounds of GI tract:
Wound Site Effect on Bicarbonate Value
Stomach or duodenum proximal to pancreatic duct Decrease
Duodenum just distal to pancreatic duct Increase
Third part of duodenum, jejunum, or ileum Probably no effect
Fluid Source Bicarbonate Values (mEq/L) (Reference Values)
Peritoneal 24.0–29.0
Pancreatic 66.0–127.0
Duodenal 4.0–21.0
Jejunal 2.0–32.0
Ileal 2.3
Gastric —
Plasma/venous blood 20.0–30.0
Ascites in Fetus or Neonate
Due To](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-116-320.jpg)
![Nonimmune (occur in 1:3000 pregnancies)
% of cases
Cardiovascular abnormalities causing congestive heart failure
(e.g., structural, arrhythmias)
40
Chromosomal (e.g., Turner's and Down syndromes are most common;
trisomy 13, 15, 16, 18)
10–15
Hematologic disorders (any severe anemia) 10
Inherited, e.g.,
Alpha-thalassemia
Hemoglobinopathies
G-6-PD deficiency
Other RBC enzyme defects
Acquired, e.g.,
Fetal-maternal hemorrhage
Twin-to-twin transfusion
Congenital infection (parvovirus B19)
Methemoglobinemia
Congenital defects of chest and abdomen
Structural, e.g.,
Diaphragmatic hernia
Cystic adenomatoid malformation of lung
Jejunal atresia
Fetal lymphatic dysplasia
Midgut volvulus
Intestinal malrotation
Peritonitis due to
GI tract perforation
Congenital infection (e.g., syphilis, TORCH [ toxoplasma, other agents, rubella, cytomegalovirus, herpes simplex] syndrome, hepatitis)
Meconium peritonitis due to complications of cystic fibrosis
Lymphatic duct obstruction
Biliary atresia
Bile ascites (rare) due to biliary tree perforation caused by congenital stenosis, choledochal cyst or stone.
Intermittent acholic stools, dark urine, fluctuating hyperbilirubinemia.
Bile-stained ascitic fluid with increased protein (2–4 gm/dL).
IV administration of iodine 131 (131
I)–labeled rose bengal appearing in ascitic fluid makes the diagnosis early before bile staining occurs.
Nonstructural, e.g.,
Congenital nephrotic syndrome
Cirrhosis
Cholestasis
Hepatic necrosis
GI tract obstruction
Lower GU tract obstruction (e.g., usually due to posterior urethral valves, urethral atresia, ureterocele) is most common cause.
Inherited skeletal dysplasias (enlarged liver causing extramedullary hematopoiesis)
Fetal tumors, most often teratomas and neuroblastomas
Vascular placental abnormalities
Genetic metabolic disorders, e.g.,
Hurler's syndrome
Gaucher's disease
Niemann-Pick disease
GM1 gangliosidosis type I
I-cell disease
Beta-glucuronidase deficiency
Immune (maternal antibodies reacting to fetal antigens, e.g., Rh, C, E, Kell)
CELIAC DISEASE (GLUTEN-SENSITIVE ENTEROPATHY, NONTROPICAL SPRUE, IDIOPATHIC STEATORRHEA)
See Fig. 7-3.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-117-320.jpg)
![WBC >15,000/cu mm in <50% of cases.
Hypoalbuminemia in £24% of cases.
Laboratory findings due to dehydration and electrolyte imbalance in severe cases.
COLITIS, ULCERATIVE, CHRONIC NONSPECIFIC
Laboratory findings parallel severity of the disease
Anemia due to blood loss (frequently Hb = 6 gm/dL).
WBC usually normal unless complication occurs (e.g., abscess).
ESR often normal or only slightly increased.
With diarrhea and fever, Hb <7.5 gm/dL and ESR >30 mm/hr indicate severe disease.
Hypoalbuminemia indicates severe disease of longer duration.
Stools
Positive for blood (gross and/or occult)
Negative for usual enteric bacterial pathogens and parasites; high total bacterial count
Changes in liver function
Microscopic changes in needle biopsy of liver.
Serum ALP often increased slightly.
Other liver function tests usually normal.
Changes in serum electrolytes due to diarrhea or to therapy with adrenal steroids or ACTH
Laboratory changes due to complications or sequelae (e.g., malabsorption due to involvement of small intestine, perforation, abscess formation, hemorrhage,
carcinoma, arthritis, sclerosing cholangitis)
m Rectal biopsy
COLON, CARCINOMA
Blood in stool (occult or gross)
Evidence of inflammation
Increased WBC and ESR
Anemia—usually hypochromic
May be the only symptom of carcinoma of right side of colon (present in >50% of these patients)
Stools sometimes negative for occult blood
Laboratory evidence of liver metastases
w Biopsy of colon lesion establishes the diagnosis
Serum CEA
m Villous tumor of rectum may cause secretory diarrhea with potassium loss and decreased serum potassium. Carcinoid tumors may cause increased 5-HIAA in
urine.
Laboratory findings due to underlying condition (e.g., hereditary polyposis, chronic nonspecific ulcerative colitis)
Laboratory findings due to complications (e.g., hemorrhage, perforation, obstruction)
DIARRHEA, ACUTE
Osmotic (Malabsorptive) Diarrhea
(Increased osmotically active solutes in bowel; diarrhea usually stops during fasting.)
Due To
Exogenous
Laxatives (e.g., magnesium sulfate, milk of magnesia, sodium sulfate [Glauber's salt], sodium phosphate, polyethylene glycol/saline)
Drugs (e.g., lactulose, colchicine, cholestyramine, neomycin, PAS)
Foods (e.g., mannitol, sorbitol [in diet candy, chewing gum, soda])
Endogenous
Congenital malabsorption
Specific (e.g., lactase deficiency, fructose malabsorption)
General (e.g., abeta- and hypobetalipoproteinemia, congenital lymphangiectasia, cystic fibrosis)
Acquired malabsorption
Specific (e.g., pancreatic disease, celiac sprue, parasitic infestation, rotavirus enteritis, metabolic disorders [thyrotoxicosis, adrenal insufficiency], jejunoileal
bypass, bacterial overgrowth, short-bowel syndrome, inflammatory disease [mastocytosis, eosinophilic enteritis])](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-119-320.jpg)
![diseases involving the small bowel, extensive resection). Abnormal pancreatic function does not affect the test.
Most common laboratory abnormalities are decreased serum carotene, albumin, and iron, increased ESR, increased stool weight (>300 gm/24 hrs) and stool fat (>7
gm/24 hrs), anemia.
w Normal D-xylose test, low serum trypsinogen, pancreatic calcification on radiograph of abdomen establish diagnosis of chronic pancreatitis. If
calcification is absent (as occurs in 70–80% of cases), abnormal contents of pancreatic secretion after secretin-cholecystokinin stimulation or
abnormal bentiromide tests establishes diagnosis of chronic pancreatitis.
Anemia is due to deficiency of iron, folic acid, vitamin B 12, or various combinations, depending on their decreased absorption.
Carbohydrate absorption indices
Oral GTT—limited value
Flat curve or delayed peak occurs in celiac disease and nontropical sprue.
Curve is normal in pancreatic insufficiency.
D-Xylose tolerance test of carbohydrate absorption
Measure total 5-hr urine excretion; may also measure serum levels at 2 hrs.
Accuracy is 90% in distinguishing normal levels in pancreatic disease from decreased levels in intestinal mucosal disease and intestinal bacterial
overgrowth, but opinions vary on usefulness. Also decreased in renal disease, myxedema, and the elderly although absorption is normal.
Disaccharide malabsorption
Due To
Primary malabsorption (congenital or acquired) due to absence of specific disaccharidase in brush border of small intestine mucosa
Isolated lactase deficiency (also called milk allergy, milk intolerance, congenital familial lactose intolerance, lactase deficiency) is most common of these
defects; occurs in ~10% of whites and 60% of blacks; infantile type shows diarrhea, vomiting, failure to thrive, malabsorption, etc.; often appears first in adults;
become asymptomatic when lactase is removed from diet.
Sucrose-isomaltose malabsorption (inherited recessive defect)
Oral sucrose tolerance curve is flat, but glucose plus fructose tolerance test is normal. Occasionally an associated malabsorption is noted with increased
stool fat and abnormal D-xylose tolerance test although intestinal biopsy is normal.
Hydrogen breath test after sucrose challenge.
Intestinal biopsy with measurement of disaccharidase activities.
Sucrose-free diet causes cessation of diarrhea.
Glucose-galactose malabsorption (inherited autosomal recessive defect that affects kidney and intestine)
Oral glucose or galactose tolerance curve is flat, but intravenous tolerance curves are normal. Glucosuria is common. Fructose tolerance test is normal.
Secondary malabsorption
Resection of >50% of disaccharidase activity
Lactose is most marked, but there may also be sucrose. Oral disaccharide tolerance (especially lactose) is abnormal, but intestinal histology and enzyme
activity are normal.
Diffuse intestinal disease—especially celiac disease in which activity of all disaccharidases may be decreased, with later increase as intestine becomes normal
on gluten-free diet; also cystic fibrosis of pancreas, severe malnutrition, ulcerative colitis, severe Giardia infestation, blind-loop syndrome, beta-lipoprotein
deficiency, effect of drugs (e.g., colchicine, neomycin, birth control pills).
Oral tolerance tests (especially lactose) are frequently abnormal, with later return to normal with gluten-free diet. Tolerance tests with monosaccharides may
also be abnormal because of defect in absorption as well as digestion.
Bacterial overgrowth—see Table 7-1
Table 7-1. Infectious Foodborne Diseases
Culture of duodenal aspirate showing >105
colony-forming units of anaerobic organisms is considered diagnostic.
[14
C]d-xylose breath test has good specificity.
Hydrogen breath tests (glucose-H2, lactulose-H2)—not recommended due to limited sensitivity and specificity.
Laboratory tests for lactase deficiency
(Similar tests for other disaccharide deficiencies can be performed.)
Oral lactose tolerance curve is flat (blood glucose rises <20–25 mg/dL in blood drawn 15, 30, 60, and 90 mins after 50–100 gm dose of lactose) but tolerance
test is normal using constituent monosaccharides (25 gm each of glucose and galactose) indicating isolated lactase deficiency rather than general mucosal
absorptive defect.
Normal: Blood glucose increases >24 mg/dL above fasting level; may increase >20–25 mg/dL in diabetics despite impaired lactose absorption.
Abnormal: glucose increases <20 mg/dL above fasting level. False abnormal test may be due to delayed gastric emptying or small bowel transit or delayed
blood collection. Poor sensitivity–largely replaced by breath hydrogen lactose test.
Stool examination](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-131-320.jpg)
![PT is prolonged, with response to parenteral vitamin K more frequent than in hepatic parenchymal cell disease.
Urine bilirubin is increased; urine urobilinogen is decreased.
Stool bilirubin and urobilinogen are decreased (clay-colored stools).
Laboratory findings due to underlying causative disease are noted (e.g., stone, carcinoma of duct, metastatic carcinoma to periductal lymph nodes).
Bile Duct Obstruction (One)
m Characteristic pattern is serum bilirubin that remains normal in the presence of markedly increased serum ALP.
BREAST-MILK JAUNDICE
(Due to the presence in mother's milk of 5-b-pregnane-3-a-20-b-diol, which inhibits glucuronyl transferase activity)
m Severe unconjugated hyperbilirubinemia. Develops in 1% of breast-fed infants by fourth to seventh day. Reaches peak of 15–25 mg/dL by second to third week,
then gradually disappears in 3–10 wks in all cases. If nursing is interrupted, serum bilirubin falls rapidly by 2–6 mg/dL in 2–6 days and may rise again if
breast-feeding is resumed; if interrupted for 6–9 days, serum bilirubin becomes normal.
No other abnormalities are present.
Kernicterus does not occur.
CHOLANGITIS, ACUTE
Marked increase in WBC (£ 30,000/cu mm) with increase in granulocytes
m Blood culture positive in ~30% of cases; 25% of these are polymicrobial.
m Laboratory findings of incomplete duct obstruction due to inflammation or of preceding complete duct obstruction (e.g., stone, tumor, scar). See
Choledocholithiasis.
m Laboratory findings of parenchymal cell necrosis and malfunction
Increased serum AST, ALT, etc.
Increased urine urobilinogen
CHOLANGITIS, PRIMARY SCLEROSING
(Chronic fibrosing inflammation of intra- and extrahepatic bile ducts predominantly in men younger than age 45 years; rare in pediatric patients; £ 75% of
cases are associated with inflammatory bowel disease, especially ulcerative colitis; slow, relentless, progressive course of chronic cholestasis to death
[usually from liver failure]. 25% of patients are asymptomatic at time of diagnosis.)
w Diagnosis should not be made if there is previous bile duct surgery, gallstones, suppurative cholangitis, bile duct tumor, or damage due to floxuridine, AIDS,
congenital duct anomalies.
w Characteristic cholangiogram is required for diagnosis; distinguishes it from primary biliary cirrhosis.
m Cholestatic biochemical profile for >6 mos
Serum ALP may fluctuate but is always increased >1.5× upper limit of normal (usually ³3× upper limit of normal).
Serum GGT is increased.
Serum AST is mildly increased in >90%. ALT is greater than AST in three-fourths of cases.
Serum bilirubin is increased in one-half of patients; occasionally is very high; may fluctuate markedly; gradually increases as disease progresses. Persistent
value >1.5 mg/dL is poor prognostic sign that may indicate irreversible, medically untreatable disease.
Increased gamma globulin in 30% of cases and increased IgM in 40–50% of cases
ANCAs in ~65% of cases and ANAs in <35% are present at higher levels than in other liver diseases, but diagnostic significance is not yet known.
In contrast to primary biliary cirrhosis, antimitochondrial antibody, smooth-muscle antibody and RF are negative in >90% of patients.
HBsAg is negative.
m Liver biopsy provides only confirmatory evidence in patients with compatible history, laboratory, and radiographic findings. Liver copper is usually increased but
serum ceruloplasmin is also increased.
Laboratory findings due to sequelae
Cholangiocarcinoma in 10–15% of patients may cause increased serum CA 19-9.
Portal hypertension, biliary cirrhosis, secondary bacterial cholangitis, steatorrhea and malabsorption, cholelithiasis, liver failure.
Laboratory findings due to underlying disease, e.g.,
£ 7.5% of ulcerative colitis patients have this disease; many fewer patients with Crohn's disease. Associated with syndrome of retroperitoneal and mediastinal
fibrosis.
CHOLECYSTITIS, ACUTE
Increased ESR, WBC (average 12,000/cu mm; if >15,000 suspect empyema or perforation), and other evidence of acute inflammatory process
Serum AST is increased in 75% of patients.
Increased serum bilirubin in 20% of patients (usually <4 mg/dL; if higher, suspect associated choledocholithiasis)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-140-320.jpg)
![Transaminase usually <100 U.
Serum bilirubin may be normal or £ 10 mg/dL.
Liver biopsy shows centrolobular cholestasis without inflammation.
CHOLESTASIS, NEONATAL
Due To
Idiopathic neonatal hepatitis 50–60%
Extrahepatic biliary atresia 20%
Metabolic disease
Alpha1-antitrypsin deficiency 15%
Cystic fibrosis
Tyrosinemia
Galactosemia
Niemann-Pick disease
Defective bile acid synthesis
Infection (e.g., CMV infection, syphilis, sepsis, GU tract infection)
Toxic causes (e.g., drugs, parenteral nutrition)
Other conditions
Paucity of bile ducts (Alagille syndrome)
Indian childhood cirrhosis
Hypoperfusion/shock
CIRRHOSIS, PRIMARY BILIARY (CHOLANGIOLITIC CIRRHOSIS, HANOT'S HYPERTROPHIC CIRRHOSIS, CHRONIC
NONSUPPURATIVE DESTRUCTIVE CHOLANGITIS, ETC.)
(Multisystem autoimmune disease; chronic nonsuppurative inflammation and destruction of small intrahepatic bile ducts producing chronic cholestasis
and cirrhosis)
w Diagnostic Criteria
Laboratory findings of
Cholestatic pattern (increased ALP) of long duration (may last for years) not due to known cause (e.g., drugs).
Antimitochondrial autoantibodies present.
Confirmed patency of bile ducts (e.g., with ultrasonography or computed tomographic [CT] scan).
Compatible liver biopsy is highly desirable.
w Serum ALP is markedly increased; is of liver origin. Reaches a plateau early in the course and then fluctuates within 20% thereafter; changes in serum level have
no prognostic value. 5'-NT and GGT parallel ALP. This is one of the few conditions that elevates both serum ALP and GGT to striking levels.
w Serum mitochondrial antibody titer is strongly positive (1:40–1:80) in ~95% of patients and is hallmark of disease (98% specificity); titer >1:160 is highly predictive
of primary biliary cirrhosis (PBC) even in absence of other findings. Does not correlate with severity or rate of progression. Titers differ greatly in patients. Similar
titers occur in 5% of patients with chronic hepatitis; low titers occur in 10% of patients with other liver disease; rarely found in normal persons. Titer usually
decreases after liver transplantation but generally remains detectable.
w Serum bilirubin is normal in early phase but increases in 60% of patients with progression of disease and is a reliable prognostic indicator; an elevated level is a
poor prognostic sign. Direct serum bilirubin is increased in 80% of patients; levels >5 mg/dL in only 20% of patients; levels >10 mg/dL in only 6% of patients.
Indirect bilirubin is normal or slightly increased.
w Laboratory findings show relatively little evidence of parenchymal damage.
AST and ALT may be normal or slightly increased (up to 1–5× normal), may fluctuate within a narrow range, and have no prognostic significance.
Serum albumin, globulin, and PT normal early; abnormal values indicate advanced disease and poor prognosis; not corrected by therapy.
w Marked increase in total cholesterol and phospholipids with normal triglycerides; serum is not lipemic; serum triglycerides become elevated in late stages.
Associated with xanthomas and xanthelasmas. In early stages, LDL and VLDL are mildly elevated and HDL is markedly elevated (thus atherosclerosis is rare). In
advanced stage, LDL is markedly elevated with decreased HDL and presence of lipoprotein X (nonspecific abnormal lipoprotein seen in other cholestatic liver
disease).
m Serum IgM is increased in ~75% of patients; levels may be very high (4–5× normal). Other serum immunoglobulins are also increased.
Hypocomplementemia
Polyclonal hypergammaglobulinemia
w Biopsy of liver categorizes the four stages and helps assess prognosis, but needle biopsy is subject to sampling error because the lesions may be spotty; findings
consistent with all four stages may be found in one specimen.
m Serum ceruloplasmin is characteristically elevated (in contrast to Wilson's disease).](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-143-320.jpg)
![Liver copper may be increased 10–100× normal; correlates with serum bilirubin and advancing stages of disease.
ESR is increased 1–5× normal in 80% of patients.
Urine contains urobilinogen and bilirubin.
Laboratory findings of steatorrhea, including the following:
Serum 25-hydroxyvitamin D and vitamin A are usually low.
PT is normal or restored to normal by parenteral vitamin K.
Laboratory findings due to associated diseases
>80% of patients have at least one other and >40% have at least two other circulating antibodies to autoimmune disease (e.g., RA, autoimmune thyroiditis
[hypothyroidism in 20% of patients], Sjögren's syndrome, scleroderma) although not useful diagnostically.
Laboratory findings due to sequelae and complications
Portal hypertension, hypersplenism
Treatment-resistant osteoporosis
Hepatic encephalopathy, liver failure
Renal tubular acidosis (due to copper deposition in kidney) is frequent but usually subclinical.
Increased susceptibility to urinary tract infection is associated with advanced disease.
Should be ruled out in an asymptomatic female with elevated serum ALP without obesity, diabetes mellitus, alcohol abuse, use of some drugs.
CIRRHOSIS OF LIVER
w Criteria for diagnosis liver biopsy or at least three of the following:
Hyperglobulinemia, especially with hypoalbuminemia
Low-protein (<2.5 g/dL) ascites
Evidence of hypersplenism (usually thrombocytopenia, often with leukopenia and less often with Coombs'-negative hemolytic anemia)
Evidence of portal hypertension (e.g., varices)
Characteristic "corkscrew" hepatic arterioles on celiac arteriography
Shunting of blood to bone marrow on radioisotope scan
Abnormality of serum bilirubin, transaminases, or ALP is often not present and therefore not required for diagnosis.
m Serum bilirubin is often increased; may be present for years. Fluctuations may reflect liver status due to insults to the liver (e.g., alcoholic debauches). Most
bilirubin is of the indirect type unless cirrhosis is of the cholangiolitic type. Higher and more stable levels occur in postnecrotic cirrhosis; lower and more
fluctuating levels occur in Laënnec's cirrhosis. Terminal icterus may be constant and severe.
m Serum AST is increased (<300 U) in 65–75% of patients. Serum ALT is increased (<200 U) in 50% of patients. Transaminases vary widely and reflect activity or
progression of the process (i.e., hepatic parenchymal cell necrosis).
Serum ALP is increased in 40–50% of patients.
m Serum total protein is usually normal or decreased. Serum albumin parallels functional status of parenchymal cells and may be useful for following progress of
liver disease; but it may be normal in the presence of considerable liver cell damage. Decreasing serum albumin may reflect development of ascites or
hemorrhage. Serum globulin level is usually increased; it reflects inflammation and parallels the severity of the inflammation. Increased serum globulin (usually
gamma) may cause increased total protein, especially in chronic viral hepatitis and posthepatitic cirrhosis.
Serum total cholesterol is normal or decreased. Progressive decrease in cholesterol, HDL, LDL with increasing severity. Decrease is more marked than in chronic
active hepatitis. LDL may be useful for prognosis and selection of patients for transplantation. Decreased esters reflect more severe parenchymal cell damage.
Urine bilirubin is increased; urobilinogen is normal or increased.
BUN is often decreased (<10 mg/dL); increased with GI hemorrhage.
Serum uric acid is often increased.
Electrolytes and acid-base balance are often abnormal and reflect various combinations of circumstances at the time, such as malnutrition, dehydration, hemorrhage,
metabolic acidosis, respiratory alkalosis. In cirrhosis with ascites, the kidney retains increased sodium and excessive water, causing dilutional hyponatremia.
Blood ammonia is increased in liver coma and cirrhosis and with portacaval shunting of blood.
Anemia reflects increased plasma volume and some increased destruction of RBCs. If more severe, rule out hemorrhage in GI tract, folic acid deficiency, excessive
hemolysis, etc.
WBC is usually normal with active cirrhosis; increased (<50,000/cu mm) with massive necrosis, hemorrhage, etc.; decreased with hypersplenism.
m Laboratory findings due to complications or sequelae, often in combination
Portal hypertension.
Ascites.
Esophageal varices.
Portal vein thrombosis.
Liver failure.
Hepatocarcinoma.
Abnormalities of coagulation mechanisms (see Chapter 11), e.g.,
Prolonged PT (does not respond to parenteral vitamin K as frequently as in patients with obstructive jaundice).
Prolonged bleeding time in 40% of cases due to decreased platelets and/or fibrinogen (see Chapter 11).
Hepatic encephalopathy.
Increased arterial ammonia.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-144-320.jpg)
![CSF glutamine >35 mg/dL (due to conversion from ammonia); correlates with depth of coma and more sensitive than arterial ammonia.
Spontaneous bacterial peritonitis—in £ 10% of alcoholic cirrhosis cases. 70% have positive blood culture; usually single organism, especially E. coli,
Pneumococcus, Klebsiella.
Hepatorenal syndrome.
Most commonly death is due to liver failure, bleeding, infections.
Laboratory findings due to causative/associated diseases or conditions Frequency in USA
• Chronic viral hepatitis (HBV with or without HDV, HCV) 10%
• Alcoholism 60–70%
• Wilson's disease Rare
• Autoimmune chronic active hepatitis
• Hemochromatosis 5%
• Mucoviscidosis
• Glycogen-storage diseases
• Galactosemia
• Alpha1-antitrypsin deficiency Rare
• Porphyria
• Fructose intolerance
• Tyrosinosis
• Infections (e.g., congenital syphilis, schistosomiasis)
• Gaucher's disease
• Ulcerative colitis
• Osler-Weber-Rendu disease
• Venous outflow obstruction (e.g., Budd-Chiari syndrome, venoocclusive disease, congestive heart failure)
• Biliary disease (e.g., primary biliary cirrhosis, sclerosing cholangitis 5–10%
• Cryptogenic 10–15%
CRIGLER-NAJJAR SYNDROME (HEREDITARY GLUCURONYL TRANSFERASE DEFICIENCY)
(Rare familial autosomal recessive disease due to marked congenital deficiency or absence of glucuronyl transferase, which conjugates bilirubin to
bilirubin glucuronide in hepatic cells [counterpart is the homozygous Gunn rat])
See Table 8-4.
Table 8-4. Differential Diagnosis of Hereditary Jaundice with Normal Liver Chemistries and No Signs or Symptoms of Liver Disease
Type I
Indirect serum bilirubin is increased; it appears on first or second day of life, rises in 1 wk to peak of 12–45 mg/dL, and persists for life. No direct bilirubin in serum or
urine.
Fecal urobilinogen is very low.
Liver function tests are normal; sulfobromsulfophthalein (BSP) is normal.
Liver biopsy is normal.
No evidence of hemolysis is found.
Untreated patients often die of kernicterus by age 18 mos.
Nonjaundiced parents have diminished capacity to form glucuronide conjugates with menthol, salicylates, and tetrahydrocortisone.
Type I should always be ruled out when persistent unconjugated bilirubin levels of 20 mg/dL are seen after 1 wk of age without obvious hemolysis and especially after
breast-milk jaundice has been ruled out.
This syndrome has been divided into two groups:
Type I Type II
Transmission Autosomal recessive Autosomal dominant
Hyperbilirubinemia More severe (usually >20 mg/dL) Less severe and more variable (usually 20 mg/dL)
Kernicterus Frequent Absent
Bile Essentially colorless Normal color
Bilirubin-glucuronide Totally absent Present](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-145-320.jpg)
![Bilirubin concentration Very low (<10 mg/dL) Only traces of conjugated bilirubin Nearly normal (50–100 mg/dL)
Stool color Pale yellow Normal
Parents Normal serum bilirubin in both parents
Partial defect (~50%) in glucuronide conjugation in both parents
One parent usually shows minimal to severe icterus
Defect in glucuronide conjugation may be pressent in only one parent
Type II
Patients have partial deficiency of glucuronyl transferase (autosomal dominant with incomplete penetrance). Not related to type I syndrome; may be homozygous form
of Gilbert's disease. Patient may not become jaundiced until adolescence. Neurologic complications are rare.
Serum indirect bilirubin = 6–25 mg/dL. Increases with fasting or removal of lipid from diet. May decrease to <5 mg/dL with phenobarbital treatment.
DUBIN-JOHNSON SYNDROME (SPRINZ-NELSON SYNDROME)
(Autosomal recessive disease due to inability to transport bilirubin-glucuronide through hepatocytes into canaliculi, but conjugation of
bilirubin-glucuronide is normal. Characterized by mild chronic, recurrent jaundice; hepatomegaly and right upper quadrant abdominal pain may be present.
Usually is compensated except in periods of stress. Jaundice [innocuous and reversible] may be produced by estrogens, birth control pills, or last
trimester of pregnancy. May resemble mild viral hepatitis.)
See Table 8-4.
m Serum bilirubin is increased (3–10 mg/dL; rarely £ 30 mg/dL); significant amount is direct.
Urine contains bile and urobilinogen.
w BSP excretion is impaired with late (1.5- to 2-hr) increase; virtually pathognomonic.
m Other liver function tests are normal.
w Urine total coproporphyrin is usually normal but ~80% is coproporphyrin I (normally 75% is coproporphyrin III); diagnostic of Dubin-Johnson syndrome. Not useful
to detect individual heterozygotes.
m Liver biopsy shows large amounts of yellow-brown or slate-black pigment in centrolobular hepatic cells (lysosomes) and small amounts in Kupffer's cells.
FATTY LIVER
Laboratory findings are due to underlying conditions (most commonly alcoholism; nonalcoholic fatty liver is commonly associated with non–insulin dependent diabetes
mellitus [£ 75%], obesity [69–100%], hyperlipidemia [20–81%]; malnutrition, toxic chemical exposure)
w Biopsy of liver establishes the diagnosis.
Nonalcoholic fatty liver is distinguished by negligible history of alcohol consumption and negative random blood alcohol assays.
Liver function tests
Most commonly, serum AST and ALT are increased 2–3×; usually ALT >AST.
Serum ALP is normal or slightly increased in <50% of patients.
Increased serum ferritin (£ 5×) and transferrin saturation in ~60% of cases.
Other liver function tests are usually normal.
Serologic tests for viral hepatitis are negative.
Cirrhosis occurs in £ 50% of alcoholic and £ 17% of nonalcoholic cases.
Biochemically different form occurs in acute fatty liver of pregnancy, Reye's syndrome, tetracycline administration.
Fatty liver may be the only postmortem finding in cases of sudden, unexpected death.1
FATTY LIVER OF PREGNANCY, ACUTE
(Incidence of 1 per 13,328 deliveries; usually occurs after 35th week of pregnancy. Medical emergency because of high maternal and fetal mortality, which
is markedly improved by termination of pregnancy.)
Often associated with toxemia
Increased AST and ALT to ~300 U (rarely >500 U) are used for early screening in suspicious cases; ratio is not helpful in differential diagnosis.
Increased WBC in >80% of cases (often >15,000/cu mm)
Evidence of DIC in >75% of patients
Serum uric acid is increased disproportionately to BUN and creatinine, which may also be increased.
Serum bilirubin may be normal early but will rise unless pregnancy terminates.
Blood ammonia is usually increased.
Blood glucose is often decreased, sometimes markedly.
Neonatal liver function tests are usually normal, but hypoglycemia may occur.
w Biopsy of liver confirms the diagnosis.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-146-320.jpg)
![GALLBLADDER AND BILE DUCT CANCER
Laboratory findings reflect varying location and extent of tumor infiltration that may cause partial intrahepatic duct obstruction or obstruction of hepatic or common bile
duct, metastases in liver, or associated cholangitis; 50% of patients have jaundice at the time of hospitalization.
Laboratory findings of duct obstruction are of progressively increasing severity in contrast to the intermittent or fluctuating changes due to duct obstruction caused by
stones. A papillary intraluminal duct carcinoma may undergo periods of sloughing, producing the findings of intermittent duct obstruction.
Anemia is present.
w Cytologic examination of aspirated duodenal fluid may demonstrate malignant cells.
m Silver-colored stool due to jaundice combined with GI bleeding may be seen in carcinoma of duct or ampulla of Vater.
Laboratory findings of the preceding cholelithiasis are present (gallbladder cancer occurs in ~3% of patients with gallstones).
GILBERT'S DISEASE
(Chronic, benign, intermittent, familial [autosomal dominant with incomplete penetrance], nonhemolytic unconjugated hyperbilirubinemia with evanescent
increases of indirect serum bilirubin, which is usually discovered on routine laboratory examinations; due to defective transport and conjugation of
unconjugated bilirubin. Jaundice is usually accentuated by pregnancy, fever, exercise, and various drugs, including alcohol and birth control pills. Rarely
identified before puberty. May be mildly symptomatic. 3–7% prevalence in total population.)
See Table 8-4.
w Presumptive diagnostic criteria
Exclusion of other diseases.
Unconjugated hyperbilirubinemia on several occasions.
Liver chemistries and hematologic parameters are normal.
w Indirect serum bilirubin is increased transiently and has been previously normal at least once in £ 33% of patients. It may rise to 18 mg/dL but usually is <4 mg/dL.
Considerable daily and seasonal fluctuation. Fasting (<400 calories/day) for 72 hrs causes elevated indirect bilirubin to increase >100% in Gilbert's disease but
not in healthy persons (increase <0.5 mg/dL) or those with liver disease or hemolytic anemia. Fasting bilirubin returns to baseline 12–24 hrs after resumption of
normal diet. Combination of basal total bilirubin >1.2 mg/dL and fasting increase of unconjugated bilirubin >1 mg/dL has sensitivity of 84%, specificity of 78%,
positive predictive value of 85%, negative predictive value of 76%. Provocative tests are rarely needed. Direct serum bilirubin is normal but may give elevated
results by liquid diazo methods but not by dry methods or chromatography. Enzyme inducers (e.g., phenobarbital) normalize unconjugated bilirubin in 1–2 wks.
Prednisone administration reduces bilirubin concentration.
Liver function tests are usually normal.
Fecal urobilinogen usually normal but may be decreased.
Urine shows no increased bilirubin.
Liver biopsy is normal.
HEART FAILURE (CONGESTIVE), LIVER FUNCTION ABNORMALITIES
Pattern of abnormal liver function tests is variable depending on severity of heart failure; the mildest cases show only slightly increased ALP and slightly decreased
serum albumin; moderately severe cases also show slightly increased serum bilirubin and GGT; one-fourth to three-fourths of the most severe cases also show
increased AST and ALT (£ 200 U/L) and LD (£ 400 U/L). All return to normal when heart failure responds to treatment. Serum ALP is usually the last to become
normal, and this may occur weeks to months later.
Serum bilirubin is frequently increased (indirect more than direct); usually 1–5 mg/dL. It usually represents combined right- and left-sided failure with hepatic
engorgement and pulmonary infarcts. Serum bilirubin may suddenly rise rapidly if superimposed myocardial infarction occurs.
AST and ALT are disproportionately increased compared with other liver function tests in left-sided heart failure.
PT may be slightly increased, with increased sensitivity to anticoagulant drugs.
Serum cholesterol and esters may be decreased.
Urine urobilinogen is increased. Urine bilirubin is increased in the presence of jaundice.
These findings may occur with marked liver congestion due to other conditions (e.g., Chiari's syndrome [occlusion of hepatic veins] and constrictive pericarditis).
HEMOCHROMATOSIS2, 3 and 4
See Fig. 8-4.
Fig. 8-4. Sequence of tests for hemochromatosis screening and treatment.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-147-320.jpg)
![m Genotyping is not used for screening to discover sporadic cases but useful to identify patient's siblings at risk because HLA-identical sibs almost always are also
homozygous for hemochromatosis gene and at high risk for developing clinical disease. May be useful to distinguish patients with primary hereditary
hemochromatosis from cirrhotic patients with secondary iron overload and siderosis.
DNA test for hereditary hemochromatosis gene is available, but diagnostic role is being evaluated. C282Y or H63D present in 69–97% of affected patients; would not
identify £ 31% of clinically affected patients. May ultimately replace HLA typing.
Adequate treatment with phlebotomy (1–3 U/wk) sufficient to maintain a mild anemia is determined by Hct (37–39%) before each phlebotomy. If >40%, an additional
treatment may be scheduled. Serum iron and ferritin are used only when anemia become refractory to establish whether iron stores are exhausted. Maintenance
phlebotomy (4–6 U/yr) can be monitored with serum ferritin to indicate normal amount of storage iron. Insulin requirement decreases in more than one-third of
diabetics; liver function tests often improve; arthritis, impotence, and sterility usually do not improve. Removal of 450–500 mL of blood causes loss of 200–250 mg of
iron.
HEMOCHROMATOSIS, NEONATAL
(Severe iron overload disorder with onset in utero. Death usually occurs soon after birth.)
Oligohydramnios or less commonly polyhydramnios may indicate intrauterine growth retardation or fetal hydrops.
m Fulminant liver failure including hyperbilirubinemia, decreased transaminases, glucose, and albumin. Increased AFP. Variable fibrinogen consumption,
thrombocytopenia, anemia, acanthocytosis.
w Marked hepatic and extrahepatic (e.g., heart, pancreas, adrenal; not spleen) siderosis with relative lack in RE cells.
Liver iron analysis not useful because high in healthy newborn.
HEPATIC ENCEPHALOPATHY
(Neurologic and mental abnormalities in some patients with liver failure)
m Blood ammonia is increased in 90% of patients but does not reflect the degree of coma. Normal level in comatose patient suggests another cause of coma. Not
reliable for diagnosis but may be useful to follow individual patients. May be increased by tight tourniquet or vigorously clenched fist; thus arterial specimen may
be preferable.
Respiratory alkalosis due to hyperventilation is frequent.
Hyponatremia and iatrogenic hypernatremia are frequent complications and are associated with a higher mortality rate.
Hypokalemic metabolic alkalosis may occur due to diuretic excess.
Serum amino acid profile is abnormal. All serum amino acids are markedly increased in coma due to acute liver failure.
CSF is normal except for increased glutamine level.
w Diagnosis is clinical; characteristic laboratory findings are supportive but not specific.
HEPATIC FAILURE, ACUTE
Due To
Infection
Viral hepatitis (e.g., hepatitis A, B, C, D, E; HSV 1, 2, 6; EBV, CMV).
Acute liver failure related to HSV is usually associated with immunosuppressive therapy.
Develops in ~1–3% of adults with acute icteric type B hepatitis with resultant death.
Other causes rare (e.g., amebic abscesses, disseminated TB).
Drugs (e.g., acetaminophen, methyltestosterone, isoniazid, halothane, idiosyncratic reaction)
Toxins (e.g., phosphorus, death-cap mushroom [Amanita phalloides])
Acute fatty liver
Pregnancy
Reye's syndrome
Drugs (e.g., tetracycline)
Ischemic liver necrosis
Shock
Budd-Chiari syndrome (acute)
Wilson's disease with intravascular hemolysis
Congestive heart failure
Extracorporeal circulation during open heart surgery
Marked infiltration by tumor
Acute leukemia
Lymphoma
Hodgkin's disease
Non-Hodgkin's lymphoma
Burkitt's lymphoma
Malignant histiocytosis
m Serum bilirubin progressively increases; may become very high.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-149-320.jpg)
![Table 8-7. Comparison of Types of Hepatitis D Virus (HDV) Infections
Occurs in 5–10% of adults with acute HBV.
HBV hepatitis is generally divided into three stages:
Stage of acute hepatitis: Usually lasts 1–6 mos with mild or no symptoms.
AST and ALT are increased >10×.
Serum bilirubin is usually normal or only slightly increased.
HBsAg gradually rises to high titers and persists; HBeAg also appears.
Gradually merges with next stage.
Stage of chronic hepatitis: Transaminases increased >50% for >6 mos duration; may last only 1 yr or for several decades with mild or severe symptoms; most
cases resolve, but some develop cirrhosis and liver failure.
AST and ALT fall to 2–10× normal range.
HBsAg usually remains high, and HBeAg remains present.
Chronic carrier stage: Patients are usually, but not always, healthy and asymptomatic.
AST and ALT fall to normal or <2× normal.
HBeAg disappears, and anti-HBe appears.
HBsAg titer falls although may still be detectable; anti-HBs subsequently develops, marking the end of carrier stage.
Anti-HBc is usually present in high titer (>1:512).
Laboratory findings due to sequelae, e.g.,
GN or nephrotic syndrome due to deposition of HBeAg or HBcAg in glomeruli, which often progresses to chronic renal failure.
HEPATITIS, ALCOHOLIC5
w Diagnosis is established by liver biopsy and history of alcohol intake. Liver biopsy should be performed for any alcoholic patient with enlarged liver as the only
way to make definite diagnosis of alcoholic hepatitis. Many alcoholics have normal liver biopsies.
m Increased serum GGT and MCV >100 together or separately are useful clues for occult alcoholism.
Ratio of desialylated transferrin to total transferrin >0.013 has been reported to have 81% sensitivity and 98% specificity for ongoing alcohol consumption.
Serum AST is increased (rarely >300 U/L), but ALT is normal or only slightly elevated.
AST and ALT are more specific but less sensitive than GGT. Levels of AST and ALT do not correlate with severity of liver disease. AST/ALT ratio >1 associated with
AST <300 U/L will identify 90% of patients with alcoholic liver disease; is particularly useful for differentiation from viral hepatitis, in which increase of AST and ALT
are about the same.
Cholestasis in £ 35% of patients.
In acute alcoholic hepatitis, GGT level is usually higher than AST level. GGT is often abnormal in alcoholics even with normal liver histology. Is more useful as index
of occult alcoholism or to indicate that elevated serum ALP is of bone or liver origin than to follow course of patient, for which AST and ALT are most useful.
Serum ALP may be normal or moderately increased in 50% of patients and is not useful as a diagnostic test.
Serum bilirubin may be mildly increased except with cholestasis; is not useful as a diagnostic test. However, if bilirubin continues to increase during a week of therapy
in the hospital, a poor prognosis is indicated.
Decreased serum albumin and increased polyclonal globulin with disproportionately increased IgA are frequent. Decreased albumin means long-standing or relatively
severe disease.
Increased PT that is not corrected by parenteral administration of 10 mg/day of vitamin K for 3 days is best indicator of poor prognosis.
Discriminant function to assess severity of alcoholic hepatitis = 4.6 × (PT [secs] – control PT) + serum bilirubin. Discriminant function >32 is equated with severe
disease.
Increased WBC (>15,000) in up to one-third of patients with shift to left (WBC is decreased in viral hepatitis); normal WBC may indicate folic acid depletion.
Anemia in >50% of patients may be macrocytic (folic acid or vitamin B12 deficiency), microcytic (iron or pyridoxine deficiency), mixed, or hemolytic.
Metabolic alkalosis may occur due to K+
loss with pH normal or increased, but pH <7.2 often indicates that disease is becoming terminal.
In terminal stage of chronic alcoholic liver disease (last week before death), there is often decrease of serum sodium and albumin and increase of PT and serum
bilirubin; AST and LD decrease from previously elevated levels.
Indocyanine green (50 mg/kg) is abnormal in 90% of patients.
Compared to nonalcoholic patients, alcoholic patients as a group show an increase in a number of blood components (e.g., AST, phosphorus, ALP, GGT, MCV, MCH,
Hb, WBC) and a decrease in others (e.g., total protein, BUN); however, these variations usually remain within the reference range. These changes may last for >6
wks after abstaining from alcohol.
Laboratory findings due to sequelae or complications](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-152-320.jpg)
![Fatty liver
Cirrhosis
Portal hypertension
Infections (e.g., GU tract, pneumonia, peritonitis)
DIC
Hepatorenal syndrome
Encephalopathy
HEPATITIS, AUTOIMMUNE CHRONIC ACTIVE
w Criteria for diagnosis (all must be present for definite diagnosis)6
Probable Definite
Increased serum AST or ALT concentrations X X
Increased serum ALP <3× normal concentration X
Increased serum total or gamma globulin or IgG
>1.5× upper limit of normal X
1.0–1.5× upper limit of normal X
Antibody titers to nucleus, smooth muscle or liver/kidney
microsome type 1 >1:80 (adults) or >1:20 (children)
X
Lower titers or presence of other antibodies X
Absence of markers for viral hepatitis (HAV, HBV, HCV, CMV, EBV) X X
Absence of excess alcohol consumption
<25 gm/day (women) or <35 gm/day (men) X
<40 gm/day (women) or <50 gm/day (men) X
Exposure to blood products
No X
Yes, but unrelated to disease X
Exposure to hepatotoxic drugs
No X
Yes, but unrelated to disease X
Compatible histologic findings and absence of biliary
lesions, copper deposits or other changes suggestive
of other causes of lobular hepatitis
X X
HEPATITIS, CHRONIC ACTIVE
(Inflammatory liver disease present >6 mos.)
Due To
Viruses
HBV (with or without HDV)
HCV (with or without hepatitis G virus [HGV])
Metabolic disorders
Wilson's disease
Alpha1-antitrypsin deficiency
Hemochromatosis
Primary biliary cirrhosis
Sclerosing cholangitis
Drugs, e.g.,
Methyldopa
Nitrofurantoin
Isoniazid
Oxyphenacetin
Nonalcoholic fatty liver
Alcoholic hepatitis
Autoimmune causes
Type I (lupoid) (anti–smooth muscle; antiactin)
Type II (anti–kidney-liver-microsomal)
Type III (anti–soluble liver antigen)
HEPATITIS A
Serum bilirubin usually 5–10× normal. Jaundice lasts a few days to 12 wks. Usually not infectious after onset of jaundice.
Serum AST and ALT increased to hundreds for 1–3 wks.
Relative lymphocytosis is frequent.
Serologic Tests for Viral Hepatitis A (HAV)7](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-153-320.jpg)
![Assess disease progression and indication for antiviral therapy
No consistent correlation between serum ALT and severity of liver pathology; significant liver damage can occur with normal ALT.
Exclude coexisting or alternative (e.g., alcohol-related) diseases
w Antibody to Hepatitis C Virus (anti-HCV) (by EIA)
Use
Screening of populations with low and high prevalence, including blood donors
Initial evaluation of patients with liver disease, including those with increased serum ALT
Positive results should be verified by a supplemental assay (i.e., recombinant immunoblot assay [RIBA]) showing reactivity with ³2 viral antigens; indeterminate in £
10% of cases.
Interpretation
Indicates past or present infection but does not differentiate between acute, chronic, and resolved infection.
Sensitivity ³97%; only ~80% in chronic carriers. Low positive predictive value in low-prevalence population.
Seroconversion: average time after exposure = 2–3 wks with EIA-3. Detected in 80% of patients within 15 wks, in >90% within 5 mos, in >97% by 6 mos after
exposure or 2–3 mos after increase in ALT. Therefore serial assay of anti-HCV and ALT for up to 1 yr after suspected acute hepatitis may be needed for diagnosis.
Negative EIA rules out HCV infection in low-risk group.
Present in 70–85% of cases of chronic posttransfusion NANB hepatitis but is relatively infrequent in acute cases. Present in 70% of IV drug abusers, 20% of
hemodialysis patients, and only 8% of homosexual men positive for HIV.
Prevalence in normal blood donors is 0.5–2.0%. In routine blood donor screening, estimates are that 40–70% of initial reactors prove not to be true positives.
Surrogate markers fail to detect one-third to one-half of blood units positive for anti-HCV. Found in 7–10% of transfusion recipients. Only one-third of anti-HCV donors
had increased ALT and 54% were positive for anti-HBc.
In one study, anti-HCV was positive in 75% of patients with hepatocellular carcinoma, 56% of patients with cirrhosis, and 7% of controls.
Present in various quality assurance and calibration sera; overall rate = 43% with much higher rates in some proficiency samples.
Because resolves slowly, is considered chronic only with evidence of activity >12 mos.
Interferences
False-positive
Autoimmune diseases (£ 80% of cases of autoimmune chronic active hepatitis).
EIA and RIBA are also found in polyarteritis nodosa (~10%) and SLE (~2%).
RF.
Hypergammaglobulinemia.
Paraproteinemia.
Passive antibody transfer.
Anti-idiotypes.
Anti–superoxide dismutase (a human enzyme used in the cloning process).
Repeated freezing and thawing or prolonged storage of blood specimens.
False-negative
Early acute infection
Immunosuppression
Immunoincompetence
Repeated freezing and thawing or prolonged storage of blood specimens
RIBA
Positive EIA should be evaluated with RIBA-2; negative RIBA indicates false-positive EIA.
Positive RIBA indicates past or previous exposure.
Confirms positive EIA in >50% of cases; in high-risk population RIBA confirms diagnosis in >88% of cases.
Increasingly replaced by HCV RNA.
HCV RNA Assay
(By reverse transcriptase PCR [RT-PCR])
Qualitative tests
Use
Diagnose acute HCV infection before seroconversion; can detect virus as early as 1–2 wks after exposure.
Detection may be intermittent; one negative RT-PCR is not conclusive.
Monitor patients on antiviral therapy
Evaluate indeterminate RIBA results](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-158-320.jpg)
![Conjugated
Premature infants with these conditions have more severe hyperbilirubinemia than full-term infants.
Biliary obstruction—usually due to extrahepatic biliary atresia but may be due to choledochal cyst, obstructive inspissated bile plugs, or bile ascites
Neonatal hepatitis
Sepsis, especially E. coli pyelonephritis (moderate azotemia, acidosis, increased serum bilirubin, slight hemolysis, normal or slightly increased AST)
Hereditary diseases (e.g., galactosemia, alpha 1-antitrypsin deficiency, cystic fibrosis, hereditary fructose intolerance, tyrosinemia, infantile Gaucher's disease, familial
intrahepatic cholestasis [Byler's disease])
In the course of hemolytic disease of the newborn—due to liver damage of unknown cause.
Differential Diagnosis
Unconjugated hyperbilirubinemia is serum level >1.5 mg/dL. Conjugated hyperbilirubinemia is direct-reacting serum level >1.5 mg/dL when this fraction is >10% of
total serum bilirubin (because in newborn with marked elevation of unconjugated bilirubin level, £ 10% of the unconjugated bilirubin will act as direct reacting in the
van den Bergh reaction).
Mixed hyperbilirubinemia shows conjugated bilirubin as 20–70% of total and usually represents disorder of hepatic cell excretion or bile transport.
Visible icterus before 36 hrs of age indicates hemolytic disorder.
Diagnostic studies should be performed whenever serum bilirubin is >12 mg/dL.
After hemolytic disease and hepatitis, the most frequent cause of hyperbilirubinemia is enterohepatic circulation of bilirubin.
Visible icterus persisting after seventh day is usually due to impaired hepatic excretion, most commonly due to breast-milk feeding or congenital hypothyroidism.
Increase in direct bilirubin usually indicates infection or inflammation of liver, but can also be seen in galactosemia and tyrosinosis.
HYPERBILIRUBINEMIA, NEONATAL NONPHYSIOLOGIC
See Fig. 8-8.
Fig. 8-8. Algorithm for workup of neonatal jaundice and anemia.
Cause should be sought for underlying pathologic jaundice if:
Total serum bilirubin is >7 mg/dL during first 24 hrs or increases by >5 mg/dL/day or visible jaundice.
Peak total serum bilirubin is >12.5 mg/dL in white or black full-term infants or >15 mg/dL in Hispanic or premature infants.
Direct serum bilirubin is >1.5 mg/dL.
Clinical jaundice lasts longer than 7 days in full-term or 14 days in premature infants or occurs before age 36 hrs or with dark urine (containing bile).
Initial tests in unconjugated hyperbilirubinemia:
Serial determinations of total and direct bilirubin
CBC including RBC morphology, platelet count, normoblast and reticulocyte counts
Blood type, mother and infant
Direct Coombs' test
Maternal blood for antibodies and hemolysins
Blood cultures
Urine microscopy and culture
Serologic tests for infection
Serum thyroxine (T4) and thyroid-stimulating hormone (TSH)
Urine for non–glucose reducing substances
HYPERBILIRUBINEMIA, NEONATAL PHYSIOLOGIC
(Transient unconjugated hyperbilirubinemia [“physiologic jaundice”] that occurs in almost all newborns)
In normal full-term neonate, average maximum serum bilirubin is 6 mg/dL (up to 12 mg/dL is in physiologic range), which occurs during the second to fourth days and
then rapidly falls to ~2.0 mg/dL by fifth day (phase I physiologic jaundice). Declines slowly to <1.0 mg/dL during fifth to tenth days, but may take 1 mo to fall to <2
mg/dL (phase II physiologic jaundice). Phase I due to deficiency of hepatic bilirubin glucuronyl transferase activity and sixfold increase in bilirubin load presented to
liver. In Asian and American Indian newborns, the average maximum serum levels are approximately double (10–14 mg/dL) the levels in non-Asians, and kernicterus
is more frequent. Serum bilirubin >5 mg/dL during first 24 hrs of life is indication for further workup because of risk of kernicterus.
In older children (and adults) icterus is apparent clinically when serum bilirubin is >2 mg/dL, but in newborns clinical icterus is not apparent until serum bilirubin is >5–7
mg/dL; therefore only half of full-term newborns show clinical jaundice during first 3 days of life.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-163-320.jpg)
![Increased In
Acute pancreatitis
Perforated or penetrating peptic ulcer, especially with involvement of pancreas
Obstruction of pancreatic duct by
Stone
Drug-induced spasm of Oddi's sphincter (e.g., codeine, morphine, meperidine, methacholine, cholinergics), to levels 2–15× normal
Partial obstruction plus drug stimulation
Chronic pancreatitis
Acute cholecystitis
Small bowel obstruction
Intestinal infarction
Acute and chronic renal failure (increased 2–3× in 80% of patients and 5× in 5% of patients)
Organ transplant (kidney, liver, heart), especially with complications (e.g., organ rejection, CMV infection, cyclosporin toxicity)
Alcoholism
Diabetic ketoacidosis
After ERCP
Some cases of intracranial bleeding (unknown mechanism)
Macro forms in lymphoma, cirrhosis
Drugs
Induced acute pancreatitis (see preceding section on serum amylase)
Cholestatic effect (e.g., indomethacin)
Methodologic interference (e.g., pancreozymin [contains lipase], deoxycholate, glycocholate, taurocholate [prevent inactivation of enzyme], bilirubin
[turbidimetric methods])
Chronic liver disease (e.g., cirrhosis) (usually £ 2× normal)
Decreased In
Methodologic interference (e.g., presence of hemoglobin, calcium ions)
Usually Normal In
Mumps
Values are lower in neonates.
Macroamylasemia
DISEASES OF THE PANCREAS
CYSTIC FIBROSIS OF PANCREAS17
(Autosomal recessive disorder with abnormal ion transport due to failure of chloride regulation; incidence of 1 in 1500 to 1 in 2000 in whites with a carrier
frequency of 1 in 20; 1 in 17,000 in American blacks; marked heterogeneity among patients.)
Quantitative Pilocarpine Iontophoresis Sweat Test (Properly Performed)
w Striking increase in sweat sodium (>60 mEq/L) and chloride (>60 mEq/L) and, to a lesser extent, potassium is present in virtually all homozygous patients; value is
3–5× higher than in healthy persons or in those with other diseases. Is consistently present throughout life from time of birth, and degree of abnormality is not
related to severity of disease or organ involvement. Sensitivity = 98%, specificity = 83%, positive predictive value = 93%. Sweat chloride is somewhat more
reliable than sodium for diagnostic purposes.
In children, chloride >60mEq/L is considered positive for cystic fibrosis.
40–60 mEq/L is considered borderline and requires further investigation.
<40 mEq/L is considered normal.
£ 80 mEq/L may be normal for adults.
On occasion 1–2% of cystic fibrosis patients have normal, borderline, or variable values.
Rare patients with borderline values have only mild disease.
Sweat potassium is not diagnostically valuable because of overlap with normal controls.
Increased sweat sodium and chloride are not useful for detection of heterozygotes (who have normal values) or for genetic counseling.
w Sweat chloride ³80 mEq/L on repeated occasions with characteristic clinical manifestations or family history confirm diagnosis of cystic fibrosis.
A broad range of sweat values is seen in patients with this disease and in normal persons but overlap is minimal.
Sweat values (mEq/L)
Chloride Sodium Potassium](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-170-320.jpg)
![Increased serum cholesterol (usually >300 mg/dL) with esters not decreased.
Other liver function tests are usually normal.
PANCREATITIS, ACUTE19
w Serum lipase increases within 3–6 hrs with peak at 24 hrs and usually returns to normal over a period of 8–14 days. Is superior to amylase; increases to a greater
extent and may remain elevated for up to 14 days after amylase returns to normal. In patients with signs of acute pancreatitis, pancreatitis is highly likely (clinical
specificity = 85%) when lipase ³5× ULN, if values change significantly with time, and if amylase and lipase changes are concordant. ( Lipase should always be
determined whenever amylase is determined.) New methodology improves clinical utility. Urinary lipase is not clinically useful. It has been suggested that a
lipase/amylase ratio >3 (and especially >5) indicates alcoholic rather than nonalcoholic pancreatitis. Acute pancreatitis or organ rejection is highly likely if lipase is
³5× ULN, but unlikely if <3× ULN. (See Fig. 8-9)
w Serum amylase increase begins in 3–6 hrs, rises rapidly within 8 hrs in 75% of patients, reaches maximum in 20–30 hrs, and may persist for 48–72 hrs. >95%
sensitivity during first 12–24 hrs. The increase may be £ 40× normal, but the height of the increase and rate of fall do not correlate with the severity of the disease,
prognosis, or rate of resolution; however, an increase of >7–10 days suggests an associated cancer of pancreas or pseudocyst, pancreatic ascites, or
nonpancreatic cause. Similar high values may occur in obstruction of pancreatic duct; they tend to fall after several days. >10% of patients with acute pancreatitis
(especially when seen more than 2 days after onset of symptoms) may have normal values, even when dying of acute pancreatitis . May also be normal in patients
with relapsing chronic pancreatitis and patients with hypertriglyceridemia (technical interference with test). Frequently normal in acute alcoholic pancreatitis. Acute
abdomen due to GI infarction or perforation rather than acute pancreatitis is suggested by only moderate increase in serum amylase and lipase (<3× ULN),
evidence of bacteremia. 10–40% of patients with acute alcoholic intoxication have elevated serum amylase (about half of amylases are salivary type); patients
often present with abdominal pain, but increased serum amylase is usually <3× ULN. Levels >25× ULN indicate metastatic tumor rather than pancreatitis.
w Serum pancreatic isoamylase can distinguish elevations due to salivary amylase, which may account for 25% of all elevated values. (In healthy persons, 40% of
total serum amylase is pancreatic type and 60% is salivary type.)
Only slight increase in serum amylase and lipase values suggests a different diagnosis than acute pancreatitis. Many drugs increase both amylase and lipase in
serum.
Serum calcium is decreased in severe cases 1–9 days after onset (due to binding to soaps in fat necrosis). The decrease usually occurs after amylase and lipase
levels have become normal. Tetany may occur. (Rule out hyperparathyroidism if serum calcium is high or fails to fall in hyperamylasemia of acute pancreatitis.)
Increased urinary amylase tends to reflect serum changes by a time lag of 6–10 hrs, but sometimes increased urine levels are higher and of longer duration than
serum levels. The 24-hr level may be normal even when some of the 1-hr specimens show increased values. Measurement of amylase levels in hourly samples of
urine may be useful. Ratio of amylase clearance to creatinine clearance is increased (>5%) and its use avoids the problem of timed urine specimens; also increased
in any condition that decreases tubular reabsorption of amylase (e.g., severe burns, diabetic ketoacidosis, chronic renal insufficiency, multiple myeloma, acute
duodenal perforation). Considered not specific; its use now discouraged by some but still recommended by others.
Serum bilirubin may be increased when pancreatitis is of biliary tract origin but is usually normal in alcoholic pancreatitis. Serum ALP, ALT, and AST may increase
and parallel serum bilirubin rather than amylase, lipase, or calcium levels. Marked amylase increase (e.g., >2000 U/L) also favors biliary tract origin. Fluctuation >50%
in 24 hrs of serum bilirubin, ALP, ALT, and AST suggests intermittent biliary obstruction.
m Serum trypsin (by RIA) is increased. High sensitivity makes a normal value useful for excluding acute pancreatitis. But low specificity (increased in large
proportion of patients with hepatobiliary, bowel, and other diseases and renal insufficiency; increased in 13% of patients with chronic pancreatitis and 50% with
pancreatic carcinoma) and RIA technology limit utility.
WBC is slightly to moderately increased (10,000–20,000/cu mm).
Hemoconcentration occurs (increased Hct). Hct may be decreased in severe hemorrhagic pancreatitis.
Glycosuria appears in 25% of patients.
Methemalbumin may be increased in serum and ascitic fluid in hemorrhagic (severe) but not edematous (mild) pancreatitis; may distinguish these two conditions but
not useful in diagnosis of acute pancreatitis.
Hypokalemia, metabolic alkalosis, or lactic acidosis may occur.
Laboratory findings due to predisposing conditions (may be multiple)
Alcohol abuse accounts for ~36% of cases.
Biliary tract disease accounts for 17% of cases.
Idiopathic origin accounts for >36% of cases.
Infections (especially viral such as mumps, coxsackievirus and CMV infections, AIDS).
Trauma and postoperative condition account for >8% of cases.
Drug effects (e.g., steroids, thiazides, azathioprine, estrogens, sulfonamides; valproic acid in children) account for >5% of cases.
Hypertriglyceridemia (hyperlipidemia types V, I, IV) accounts for 7% of cases.
Hypercalcemia from any cause.
Tumors (pancreas, ampulla).
Anatomic abnormalities of ampullary region causing obstruction (e.g., annular pancreas, Crohn's disease, duodenal diverticulum).
Hereditary.
Renal failure; renal transplantation.
Miscellaneous (e.g., collagen vascular disease, pregnancy, ischemia, scorpion bites, parasites obstructing pancreatic duct [ Ascaris, fluke], Reye's syndrome,
fulminant hepatitis, severe hypotension, cholesterol embolization).
Laboratory findings due to complications
Pseudocysts of pancreas.
Pancreatic abscess.
Polyserositis (peritoneal, pleural, pericardial, synovial surfaces). Ascites may develop, cloudy or bloody or “prune juice” fluid, 0.5–2.0 L in volume, containing
increased amylase with a level higher than that of serum amylase. No bile is evident (unlike in perforated ulcer). Gram stain shows no bacteria (unlike in infarct
of intestine). Protein >3 gm/dL and marked increase in amylase.
ARDS (with pleural effusion, alveolar exudate, or both) may occur in ~40% of patients; arterial hypoxemia is present.
DIC.
Hypovolemic shock.
Others.
Prognostic laboratory findings
On admission
WBC >16,000/cu mm
Blood glucose >200 mg/dL](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-173-320.jpg)
![Serum LD >350 U/L
Serum AST >250 U/L
Age >55 yrs
Within 48 hrs
Serum calcium <8.0 mg/dL
Decrease in Hct >10 points
Increase in BUN >5 mg/dL
Arterial pO2 <60 mm Hg
Metabolic acidosis with base deficit >4 mEq/L
Mortality
1% if three signs are positive
15% if three or four signs are positive
40% if five or six signs are positive
100% if seven or more signs are positive
Degree of amylase elevation has no prognostic significance.
PANCREATITIS, CHRONIC
See also Malabsorption.
w Cholecystokinin-secretin test measures the effect of IV administration of cholecystokinin and secretin on volume, bicarbonate concentration, and amylase output
of duodenal contents and increase in serum lipase and amylase. This is the most sensitive and reliable test (gold standard) for chronic pancreatitis, especially in
the early stages. Is technically difficult and is often not performed accurately; gastric contamination must be avoided. Some abnormality occurs in >85% of patients
with chronic pancreatitis. Amylase output is the most frequent abnormality. When all three are abnormal, there is a greater frequency of abnormality in the tests
listed below.
Normal duodenal contents
Volume: 95–235 mL/hr
Bicarbonate concentration: 74–121 mEq/L
Amylase output: 87,000–267,000 mg
Serum amylase and lipase increase after administration of cholecystokinin and secretin in ~20% of patients with chronic pancreatitis. They are more often
abnormal when duodenal contents are normal. Normally serum lipase and amylase do not rise above normal limits.
Fasting serum amylase and lipase are increased in 10% of patients with chronic pancreatitis.
Serum pancreolauryl test
Fluorescein dilaurate taken with breakfast is acted on by a pancreas-specific cholesterol ester hydrolase, releasing fluorescein, which is absorbed from gut and
measured in serum; preceded by administration of secretin and followed by administration of metoclopramide. Reported sensitivity = 82%, specificity 91%. 20
Diabetic OGTT results in 65% of patients with chronic pancreatitis and frank diabetes in >10% of patients with chronic relapsing pancreatitis. When GTT is normal in
the presence of steatorrhea, the cause should be sought elsewhere than in the pancreas.
w Laboratory findings due to malabsorption (occurs when >90% of exocrine function is lost) and steatorrhea.
Bentiromide test is usually abnormal with moderate to severe pancreatic insufficiency.
Schilling test may show mild malabsorption of Vitamin B12.
Xylose tolerance test and small bowel biopsy are not usually done but are normal.
Chemical analysis of fecal fat demonstrates steatorrhea. It is more sensitive than tests using triolein 131
I.
Triolein 131
I testing is abnormal in one-third of patients with chronic pancreatitis.
Starch tolerance test is abnormal in 25% of patients with chronic pancreatitis.
Laboratory findings due to causes of chronic pancreatitis and pancreatic exocrine insufficiency
Alcoholism in 60–70%
Idiopathic in 30–40%
Obstruction of pancreatic duct (e.g., trauma, pseudocyst, pancreas divisum, cancer or obstruction of duct or ampulla)
Other causes occasionally (e.g., cystic fibrosis, primary hyperparathyroidism, heredity, protein caloric malnutrition, miscellaneous [Z-E syndrome, Shwachman
syndrome, alpha1-antitrypsin deficiency, trypsinogen deficiency, enterokinase deficiency, hemochromatosis, parenteral hyperalimentation])
w Radioactive selenium scanning of pancreas yields variable findings in different clinics.
CT, ultrasonography, ERCP are most accurate for diagnosing and staging chronic pancreatitis.
PSEUDOCYST OF PANCREAS
Serum direct bilirubin is increased (>2 mg/dL) in 10% of patients.
Serum ALP is increased in 10% of patients.
Fasting blood sugar is increased in <10% of patients.
Duodenal contents after secretin-pancreozymin stimulation usually show decreased bicarbonate content (<70 mEq/L) but normal volume and normal content of
amylase, lipase, and trypsin.
w Findings of pancreatic cyst aspiration21
Best when panel of tests is used.
High fluid viscosity and CEA indicate mucinous differentiation and exclude pseudocyst, serous cystadenoma, other nonmucinous cysts or cystic tumors.
Increased CA 72-4, CA 15-3, and tissue polypeptide antigen are markers of malignancy; if all are low, pseudocyst or serous cystadenoma is most likely.
CA 125 is increased in serous cystadenoma.
Pancreatic enzymes, leukocyte esterase, and NB/70K are increased in pseudocysts.
Cytologic examination.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-174-320.jpg)
![(RBC and WBC are cells/cu mm)
In normal CSF, minimal blood contamination may cause £ 2 PMN/25 RBCs, or £ 10 PMN/25–100 RBCs.
CSF WBC count (>3000/cu mm) with predominantly PMNs strongly suggests bacterial cause and is >2000/cu mm in 38% of cases. When WBC <1000/cu mm in
bacterial meningitis, one-third of cases have >50% lymphocytes or mononuclear cells. However, WBCs are usually PMNs in early stages of all types of meningitis;
mononuclear cells only appear in a second specimen 18–24 hrs later. Low WBC counts do not rule out acute bacterial meningitis.
Neutrophilic leukocytes are found in:
Bacterial infections (e.g., Nocardia, Actinomyces, Arachnia, Brucella)
Fungal infections (Blastomyces, Coccidioides, Candida, Aspergillus, Zygomycetes, Cladosporium, Allescheria)
Chemical meningitis
Other conditions (e.g., SLE)
Lymphocytic cells are found in:
Bacterial infections (e.g., Treponema pallidum, Leptospira, Actinomyces israelii, Arachnia propionica, 90% of Brucella cases, Borrelia burgdorferi [Lyme disease],
Mycobacterium tuberculosis)
Fungal infections (e.g., Cryptococcus neoformans, Candida spp., Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitides, Sporotrichum
schenckii, Allescheria boydii, Cladosporium trichoides)
Parasitic diseases (e.g., toxoplasmosis, cysticercosis)
Viral infections (e.g., mumps, lymphocytic choriomeningitis, infection with human T-cell leukemia virus [HTLV] type III or echovirus)
Parameningeal disorders (e.g., brain abscess)
Noninfectious disorders (e.g., neoplasms, sarcoidosis, multiple sclerosis, granulomatous arteritis)
Eosinophils may be found in:
Lymphoma
Helminth infection (e.g., angiostrongyliasis, cysticercosis)
Rarely other infections (e.g., TB, syphilis, Rocky Mountain spotted fever, coccidioidomycosis)
Microbiology/Serology
Smears for Gram and acid-fast stains must be routinely centrifuged on all CSF specimens because other findings may be normal in meningitis. Occasionally animal
inoculations may be required. Gram stain of CSF sediment is negative in 20% of cases of bacterial meningitis because at least 10 5
bacteria/mL of CSF must be
present to demonstrate 1–2 bacteria/100× microscopic field. Gram stain is positive in 90% of cases due to pneumococci, 85% of cases due to Haemophilus
influenzae, 75% of cases due to meningococci, and 50% of cases due to Listeria monocytogenes, but only 30–50% of cases due to gram-negative enteric bacilli. If
antibiotics have been given before CSF obtained, Gram stain may be negative. Stains are positive in <60% of cases of treated bacterial meningitis, <5% of cases of
TB meningitis, 20–70% of cases of fungal meningitis and <2% of cases of brain abscess. Sensitivity of Gram stain is increased by using fluorescent techniques with
acridine orange.
Positive CSF culture has sensitivity of 92%, specificity of 95%, false-negative rate of 8%, and false-positive rate of 5%.
Limulus amebocyte lysate is a rapid specific indicator of endotoxin produced by gram-negative bacteria ( Neisseria meningitidis, H. influenzae type b, Escherichia coli,
Pseudomonas). Is not affected by prior antibiotic therapy; is more rapid and sensitive than CIE. Often is not routinely available.
Serologic methods are often preferred (e.g., positive in 85% of coccidioidal cases compared with culture, which is positive in 37% of cases) especially in syphilis,
brucellosis, Lyme disease.
Blood and CSF serology are positive in CNS syphilis; positive in 7–10% of active cases of infectious mononucleosis.
PCR to detect HSV and human enteroviruses in meningitis and encephalitis.
Antigen detection (latex agglutination) for H. influenzae type b, C. neoformans, N. meningitidis, Streptococcus pneumoniae, Streptococcus agalactiae has replaced
CIE.
Use
Abnormal CSF chemistries or cell count with negative Gram stain and culture (e.g., prior antibiotic therapy).
Not indicated for screening or if chemistry is normal and CSF cell count is <50/cu mm unless patient is immunocompromised. Not indicated if Gram stain is
positive.
Interpretation
Negative results are not conclusive; positive results should be confirmed by culture, especially to determine antibiotic susceptibility. Test for H. influenzae type b
antigen in CSF has reported sensitivity of 74%, specificity of 100%, positive predictive value of 100%, negative predictive value of 99%.
Antigen detection is less sensitive in urine and serum than in CSF specimens.
Specific antigens have also been detected in urine and other body fluids in nonmeningeal infections (e.g., pneumococcal pneumonia, H. influenzae epiglottitis,
legionnaire's disease).
Interferences
False-positive results for group B streptococci may occur due to colonization of perineum.
Misleading positive results with H. influenzae type b may occur in both urine and CSF due to recent immunization with H. influenzae type b vaccine.
CSF Chemistries
CSF glucose
Decreased by utilization by bacteria (pyogens or tubercle bacilli), WBCs, or occasionally cancer cells in CSF.
Lags behind blood glucose by ~1 hr.
May rapidly become normal after onset of antibiotic therapy.
Is decreased in only ~50% of cases of bacterial meningitis.
<45 mg/dL is almost always abnormal; <40 mg/dL is always abnormal.
Normally is ~50–65% of blood glucose, which should always be drawn simultaneously. In acute bacterial meningitis, CSF/serum ratio of glucose is usually <0.5;
a ratio <0.4 has 80% sensitivity and 96% specificity for distinguishing acute bacterial meningitis from acute viral meningitis; a ratio <0.25 is found in <1% of
acute viral meningitis cases and in 44% of acute bacterial meningitis cases, even when CSF glucose is normal. A ratio of <8.0 is significant in infants.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-177-320.jpg)
![CSF, NORMAL VALUES
Measurement of these components should always be performed on simultaneously drawn blood samples.
Appearance Clear, colorless: no clot
Total cell count
Adults, children 0–6/cu mm (all mononuclear cells)
Infants <19/cu mm
Neonates <30/cu mm
Glucose 45–80 mg/dL (20 mg/dL less than
blood level)
Ventricular fluid 5–10 mg/dL
higher than lumbar fluid
Total protein Cisternal: 15–25 mg/dL
Ventricular: 5–15 mg/dL
Lumbar: 15–45 mg/dL 3 mos–60 yrs
15–100 mg/dL neonates
15–60 mg/dL >60 yrs
Albumin 10–35 mg/dL
Protein electrophoresis
Transthyretin (prealbumin) 2–7%
Albumin 56–76%
Alpha1 globulin 2–7%
Alpha2 globulin 4–12%
Beta globulin 8–18%
Gamma globulin 3–12%
IgG <4.0 mg/dL
<10% of total CSF protein
Albumin index (ratio) <9.0
IgG synthesis rate 0.0–8.0 mg/day
IgG index (ratio) 0.28–0.66
CSF IgG/albumin ratio 0.09–0.25
Oligoclonal bands Negative
Myelin basic protein 0.0–4.0 ng/mL
Chloride 120–130 mEq/L
(20 mEq/L above serum values)
Sodium 142–150 mEq/L
Potassium 2.2–3.3 mEq/L
Carbon dioxide 25 mEq/L
pH 7.35–7.40
Transaminase (AST) 7–49 U
LD ~10% of serum level
LD-1 38–58% (LD-1 > LD-2)
LD-2 26–36%
LD-3 12–24%
LD-4 1–7%
LD-5 0–5%
CK 0–5 U/L
Bilirubin 0
Urea nitrogen 5–25 mg/dL
Amino acids 30% of blood level
Xanthochromia 0
Total volume (adults) ~140 mL
Generation rate 0.35 mL/min = 500 mL/day
DEXAMETHASONE SUPPRESSION TEST (DST)
Blood is drawn at 11 p.m., 8 a.m., 12 noon, 4 p.m., and 11 p.m. for plasma cortisol. 1 mg of dexamethasone is given immediately after the first sample is taken. An
abnormal test result is failure of suppression of plasma cortisol to £5 µg/dL in any sample after the first. Plasma dexamethasone should also be measured to avoid
false values due to aberrant clearance of dexamethasone.
Use
A positive DST result “rules in” the diagnosis of melancholia (endogenous depression), but a negative DST result does not rule it out, because results may be positive
in only 40–50% of such patients.
In the presence of a positive DST result, appropriate drug treatment (e.g., tricyclic antidepressants) that results in normalization of DST with clinical recovery is a good
prognostic sign, whereas failure of DST to normalize suggests a poor prognosis and the need for continued antidepressant therapy. Despite clinical improvement,
treatment should be continued until DST results become negative (usually within 10 days). With relapse, DST may become abnormal when symptoms are still mild,
before fully developed syndrome is present. The need to continue treatment is indicated if a positive DST result that became negative with therapy reverts to positive
after drug treatment is discontinued or the drug dosage is lowered.
Interference
Certain drugs or substances that cause nonsuppression, especially phenytoin, barbiturates, meprobamate, carbamazepine, and alcohol (chronic high doses or
withdrawal within 3 wks) can interfere with DST.
Enhanced suppression may be caused by benzodiazepines (high doses), corticosteroids (spironolactone, cortisone, artificial glucocorticoids such as prednisone
[topical and nasal forms]), and dextroamphetamine.
Other drugs that are said to interfere include estrogens (not birth control pills), reserpine, narcotics, and indomethacin.
Medical conditions including weight loss to 20% below ideal body weight, pregnancy or abortion within 1 mo, endocrine diseases, systemic infections, serious liver](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-180-320.jpg)
![GLOMUS JUGULARE TUMOR
CSF protein may be increased.
GUILLAIN-BARRÉ SYNDROME
w CSF shows albumino-cytologic dissociation with normal cell count and increased protein (average 50–100 mg/dL). Protein increase parallels increasing clinical
severity; increase may be prolonged. CSF may be normal at first.
Laboratory findings due to preceding disease may be present (e.g., acute infections of respiratory or GI tract [e.g., EBV, Campylobacter, VZV, M. pneumoniae, CMV,
hepatitis, other viral, and rickettsial infections], Refsum's disease, immune disorders, endocrine disturbances, exposure to toxins, neoplasms).
LEUKEMIC INVOLVEMENT OF CNS
Intracranial hemorrhage is principal cause of death in leukemia (may be intracerebral, subarachnoid, subdural)
More frequent when WBC is >100,000/cu mm and with rapid increase in WBC, especially in blastic crises
Platelet count frequently decreased.
Evidence of bleeding elsewhere
CSF findings of intracranial hemorrhage
w Meningeal infiltration of leukemic cells
CNS is involved in 5% of patients with ALL at diagnosis and is the major site of relapse.
Meninges are involved in <30% of patients with malignant lymphoma; most prevalent in diffuse large cell (“histiocytic”), lymphoblastic, and immunoblastic
leukemia; occurs in one-third to one-half of patients with Burkitt's lymphoma and 15–20% of patients with non-Hodgkin's lymphoma.
Hodgkin's disease seldom involves CNS.
Involvement by CLL, well-differentiated lymphocytic lymphoma, and plasmacytoid lymphomas is very rare.
CSF may show
Increased pressure and protein.
Glucose decreased to <50% of blood level.
w · Increased cells that are often not recognized as blast cells because of poor preservation and that may be identified by cytochemical, immunoenzymatic,
immunofluorescent, and flow cytometry techniques.
w · Malignant cells are found in 60–80% of patients with meningeal involvement.
Complicating meningeal infection (e.g., various bacteria, opportunistic fungi)
LEUKODYSTROPHY, METACHROMATIC
(Rare lipidosis due to deficiency of arylsulfatase A; infantile and adult forms)
m Urine sediment may contain metachromatic lipids (from breakdown of myelin products).
CSF protein may be normal or increased £ 200 mg/dL.
w Biopsy of dental or sural nerve stained with cresyl violet showing accumulation of metachromatic sulfatide is diagnostic. Also increased in brain, kidney, liver.
w Conjunctival biopsy shows metachromatic inclusions within Schwann cells.
See Metabolic and Hereditary Diseases, Chapter 12, for other conditions that affect the CNS.
LINDAU-VON HIPPEL DISEASE (HEMANGIOBLASTOMAS OF RETINA AND CEREBELLUM)
Laboratory findings due to associated conditions (e.g., polycythemia, pheochromocytomas, renal cell carcinoma, cysts of kidney and epididymis, benign cysts and
nonfunctional neuroendocrine tumors of pancreas).
MENINGITIS, ASEPTIC
CSF
Protein is normal or slightly increased.
Increased cell count shows predominantly PMNs at first, mononuclear cells seen later.
Glucose is normal.
Bacterial cultures are negative.
If glucose levels are decreased, rule out TB, cryptococcosis, leukemia, lymphoma, metastatic carcinoma, sarcoidosis, drug induction.
Due To
Infections
Viral (especially poliomyelitis; infection with coxsackievirus, echovirus, HIV, EBV; lymphocytic choriomeningitis; and many others). Culture positive in ~40% of
cases, especially with enteroviruses.
Bacterial (e.g., incompletely treated or very early bacterial meningitis, bacterial endocarditis, parameningeal infections such as brain abscess, epidural abscess,
paranasal sinusitis).
Spirochetal (e.g., leptospirosis, syphilis, Lyme disease).
Tuberculous (CSF glucose levels may not be decreased until later stages).
Fungal (e.g., Candida, Coccidioides, Cryptococcus).
Protozoan (e.g., Toxoplasma gondii).](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-185-320.jpg)
![Benign polyneuritis associated with cervical lymph node tuberculosis or sarcoidosis
NEURITIS OF ONE NERVE OR PLEXUS
Laboratory findings due to causative disease
Infections (e.g., diphtheria, herpes zoster, leprosy)
Sarcoidosis
Tumor (leukemia, lymphoma, carcinomas)—may find tumor cells in CSF.
Serum sickness
Bell's palsy
Idiopathic
Facial Palsy, Peripheral Acute
Laboratory findings due to causative disease
Idiopathic (Bell's palsy)—occasional slight increase in cells in CSF
Infection
Viral (e.g., VZV, HSV, HIV, EBV infection, poliomyelitis, mumps, rubella)
Bacterial (e.g., Lyme disease, syphilis, leprosy, diphtheria, cat-scratch disease, M. pneumoniae infection)
Parasitic (e.g., malaria)
Meningitis
Encephalitis
Local inflammation (otitis media, mastoiditis, osteomyelitis, petrositis)
Trauma
Tumor (acoustic neuromas, tumors invading the temporal bone)
Granulomatous (e.g., sarcoidosis) and connective tissue diseases
Diabetes mellitus
Hypothyroidism
Uremia
Drug reaction
Postvaccinal effect
Paget's disease of bone
Melkersson-Rosenthal syndrome
Lyme disease and Guillain-Barré syndrome may produce bilateral palsy.
Hemianopsia, Bitemporal
Laboratory findings due to causative disease
Usually pituitary adenoma
Also metastatic tumor, sarcoidosis, Hand-Schuller-Christian disease, meningioma of sella, and aneurysm of circle of Willis
Ophthalmoplegia
Laboratory findings due to causative disease
Diabetes mellitus
Myasthenia gravis
Hyperthyroid exophthalmos
Trigeminal Neuralgia (Tic Douloureux)
Laboratory findings due to causative disease
Usually idiopathic.
May also stem from multiple sclerosis or herpes zoster.
Retrobulbar Neuropathy
CSF is normal or may show increased protein and £ 200/cu mm lymphocytes.
m Multiple sclerosis ultimately develops in 75% of these patients.
PRION DISEASES
(Due to proteinaceous infectious particles that do not use nucleic acids to mediate transmission)
Causes
Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, kuru, Gerstmann-Sträussler-Scheinker disease, fatal familial insomnia
Scrapie (sheep)
Mad cow disease (bovine spongiform degeneration)
w Diagnosis based on biopsy showing pathologic changes and demonstration of prions or a known prion gene mutation.
PSEUDOTUMOR CEREBRI
(Benign intracranial hypertension with neurologic complex of headache and papilledema without mass lesion or ventricular obstruction)
CSF normal except for increased pressure
Laboratory findings due to associated conditions (only obesity has been reported consistently) (e.g., Addison's disease, infection, metabolic conditions [acute
hypocalcemia and other electrolyte disturbances, empty sella syndrome, pregnancy], drugs [psychotherapeutic drugs, sex hormones and oral contraceptives,](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-190-320.jpg)
![corticosteroid administration, usually after reduction of dosage or change to different preparation], immune diseases [SLE, polyarteritis nodosa, serum sickness], other
conditions [sarcoidosis, Guillain-Barré syndrome, head trauma, various anemias])
REFSUM'S DISEASE
(Rare hereditary recessive lipidosis of the nervous system with retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, nerve deafness, and
ichthyosis)
CSF shows albuminocytologic dissociation (normal cell count with protein usually increased to 100–700 mg/dL).
RETARDATION, MENTAL
Laboratory findings due to underlying causative condition (see appropriate separate sections)
Prenatal
Infections (e.g., syphilis, rubella, toxoplasmosis, CMV infection)
Metabolic abnormalities (e.g., diabetes mellitus, eclampsia, placental dysfunction)
Chromosomal disorders (e.g., Down syndrome, trisomy 18, cri du chat syndrome, Klinefelter's syndrome)
Metabolic abnormalities
Amino acid metabolism (e.g., phenylketonuria, maple syrup urine disease, hemocystinuria, cystathioninuria, hyperglycemia, argininosuccinicaciduria,
citrullinemia, histidinemia, hyperprolinemia, oasthouse urine disease, Hartnup's disease, Joseph's syndrome, familial iminoglycinuria)
Lipid metabolism (e.g., Batten disease, Tay-Sachs disease, Niemann-Pick disease, abetalipoproteinemia, Refsum's disease, metachromatic leukodystrophy)
Carbohydrate metabolism (e.g., galactosemia, mucopolysaccharidoses)
Purine metabolism (e.g., Lesch-Nyhan syndrome, hereditary orotic aciduria)
Mineral metabolism (e.g., idiopathic hypercalcemia, pseudohypoparathyroidism and pseudopseudohypoparathyroidism)
Other syndromes (e.g., tuberous sclerosis, Louis-Bar's syndrome)
Perinatal
Kernicterus
Prematurity
Anoxia
Trauma
Postnatal
Poisoning (e.g., lead, arsenic, carbon monoxide)
Infections (e.g., meningitis, encephalitis)
Metabolic abnormalities (e.g., hypoglycemia)
Postvaccinal encephalitis
Cerebrovascular accidents
Trauma
REYE'S SYNDROME
(Acute noninflammatory encephalopathy with fatty changes in liver and kidney and rarely in heart and pancreas. Occurs typically in child recovering from
influenza, varicella, or nonspecific viral illness and is associated with use of aspirin.)
w Diagnostic Criteria
CSF shows <8 WBC/cu mm.
Serum AST, ALT, or ammonia ³ 3× ULN
Fatty liver seen histologically.
See Hepatic Failure, Acute.
SEIZURES THAT MAY BE ACCOMPANIED BY LABORATORY ABNORMALITIES
Associated Conditions
Neoplasms
Circulatory disorders (e.g., thrombosis, hemorrhage, embolism, hypertensive encephalopathy, vascular malformations)
Hematologic disorders (e.g., sickle cell anemia, leukemia)
Metabolic abnormalities
Carbohydrate metabolism (e.g., hypoglycemia, glycogen storage disease)
Amino acid metabolism (e.g., phenylketonuria, maple syrup urine disease)
Lipid metabolism (e.g., leukodystrophies, lipidoses)
Electrolyte balance (e.g., decreased sodium, calcium, and magnesium, increased sodium)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-191-320.jpg)
![Protein is usually increased. Protein is particularly increased with meningioma of the olfactory groove and with acoustic neuroma.
w · Tumor cells may be demonstrable in 20–40% of patients with all types of solid tumors, but failure to find malignant cells does not exclude meningeal neoplasm.
Glucose may be decreased if cells are present.
Brain stem gliomas, which are characteristically found in childhood, are usually associated with normal CSF.
Usually normal in diencephalic syndrome of infants due to glioma of hypothalamus.
Laboratory findings due to underlying causative disease (e.g., primary brain tumors, metastatic tumors, leukemias and lymphomas, infections [tuberculoma,
schistosomiasis, cryptococcosis, hydatid cyst], pituitary adenomas [CSF protein and pressure usually normal])
Laboratory findings due to associated genetic conditions (e.g., tuberous sclerosis, neurofibromatosis, Turcot's syndrome)
VON RECKLINGHAUSEN'S DISEASE (MULTIPLE NEUROFIBROMAS)
CSF findings of brain tumor if acoustic neuroma occurs.
1
Larson EB, et al. Diagnostic tests in the evaluation of dementia. A prospective study of 200 elderly outpatients. Arch Intern Med 1986;146:1917.
2
Spands A, Harrell FE, Durack DT. Differential diagnosis of acute meningitis. an analysis of the predictive value of initial observations. JAMA 1989;262:2700.
3
Bailey EM, Domenico P, Cunha, BA. Bacterial or viral meningitis. Postgrad Med 1990;88:217.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-193-320.jpg)
![Table 10-1. Increased Serum Enzyme Levels in Muscle Diseases
Creatine kinase (CK) is the test of choice. It is more specific and sensitive than AST and LD and more discriminating than aldolase, but AST is more significantly
associated with inflammatory myopathy and more useful in these cases. (See Chap. 3)
Increased In
Polymyositis
Muscular dystrophy
Myotonic dystrophy
Some metabolic disorders
Malignant hyperthermia
Prolonged exercise; peak 24 hrs after extreme exercise (e.g., marathon); smaller increases in well-conditioned atheletes
Normal In
Scleroderma
Acrosclerosis
Discoid LE
Muscle atrophy of neurologic origin (e.g., old poliomyelitis, polyneuritis)
Hyperthyroid myopathy
Decreased In
RA (approximately two-thirds of patients)
Skeletal Muscle Disorders That May Cause Increased Serum CK-MB
Drugs (e.g., alcohol, cocaine, halothane [malignant hyperthermia], ipecac)
Dermatomyositis/polymyositis
Muscular dystrophy (Duchenne's, Becker's)
Exercise myopathy; slight-to-significant increases in 14–100% of persons after extreme exercise (e.g., marathons); smaller increases in well-conditioned athletes
Familial hypokalemic periodic paralysis
Endocrine (e.g., hypoparathyroid, acromegaly; hypothyroidism rarely increases CK-MB £6% of total)
Rhabdomyolysis
Infections
Viral (e.g., HIV, EBV, influenza virus, picornaviruses, coxsackievirus, echovirus, adenoviruses)
Bacterial (e.g., Staphylococcus, Streptococcus, Clostridium, Borrelia)
Fungal
Parasitic (e.g., trichinosis, toxoplasmosis, schistosomiasis, cysticercosis)
Skeletal muscle trauma (severe)
MYOGLOBINEMIA AND MYOGLOBINURIA
DISEASES OF SKELETAL MUSCLES
ADYNAMIA EPISODICA HEREDITARIA (GAMSTORP'S DISEASE)
w Transient increase in serum potassium occurs during the attack; attack is induced by administration of potassium.
Urine potassium excretion is unchanged before or during the attack.
DYSTROPHY, MUSCULAR
(Genetic primary myopathies)
See Table 10-2 and Fig. 10-1.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-195-320.jpg)
![Thyroid function tests are normal.
Laboratory findings due to myocardial damage in most female carriers older than age 16 yrs.
Limb-Girdle Dystrophy
(Heterogeneous group of disorders in both sexes; autosomal recessive disorder that begins in second decade and progresses to disability by 30 yrs of
age and death by 50 yrs of age)
Serum CK is increased in 70% of patients to average of 10× ULN. Not useful to detect carriers. Not useful to distinguish it from other autosomal recessive forms of
dystrophy, myopathy, or neurologic disorders (e.g., hereditary proximal spinal muscular atrophy).
Facioscapulohumeral Dystrophy
(Begins in late adolescence; normal life span)
Serum CK is increased in 75% of patients to average 3× ULN. Frequently normal by 50 yrs of age.
DYSTROPHY, MYOTONIC
(Autosomal dominant disorder that presents in adolescence)
Serum CK is increased in 50% of patients to average of 3× ULN.
Increased creatine in urine may occur irregularly.
Findings due to atrophy of testicle and androgenic deficiency are noted.
Urine 17-KS are decreased.
Thyroid function may be decreased.
EOSINOPHILIA-MYALGIA SYNDROME
(Associated with ingestion of L-tryptophan; patient may also have arthralgias, fatigue, fever, edema, and skin, lung, and neurologic changes.)
w Diagnostic Criteria
Eosinophil count >1000/cu mm.
Muscle biopsy specimen shows inflammation.
No evidence of trichinosis on biopsy or serologic tests.
Absence of infection, neoplasm, or primary connective tissue disease that could cause myalgia.
Generalized myalgia sufficiently severe to impair daily activity.
Moderate increase of serum aldolase and LD but serum CK shows minimal or no increase.
Mild to moderate increase of AST, ALT, GGT.
ESR is normal or increased.
CRP, serum globulin, serum protein electrophoresis, IgE are normal.
HYPERTHERMIA, MALIGNANT2
(Rare autosomal dominant syndrome triggered by various inhalational and local anesthetic agents, muscle relaxants [e.g., succinylcholine, tubocurarine],
and various types of stress causing hyperthermia, muscle rigidity, and 70% fatality)
Due To
Excess heat production
Exertional
Heat stroke
Malignant hyperthermia of anesthesia
Neuroleptic malignant syndrome (in ~0.2% of patients who receive various phenothiazines, butyrophenones, or thioxanthenes; most often haloperidol)
Lethal catatonia
Thyrotoxicosis
Pheochromocytoma
Drugs (e.g., salicylate intoxication, cocaine, amphetamines)
Delirium tremens
Status epilepticus
Generalized tetanus
Decreased heat dissipation
Heat stroke
Dehydration
Anticholinergic agents
Autonomic dysfunction
Extensive occlusive dressings
Neuroleptic malignant syndrome
Disorders of hypothalamic function
Encephalitis
Cerebrovascular accidents
Trauma](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-197-320.jpg)
![Anti-DNA antibodies in 40% of cases.
ANA, anti–parietal cell, anti–smooth muscle, antimitochondrial, antithyroid antibodies, RF, etc., may be found.
Thymic tumor develops in up to 15–20% of generalized MG patients; 70% of patients have thymic hyperplasia with germinal centers in medulla.
CBC, ESR, thyroid function tests, serum enzymes, and electrolyte levels are normal.
May be associated with thyrotoxicosis, RA, PA, SLE.
High frequency of associated diabetes mellitus is seen, especially in older patients; therefore GTT should be performed with or without cortisone.
Always rule out cancer of lung.
MYOPATHY ASSOCIATED WITH ALCOHOLISM
Acute
Increased serum CK, AST, and other enzymes. Serum CK increased in 80% of patients; rises in 1–2 days; reaches peak in 4–5 days; lasts ~2 wks. CK in CSF is
normal, even when serum level is elevated.
Gross myoglobinuria.
Acute renal failure (some patients).
Chronic—may show some or all of the following changes.
Increased serum CK in 60% of patients to average of 2× ULN
Increased AST and other enzymes due to liver as well as muscle changes
Increased urine creatine
Diminished ability to increase blood lactic acid with ischemic exercise
Abnormalities on muscle biopsy (support the diagnosis)
Myoglobinuria
MYOPATHY: MYOTUBULAR, MITOCHONDRIAL, AND NEMALINE (ROD)
Routine laboratory studies including serum enzymes are normal.
w Muscle biopsy with histochemical staining establishes the diagnosis.
PARALYSIS, FAMILIAL PERIODIC
See Table 10-3.
Table 10-3. Types of Periodic Paralysis
w Serum potassium is decreased during the attack.
Urine potassium excretion decreases at the same time.
Serum enzymes are normal.
POLYMYOSITIS
(Nongenetic primary inflammatory myopathy; may be idiopathic or due to infection or may be associated with skin disease [dermatomyositis] or collagen
or malignant disease; 10–20% of patients older than 50 yrs of age have a neoplasm.)
m Serum enzymes
Serum CK is the most useful. Increased in 70% of patients. Levels may vary greatly (£50× normal). Degree of increase is highest in children and usually reflects
the activity of the disease but can be normal in active disease; decrease usually occurs 3–4 wks before improvement in muscle strength and increase occurs
5–6 wks before clinical relapse; the level frequently becomes normal with steroid therapy (in ~3 mos) or in chronic myositis.
Serum aldolase is increased in 75% of patients.
Serum LD is increased in 25% of patients.
Serum AST is increased in ~25% of the patients.
Serum alpha-hydroxybutyric dehydrogenase may be increased, paralleling the increased LD.
w Muscle biopsy findings are definitive; also for dermatomyositis and inclusion-body myositis. They also help to exclude other types of myositis.
Total eosinophil count is frequently increased. WBC may be increased in fulminant disease.
Mild anemia may occur.
ESR is moderately to markedly increased; may be normal; not clinically useful.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-199-320.jpg)
![TELOPEPTIDE, N-TERMINAL AND C-TERMINAL TELOPEPTIDE, URINE
(Antibodies to intermolecular cross-links of type I bone collagen are recently developed markers of bone resorption.)
Use
Serial changes decide course of therapy and monitor response to therapy. Failure to change >30% after 4–8 wks of therapy may suggest need to change therapy.
More specific to bone than pyridinoline, hydroxyproline, or calcium
Not for diagnosis of osteoporosis
Increased In (Indicates Bone Resorption)
Paget's disease
Osteoporosis
Primary hyperparathyroidism
Metastatic bone cancer
DISEASES OF SKELETAL SYSTEM
EMBOLISM, FAT
(Occurs after trauma [e.g., fractures, insertion of femoral head prosthesis])
Unexplained decrease in Hb in 30–60% of patients
Decreased platelet count in 80% of patients with rebound in 5–7 days
mFree fat in urine in 50% of patients and in stained blood smear
mFat globules in sputum (some patients) and BAL washings
mFat globulinemia in 42–67% of patients and in 17–33% of controls
Decreased arterial pO2 with normal or decreased pCO2
Arterial blood gas values are always abnormal in clinically significant fat embolism syndrome; are the most useful and important laboratory data. Patients show
decreased lung compliance, abnormal ventilation-perfusion ratios, and increased shunt effect.
Increased serum lipase in 30–50% of patients; 3–4 days after injury; increased free fatty acids; not of diagnostic value
Increased serum triglycerides
Normal CSF
Hypocalcemia is a common nonspecific finding (due to binding to free fatty acids).
w Laboratory findings alone are inadequate for diagnosis, prognosis, or management.
HYPOPHOSPHATEMIA, PRIMARY (FAMILIAL VITAMIN D—RESISTANT RICKETS)
(Hereditary metabolic defect in phosphate transport in renal tubules and possibly intestine)
m Serum phosphorus is markedly decreased.
Serum calcium is relatively normal.
Serum ALP is moderately increased.
Stool calcium is increased, and urine calcium is decreased.
w Administration of vitamin D does not cause serum phosphorus to increase (in contrast to ordinary rickets), but urine and serum calcium may be increased with
sufficiently large dose.
Serum phosphorus usually remains low; increase of >4 mg/dL may indicate renal injury due to vitamin D toxicity.
Treatment is monitored by choosing dose of vitamin D that does not increase serum calcium by >11 mg/dL or urine calcium by >200 mg/day.
Renal aminoaciduria is absent, in contrast to ordinary rickets.
OSTEOECTASIA, FAMILIAL
(Uncommon inherited disorder of membranous bone characterized by painful swelling of the periosteal soft tissue and spontaneous fractures)
Serum ALP is increased.
Serum acid phosphatase and aminopeptidase are also increased.
OSTEOMYELITIS](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-201-320.jpg)
![See Table 10-8.
Table 10-8. Erythrocyte Sedimentation Rate (ESR) in Differential Diagnosis of Juvenile Rheumatoid Arthritis
Latex fixation and other serologic tests for RF are negative, but RF and circulating immune complexes can be demonstrated by various special techniques.
Reported incidence of ANAs is 4–88% depending on clinical type and laboratory technique.
ARTHRITIS, RHEUMATOID (RA)
See Table 10-6 and Table 10-7.
Table 10-6. Comparison of Rheumatoid Arthritis and Osteoarthritis
Table 10-7. Serologic Tests in Various Rheumatoid Diseases
w American Rheumatism Association has 11 criteria for diagnosis of RA; seven are required for diagnosis of classic RA, five for definite RA, and three for probable
RA. Four laboratory findings included in these criteria are positive serum test for RF (by any method; positive in <5% of normal control subjects), poor mucin
clotting of synovial fluid, characteristic histologic changes in synovium, and characteristic histologic changes in rheumatoid nodules.
w Serologic tests for RF (autoantibodies to immunoglobulins) using nephelometry, latex, bentonite, or sheep or human RBCs
Use slide test only for screening; confirm positive result with tube dilution (nephelometry). Significant titer is ³1:80. In RA, titers are often 1:640 to 1:5120 and
sometimes £1:320,000. Titers in conditions other than RA are usually <1:80.
Gives useful objective evidence of RA, but a negative result does not rule out RA. Negative in one-third of patients with definite RA. Positive result in <50%
during first 6 mos of disease. Various methods show sensitivity of 50–75% and specificity of 75–90%. Positive in 80% of “typical” cases; high titers in patients
with splenomegaly, vasculitis, subcutaneous nodules, or neuropathy. Titer may decrease during remission but rarely becomes negative. Progressive increases
in titer during the first 2 yrs indicate a more severe course.
Positive in 5–10% of healthy population; progressive increase with age in £25–30% of persons older than 70 yrs.
Positive in 5% of rheumatoid variants (arthritis associated with ulcerative colitis, regional enteritis, Reiter's syndrome, juvenile RA, rheumatoid spondylitis,
tophaceous gout, pseudogout).
Positive in 5% of cases of scleroderma, mixed connective tissue disease, polymyositis, polymyalgia rheumatica.
Positive in 10–15% of patients with SLE.
Positive in 90% of patients with primary Sjögren's syndrome or cryoglobulinemic purpura.
Positive in 10–40% of patients with Waldenström's macroglobulinemia, chronic infections (e.g., syphilis, leprosy, brucellosis, TB, SBE), viral infections (e.g.,
hepatitis, EBV infection, influenza, vaccinations [positive in £10% of cases of parvovirus B19–associated arthritis]), parasitic diseases (e.g., malaria,
schistosomiasis, trypanosomiasis, filariasis), chronic liver disease, infectious hepatitis, chronic pulmonary interstitial fibrosis, etc.
Positive in £20% of cases of psoriatic arthritis.
Positive in 25% of cases of sarcoid arthritis.
Negative in osteoarthritis, ankylosing spondylitis, rheumatic fever, suppurative arthritis.
ANA present in up to 28% of patients (see Table 10-7).
Serum complement is usually normal except in patients with vasculitis; depressed level is usually associated with very high levels of RF and immune complexes, and
Table 16-1).
Immune complexes—monoclonal RF and C1q-binding assays are positive more frequently than other assays in RA but correlate poorly with disease activity. Positive](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-206-320.jpg)
![Increased acute-phase reactants
Increased ESR parallels the clinical course.
Increased CRP.
WBC is increased (10,000–20,000/cu mm), as is the granulocyte count.
Serum globulins are increased in long-standing disease.
Nonbacterial cystitis, prostatitis, or seminal vesiculitis and subclinical infection of ileum and colon may be found.
Significance of culturing various organisms or of serologic evidence of preceding infections is not determined.
HLA-B27 is found in up to 90% of white patients; not diagnostically useful.
SJöGREN'S SYNDROME3, 4
(Primary systemic autoimmune disease associated with decreased salivary and lacrimal gland secretion or may be secondary to RA, SLE, scleroderma, or
vasculitis in one-half to two-thirds of patients. 90% of patients are female.)
w Diagnostic Criteria
A. Primary Sjögren's syndrome
1. Symptoms and objective signs of dry eyes and
2. Symptoms and objective signs of dry mouth, including biopsy of minor salivary gland and
3. Laboratory evidence of systemic autoimmune disease
a. Increased RF titer ³1:320 (RF is present in £90% of primary and secondary Sjögren's syndrome)
b. Increased ANA titer ³1:320 or
c. Presence of anti-SS-A (Ro) or anti-SS-B (La) antibodies
B. Secondary Sjögren's syndrome: above criteria plus sufficient features for diagnosis of
SLE—found in 4–5% of patients with Sjögren's syndrome; Sjögren's syndrome is found in 50–98% of patients with SLE.
RF—found in 30–55% of patients with Sjögren's syndrome; Sjögren's syndrome is found in 20–100% of patients with RA.
Primary biliary cirrhosis—found in 3% of patients with Sjögren's syndrome; Sjögren's syndrome is found in 50–100% of patients with primary biliary cirrhosis.
Polymyositis, generalized scleroderma.
C. Not due to sarcoidosis; HIV, HTLV, HBV, HCV infection; or preexisting lymphoma; fibromyalgia; or other causes of keratitis sicca or enlarged salivary glands.
w ANAs in speckled or homogeneous pattern are present in 65% of patients, more frequently in those with primary type. Anti-SS-A (Ro) is present in £88% of
patients with primary type and <10% of those with secondary Sjögren's syndrome. Anti-SS-B (La) is present in £73% of patients with primary Sjögren's syndrome
and <5% of those with secondary Sjögren's syndrome. Anti–salivary duct antibody is rare (<30%) in primary Sjögren's syndrome and frequent (76–83%) in
secondary Sjögren's syndrome. Patients with primary Sjögren's syndrome also have higher levels of tissue antibodies (e.g., thyroglobulin [in 35%], gastric parietal,
smooth muscle). Anti-dsDNA is not found.
Mild normochromic, normocytic anemia occurs in 50% of patients.
Leukopenia occurs in up to one-third of patients.
ESR is usually increased.
Serum protein electrophoresis shows increased gamma globulins (usually polyclonal), largely due to IgG.
Laboratory findings due to concomitant diseases
Immune complex GN may occur, but chronic tubulointerstitial nephritis is more characteristic.
SPONDYLITIS, ANKYLOSING RHEUMATOID (MARIE-STRÜMPELL DISEASE)
w No diagnostic laboratory test exists for this disorder.
ESR is increased in £80% of patients.
Mild to moderate hypochromic anemia develops in £30% of patients.
Serologic tests for RF are positive in <15% of patients with arthritis of only the vertebral region.
CSF protein is moderately increased in £50% of patients.
Secondary amyloidosis develops in 6% of patients.
Laboratory findings due to carditis and aortitis with aortic insufficiency, which occur in 1–4% of patients.
Laboratory findings of frequently associated diseases (e.g., chronic ulcerative colitis, regional ileitis, psoriasis) are noted.
Histocompatibility antigen HLA-B27 is found in 95% of these white patients and in lesser numbers with variants of this condition. ~20% of carriers of HLA-B27 have
ankylosing spondylitis, but it is not helpful in establishing the diagnosis.
1
Rosalki SB. Serum enzymes in diseases of skeletal muscle. Clin Lab Med 1989;9:767.
2Simon HB. Hyperthermia. N Engl J Med 1993;329:483.
3
Collins RD Jr, Ball GV. Sjögren's syndrome: distinguishing primary from secondary. J Musculoskeletal Med 1984;1(5):42.
4
Fox RI. Sjögren's syndrome. Controversies and progress. Clin Lab Med 1997;17:431.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-210-320.jpg)
![Abnormally Shaped RBCs
Round
Macrocytes Increased erythropoiesis (reticulocytosis)
Round macrocytes Liver disease; alcoholism; postsplenectomy; hypothyroidism; increased MCV
Oval (macro-ovalocytes) Megaloblastic anemia; cancer chemotherapy; myelodysplastic syndromes; increased MCV
Microcytes Hypochromic anemias; decreased MCV
Spherocytes Hereditary spherocytosis; immunohemolytic anemia; recent blood transfusion; usually
decreased MCV, increased MCHC
Stomatocytes Hereditary stomatocytosis
Rh null disease Acute alcoholism (transient) Certain drugs (e.g., phenothiazines)
Neoplastic, cardiovascular, hepatobiliary diseases
Artifactual
Target cells HbC disease or trait; HbD; HbE; HbS; thalassemia; iron-deficiency anemia; liver disease;
postsplenectomy state; artifactual; decreased osmotic fragility
Elongated
Elliptocytes Hereditary (>25% in smear) Microcytic anemia (<25% in smear)
Ovalocytes Megaloblastic anemia
Teardrop (dacryocyte) Spent polycythemia
Myelofibrosis
Thalassemia (especially homozygous beta type)
Sickle cells Sickle cell disorders (not in S trait)
HbC crystalloids HbC trait or disease
Spiculated
Acanthocytes Abetalipoproteinemia (many are present)
Postsplenectomy state (few are present)
Fulminating liver disease (variable number)
Burr cells (echinocytes; crenated RBCs) Usually artifactual; stomach cancer; GI bleeding; uremia; pyruvate kinase deficiency;
hypophosphatemia; hypomagnesemia
Schistocytes (helmet, triangle) Microangiopathic hemolytic anemia (e.g., DIC, thrombotic thrombocytopenic purpura
[TTP]); prosthetic heart valves or severe valvular heart disease; severe burns; snakebite
“Bite” cells Hemolysis, e.g., due to certain drugs with or without G-6-PD deficiency, unstable Hb
RBC fragmentation (seen on peripheral blood smear
>10/1000 RBCs] and on histogram of RBC size with
automated cell counters)
Cytotoxic chemotherapy for neoplasia; autoimmune hemolytic anemia; severe iron
deficiency; megaloblastic anemia; acute leukemia; myelodysplasia; inherited structural
abnormality of RBC membrane protein spectrin
*
Not seen with Wright's stain; requires supravital stain, e.g., cresyl violet.
BLOOD VOLUME
Blood volume determination is usually done using albumin tagged with iodine 125 ( 125
I) or 131
I; red cell mass may be measured by labeling RBCs with 51
Cr.
Interferences
In the presence of active hemorrhage, the isotope is lost via the bleeding site and a false value is produced.
Use
Differential diagnosis of polycythemia
Radioisotopes should not be administered to children or pregnant women.
BONE MARROW ASPIRATION
Use When the Following Diagnoses Are Suspected
Aplastic anemia, agranulocytosis
Leukemia lymphomas
Megaloblastic anemias
Lipid storage diseases
Metastatic cancer
Multiple myeloma
Waldenström's macroglobulinemia
Idiopathic thrombocytopenic purpura (ITP)
Hypersplenism
Iron-deficiency anemia
Indicated for diagnosis and for posttreatment follow-up of acute leukemia and cytopenia.
BONE MARROW BIOPSY
Use When the Following Diagnoses Are Suspected
Disorders in which bone marrow aspiration is indicated (see previous section)
Granulomatous diseases
Amyloidosis](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-213-320.jpg)
![FLOW CYTOMETRY
Use
Diagnosis of leukemias, myelodysplasia, and lymphomas by immunophenotyping
Diagnosis of DNA content and DNA synthetic activity of tumors
Enumeration of lymphocyte subsets (e.g., CD4+
T cells as surrogate marker for disease progression in AIDS)
Stem cell (counting) transplantation
Measurement of cell-bound antibody and sorting of subpopulations that differ in amount of bound antibody
Use of anti-HbF monoclonal antibodies to detect HbF (can detect <0.05% fetal RBCs)
More accurate than Kleihauer-Betke stain for quantitation of fetal-maternal hemorrhage
Detect increased number of RBCs containing decreased HbF (“F” cells) in patients with hemoglobinopathies, some patients with myelodysplasia
Reticulocyte counting
HLA-B27 determination
Mitogen stimulation evaluation
Neutrophil function studies (e.g., phagocytosis, oxidative burst)
GENE REARRANGEMENT (bcr) ASSAY
wPCR has replaced Southern blot hybridization as preferred (more sensitive and specific) method to demonstrate reciprocal translocation of DNA from chromosome 9
(including the abl locus) to 22 (breakpoint cluster [ bcrs]), giving rise to shorter chromosome 22 (Ph1
). bcr gene rearrangement is molecular equivalent of Ph1
translocation. Can be done on peripheral blood as well as marrow and is more sensitive than routine cytogenetic analysis.
Use
To diagnose Ph1
-negative cases (5% of CML patients) or to confirm Ph1
-positive CML
To diagnose CML patients who present in blast crisis or are in blast transformation
To rule out CML in myeloproliferative disorders with similar morphologic features
To monitor CML patients treated with marrow transplant, chemotherapy, or interferon
To detect minimal-residual disease
To confirm complete remission
To provide early detection of relapse
To purge bcr-positive cells from autologous bone marrow before infusion
Positive bcr gene rearrangement in acute leukemia indicates poor prognosis, especially in ALLs.
Finding of same gene rearrangement in lymphocytes in a distant site biopsy is proof of metastasis.
To diagnose many genetic disorders (e.g., HbS, HbC, beta thalassemias).
Interferences
False-negative PCR in Ph1
-positive patients may occur due to therapy with interferon alpha or, less commonly, with hydroxyurea.
Contamination of PCR material.
Interpretation
Found in 95% of patients with CML, 5–10% of patients with ALL, and 1–2% of patients with acute myelogenous leukemia (AML). This rearrangement of bcr is typical
of Ph1
-positive chronic myelogenous leukemia patients and is found in ~30% of Ph 1
-positive AML patients.
GENE REARRANGEMENT ASSAY FOR IMMUNOGLOBULIN HEAVY (IGH) AND LIGHT (IGL-KAPPA) CHAINS AND GENE
REARRANGEMENT ASSAY FOR BETA AND GAMMA T-CELL RECEPTOR
Use
Allows classification of almost all cases of ALL as T, B, or pre-B types. Used to confirm pathologic-immunologic diagnoses of T-cell and B-cell lymphomas that are
difficult to classify.
Interpretation
Virtually all cases of non-T, non-B leukemias are recognized as pre-B types.
£90% of cases of non-Hodgkin's lymphoma are derived from B cells. Their immunophenotypic abnormalities can be used to distinguish them from benign reactions in
lymph nodes.
GENETIC HEMATOLOGIC DISEASES, MOLECULAR DIAGNOSIS](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-217-320.jpg)
![Acquired (autoimmune) hemolytic anemia
Marked Increase In
Any rapid intravascular hemolysis
Iron, Radioactive (59
Fe), RBC Uptake
59
Fe is injected IV, and blood samples are drawn in 3, 7, and 14 days for measurement of radioactivity.
Use
Study of kinetics of iron metabolism
Decreased In
Pure red cell aplasia—the rate of uptake of 59
Fe is markedly decreased.
IRON, SERUM
Use
Differential diagnosis of anemias
Diagnosis of hemochromatosis and hemosiderosis
Should always be measured with TIBC for evaluation of iron deficiency.
Diagnosis of acute iron toxicity
Interferences
Falsely increased by hemolysis, iron contamination of glassware
Falsely decreased in lipemic specimens
Iron dextran administration causes increase for several weeks (may be >1000 µg/dL)
Increased In
Idiopathic hemochromatosis
Hemosiderosis of excessive iron intake (e.g., repeated blood transfusions, iron therapy, use of iron-containing vitamins) (may be >300 µg/dL)
Decreased formation of RBCs (e.g., thalassemia, pyridoxine-deficiency anemia, PA in relapse)
Increased destruction of RBCs (e.g., hemolytic anemias)
Acute liver damage (degree of increase parallels the amount of hepatic necrosis) (may be >1000 µg/dL); some cases of chronic liver disease
Use of progesterone birth control pills (may be >200 µg/dL) and pregnancy
Premenstrual elevation 10–30%
Acute iron toxicity; ratio of serum iron/TIBC not useful for this diagnosis.
Decreased In
Iron-deficiency anemia
Normochromic (normocytic or microcytic) anemias of infection and chronic diseases (e.g., neoplasms, active collagen diseases)
Nephrosis (due to loss of iron-binding protein in urine)
PA at onset of remission
Menstruation (decreased 10–30%)
Diurnal variation—normal values in midmorning, low values in midafternoon, very low values (~10 µg/dL) near midnight. Diurnal variation disappears at levels <45
µg/dL.
IRON (HEMOSIDERIN), STAINABLE, IN BONE MARROW
(Present in RE cells and developing normoblasts [sideroblasts])
Use
Is the gold standard for diagnosis of iron deficiency; its presence almost invariably rules out iron-deficiency anemia. Marrow iron disappears before the peripheral blood
changes. Only individuals with decreased marrow iron are likely to benefit from iron therapy.
Diagnosis of iron overload.
Interferences
May be normal or increased by injections of iron dextran (which is used very slowly) despite other evidence of iron-deficiency anemia.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-220-320.jpg)
![Increased In
Idiopathic hemochromatosis
Hemochromatosis secondary to
Increased intake (e.g., Bantu siderosis, excessive medicine ingestion).
Anemias with increased erythropoiesis (especially thalassemia major; also thalassemia minor, some other hemoglobinopathies, paroxysmal nocturnal
hemoglobinuria, ‘sideroachrestic' anemias, refractory anemias with hypercellular bone marrow, etc.). In hemolytic anemias, decrease or absence may signify
acute hemolytic crisis.
Liver injury (e.g., after portal shunt surgery).
Atransferrinemia.
Megaloblastic anemias in relapse
Uremia (some patients)
Chronic infection (some patients)
Chronic pancreatic insufficiency
Decreased In
Iron deficiency (e.g., inadequate dietary intake, chronic bleeding, malignancy, acute blood loss). Rapidly disappears after hemorrhage.
Polycythemia vera (usually absent in polycythemia vera but usually normal or increased in secondary polycythemia)
PA in early phase of therapy
Collagen diseases (especially RA, SLE)
Infiltration of marrow (e.g., malignant lymphomas, metastatic carcinoma, myelofibrosis, miliary granulomas)
Uremia
Chronic infection (e.g., pulmonary TB, bronchiectasis, chronic pyelonephritis)
Miscellaneous conditions (e.g., old age, diabetes mellitus)
Myeloproliferative diseases–iron stores may be absent without other evidence of iron deficiency.
Serum iron and TIBC may be normal in iron-deficiency anemia, especially if Hb is <9 gm/dL.
IRON-BINDING CAPACITY, TOTAL (TIBC), SERUM
(TIBC [µmol/L] = transferrin [mg/L] × 0.025)
Unsaturated iron-binding capacity = TIBC – serum iron (µg/dL).
Use
Differential diagnosis of anemias
Should always be performed whenever serum iron is measured to calculate percent saturation.
Increased In
Iron deficiency
Acute and chronic blood loss
Acute liver damage
Late pregnancy
Use of progesterone birth control pills
Decreased In
Hemochromatosis
Cirrhosis of the liver
Thalassemia
Anemias of infection and chronic diseases (e.g., uremia, RA, some neoplasms)
Nephrosis
Hyperthyroidism
KLEIHAUER-BETKE TEST
(Acid-eluted stained smear of maternal blood shows pale maternal RBCs but pink fetal RBCs. Detects HbF. Quantitates amount [in mL] of fetal blood in
maternal circulation. Normal <1%. Now measured more accurately by flow cytometry with anti-HbF antibodies.)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-221-320.jpg)
![Increased In
Myeloproliferative diseases (especially polycythemia vera and CML)
Pregnancy
Use of oral contraceptive drugs
Decreased In
Hepatitis and cirrhosis
WHITE BLOOD CELL (WBC) DIFFERENTIAL COUNT
Use
Diagnosis of myeloproliferative disorders, myelodysplasias, various other hematologic disorders
Support diagnosis of various infections and inflammation
Is often ordered inappropriately and has almost no value as a screening test. The neutrophil and band counts may be useful in acute appendicitis and neonatal sepsis
with moderate sensitivity and specificity.
Interferences
Associated with automated WBC counters (artifact is corrected when manual WBC counts are performed)
Leukocyte fragility due to immunosuppressive and antineoplastic drugs
Lymphocyte fragility in lymphocytic leukemia
Excessive clumping of leukocytes in monoclonal gammopathies (e.g., multiple myeloma), cryofibrinogenemia (e.g., SLE), in presence of cold agglutinins
Causes of Neutropenia/Leukopenia
See Fig. 11-4.
Fig. 11-4. Algorithm for causes of neutropenia.
(Absolute neutrophil count [total WBC × % segmented neutrophils and bands] <1800/cu mm; <1000 in blacks.)
Decreased/ineffective production
Infections, especially
Bacterial (e.g., overwhelming bacterial infection, septicemia, miliary TB, typhoid, paratyphoid, brucellosis, tularemia)
Viral (e.g., infectious mononucleosis, hepatitis, influenza, measles, rubella, psittacosis)
Rickettsial (e.g., scrub typhus, sandfly fever)
Other (e.g., malaria, kala-azar)
Drugs and chemicals, especially
Sulfonamides
Antibiotics
Analgesics
Marrow depressants
Arsenicals
Antithyroid drugs
Many others
Ionizing radiation
Hematopoietic diseases
Folic acid and vitamin B12 deficiency
Aleukemic leukemia
Aplastic anemia
Myelophthisis
Decreased survival
Felty's syndrome
SLE
Autoimmune and isoimmune neutropenias
Splenic sequestration
Drugs
Abnormal distribution
Hypersplenism](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-231-320.jpg)
![Miscellaneous
Severe renal injury
Neonatal and Infantile Causes
(Neutrophil count <5000/cu mm during first few days or <1000/cu mm by end of first week of life)
Maternal causes
Associated with maternal neutropenia (e.g., SLE)
Maternal drug ingestion and often associated with thrombocytopenia (e.g., sulfa drugs, thiazides, propylthiouracil, phenothiazines, trimethadione, amidopyrine)
Associated with maternal isoimmunization to fetal leukocytes
Inborn errors of metabolism (e.g., chronic tyrosinosis, maple syrup urine disease, ketotic hyperglycinemia, methylmalonic acidemia, isovaleric acidemia, propionic
acidemia)
Immune defects (e.g., X-linked agammaglobulinemia, dysgammaglobulinemia)
Associated with phenotypic abnormalities (e.g., cartilage hair dysplasia, dyskeratosis congenita, Shwachman-Diamond syndrome [chronic hypoplastic
neutropenia associated with pancreatic insufficiency])
Infantile genetic agranulocytosis
Disorders of uncommitted stem cell proliferation
Cyclic neutropenia
Reticular dysgenesis (granulocytes and lymphocytes do not develop normally, absent thymus, low immunoglobulin concentrations, platelets and RBCs are
unaffected)
Disorders of myeloid stem cell proliferation
Kostmann's agranulocytosis (moderate to severe neutropenia that may be associated with dysgammaglobulinemia, frequent chromosomal abnormalities, normal
granulocytic maturation up to promyelocyte or myelocyte stage)
Benign chronic granulocytopenia of childhood
In children
Adult type PA
Defective secretion or type of gastric intrinsic factor (normal gastric mucosa and acid secretion, no antibodies to intrinsic factor or parietal cells, no
associated endocrine deficiency)
Imerslund-Graesbeck syndrome
Pregnancy–progressive decrease in granulocyte count during pregnancy. Serum B12 is normal in megaloblastic anemia of pregnancy.
Causes of Neutrophilia
(Absolute neutrophil count >8000/cu mm)
See Table 11-4 and Table 11-5.
Table 11-4. Some Common Causes of Leukemoid Reaction
Table 11-5. Comparison of Leukemia and Leukemoid Reaction
Acute infections
Localized (e.g., pneumonia, meningitis, tonsillitis, abscess)
Generalized (e.g., acute rheumatic fever, septicemia, cholera)
Inflammation (e.g., vasculitis)
Intoxications
Metabolic (uremia, acidosis, eclampsia, acute gout)
Poisoning by chemicals, drugs, venoms, etc. (e.g., mercury, epinephrine, black widow spider)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-232-320.jpg)
![Cytogenetic studies show normal chromosome numbers but structural instability causing breaks, gaps, constrictions, rearrangements.
Laboratory findings due to anemia, hemorrhage, infection, renal abnormalities.
ANEMIA, HEMOLYTIC, ACQUIRED
Laboratory findings due to increased destruction of RBCs
RBC survival time differentiates intrinsic defect from factor outside RBC.
Blood smear often shows marked spherocytosis. Anisocytosis, poikilocytosis, and polychromasia are seen.
Slight abnormality of osmotic fragility occurs.
Increased indirect serum bilirubin (<6 mg/dL) because of compensatory excretory capacity of liver).
Urine urobilinogen is increased (may vary with liver function; may be obscured by antibiotic therapy altering intestinal flora). Bile is absent.
Hemoglobinemia and hemoglobinuria are present when hemolysis is very rapid.
Haptoglobins are decreased or absent in chronic hemolytic diseases (removed after combination with free Hb in serum).
WBC is usually elevated.
Laboratory findings due to compensatory increased production of RBCs
Normochromic, normocytic anemia. MCV reflects immaturity of circulating RBCs. Polychromatophilia is present.
Reticulocyte count is increased.
Erythroid hyperplasia of bone marrow is evident.
Laboratory findings due to mechanism of RBC destruction, e.g.,
Positive direct Coombs' test.
Warm antibodies.
Cold agglutinins.
Biological false-positive test for syphilis may occur.
Laboratory findings due to underlying conditions
Malignant lymphoma
Collagen diseases (e.g., SLE)
DIC
Idiopathic pulmonary hemosiderosis
Infections, especially Mycoplasma infection; infectious mononucleosis, malaria, cholera
Paroxysmal nocturnal hemoglobinuria
Physical/chemical (e.g., burns, drugs, toxins [phenylhydrazine, benzene])
Antibody-induced
Drug induced (e.g., quinidine, quinine, penicillins, cephalothin, alpha methyldopa)
Autoantibody (warm, cold)
Alloantibody (erythroblastosis fetalis, incompatible transfusion)
Paroxysmal cold hemoglobinuria
ANEMIA, HEMOLYTIC, MICROANGIOPATHIC
(Traumatic intravascular hemolysis due to fibrin strands in vessel lumens)
See Table 11-1, Table 11-9, Table 11-10 and Fig. 11-6.
Fig. 11-6. Algorithm for workup of microcytic hypochromic anemia. (CBC = complete blood cell count; FEP = free erythrocyte protoporphyrin; Rx = therapy.)
wPeripheral blood smear establishes the diagnosis by characteristic burr cells, schistocytes, helmet cells, microspherocytes.
Nonimmune hemolytic anemia varies in severity depending on underlying condition (see Anemia, Hemolytic, Acquired).
Laboratory findings of hemolysis, e.g., increased serum LD, decreased haptoglobin, hemosiderinuria; hemoglobinemia and hemoglobinuria are less common.
Iron deficiency due to urinary loss of iron.
Direct Coombs' test is usually negative.
Laboratory findings due to causative disease
Due To
Renal disease (e.g., malignant hypertension, renal graft rejection)
Cardiac valvular disease (e.g., intracardiac valve prostheses, bacterial endocarditis, severe valvular heart disease)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-240-320.jpg)
![Severe liver disease (e.g., cirrhosis, eclampsia)
DIC
Autoimmune disorders (e.g., periarteritis nodosa, SLE)
TTP
Snakebite
Some disseminated neoplasms
ANEMIA, HEMOLYTIC, HEREDITARY NONSPHEROCYTIC
(This heterogeneous group may be due to pyruvate kinase deficiency, variants of G-6-PD deficiency, Hb Zurich, other rare congenital enzyme defects [e.g.,
glutathione])
wCharacterized by persistent hemolysis without demonstrable autoantibodies, abnormal hemoglobins, altered RBC morphology, or other obvious findings indicating
etiology. Hemolytic anemia may be severe; may begin in newborn; may be precipitated by certain drugs.
RBCs show Howell-Jolly bodies, Pappenheimer bodies, Heinz bodies, basophilic stippling; slight macrocytosis may be present.
Increase in reticulocyte count is marked, even with mild anemia.
Bone marrow shows marked erythroid hyperplasia; normal hemosiderin is present.
WBC, platelet count, Hb electrophoresis, osmotic fragility, and mechanical fragility are normal.
Autohemolysis is present in some cases but not in others; reduction by glucose is less than in normal blood.
ANEMIA, IRON-DEFICIENCY
See Table 11-1, Table 11-9, Table 11-10, Fig. 11-3 and Fig. 11-6.
Due To
(Usually a combination of these factors)
Chronic blood loss (e.g., menometrorrhagia; bleeding from GI tract, especially from carcinoma of colon; hiatus hernia; peptic ulcer; intestinal parasites; marathon
runners)
Decreased dietary intake (e.g., poverty, emotional factors)
Decreased absorption (e.g., steatorrhea, gastrectomy, achlorhydria)
Increased requirements (e.g., pregnancy, lactation)
The cause of iron deficiency should always be ascertained to avoid overlooking occult carcinoma. In adults, iron deficiency usually means blood loss. If no GI or
gynecologic cause is apparent, endoscopy must be performed.
Laboratory Findings
wDecreased serum ferritin is the most sensitive and specific test and is first test to reflect iron deficiency; decreased before anemia but may be increased when there
is coexisting liver disease, inflammation, or other conditions that increase ferritin . Thus iron deficiency is suggested by serum ferritin <25 ng/mL in a patient with
inflammation, <50 ng/mL in a hemodialysis patient, and <100 ng/mL in liver disease; <12 ng/mL always indicates iron deficiency. Serum ferritin >200 ng/mL
generally indicates adequate iron stores regardless of underlying conditions. Ferritin usually distinguishes iron deficiency from thalassemia in uncomplicated cases.
wHb is decreased (usually 6–10 gm/dL) out of proportion to decrease in RBC (3.5–5.0 million/cu mm); thus decreased MCV (<80 fL) is a sensitive indicator; MCH is
decreased (<30 pg); decreased MCHC (25–30 gm/dL) is poor indicator as it is usually normal until anemia is severe.
wIncreased RDW is found more often in iron deficiency than in thalassemia; increased RDW may be the first indication of iron deficiency; sensitivity = 89%; negative
predictive value of normal RDW = 93%; positive predictive value = 45%; specificity = only 45%.
wHypochromia and microcytosis parallel severity of anemia. Polychromatophilia and nucleated RBCs are less common than in PA or thalassemia. Diagnosis from
peripheral blood smear is difficult and unreliable. Target cells may be present but are more common in thalassemias; basophilic stippling and polychromasia also
favor thalassemia although absent in 50% of cases. Anisocytosis is less marked in thalassemia.
wRatio of microcytic to hypochromic RBCs (measured with automated hematology analyzer) is <0.9 in iron deficiency but >0.9 in beta-thalassemia.
wSerum iron is decreased (usually 40 µg/dL), TIBC is increased (usually 350–460 µg/dL), and transferrin saturation is decreased (<15%). TIBC may be normal or
moderately increased in many patients with uncomplicated iron deficiency. Serum transferrin may be normal or increased (calculated transferrin = TIBC × 0.7).
These have limited value in differential diagnosis because they are often normal in iron deficiency and abnormal in anemia of chronic disease and may be affected
by recent iron therapy.
wAs iron deficiency progresses, decreased serum ferritin is followed in order by anisocytosis, microcytosis, elliptocytosis, hypochromia, decreases in Hb, decreases
in serum iron, and decreases in transferrin saturation.
mSerum transferrin receptor assay increases only after iron stores are depleted (i.e., decline in serum ferritin below reference range and compensatory erythropoiesis
begins) but before changes are seen in other markers of tissue iron deficiency (e.g., transferrin saturation, MCV, erythrocyte protoporphyrin). Particularly useful in
differentiating iron-deficiency anemia from anemia of chronic disease and in diagnosing iron-deficiency anemia in patients with chronic disease. Increased
sensitivity and specificity when combined with ferritin.
wBone marrow shows normoblastic hyperplasia with decreased hemosiderin, later absent, and decreased percentage of sideroblasts. Decreased to absent iron is the
gold-standard test for diagnosis of iron deficiency.
Reticulocytes are normal or decreased, unless there is recent hemorrhage or administration of iron.
mFree erythrocyte protoporphyrin is increased and is useful screening test because it can be done on fingerstick sample. Is increased before anemia. Also increased
in lead poisoning, anemia of chronic disease, and most sideroblastic anemias but is normal in thalassemias.
WBC is normal or may be slightly decreased in 10% of cases; may be increased with fresh hemorrhage.
Serum bilirubin and LD are not increased.
Platelet count is usually normal but may be slightly increased or decreased; often increased in children.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-241-320.jpg)
![Serum indirect bilirubin is increased (<4 mg/dL).
Urine urobilinogen and coproporphyrin I are increased.
Stool urobilinogen is increased.
50% of PA patients have thyroid antibodies.
Increased frequency of gastric adenocarcinoma and gastric carcinoids.
wCharacteristic Response of Laboratory Tests to Specific Treatment of PA or Folate Deficiency
RBC count reaches normal between 8th and 12th week regardless of severity of anemia; Hb concentration may rise at a slower rate, producing hypochromia with
microcytosis. Peripheral blood is normal in 1–2 mos.
Characteristic reticulocyte response is proportional to severity of anemia. Reticulocyte count begins to rise by 4th day after treatment and reaches maximum on 8th to
9th day; returns to normal by 14th day. Daily injection of 200 µg of folinic acid or citrovorum factor causes a reticulocyte response in patients with folate deficiency but
not in those with B12 deficiency.
Megaloblasts disappear from marrow in 24–48 hrs followed by reversal of megaloblastic changes in myeloid cells a few days later.
Serum folate decreases (in PA) at the same time reticulocytosis takes place.
Serum iron decreases to normal or less than normal at the same time reticulocytosis takes place.
Serum uric acid increases; peak precedes maximum reticulocyte count by ~24 hrs; remains increased as long as rapid RBC regeneration goes on.
Serum LD decreases but is not yet normal by eighth day.
Serum bilirubin becomes normal.
Serum ALP increases to normal.
Serum cholesterol rises to greater than normal levels; most marked at peak of reticulocyte response.
Increased urinary urobilinogen and coproporphyrin I immediately revert to normal, preceding reticulocyte response.
Achlorhydria persists.
RBC cholinesterase activity increases.
In Children
Adult type PA (very rare condition of gastric atrophy with lack of intrinsic factor production at birth; antibodies to intrinsic factor are present; parietal cell antibodies in
50% of cases; corrected by administration of intrinsic factor; frequent endocrine dysfunction such as hypoparathyroidism and hypoadrenalism)
Congenital absence of intrinsic factor (PA develops at age 12–18 mos; corrected by exogenous gastric intrinsic factor; normal gastric mucosa and acid secretion, no
antibodies to intrinsic factor or parietal cells, no associated endocrine deficiency)
Imerslund-Graesbeck syndrome (rare autosomal recessive defective ileal receptor of B 12 prevents absorption; ileum is normal histologically; normal gastric and
endocrine function; proteinuria and renal tubular dysfunction are present; decreased folate and normal B 12 concentrations; responds to parenteral B12 therapy)
ANEMIA, MEGALOBLASTIC, OF PREGNANCY AND PUERPERIUM
Anemia may have been present during previous pregnancy with spontaneous remission after delivery.
Hematologic abnormalities are less marked than in PA.
If achlorhydria is present, it often disappears after delivery.
Therapeutic response to folic acid but usually not to vitamin B 12
Urinary excretion of formiminoglutamic acid is increased.
ANEMIA, MEGALOBLASTIC, REFRACTORY TO FOLIC ACID OR VITAMIN B12
Due To
Inborn errors of metabolism
Transcobalamin II deficiency (absence of transport protein for vitamin B 12 with profound megaloblastic anemia in infancy; serum B12 is usually normal; may
respond to huge doses of parenteral B12)
Intrinsic factor deficiency (juvenile PA)
Enzyme defects (e.g., congenital methylmalonicacidemia, congenital homocystinemia, 5-methyltetrahydrofolate transferase deficiency, hereditary orotic aciduria)
Drug effects
Antifolate drugs (e.g., methotrexate, trimethoprim)
Interference with absorption of folate (e.g., anticonvulsants, oral contraceptives, alcohol) or vitamin B 12 (e.g., colchicine, PAS, phenformin)
Inactivation of vitamin B12 by nitrous oxide
Antimetabolites
Mild megaloblastic anemia
Purine inhibitors (e.g., 6-mercaptopurine, azathioprine [Imuran])
Pyrimidine inhibitors (e.g., 5-fluorouracil)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-246-320.jpg)
![Normochromic, normocytic or macrocytic (if hypochromic, rule out associated iron deficiency)
No anisocytosis or poikilocytosis
Reticulocyte count is not increased.
Serum iron is usually decreased and responds only to treatment of hypothyroidism unless concomitant iron deficiency is present.
Decreased total blood volume and plasma volume.
Normal RBC survival
Concurrent iron-deficiency anemia or PA may be present.
Hypogonadism
Normochromic, normocytic; only occurs in men.
Hypoadrenalism
Hct is pseudonormal at presentation due to plasma volume depletion; corticosteroid therapy unmasks anemia. Is corrected by 1–2 mos of therapy.
Chronic Renal Disease
Blood smear frequently shows burr cells or schistocytes.
Usually normochromic, normocytic; hypochromic microcytosis may be due to chronic disease or iron deficiency. Severity of anemia roughly parallels severity of renal
disease but when dialysis is required, anemia is almost always severe.
Decreased serum iron and transferrin. Serum iron, TIBC, and ferritin often are not helpful and bone marrow specimen stained for iron may be necessary for diagnosis
of iron deficiency. Concurrent iron deficiency due to GI tract blood loss may be present. Anemia responds to erythropoietin therapy.
Bone marrow usually shows erythroid hypoplasia.
Decreased serum erythropoietin.
Decreased RBC survival by chromium 59 (59
Cr) studies.
Chronic Liver Disease
mIncreased MCV (100–125 fL) in one-third to two-thirds of patients. Indices resemble those in other megaloblastic anemias. Low MCHC may indicate associated iron
deficiency.
wUniform round macrocytosis is the cardinal finding. Target cells and stomatocytes may be present. Presence of hypochromic macrocytes or microcytes may suggest
misleading diagnosis of iron deficiency. Spur cell (acanthocyte) hemolysis may be due to abnormal lipid metabolism.
Hemolytic anemia or true folate deficiency is frequent in alcoholic liver disease. Reticulocyte count is usually increased.
Serum iron, TIBC, and ferritin are often not helpful, and bone marrow specimen stained for iron may be necessary for diagnosis of iron deficiency.
Decreased RBC survival by 59
Cr studies.
ANEMIA, PATHOGENESIS CLASSIFICATION
Anemias may be classified according to pathogenesis, which is convenient for understanding the mechanism or according to RBC indices and peripheral blood smear
and reticulocyte count (see Fig. 11-3), which is convenient for workup of a clinical problem.
Marrow hypofunction with decreased RBC production
Marrow replacement (myelophthisic anemias due to tumor or granulomas [e.g., TB]). In absence of severe anemia or leukemoid reaction, nucleated RBCs in
blood smear suggest miliary TB or marrow metastases.
Marrow injury (hypoplastic and aplastic anemias)
Nutritional deficiency (e.g., megaloblastic anemias due to lack of vitamin B 12 or folic acid)
Endocrine hypofunction (e.g., pituitary, adrenal, thyroid; anemia of chronic renal failure)
Marrow hypofunction due to decreased Hb production (hypochromic microcytic anemias)
Deficient heme synthesis (iron-deficiency anemia, pyridoxine-responsive anemias)
Deficient globin synthesis (thalassemias, hemoglobinopathies)
Excessive loss of RBCs
Hemolytic anemias due to genetically defective RBCs
Abnormal shape (hereditary spherocytosis, hereditary elliptocytosis)
Abnormal Hb (sickle cell anemia, thalassemias, HbC disease)
Abnormal RBC enzymes (G-6-PD deficiency, congenital nonspherocytic hemolytic anemias)
Hemolytic anemias with acquired defects of RBC and positive Coombs' test](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-248-320.jpg)
![Autoantibodies, as in SLE, malignant lymphoma
Exogenous allergens, as in penicillin allergy
Excessive loss of normal RBCs
Hemorrhage
Hypersplenism
Chemical agents (e.g., lead)
Infectious agents (e.g., Clostridium welchii, Bartonella, malaria)
Miscellaneous diseases (e.g., uremia, liver disease, cancers)
Physical agents (e.g., burns)
Mechanical trauma (e.g., artificial heart valves, tumor microemboli). Blood smear shows fragmented bizarre-shaped RBCs in patients with artificial heart valves.
Anemias are often multifactorial; the resultant characteristics depend on which factor predominates. The diagnosis must be reevaluated after the apparent causes
have been treated.
ANEMIA, PYRIDOXINE-RESPONSIVE
Severe hypochromic microcytic anemia is present.
Blood smear shows anisocytosis, poikilocytosis with many bizarre forms, target cells, hypochromia. Polychromatophilia and reticulocytosis are not increased.
Serum iron is increased; TIBC is somewhat decreased; transferrin saturation is markedly increased. Marrow sideroblasts and blood siderocytes are increased. Marrow
and liver biopsy show increased hemosiderin.
Bone marrow usually shows normoblastic hyperplasia; occasionally it is megaloblastic.
Response to pyridoxine is always incomplete. Even when Hb becomes normal, morphologic changes in RBCs persist.
Tryptophan tolerance test demonstrates pyridoxine deficiency. It may be positive in pyridoxine-responsive anemia, or it may be normal. A positive test produces
abnormally large urinary excretion of xanthurenic acid.
ANEMIA, SIDEROBLASTIC
(Miscellaneous group of diseases characterized by increased sideroblasts [erythroblasts containing iron inclusions] in marrow)
See Table 11-9.
Hereditary
(X-linked transmission)
Usual onset in young adulthood but may be in childhood or infancy
Anemia is usually severe, hypochromic, microcytic; smear shows anisocytosis, poikilocytosis, elliptocytes, target cells, basophilic stippling mixed with
normal-appearing RBCs (dimorphic RBC population).
WBC and platelets are usually normal.
wBone marrow shows erythroid hyperplasia with normoblastic maturation; 10–40% of normoblasts are ringed sideroblasts; normal or increased iron.
Megaloblastic changes indicate complicating folate deficiency.
Transferrin saturation is increased.
<50% of patients respond to pyridoxine therapy.
Idiopathic Refractory
Usual onset in older adulthood (rarely <50 yrs)
wDimorphic anemia is usually moderate, normocytic, or macrocytic with a small population of hypochromic RBCs on blood smear, some of which show marked
stippling. Reticulocytes are usually not increased.
WBCs are variable but usually normal. WBCs may show morphologic changes (hypogranular, Pelger-Huët–like neutrophils). Blasts are <1%.
Platelet counts are variable. Abnormal thrombopoiesis with abnormal morphology (e.g., hypogranular, large platelets or fragments, large nuclei).
Bone marrow shows erythroid hyperplasia; 45–95% of normoblasts are ringed sideroblasts; excessive hemosiderin. Megaloblastic changes due to complicating folate
deficiency are found in 20% of patients. Dysgranulopoiesis and dysmegakaryopoiesis may be evident.
Serum ferritin and iron stores are increased due to ineffective erythropoiesis. Transferrin saturation is increased (>90% in 33% of patients). However, some patients
may be iron deficient or have normal iron status. Iron overload is principal feature that determines long-term prognosis.
Acute leukemia develops in ~10% of patients.
Secondary Due To](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-249-320.jpg)
![Associated with lymphoproliferative and autoimmune disorders, chronic HCV infection, Sjögren's syndrome, syndrome of essential mixed cryoglobulinemia,
immune-complex nephritis (e.g., membranoproliferative GN, vasculitis).
High-titer RF without definite rheumatic disease.
C4 levels decreased.
Type III (mixed polyclonal immunoglobulin, most commonly IgM-IgG combinations, usually with RF)
Causes ~50% of cases.
Usually present in small amounts (<1 mg/dL serum) in normal persons.
Most commonly associated with lymphoproliferative disorders, connective tissue diseases (e.g., SLE); vasculitis and/or nephritis in chronic inflammatory
diseases of bowel or liver or rheumatic diseases or persistent infections (e.g., bacterial endocarditis, HCV, fungal, parasitic).
Recurrent purpura may occur.
wHyperviscosity syndrome is likely at IgM >4.0 gm/dL; clinically unpredictable at 2.0–4.0 gm/dL; therefore serum viscosity should be measured. Viscosity increases
exponentially with IgM concentration.
m Cryoprecipitate may be seen in serum.
m May cause erroneous WBC when electronic cell counter is used.
m Rouleaux formation may occur.
ESR may be increased at 37°C but is normal at room temperature.
Laboratory findings of associated conditions
Liver disease—e.g., serologic evidence of viral hepatitis.
Renal disease—e.g., immune glomerular disease. Renal failure develops in ~50%, and marked proteinuria occurs in ~25%.
Skin biopsy showing cutaneous vasculitis.
ELLIPTOCYTOSIS, HEREDITARY
(Autosomal dominant trait affecting 1 in 2500 persons in United States. >10 variants are known.)
wBlood smear shows 25–100% elliptical RBCs. In healthy individuals, £10% of RBCs may be elliptical. Also seen frequently in thalassemias, hemoglobinopathies,
iron deficiency, myelophthisic anemias, megaloblastic anemia; these must be ruled out to establish the diagnosis in a congenital hemolytic anemia with marked
elliptocytosis. Only a few abnormal RBCs are present at birth with gradual increase to stable value after ~3 mos of age. Hemolysis is rare in newborns. Splenectomy
does not relieve elliptocytosis despite clinical improvement.
Severity of disease varies from severe hemolytic disease to asymptomatic carrier status.
Degree of hemolysis does not correlate with proportion of abnormal RBC.
Elliptocytes are the only hematologic abnormality seen in ~85% of patients; such patients are asymptomatic. Spherocytes are present in some forms.
Mild normocytic normochromic anemia (Hb = 10–12 gm/dL) in 10–20% of patients.
~12% of patients show a chronic congenital hemolytic anemia (Hb <9 gm/dL) with decreased RBC survival time, moderate anemia, increased serum bilirubin,
increased reticulocyte count, increased osmotic fragility, and autohemolysis.
Severe in ~5% of patients (homozygous)—transfusion-dependent anemia with misshapen RBCs resembling hereditary pyropoikilocytosis.
wElliptocytes are found in at least one parent and may be present in siblings.
Mechanical fragility is increased.
Osmotic fragility and autohemolysis are normal in patients without hemolytic anemia.
Hb electrophoresis is normal.
Laboratory findings due to complications (e.g., gallstones, hypersplenism).
ERYTHROCYTE PYRUVATE KINASE DEFICIENCY
(Congenital autosomal recessive nonspherocytic hemolytic anemia showing wide range of clinical and laboratory findings from severe neonatal anemia
requiring transfusion to fully compensated hemolytic process in healthy adults; due to deficiency of pyruvate kinase [10–25% of normal] in RBCs)
wAssay of RBC pyruvate kinase activity demonstrates heterozygous carrier state in persons who are hematologically normal.
Beyond early childhood Hb is usually 7–10 g/dL.
Peripheral smear shows no characteristic changes (i.e., few or no spherocytes, occasional tailed poikilocytes, macrocytosis, reticulocytosis).
Abnormal autohemolysis test is poorly corrected by glucose.
Normal osmotic fragility.
If an infant has been transfused, the assay should be performed 3–4 mos later.
mDiagnosis is difficult to make. May be suggested by increased Hb oxygen affinity (P50) due to elevated 2,3-diphosphoglycerate. Laboratory findings due to
complications (e.g., cholelithiasis, hemosiderosis)
Other rare deficiencies of RBC enzymes also exist.
ERYTHROCYTOSIS, CLASSIFICATION
Polycythemia vera
Hereditary erythrocytosis (rare conditions)
High oxygen-affinity hemoglobinopathies
Decreased RBC 2,3-diphosphoglycerate (due to high RBC adenosine triphosphate or autosomal recessive diphosphoglycerate mutase deficiency)
Increased production of erythropoietin (autosomal recessive)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-253-320.jpg)
![Erythropoietin-receptor mutations (autosomal dominant)
Unknown causes
Secondary polycythemia
Relative polycythemia
Neonatal thick blood syndrome
Factitious polycythemia (due to blood doping or ingestion of steroids by athletes)
GLUCOSE 6-PHOSPHATE DEHYDROGENASE (G-6-PD) DEFICIENCY IN RBC
(Inherited sex-linked disorder. Is the most frequent inherited RBC enzyme disorder.)
May be associated with several different clinical syndromes. Classes 2 and 3 represent 90% of cases. Classes 4 and 5 show no clinical findings.
Class 1 (<5% of normal RBC enzyme activity)—rare, chronic, congenital, nonspherocytic hemolytic anemia worsened by oxidant drugs or febrile illness. Not
improved by splenectomy.
Class 2 (<10% of normal RBC enzyme activity)—episodic acute hemolytic crises induced by some oxidant drugs (e.g., primaquine, sulfonamides, acetanilid) or
acidosis. Splenectomy is not helpful.
Class 3 (RBC G-6-PD activity = 10–60% of normal)—oxidant drugs or infection (e.g., pneumonia, infectious hepatitis) induce acute self-limited (2–3 days)
hemolysis in persons without previously recognized hematologic disease. Also reported in hepatic coma, hyperthyroidism, myocardial infarction (after first
week), megaloblastic anemias, and chronic blood loss.
Many other genetic and clinical variants.
wAfter standard dose of primaquine in adult, intravascular hemolysis is evidenced by the following:
Decreasing Hct usually begins in 2–4 days; reaches nadir by 8–12 days.
Heinz bodies and increased serum bilirubin occur during first few days of hemolysis.
Reticulocytosis begins at about fifth day; reaches maximum in 10–20 days.
Hemolysis subsides spontaneously even if primaquine is continued.
wIn vitro tests of Heinz body formation when patients' RBCs are exposed to acetylphenylhydrazine.
Hb varies from 7 gm/dL to normal; is lower when due to exogenous agent; is usually normochromic, normocytic.
Peripheral smear shows varying degree of nucleated RBCs, spherocytes, poikilocytes, crenated and fragmented RBCs, and Heinz bodies but is not distinctive.
wDiagnosis is established by RBC assay for G-6-PD (using fluorescence); heterozygotes have two RBC populations and proportions of each determine degree of
deficiency detected.
mScreening test using fluorescent spot test is available.
In Newborn
5% develop neonatal jaundice after first 24 hrs (in contrast to erythroblastosis fetalis). Serum indirect bilirubin usually reaches peak at third to fifth day (often >20
mg/dL). When jaundice appears late in first week, peak serum level may occur during second week of life.
In Asian and Mediterranean infants, neonatal jaundice and kernicterus is more common. Significant portions of the bilirubin may be conjugated.
In American black infants at term, incidence of neonatal jaundice is not increased; occurs after exposure to certain drugs (e.g., synthetic vitamin K,
naphthalene).
Decreased In
American black males (13%)
American black females (3%; 20% are carriers)
Some other ethnic groups (e.g., Greeks, Sardinians, Sephardic Jews)
All persons with favism (but not all persons with decreased G-6-PD have favism)
Increased In
PA to three times normal level; remains elevated for several months, even after administration of vitamin B 12.
Idiopathic thrombocytopenic (ITP; Werlhof's disease); becomes normal soon after splenectomy.
GRAFT-VERSUS-HOST DISEASE
(Due to small lymphocytes [mature marrow T cells] in transplant of donor organs or tissues to immunocompromised host [e.g., bone marrow transplant
recipients, infants with congenital immunodeficiency syndromes, but not AIDS patients])
Acute
(Within days but <1–2 mos after transplantation)
wLaboratory findings due to selective epithelial damage involving
Liver: increased serum bilirubin, ALP, AST; may progress to liver failure with encephalopathy, ascites, coagulation disorders.
Intestine: bloody diarrhea, paralytic ileus.
Positive biopsy of liver, skin, colon, upper GI tract.
Acute condition causes persistent severe immunoincompetence with profound immunodeficiency and susceptibility to infection. Transfusion-associated
graft-versus-host disease often causes bone marrow aplasia with pancytopenia; is usually severe in contrast to graft-versus-host disease after bone marrow
transplant.
Chronic](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-254-320.jpg)
![w >100 days but occasionally as early as 40–50 days after transplantation).
Liver: changes of chronic cholestasis (in 80% of cases); often resembles acute graft-versus-host disease; rarely progresses to cirrhosis.
Abnormalities of cellular immunity (e.g., decreased B cells, defects in number and function of CD4+ T cells, increased number of nonspecific suppressor cells,
impaired antibody production against specific antigens).
Thrombocytopenia.
Skin changes resemble lichen planus and, later, scleroderma.
Biopsy shows changes in affected organs.
In a recent report serum catalase showed sensitivity of 100%, specificity of 88% compared to 88% and 28%, respectively, for 5'-NT. 7
GRANULOMATOUS DISEASE, CHRONIC
(Rare heterogeneous disorder characterized by chronic recurrent suppurative infections by catalase-positive organisms [e.g., S. aureus, Aspergillus spp.;
also seen frequently are Serratia marcescens, Pseudomonas cepacia, Klebsiella spp., Escherichia coli, Nocardia, Chromobacterium violaceum], which
usually have low virulence [e.g., Salmonella, Candida albicans]. Due to abnormality of nicotinamide-adenine dinucleotide phosphate oxidase system,
PMNs and monocytes ingest normally but fail to kill certain bacteria and fungi; ~60% are X-linked membrane abnormalities, ~40% due to autosomal
recessive inheritance (most are cytosol abnormalities), 5% are membrane abnormalities, <1% due to autosomal dominant inheritance.)
wFailure of these cells to reduce nitroblue tetrazolium to purple formazan on slide test provides a simple rapid diagnosis in patients and in heterozygotes for the
X-linked form (carriers). Nitroblue tetrazolium test now replaced by flow cytometry respiratory burst assay.
wOther confirmatory tests in reference laboratory for absent (or severely reduced) production of oxygen radicals include measurement of oxygen consumption,
hydrogen peroxide or superoxide production, and chemiluminescence of phagocytes.
wPrenatal diagnosis has been established using nitroblue tetrazolium test on fetal blood leukocytes. Fetal DNA from chorionic villus or amniocytes can also be
analyzed for specific mutation.
WBCs show morphologically normal appearance and granules on routine Wright's- and Giemsa-stained smears.
Serum complement and immunoglobulin levels are normal.
Laboratory findings due to infection (leukocytosis, anemia, increased ESR, elevated gamma globulin levels)
Laboratory findings due to abscesses of lung, liver, osteomyelitis
Laboratory findings due to granulomas causing obstruction (e.g., GI tract, GU tract)
HEAVY-CHAIN DISEASES
Gamma
(Rare disorder with excessive production of heavy-chain proteins, producing homogeneous serum and/or urine protein spike)
wSerum protein electrophoresis/immunofixation
Monoclonal gamma heavy chain in serum, which may be broad or hypogammaglobulinemia.
Localized spikes or bands may be absent.
Normal immunoglobulins are usually decreased. Gamma globulin almost absent.
Serum tests
Normal level of total serum protein but increased globulin (>2 gm/dL) and decreased albumin.
Increased uric acid (>8.5 mg/dL).
Increased BUN (30–50 mg/dL).
Urine tests
Trace to 1+ protein (0.5–20 gm/day).
Negative for Bence Jones protein.
Gamma heavy chain identical to that of abnormal serum protein varies from undetectable to 20 gm/day (usually <1 gm).
Hematologic findings
Normocytic, normochromic anemia (usually Coombs'-positive autoimmune hemolytic), leukopenia, and thrombocytopenia common (probably due to
hypersplenism).
Eosinophilia sometimes marked; relative lymphocytosis.
Vacuolated mononuclear cells sometimes seen.
Bone marrow and lymph nodes contain increased numbers of plasma cells, lymphocytes, and many atypical lymphoplasmacytoid cells. In terminal phase is
similar to plasma cell leukemia.
mHistologic findings of associated lymphoma, e.g., extranodal non-Hodgkin's lymphoma in ~75% of cases. ~50% of cases were preceded by or associated with
neoplasias (e.g., lymphoma, leukemia, carcinoma), autoimmune disorders (especially RA), or other disorders (e.g., infections, hypogammaglobulinemia, Down
syndrome)
Marked susceptibility to bacterial infection.
Mu
(Usually associated with CLL or a lymphoma)
wDiagnostic Criteria
Serum protein electrophoresis immunofixation shows monoclonal Mu heavy chain.
Hypogammaglobulinemia with a monoclonal peak in 40% of patients.
Bence Jones proteinuria in two-thirds of patients; most excrete large amounts of kappa light chains.
Bone marrow shows vacuolated plasma cells.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-255-320.jpg)
![HbE–Beta-Thalassemia
Is most common symptomatic thalassemia in Southeast Asia.
mHemolytic anemia varies in severity from moderate to marked (thalassemia major or intermedia phenotype).
mSmear shows severe hypochromia and microcytosis, marked anisopoikilocytosis with many teardrop and target forms. Nucleated RBCs and basophilic stippling may
be present.
HbE–Alpha-Thalassemia
Analogous to alpha-thalassemia 1 and 2 and HbH
In American blacks, 28% have mild alpha-thalassemia without microcytosis, 3% have homozygotic alpha-thalassemia with microcytosis, 1% have microcytosis due to
beta-thalassemia. Median Hb is ~ 1 gm/dL lower in blacks without iron deficiency than in whites.
Alpha- or beta-thalassemia or HbE occur in ~50% of Southeast Asians and causes microcytosis.
HEMOGLOBIN F (HbF), HEREDITARY PERSISTENCE
Inherited persistence of increased HbF in adult without clinical manifestations due to many different genetic lesions (probably autosomal dominant). Incidence is
<0.2%.
Decreased MCV and MCHC
wHb electrophoresis shows increased HbF (20–30%) and 60–70% HbA.
wMay be pancellular (HbF is increased in all RBCs) or heterocellular (HbF is increased only in some RBCs), as distinguished by Kleihauer-Betke stain of peripheral
blood smear.
May be associated with other hemoglobinopathies but is different from the increase of HbF that is found in some hemoglobinopathies.
HEMOGLOBINOPATHIES, LABORATORY SCREENING
Normocytic normochromic RBC except in
Thalassemia syndromes—microcytic hypochromic
HbC, HbD, HbE diseases—microcytic normochromic
Osmotic fragility—normal or decreased (especially in thalassemia)
Symmetric shift in HbC, HbD, HbE, diseases
Asymmetric shift in other hemoglobin diseases
Target cells—in many of hemolytic diseases due to hemoglobinopathies; 50% of RBCs in HbC, HbD, HbE diseases
Sickle cell test (Hb solubility test may be negative with <10% HbS; or monoclonal antibody test)—recognizes HbS
Supravital stain (e.g., brilliant cresyl blue test for inclusion bodies [Heinz bodies])—these Heinz bodies may confirm suspicion of alpha-thalassemia minor in patient
with microcytic anemia with normal Hb electrophoresis.
Hb electrophoresis
Distinguish sickle cell anemia and trait.
Usually cellulose acetate at alkaline pH confirmed by agar at acid pH or isoelectric focusing.
Electrophoresis of separated globin chains can substantiate alpha-chain abnormality.
Distinguish various types of Hb.
Alkali denaturation for HbF
Kleihauer-Betke stain of blood smear identifies RBCs containing HbF.
Flow cytometry
Isopropanol precipitation test screen for unstable hemoglobins, which may not be detected on routine electrophoresis because they migrate with HbA.
wReference laboratory tests
Measurement of globin-chain synthesis ratios for confirmation of alpha- and beta-thalassemias.
DNA analysis can detect gene deletions and point mutations, which disclose most types of alpha- and beta-thalassemia).
Prenatal diagnosis during first trimester using DNA from chorionic villi or, after 16th week, from fetal cells by amniocentesis.
HEMOGLOBINS, UNSTABLE
(E.g., Hb Koln, Hb Zurich)
Usually autosomal dominant inheritance
mLaboratory evidence of episodes of hemolytic anemia of varying degrees of severity precipitated by infection or drugs (e.g., antimalarials, sulfonamides, acetanilid,
nitrofurantoin, nalidixic acid, toluidine blue)
Peripheral blood smear shows hypochromia, macrocytosis, anisocytosis, poikilocytosis, increased reticulocytes
Supravital stain shows preexistent Heinz bodies (precipitation of abnormal Hb); may be few or absent if spleen is present.
Excess precipitation of Hb at 37°C in 17% isopropanol compared to normal.
Hb electrophoresis is often normal.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-257-320.jpg)
![Most patients have some preexisting liver disease.
Amniocentesis, Indications
Prior immunized pregnancy with maternal antibody titer >1:8 in albumin
History of hemolytic disease of newborn
After the first amniocentesis at 24th week, repeat every 2–3 wks to measure presence and increase in bilirubin pigments; the rise in these pigments according to age
of fetus correlates with severity of disease and is indication for intrauterine transfusion, repeat examination, or immediate delivery. Lecithin/sphingomyelin ratio should
also be measured to determine pulmonary maturity (see Chapter 14).
ABO hemolytic disease alone does not cause fetal loss and therefore is not an indication for amniocentesis.
Indications for Selection of Patients for Immunosuppression of Rh Sensitization 10
(Passive immunization using RhIg anti-D, which should be administered within hours of delivery. Less protective for £13 days.)
Nonimmunized mother must be RhO. (D) negative and weak D (D+W [formerly Du
.]) negative regardless of ABO blood group. 1.8% of Rh-negative women become
sensitized late in pregnancy.
D+W women are classified as Rh positive and are not considered at risk for Rh immunization.
Other indications (unless the father or fetus is known and documented to be Rh negative) (because of prenatal typing errors £3%) include:
Abortion (spontaneous, therapeutic, threatened)
Abruptio placentae
Abdominal trauma during pregnancy
Administration of whole blood, RBCs, granulocytes, or platelet concentrates from Rh-positive donors to Rh-negative patients of childbearing age
Amniocentesis
Ectopic pregnancy
External cephalic version
Chorionic villus sampling
Death in utero
Manual removal of placenta
Percutaneous umbilical blood sampling
Placenta previa
Trophoblastic disease or neoplasm (not complete hydatiform mole)
Tubal ligation
Immune thrombocytopenic purpura
Whenever a positive D+W test is found in a woman known to be D+W negative before delivery, the postpartum blood should be tested to confirm fetal-maternal
hemorrhage and to quantify the volume of fetal cells in maternal circulation.
Maternal serum must have no Rh antibodies. If antenatal RhIg has been administered, mother's postpartum serum will contain anti-D (usually weakly reactive [direct
antiglobulin test] low titer [£4]), which does not indicate existing immunization, and she should receive postpartum immunoprophylaxis.
Baby must be RhO (D) positive or D+W positive and have negative direct Coombs' test (cord blood).
Protocol to determine postpartum candidacy for RhIg administration:
Test mother to determine if she is Rh negative; do not perform D+W test.
If mother is Rh negative, test cord RBCs; if these are Rh positive or D+W positive, mother is a candidate. Even if baby (cord RBCs) is Rh O negative, D+W typing
is still necessary as D+W–positive cord RBCs can cause Rh sensitization.
Quantitate fetal-maternal hemorrhage to determine dose of RhIg. Use microscopic D+W test for routine screening to detect Rh-positive fetal cells; detects
fetal-maternal hemorrhage of ~35 mL of fetal blood in a woman of average size. This is often omitted due to difficulty in reading test and low predictive value of
positive test.
RhIg half-life is 21–30 days (standard dose). Thus most women have positive antibody screen. Records must be kept of antenatal RhIg to avoid classifying this as
active immunization.
Erythroblastosis, ABO
ABO incompatibility causes approximately two-thirds of cases; Rh incompatibility causes less than one-third of cases, and the latter are more severe. Minor blood
factors (e.g., c, E, Kell) cause 2% of cases.
wMother is group O with group A1 or B infant; rarely is mother group A2 with group A1 or B infant.
wInfant's serum shows positive indirect Coombs' test with adult RBCs of same group varying up to moderately positive, but positive test is not dependable.
Infant's RBCs show a negative direct Coombs' test (by standard methods) due to antibody derived from mother that has crossed placenta.
Both Coombs' reactions have disappeared after the fourth day.
Marked microspherocytosis is present.
Osmotic fragility is increased.
Anti-A or anti-B titer in mother's serum is not useful because no correlation exists between the occurrence of hemolytic disease and the presence or height of the titer.
If mother's serum does not hemolyze RBCs of same type as infant's, the diagnosis should be questioned.
Rapidly developing anemia is rare; serial bilirubin determinations are indicators for exchange transfusion to prevent a level of 20 mg/dL. Infants may show jaundice in
first 24 hrs but rarely require exchange transfusion for anemia or hyperbilirubinemia.
For exchange transfusion, use group O, Rh-type–specific blood or group O, Rh-negative blood.
Infants born subsequently to same parents do not have more serious disease, and they may have less serious disease.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-262-320.jpg)
![Metabolic disorders (e.g., uremia, malnutrition, diabetes mellitus)
Protein deficiency (e.g., nephrotic syndrome)
Immunosuppression (e.g., drugs, neoplasms, splenectomy)
Respiratory tract disorders
Anatomic (e.g., tracheoesophageal fistula, cleft palate, gastroesophageal reflux
Other (e.g., cystic fibrosis, immotile cilia, allergy)
Prematurity
IMMUNODEFICIENCY, SCREENING TESTS
See Fig. 11-8 and Table 11-17.
Fig. 11-8. Algorithm for workup of recurrent infections. (G-6-PD = glucose-6-phosphate dehydrogenase; hyper-IgE = hyperimmunoglobulinemia E; Ig =
immunoglobulin; NBT = nitroblue tetrazolium.)
Cell mediated
HIV serology.
Total lymphocyte count (lymphopenia usually indicates T-cell dysfunction because most circulating lymphocytes are T cells).
T lymphocyte subsets. T cell–deficient patients tend to have chronic recurrent Candida infection of scalp, nails, mucous membranes.
Anergy skin tests (purified protein derivative [tuberculin], Candida).
B-cell deficiency should be suspected with recurrent, complicated, or severe pyogenic infections.
Humoral immunity
Antibody defects
Serum IgG, IgM, IgA, anti-A, anti-B isohemagglutinins
Serum IgG antibody titers before and after vaccinations (e.g., diphtheria, tetanus, Pneumococcus, H. influenzae type b)
Complement defects
CH50
C1-4 deficiencies associated with pyogenic infections and autoimmunity
C3, C5-9 deficiencies associated with neisserial infections
Phagocyte defects
WBC and differential counts
Serum IgE
Nitroblue tetrazolium test now replaced by flow cytometry respiratory burst assay
IMMUNOGLOBULIN A (IgA) DEFICIENCY, SELECTIVE
(Immunodeficiency syndrome with lack of IgA-producing cells in intestinal lamina propria)
See Table 11-6 and Table 11-7.
wSerum IgA is very low (<5 mg/dL).
wSerum IgM and IgG are usually normal.
Serum antibodies to IgA in >40% of patients; therefore IV or IM blood products that contain IgA (e.g., immune serum globulin) are contraindicated.
Peripheral blood lymphocytes bearing IgA, IgM, and IgG are normal.
Plasma cells producing IgA are absent in GI and respiratory epithelium.
Clinical—asymptomatic or recurrent pyogenic respiratory infections; increased incidence of allergic disease (e.g., asthma, eczema), autoimmune diseases (e.g., RA,
SLE), GI complications (e.g., celiac disease, malabsorption, chronic giardiasis). Found in >1 in 400 persons in general population.
IRRADIATION, HEMATOLOGIC EFFECTS](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-267-320.jpg)
![patients.
Urine lysozyme may be increased in acute nonlymphocytic leukemia (M4 and M5).
wLaboratory findings due to complications
Meningeal leukemia occurs in 25–50% of children and 10–20% of adults with acute leukemia; CSF shows pleocytosis and increased pressure and LD. CSF
should be examined routinely as “sanctuary” for leukemic cells during chemotherapy and to rule out occult infection. Cranial irradiation may be indicated if
leukemic cells in CSF, WBC ³100,000/cu mm, or Ph1
chromosome is present.
With large leukemic cell burden, hyperuricemia (may have urate nephropathy), hyperkalemia, hyperphosphatemia with secondary hypocalcemia are common.
Infection causes 90% of deaths. Most important pathogens are enteric gram-negative rods (especially Pseudomonas aeruginosa, E. coli) and S. aureus. With
cumulative immunosuppression, fungi (especially C. albicans), viruses (especially VZV and other herpesviruses), and P. carinii.
Hemolytic anemia.
Laboratory findings due to predisposing conditions
Inherited syndromes
Genetic (e.g., Down syndrome, Bloom's syndrome, Klinefelter's syndrome, Fanconi's anemia)
Immunodeficiency (e.g., ataxia-telangiectasia, common variable immunodeficiency, severe combined immunodeficiency, Wiskott-Aldrich syndrome)
Ionizing radiation (therapeutic or accidental)
Chemotherapeutic drugs (e.g., alkylating agents)
Toxins (e.g., benzene)
Complete remission is possible with drug therapy (e.g., prednisone in ALL).
WBC falls (or rises) to normal in 1–2 wks with replacement of lymphoblasts by normal PMNs and return of RBC and platelet counts to normal; bone marrow may
become normal. Maximum improvement in 6–8 wks.
Laboratory findings due to toxic effect of therapeutic agents
Amethopterin toxicity causes a macrocytic type of anemia with megaloblasts in marrow, rather than blast cells in marrow as with leukemic normocytic anemia.
Cyclophosphamide can cause hematuria.
L-Asparaginase can cause coagulopathies, hyperglycemia, etc.
Daunorubicin can cause cardiac toxicity with fibrosis.
In childhood ALL, 7× increase in all cancers and 22× increase in CNS tumors.
LEUKEMIA, HAIRY CELL (LEUKEMIC RETICULOENDOTHELIOSIS)
(Rare condition of splenomegaly and infrequent lymphadenopathy with characteristic pathologic changes in marrow and spleen)
wDiagnosis is established by finding the characteristic mononuclear cells (that show long delicate cytoplasmic projections) in the peripheral blood (vary from
0%–90%) or bone marrow, which show a characteristic diffuse intense histochemical reaction of tartrate-resistant acid phosphatase (isoenzyme 5) activity (mild to
moderate staining of leukocytes may be seen in Sézary syndrome, CLL, infectious mononucleosis, and in various histiocytes). Cells bear B lymphocyte markers.
Isoenzyme 5 may also be increased in the serum. Hairy cells increased to frankly leukemic levels in £ 20% of cases.
Hypersplenism with pancytopenia in >50% of cases
Thrombocytopenia (in 75% of cases), usually <80,000/cu mm
Anemia (usually normochromic), usually 7–10 gm/dL
Leukopenia (in >60% of cases), usually <4000/cu mm
Abnormal platelet function may be found.
ESR may be increased.
wBone marrow reticulin fibrosis causes dry tap requiring core biopsy; hairy cells are readily seen.
Leukocyte ALP activity is markedly increased in some patients.
Laboratory findings due to infection (e.g., pyogenic bacteria, opportunistic organisms)
LEUKEMIA, LYMPHOBLASTIC, ACUTE (ALL)
Primarily affects children; comprises >85% of childhood leukemias. Children with Down syndrome have 15× higher incidence of leukemia (especially ALL). Increased
incidence also in immunodeficiency syndromes (e.g., ataxia-telangiectasia), osteogenesis imperfecta, Poland's syndrome, and sibs of ALL patients. High relapse rate.
In adults, 80% of ALL cases are B-cell and 20% are T-cell lineage.
Classified as L-1, L-2, L-3 (French-American-British [FAB] classification system) based on cell morphology; cannot be differentiated by cytochemical stains. ~25% of
cells in L-1 and L-2 have T-cell antigens; rest are null cells (B-lineage ALL that lack CD10 expression). L-3 cells usually have B-cell (Burkitt's) antigens. L-1 is more
common in childhood ALL and L-2 is more common in adult ALL.
wWBC increased; may be >100,000/cu mm but normal or low in some patients. Moderate to severe thrombocytopenia.
Variable degree of anemia.
wMarrow usually shows >50% lymphoblasts.
mHigh incidence of meningeal involvement; CSF may show increased protein and cells (some recognized as leukemic).
mPh1
chromosome is present in ~20% of adults and <5% of children. Uniformly poor prognostic sign. Most commonly in non–T-cell, non–B-cell ALL; never in T-cell
ALL.
Serum LD, uric acid, ESR often increased.
LEUKEMIA, LYMPHOCYTIC, CHRONIC (CLL)
(30% of all leukemias in United States; <5% are T-cell type)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-269-320.jpg)
![Fig. 11-9. Transformation of myeloproliferative syndromes. (CML = chronic myelogenous leukemia.)
Types of chronic myeloid leukemias
Chronic myelogenous leukemia
Chronic myelomonocytic leukemia
Mast cell leukemia (rare)
Chronic monocytic leukemia (rare)
Chronic eosinophilic leukemia (rare)
Classified into chronic, accelerated, and blast crisis phases.
Chronic Phase
wWBC is usually 50,000–300,000/cu mm when disease is discovered, predominantly neutrophils and myelocytes with no leukemic hiatus. In earlier stages the more
mature forms predominate, with sequentially fewer younger forms and only an occasional blast cell; later the younger cells predominate.
Absolute basophilia is invariably present; may precede clinical symptoms by many years.
Eosinophilia may be present but has less diagnostic utility than basophilia.
Absolute monocytosis but relative monocytopenia is typical.
Lymphocytes are normal in absolute number but relatively decreased.
Decreased leukocyte ALP score in 95% of untreated cases. Leukocyte ALP score can rise to normal or high levels with infection, inflammation, or secondary
malignant disease, after splenectomy, during remission due to chemotherapy, or at onset of blast crisis.
mAnemia is usually normochromic, normocytic; absent in early stage and severe in late stage. Blood smear shows few normoblasts, slight polychromatophilia,
occasional stippling. Reticulocyte count is usually <3%. Anemia is due to myelophthisis; also due to bleeding (skin and GI tract), hemolysis, and insufficient
compensatory hematopoiesis. Degree of anemia is a good index of extent of leukemic process and therefore of prognosis.
mPlatelet count is increased in 30–50% of cases; may be normal; decreased in terminal stages with findings of thrombocytopenic purpura. Low count may increase
with therapy. Bleeding manifestations are usually due to thrombocytopenia. Megakaryocytes in blood in ~25% of cases.
wBone marrow
Hyperplasia of granulocytic elements occurs, with increase in myeloid/erythroid ratio. Myeloblasts <5% of all cells initially.
Granulocytes are more immature than in the peripheral blood.
Number of eosinophils and basophils is increased.
Megakaryocytes may be increased.
Hemosiderin deposits are increased.
Focal or diffuse reticulin fibrosis in approximately one-third of cases.
Macrophages (pseudo-Gaucher's cells) in approximately one-third of cases.
wPhiladelphia chromosome t(9;22)(q34q11)(Ph1
) due to chimeric bcr-abl gene on chromosome 22 is found in 95% of early chronic-phase cases; persists in chronic
stable phase when marrow and blood appear normal. Presence of Ph1
affects response to therapy and survival. Persists during blast phase when additional
abnormalities may appear in £ 8% of cases (e.g., chronic myelomonocytic leukemias). Other cytogenic abnormalities occur in one-third of the 5% of patients who are
Ph1
-negative. Ph1
chromosome has also been found in ~20% of adults with ALL, 2% of adults with AML, 5% of children with ALL. Ph 1
chromosome in acute leukemia
indicates a poor prognosis. Ph1
is present in granulomonocytic, erythroid, and megakaryocytic lines as well as some B lymphocytes. If karyotyping is negative, Ph 1
may be revealed by Southern blot, fluorescence in situ hybridization, or RT-PCR, which are more sensitive. PCR can detect 1 Ph 1
-positive cell in 105
to 106
normal
cells.
Needle aspiration of spleen
Number of immature leukocytes is increased.
Normoblastosis is present.
Megakaryopoiesis is increased.
Serum and urine uric acid are increased, especially with high WBC and antileukemic therapy. Urinary obstruction may develop because of intrarenal and extrarenal
uric acid crystallization.
Serum LD is increased; rises several weeks before relapse and falls several weeks before remission. LD is useful for following course of therapy.
Increased serum AST and ALT show less increase than in acute leukemia; are normal in half of patients.
Serum protein electrophoresis shows decreased albumin with increased alpha and gamma globulins.
Direct Coombs' test is positive in £ 20% of patients at some time in course of disease; overt hemolysis in ~25% of these patients.
Laboratory findings due to leukemic infiltration of organs (e.g., kidney [hematuria common; uremia rare], heart, liver). With increasing survival in blast crisis,
meningeal leukemia has become more frequent (up to 40%) with leukemic cells in CSF indicative of need for intrathecal chemotherapy.
Serum vitamin B12 level is increased (often >1000 µg/mL); B12-binding capacity is increased.
Peripheral blood remission due to drugs–decreased WBC to nearly normal levels (decrease in spleen size is usually parallel) with only rare immature cells, correction
of anemia, control of thrombocytosis, and occasional rise of LAP score to normal; marrow continues to show granulocytic hyperplasia and Ph 1
chromosome.
Thyroid uptake of radioactive iodine is normal.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-271-320.jpg)
![Accelerated Phase
(Experienced by ~50% of patients before a blast crisis)
wCombination of various criteria described in literature
Rapidly increasing WBC (>50,000/cu mm) (doubling time <5 days) showing increasing immaturity and increased number of blasts (>5–15% in marrow, >15% in
blood), basophilia (>10% in marrow, >20% in blood).
Hb <7.0 g/dL not due to therapy.
Platelets <100,000/cu mm not due to therapy or >1 million/cu mm despite therapy.
Increased leukocyte ALP score.
New karyotypic abnormalities (e.g., trisomy 8, trisomy 18, additional Ph 1
chromosomes).
Myelofibrosis in some cases.
Associated with clinical symptoms.
Increasing doses of drugs are needed to lower neutrophil count.
Blast Crisis
(Occurs abruptly without an accelerated phase in 50% of cases)
wDiagnosed by >30% blasts in marrow or peripheral blood or extramedullary proliferation of blasts (chloroma), or large foci of blasts in bone marrow biopsy.
Approximately one-third of patients with CML in blast crisis have lymphoid transformation (cells show morphologic, antigenic, enzymatic [TdT], and other lymphoid
characteristics). Patients are increasingly refractory to therapy in blast phase and die of acute leukemia or complications in 3–6 mos.
Platelet count <15,000 or >1 million/cu mm, blasts in peripheral blood, absence of Ph 1
, and moderate to marked myelofibrosis at time of diagnosis are poor prognostic
signs. WBC <25,000/cu mm or Hb >14 gm/dL are good prognostic signs.
Juvenile Chronic Myelogenous Leukemia14
Differs from adult CML
Aggressive disease.
95% of patients are <4 yrs old.
Leukocytosis (usually <100,000/cu mm) with absolute monocytosis (>450/cu mm).
Immature myeloid cells in peripheral blood in >70% of cases.
<25% marrow blasts.
Absent Ph1
.
Increased HbF (typically 20–80%); is only leukemia with this increase.
Lymphadenopathy in 20% of cases.
Skin involvement with monocytic infiltrate is very common; may be preceded by neurofibromatosis.
Viral studies (CMV, EBV, rubella) are usually negative.
Leukocyte ALP is not useful; may be normal, low, or increased.
LEUKEMIA, PLASMA CELL
wWBC usually >15,000, with >20% plasma cells or >2000/cu mm in peripheral blood varying from typical plasmacytes to immature and atypical forms; absolute
plasma cell count >2000/cu mm. Occasionally, special studies (cytochemical stains, cell surface and cytoplasmic markers, electron microscopy) are needed to
confirm identity of plasma cells.
wPlasma cell monoclonality.
~60% of cases are primary and the rest occur in 2% of previously diagnosed cases of multiple myeloma. Primary cases have smaller M protein peak in serum, higher
platelet count, younger age, and longer survival.
Other findings (see Myeloma, Multiple)
LEUKEMIA, PROLYMPHOCYTIC
(Rare variant of CLL; may occur de novo or from CLL)
Compared to CLL, is characterized by more rapid clinical course, poorer prognosis, slightly older patient age, larger spleen, less frequent lymphadenopathy, higher
prolymphocyte count (>55%), and immunologic differences (mouse erythrocytes, rosettes, surface immunoglobulin staining).
WBC >100,000/cu mm in 65% of patients.
~80% are B-cell and 20% are T-cell type, which show different chromosomal abnormalities.
LEUKEMIA, RISK FACTORS
Ionizing radiation
Oncogenic viruses
Chemical agents (e.g., benzene compounds)
Genetic disorders (e.g., trisomy 21, Fanconi's syndrome, Bloom's syndrome, ataxia-telangiectasia)
Advanced maternal age
LEUKEMIAS, NONLYMPHOCYTIC, ACUTE15,16
wFrench-American-British (FAB) Classification
Has 85% concordance. Based on morphology and cytochemistry. Advances in immunophenotyping and cytogenetics provide additional essential information.
M-1, M-2, M-3 leukemias are predominantly granulocytic.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-272-320.jpg)
![M-0 Acute Myelogenous Leukemia
Incidence: ~5% of AML cases
³ 30% blasts
Minimal differentiation.
M-1 Acute Myeloid Leukemia with Minimal Maturation
Incidence: 20% of AML cases
>90% of nonerythroid nucleated cells are blasts, predominantly type 1.
<10% of nonerythroid nucleated cells are of maturing granulocytic lineage. Occasional Auer rods may be present
M-2 Acute Nonlymphocytic Leukemia with t(8;21)
Incidence: 30% of AML cases
Patient age: young (mean = 28 yrs)
Clinical findings: splenomegaly in 28%; chloromas, especially of face area, in 20%
Morphology: myeloblasts often with Auer rods (90%) are heterogeneous, hypogranular, and frequently show pseudo-Pelger-Huët abnormalities. Sum of type I and II
blast cells is 30–89% of nonerythroid cells (differs from M-1 in which the sum of type I and II blast cells is >90% of nonerythroid cells and ³ 3% of these are peroxidase
or Sudan black positive); monocytic cells are <20%; granulocytes from promyelocytes to polynuclear types are >10%. Maturation toward granulocytes is often
abnormal; eosinophil precursors are frequently increased and may contain Auer rods.
Histochemistry: cells contain granulocyte but not monocyte enzymes; Sudan black and myeloperoxidase is abnormal (punctate rather than diffuse).
Karyotype: t(8;21)(q22;q22); critical region 21q translocated to 8q; frequent loss of sex chromosome. Increased predilection for this leukemia in Down syndrome
(trisomy 21).
Oncogenes: c-ets-2 translocates from 21q to 8q but expression data for the gene are unknown; c- mos remains at 8q and c-myc translocates to 21q but both are
probably not important.
Prognosis: 75–85% complete remission rate after chemotherapy but median survival (9.5 mos) is of average duration.
M-3 Acute Promyelocytic Leukemia
Incidence: 10% of AML cases
Patient age: median of 31 yrs
Clinical findings: typically present with bleeding diathesis; £ 47% die of early fatal hemorrhage. DIC in £ 80% of cases.
Morphology: <30% blasts in most cases. Predominantly neoplastic promyelocytes with coarse azurophilic granules and multiple Auer rods; a variant ( M-3V is ~30% of
M-3 cases) shows hypo/microgranular promyelocytes on electron microscopy. Leukemic cell count in peripheral blood is usually not high (5000–15,000/cu mm).
Unusual feature: blast cells occasionally can be induced to differentiate into mature granulocytes or macrophages by various agents.
Karyotype: t(15;17)(q22;q12) occurs frequently.
Oncogene: none known
M-4 Acute Myelomonocytic Leukemia
Incidence: 25% of AML cases
Marrow morphology: ³ 30% of nonerythroid nucleated cells are myelomonocytic blasts; 2–80% of these are of granulocytic lineage and 20–80% are of monocytic
lineage. Peripheral blood typically shows myelomonocytic blasts and >500/cu mm monocytes; serum lysozyme is often elevated.
A variant (M-4Eo) shows 1–30% abnormal eosinophils (precursors).
Histochemistry: very weak staining for nonspecific esterase; can be distinguished from granulocytic types by monoclonal antibodies demonstrating specific antigens.
Karyotype: almost all patients show inversion of chromosome 16 [inv(16)(p13;q22)]; <10% show balanced translocation between short arm of one chromosome 16
and long arm of other chromosome 16 [t(16;16)(p13.1;q22)].
Oncogene: unknown
Molecular oncology: disruption of metallothionein genes by the chromosomal abnormality
Prognosis: 70–90% complete remission rate, probably with prolonged median duration (>18 mos). More than one-third have relapse in CNS including myeloblastomas
(compared with 5% of all patients with acute nonlymphocytic leukemia, who rarely show CNS myeloblastomas).
M-5 Acute Monocytic Leukemia with t(9;11)
Incidence: 10% of acute monoblastic leukemia patients
Patient age: often children and young adults
Clinical findings: leukemic cells may infiltrate skin or gums; serum lysozyme is often elevated.
Morphology: >30% of nonerythroid nucleated cells are blasts; >80% are of monocytic lineage. Can be distinguished from granulocytic types by monoclonal antibodies](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-273-320.jpg)
![w•Dysmegakaryocytopoiesis.
Increased or decreased number.
Atypical, bizarre, or giant platelets, often with giant abnormal granules, are seen in most cases. Marrow megakaryocytes are often atypical or bizarre.
Platelet function defects with prolonged BT and aggregation abnormalities are very common.
Other clinicopathologic forms include refractory anemias of various types, pure red cell aplasia, paroxysmal nocturnal hemoglobinuria, chronic idiopathic
neutropenia, chronic idiopathic thrombocytopenia, etc.
Low granulocyte or platelet count or elevated bone marrow blast count are independent indicators of poor outcome. 5q– karyotype is often found in refractory anemia
and carries a relatively good prognosis. Monosomy 7 and trisomy 8 are frequently found in other subclasses of myelodysplasia and are associated with poor
prognosis.
Poor prognosis is indicated by (in decreasing order of importance) >5% blasts in marrow, circulating blasts, abnormal karyotypes, granulocytopenia (<1000/cu mL),
monocytopenia, thrombocytopenia (<140,000/cu mL), ineffective erythropoiesis, presenting Hb of <9.0 gm/dL, hemolysis, <20% ringed sideroblasts in marrow,
abnormal localization of blasts in center of marrow rather than in subendostial areas, circulating CD34 +
cells.
MYELOMA, MULTIPLE
See Table 11-22, Table 11-23 and Table 11-24.
Table 11-22. Comparison of Diseases with Monoclonal Immunoglobulins
Table 11-23. Immunochemical Frequency of Monoclonal Gammopathies
Table 11-24. Comparison of Immunoproliferative Disorders
w Diagnostic Criteria
Bone marrow shows sheets or >20% plasma cells and
Abnormality of immunoglobulin formation (monoclonal spike >4 gm/dL or Bence Jones proteinuria >0.5 gm/24 hrs)
If monoclonal spike is <4 gm/dL, then substitute criteria:
Reciprocal depression of normal immunoglobulins or
Panhypogammaglobulinemia and osteolytic bone lesions or
Plasmacytosis not due to other causes (see Plasma Cells)
Very increased serum total protein is due to increase in globulins (with decreased albumin/globulin ratio [A/G]) in one-half to two-thirds of the patients.
Serum protein immunoelectrophoresis or immunofixation characterizes protein as monoclonal (i.e., one light-chain type) and classifies disease by identifying specific
heavy chain. It reveals abnormal immunoglobulins in 80% of patients. A serum or urine monoclonal paraprotein can be identified in £99% of patients with multiple
myeloma.
Percent of Patients Immunoelectrophoresis or Immunofixation Shows
£99% Monoclonal protein in serum or urine
90% Serum monoclonal spike
20% Both serum and urine monoclonal protein
20% Monoclonal light chains in urine only
<2% Hypogammaglobulinemia only without serum or urine paraprotein](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-280-320.jpg)
![Findings of secondary polycythemia (e.g., decreased oxygen saturation) are not present (see next section).
Serum erythropoietin is normal.
Leukocyte ALP score is normal or mildly increased.
Bone marrow shows normal cellularity and megakaryocyte count; no myelofibrosis; iron may be absent.
Hypercholesterolemia is frequent.
Laboratory findings due to complications (e.g., thromboembolism)
POLYCYTHEMIA, SECONDARY
mDiagnosis is suggested by erythrocytosis without increased WBC, platelets, or splenomegaly; causes listed below should be sought.
Hct is slightly increased.
Leukocyte ALP score is normal or slightly increased.
Increased plasma cholesterol is frequent.
Serum erythropoietin is usually increased or normal.
Due To
Physiologically Appropriate
Hypoxia with decreased arterial oxygen saturation
Decreased atmospheric pressure (e.g., high altitudes).
Chronic heart disease.
Congenital (e.g., pulmonary stenosis, septal defect, patent ductus arteriosus)
Acquired (e.g., chronic rheumatic mitral disease)
Arteriovenous aneurysm.
Impaired pulmonary ventilation.
Alveolar-capillary block (e.g., Hamman-Rich syndrome, sarcoidosis, lymphangitic cancer).
Alveolar hypoventilation (e.g., bronchial asthma, kyphoscoliosis).
Restriction of pulmonary vascular bed (e.g., primary pulmonary hypertension, mitral stenosis, chronic pulmonary emboli, emphysema).
Abnormal hemoglobin pigments (methemoglobinemia or sulfhemoglobinemia due to chemicals, such as aniline and coal tar derivatives) or high-oxygen-affinity
hemoglobinopathies (50% of hemoglobinopathy cases show an abnormality on standard Hb electrophoresis). ( Hb oxygen affinity [P50] is the oxygen tension at
which Hb becomes 50% saturated. Normal = 27.5 mm Hg. Usually <20 mm Hg in these conditions. Decreased P50 indicates increased oxygen affinity and
increased P50 indicates decreased oxygen affinity. May be increased by high-affinity hemoglobinopathies, carboxyhemoglobinemia, decreased RBC
2,3-diphosphoglycerate, alkalosis. May be decreased by hemoglobinopathies, increased RBC 2,3-diphosphoglycerate, acidosis.) Carboxyhemoglobinemia
(“smoker's erythrocytosis”) can be detected by oximetry but not from P50.
Physiologically Inappropriate
Increased erythropoietin secretion, e.g.,
Associated with tumors and miscellaneous conditions (may be first sign of an occult curable tumor)
Renal disease (hypernephroma, benign tumors, hydronephrosis, cysts, renal artery stenosis, long-term hemodialysis; occurs in up to 5% of renal cell
carcinomas; occurs in £17% of kidney transplant recipients)
Hemangioblastoma of cerebellum (occurs in 15–20% of cases)
Uterine fibromyoma
Hepatocellular carcinoma (5–10% of cases)
Others
Increased androgen
Pheochromocytoma
Cushing's syndrome (adrenocortical hyperplasia or tumor)
Masculinizing ovarian tumor (e.g., arrhenoblastoma)
Factitious (use of androgens by athletes)
POLYCYTHEMIA VERA
See Table 11-25, Fig. 11-9 and Fig. 11-10.
Table 11-25. Comparison of Polycythemia Vera, Secondary Polycythemia, and Ralative Polycythemia](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-284-320.jpg)
![Hematuria without any other demonstrable cause may be found.
Hyposthenuria may occur.
Sickle cells are found postmortem regardless of cause of death.
Sickle Cell Anemia
(Homozygous HbSS disease; occurs in 1 in 625 American blacks)
wHb electrophoresis: HbS is 80–100%, and HbF comprises the rest (see Hemoglobin, Fetal); HbA is absent.
wSickle cell preparation is positive; because other Hb variants migrate with HbS on electrophoresis, confirming Hb as a sickle type is important. Sickle solubility test is
positive but does not differentiate anemia from other HbS genetic variants and may be falsely negative if Hb <5 g/dL.
wBlood smear shows a variable number of RBCs with target cells (especially in HbSC disease), abnormal shapes, nucleated RBCs, Howell-Jolly bodies, spherical
cells, polychromasia. Sickle cells in smear when RBCs contain >60% HbS (except in HbS-persistent HbF). After autosplenectomy, basophilic stippling,
Pappenheimer bodies, nucleated RBCs also present.
Normocytic normochromic anemia (Hb = 5–10 gm/dL; normal MCV).
Reticulocyte count is increased (5–30%); may cause slight increase in MCV.
WBC is increased (10,000–30,000/cu mm) during a crisis, with normal differential or shift to the left. Infection may be indicated by intracellular bacteria (best seen on
buffy coat preparations), Döhle's bodies, toxic granules, and vacuoles of WBCs, Westergren ESR >20 mm/hr.
Platelet count is increased (300,000–500,000/cu mm), with abnormal forms.
Bone marrow shows hyperplasia of all elements.
mDecreased ESR becomes normal after blood is aerated. ESR in normal range may indicate intercurrent illness or crisis.
Osmotic fragility is decreased (more resistant RBCs).
Mechanical fragility of RBCs is increased.
RBC survival time is decreased (17 days in HbSS, 28 days in HbSC).
Laboratory findings of hemolysis (e.g., increased indirect serum bilirubin [£6 mg/dL], increased urobilinogen in urine and stool, but urine is negative for bile).
Hemosiderin appears in urine sediment.
Hematuria is frequent.
Renal concentrating ability is decreased, leading to a fixed specific gravity in virtually all patients after the first few years of life.
Serum uric acid may be increased.
Serum ALP is increased during crisis, representing vaso-occlusive bone injury as well as liver damage.
Leukocyte ALP activity is decreased.
Laboratory findings due to complications
·Infections due to immunocompromised status (functional asplenia); e.g., Salmonella osteomyelitis occurs more commonly in sickle cell syndromes; marked increase
in susceptibility to pneumococcal and H. influenzae sepsis and meningitis, E. coli and meningococci infections, staphylococcal osteomyelitis, M. pneumoniae.
·
Vaso-occlusive crisis, e.g., infarction of lungs, brain, bowel; spleen completely infarcted by middle age, causing Howell-Jolly bodies, target cells. Bone marrow
necrosis causing fat emboli syndrome; bone disorders (e.g., avascular necrosis of hip; dactylitis).
·
Kidney (see Nephropathy, Sickle Cell, Chapter 14).
·
Stasis and necrosis of liver—increased direct serum bilirubin £40 mg/dL, bile in urine, other findings of obstructive type of jaundice.
·
Hyperhemolytic crisis—superimposed further hemolysis due to bacterial or viral infections; Hb falls from usual 6–10 g/dL to £5 g/dL in a few days with increasing
reticulocyte count. When hemolysis is present, G-6-PD deficiency should be ruled out as this is also common in blacks.
·Aplastic crisis—acute, self-limited episode of erythroid aplasia lasting 5–10 days due to parvovirus B19; falling Hct and reticulocyte count may require prompt
transfusion. Recovery is marked by return of reticulocytosis, usually with resolution of infection.
·
Hypoplastic crisis—infection or inflammation causes brief suppression of bone marrow with accentuated brief drop in Hct and reticulocyte count.
·Splenic sequestration crisis—seen mostly in children age 5 mos to 5 yrs (before fibrosis of spleen has occurred); enormous enlargement of spleen associated with
precipitous drop in Hct and hypovolemic shock. Over age 2 yrs, occurs more often with other HbS syndromes.
·
Megaloblastic crisis—rare occurrence of sudden cessation of erythropoiesis due to folate depletion in persons with inadequate folate (e.g., due to pregnancy,
alcoholism, poor diet).
·
Bilirubin gallstones in 30% of patients by age 18 and 70% by age 30, may cause cholecystitis or biliary obstruction.
w·Anemia and hemolytic jaundice are present throughout life after age 3–6 mos; hemolysis and anemia are increased only during hematologic crises.
wNewborn screening by Hb electrophoresis on cord blood or filter paper spot.
·
In newborns with HbSS, anemia is rarely present. May cause unexplained prolonged jaundice. May be difficult to distinguish HbSS from HbAS in neonates because
of large amount of HbF, which may obscure the HbA. HbA is also not produced in HbS–beta 0
-thalassemia, so an FS pattern on electrophoresis may indicate either.
HbS–beta+
-thalassemia usually has an FSA phenotype, which requires careful differentiation from sickle cell trait (phenotype FAS). Percent of RBCs that will sickle
is much lower in newborn (as low as 0.5%) than in older children. Diagnosis of HbSS is excluded by HbA on Hb electrophoresis of infant's blood or if mother has
negative sickle cell preparation. In newborn, cellulose agar electrophoresis is useless to detect HbS because of the small amount present, and acidic citrate agar gel
is needed. For exchange transfusion, sickle cell test must be performed on donor blood from blacks because these RBCs may sickle in presence of hypoxia as in
RDS. Hb solubility tests (e.g., Sickledex) are usually not suitable on cord blood because a positive result may be easily obscured by a large amount of HbF. Most
children are anemic and symptomatic by age of 1 yr; anemia and hemolysis are present throughout life.
wAntenatal diagnosis is possible as early as 7–10 wks' gestation by gene analysis of fetal DNA on amniotic fluid cells or chorionic villi. Also detects HbSC disease.
Diagnosis can also be made by fetal blood sampling.
HbSC Disease
(Occurs in 1 in 833 American blacks)
wHb electrophoresis: HbA is absent; HbS and HbC are present in approximately equal amounts (30–60%); HbF is usually not seen (2–15%).
wBlood smear shows tetragonal crystals within RBC in 70% of patients; RBCs tend to be microcytic with MCV usually low or low normal but high MCHC; rare true
sickle cells, occasional spherocytes, typical distorted RBCs in which Hb is concentrated more in one area of cell than another.
mA valuable diagnostic aid is the presence of target cells with normal MCV.
wOther findings are the same as for sickle cell anemia, but there is less marked destruction of RBCs, anemia, etc., and the disease is less severe clinically.
Hematologic crises may cause a more marked fall in RBC than occurs in HbSS disease.
Sickle Cell–Beta-Thalassemia Disease](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-288-320.jpg)
![·
Homozygous beta0
—HbA is absent; HbF and HbA2 are present.
·
Homozygous beta+
—HbA, HbA2, and HbF are all detected.
·
HbF = 10–90%; HbA is decreased; HbA2 may be normal, low, or high.
wMarked hypochromic microcytic regenerative hemolytic anemia is present. Often Hb = 2.0–6.5 g/dL, Hct = 10–24%, RBC = 2–3 million, indices are decreased.
wBlood smear shows marked anisocytosis, poikilocytosis, target cells, spherocytes, and hypochromic, fragmented, and bizarre RBCs; also many nucleated
RBCs—basophilic stippling, Cabot's ring bodies, siderocytes.
Reticulocyte count is increased.
WBCs are often increased, with normal differential or marked shift to left.
Platelets are normal.
Bone marrow is cellular and shows erythroid hyperplasia and increased iron.
Serum iron and TIBC are increased. After age 5 yrs, iron-binding capacity is usually saturated.
Laboratory findings of hemolysis and liver dysfunction (e.g., increased serum LD, AST, ALT, and indirect bilirubin [1–3 mg/dL], urine and stool urobilinogen; serum
haptoglobin and hemopexin are very decreased or absent).
Liver dysfunction causing disturbance of factors V, VII, IX, XI, prothrombin
RBC survival time is decreased.
Osmotic fragility is decreased.
Mechanical fragility is increased.
Laboratory findings due to complications, e.g.,
·
Secondary hypersplenism (usually occurs between age 5–10 yrs, detected when transfusion requirement is >200–250 mg/kg body weight, at which time
splenectomy is indicated).
m•Hemosiderosis (hepatic fibrosis and cirrhosis; endocrinopathies with hypofunction of pituitary, thyroid, etc.).
Proteinuria, hyposthenuria, failure to acidify urine, and increased urobilin and urobilinogen with dark color may be present.
mBeta-thalassemia trait demonstrated in both parents.
wPrenatal diagnosis is possible at 16 wks' gestation in 85% of cases by DNA analysis of amniotic cells; the remaining cases can be diagnosed by alpha-/beta-chain
ratios in fetal blood (obtained by fetoscopy).
Alpha-Thalassemia 2
See Table 11-29.
Table 11-29. Classification of Alpha-Thalassemia Syndromes
mOne alpha allele is deleted, which causes asymptomatic but transmissible trait. Occurs in £30% of black populations. Coincident with sickle cell or HbC trait,
reduces the proportion of HbS or HbC below the usual 35–40% (also slightly decreasing the clinical severity); thus <35% variant Hb is good evidence for coexisting
alpha-thalassemia in such patients. No clinical or hematologic findings.
wDefinitive diagnosis of older silent carrier depends on special techniques (globin synthesis rates).
Alpha-Thalassemia 1
Two copies of alpha-globin gene are deleted from same chromosome.
Minimal hypochromic, microcytic anemia, increased target cells, anisocytosis, resembling beta-thalassemia trait but without increased HbA 2
HbE–Alpha-Thalassemia
HbH Disease
Inheritance of alpha-thalassemia 1 from one parent and alpha-thalassemia 2 from other causing absence of three of four alpha-globin alleles and excess of
beta-globins (HbH). May also be due to deletion of two alpha-globin genes and presence of alpha-chain variant Hb Constant Spring. Acquired form may occur during
course of myeloproliferative disorders due to relative suppression of alpha-chain gene.
Hypochromic, microcytic hemolytic anemia is moderate to mild (Hb = 7–11 gm/dL), accentuated by infection, drugs, pregnancy, etc.
Most RBCs are microcytic, hypochromic; many target or deformed RBCs
wCharacteristic patterns on RBC and platelet histograms due to very small RBCs; may cause inaccurate platelet count.
mSupravital stain shows granular inclusions (precipitated beta chains), which are very marked after splenectomy
wIsoelectric focusing is more sensitive than Hb gel electrophoresis for variants present in small amounts](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-292-320.jpg)
![May present with neonatal jaundice.
Hydrops Fetalis
Deletion of all four alpha-globin genes with no normal Hb causes stillbirth or prompt postnatal death due to severe hypoxemia (despite cord Hb £10 g/dL).
wPrenatal diagnosis by Southern blot of amniotic fluid DNA or chorionic villus sample, or by PCR techniques.
THICK BLOOD SYNDROME, NEONATAL
wHct >64% in a heparinized sample or >67% in an unheparinized sample.
wWhen Hct is 60–64%, diagnosis must be made with a microviscosimeter. If <60%, hyperviscosity is not found.
Hyperbilirubinemia, hypoglycemia, platelet count <130,000/cu mm, or abnormal blood smear (burr cells, fragmented RBCs, increased erythroid elements) are found in
~50% of cases.
Therapeutic replacement of blood with plasma exchange transfusion aims to reduce Hct to 50–60% range.
Due To
Transfusion (e.g., maternal-fetal, twin to twin)
Hypoxemia (e.g., postmaturity, small-for-gestational-age neonates)
Decreased deformability of RBC membranes (e.g., sickle cell anemia, spherocytosis)
THYMIC HYPOPLASIA (DiGEORGE SYNDROME)
(Hypoplasia or aplasia of thymus and parathyroid and anomalies of other structures formed at same time [e.g., cardiac defects, renal abnormalities, facial
abnormalities such as cleft palate] due to chromosome band 22q11 deletions)
See Table 11-6 and Table 11-7.
w Proposed Diagnostic Criteria
Involvement of two or more of the following organ systems:
Thymus
Parathyroid
Cardiovascular
Hypocalcemia may be transient; may cause neonatal seizures.
Serum immunoglobulins are usually near normal for age but may be decreased, especially IgA. IgE may be increased.
Decreased T cells and relative increase in B cell percentage. Normal ratio of helper and suppressor types.
With complete syndrome, susceptible to opportunistic infection ( P. carinii, fungi, viruses) and to graft-versus-host disease from blood transfusion. In partial syndrome
(with variable amount of hypoplasia), growth and response to infection may be normal.
Thymus is often absent; when found, histology appears normal.
Lymph node follicles appear normal, but paracortical areas and thymus-dependent areas of spleen show variable amount of depletion. Incidence of cancer and of
autoimmune disease is not increased.
TUMOR OF BONE MARROW
(Due to leukemia, metastases, agnogenic myeloid metaplasia)
“Leukoerythroblastic” peripheral blood picture
WBC may be increased, decreased, or normal.
Peripheral blood may show left shift in myeloid series, thrombocytopenia, nucleated RBCs, schistocytes, teardrop RBCs.
wMay show tumor cells in peripheral blood (“carcinocythemia”), especially in patients receiving high-dose chemotherapy before autologous marrow transplant and in
those receiving growth factor therapy.
wBone marrow examination establishes diagnosis.
TUMOR OF THYMUS
(>40% of patients have parathymic syndromes noted in the following, which are multiple in one-third)
mAssociated with
Myasthenia gravis in ~35% of cases. May appear up to 6 yrs after excision of thymoma in 5% of cases. Thymoma develops in 15% of patients with myasthenia gravis.
Acquired hypogammaglobulinemia. 7–13% of adults with this condition have an associated thymoma; does not respond to thymectomy.
Pure red cell aplasia found in approximately 5% of thymoma patients. 50% of patients with pure red cell aplasia have thymoma, of whom 25% benefit from
thymectomy; onset followed thymectomy in 10% of cases. May be accompanied or followed, but not preceded, by granulocytopenia or thrombocytopenia or both in
one-third of cases; thymectomy is not useful therapy. Pure red cell aplasia occurs in one-third of patients with hypogammaglobulinemia and thymoma.
Autoimmune hemolytic anemia with positive Coombs' test and increased reticulocyte count
Cushing's syndrome](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-293-320.jpg)
![MEN (usually type I)
SLE
Miscellaneous disorders (e.g., giant cell myocarditis, nephrotic syndrome)
Cutaneous disorders (e.g., mucocutaneous candidiasis, pemphigus)
WISKOTT-ALDRICH SYNDROME
(Rare immunologic X-linked recessive condition characterized by eczema, repeated infections, and thrombocytopenia with death by age 10 due to
infection, hemorrhage, or lymphoma [12% incidence]. Severe impairment of humoral and cellular immunity)
See Table 11-6 and Table 11-7.
wPlatelet count is decreased (average 15,000–30,000/cu mL) and small appearance on smear is diagnostic. Bleeding tendency (skin, GI tract) with frequent death
due to intracranial hemorrhage. Decreased survival time of patients' platelets. Megakaryocytes appear normal.
Impaired maturation of hematopoietic stem cells.
Marked susceptibility to high-grade encapsulated organisms and to opportunistic infections (e.g., bacteria, fungi, P. carinii, chronic viral infections) and autoimmune
disease is seen.
Highly variable immunoglobulin levels, even within the same patient; predominant pattern is decreased serum IgM, increased IgA and IgE, normal IgG.
Normal levels of circulating T and B cells; severely impaired cell-mediated and humoral immunity that decreases with age.
EBV-associated lymphoid cancers (especially B immunoblastic non-Hodgkin's lymphoma with predilection for CNS) and autoimmune disorders in older persons.
wScanning electron microscopy of fetal lymphocytes from umbilical vein establishes prenatal diagnosis.
Tests of Coagulation
See Table 11-30, Table 11-31 and Table 11-32.
Table 11-30. Comparison of Coagulation disorders with Platelet or Vascular Disorders
Table 11-31. Screening Tests for Presumptive Diagnosis of Common Bleeding Disordersa
Table 11-32. Summary of Coagulation Studies in Hemorrhagic Conditions
ANTICOAGULANTS, CIRCULATING
(Usually antibodies that inhibit function of specific coagulation factors, especially VIII or IX; occasionally V, XI, XIII, vWF)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-294-320.jpg)
![Thrombasthenia
COAGULATION (CLOTTING) TIME (LEE-WHITE CLOTTING TIME)
Use
See Table 11-33.
Table 11-33. Effect of Anticoagulant Drugs on Coagulation Tests
Former routine method for control of heparin therapy but now replaced by aPTT. It is not a reliable screening test for bleeding conditions because it is not sensitive
enough to detect mild conditions but only detects severe ones. Normal coagulation time does not rule out a coagulation defect. Many variables exist in the technique of
performing the test. Routine preoperative bleeding and coagulation times are of little value for routine preoperative screening.
Prolonged In
Severe deficiency (<6%) of any known plasma clotting factors except factor XIII (fibrin-stabilizing factor) and factor VII
Afibrinogenemia
Presence of a circulating anticoagulant (including heparin)
Normal In
Thrombocytopenia
Deficiency of factor VII
Von Willebrand's disease
Mild coagulation defects due to any cause
Interferences
Increased In
Anticoagulants
Tetracyclines
Decreased In
Corticosteroids
Epinephrine
FIBRINOGEN DEGRADATION PRODUCTS
(Latex agglutination rapid test kit detects increased level [10 µg/mL] in serum and parallels results with hemagglutination inhibition [HAI] method. Detects
major breakdown products of fibrin or fibrinogen. Does not distinguish between fibrinolysis and fibrinogenolysis.)
Use
Aid in diagnosis of DIC
Increased in Serum
DIC
In association with fibrinolytic therapy
Thromboembolic events
Pulmonary embolism—peak values may be transient.
Postoperative deep venous thrombosis.
AMI during first 24–48 hrs.
Certain disorders of pregnancy.
Small increases with exercise, anxiety, stress, severe liver disease.
Increased in Urine](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-298-320.jpg)
![all coagulation factors that contribute to thrombin formation except factors VII and XIII.
The test may not detect mild clotting defects (25–40% of normal levels), which seldom cause significant bleeding.
Not recommended for preoperative screening of asymptomatic adult unless patient has specific clinical indication (e.g., active bleeding, known or suspected bleeding
disorders [including anticoagulant use], liver disease, malabsorption, malnutrition, other conditions associated with acquired coagulopathies, in which procedure may
interfere with normal coagulation).
Prolonged By
Defect in factors (assays <30% of normal; intrinsic pathway)
I (fibrinogen)
II (prothrombin)
V (labile factor)
VIII*
IX*
X (Stuart-Prower factor)
XI*
XII (Hageman factor)
Presence of specific inhibitors of clotting factors * (most frequently antibody against factor VIII, which occurs in ~15% of multitransfused patients with severe
hemophilia A and less frequently in mild/moderate hemophilia A; and against circulating lupus anticoagulant). Mixing equal parts of patient's plasma and normal
plasma corrects aPTT (or PT) if due to coagulation factor deficiency but not if due to an inhibitor.
Heparin
Warfarin
Lupus anticoagulant*
*May cause isolated prolonged aPTT.
Normal In
Thrombocytopenia
Platelet dysfunction
Von Willebrand's disease (may be prolonged in some patients)
Isolated defects of factor VII
Interferences
Very increased or decreased Hct (e.g., polycythemia) that alters citrate concentration or inadequate citrate in collection tube
Specimen contamination with EDTA
Clots in specimen
Partially filled collection tube
Values may be falsely very high if plasma is very turbid or icteric when photoelectric machines are used.
Drugs other than heparin
Hirudin analogues and argatroban, warfarin
Less frequently (e.g., hematin, hydroxyethyl starch, suramin, Taularidine [an additive in some IV medications])
Drugs that may inhibit heparin action (e.g., antihistamines, digitalis, nicotine, penicillin (IV), protamine, tetracycline, phenothiazine)
PLASMINOGEN
(Normal adults = 76–124% for males, 65–153% for females; infants = 27–59%)
Use
Is one indicator of fibrinolytic activity
Monitor fibrinolytic therapy with streptokinase or urokinase
May Be Decreased In
Some familial or isolated cases of idiopathic deep venous thrombosis; autosomal deficiency or dysplasminogenemia
Diabetic patients with thrombosis
DIC and systemic fibrinolysis
Behçet's disease
Cirrhosis of the liver
PLATELET AGGREGATION STUDIES](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-300-320.jpg)
![Table 11-35. Some Congenital Hemorrhagic Diseases due to Disorders of Platelet-Vessel Wall
Table 11-36. Comparison of Congenital Disorders of Platelet Function
Fig. 11-17. Evaluation of hemostatic abnormalities. (Prothrombin time and activated partial thromboplastin time—see Fig. 11-15 and Fig. 11-16.) (BT = bleeding time;
DAT = direct antiglobulin test [Coombs‘]; DIC = disseminated intravascular coagulation; HUS = hemolytic uremic syndrome; ITP = idiopathic thrombocytopenic
purpura; TTP = thrombic thrombocytopenic purpura.)
Increased In
(>450,000/cu mm; <1 million/cu mm in 97% of patients).
Myeloproliferative disease (e.g., polycythemia vera, CML, agnogenic myeloid metaplasia, essential thrombocythemia)
Malignancy, especially disseminated, advanced, or inoperable, accounts for ~13% of cases in hospital patients.
Patients recently having surgery, especially splenectomy (accounts for ~19% of cases in hospital patients); or experiencing severe trauma, massive acute
hemorrhage, or thrombotic episodes.
Infections account for ~31% of cases in hospital patients.
Chronic inflammation as in inflammatory bowel disease, collagen diseases, and RA
Iron-deficiency anemia
Miscellaneous disease states (e.g., cardiac disease, cirrhosis of the liver, chronic pancreatitis, ARDS in neonates, burns, hypothermia, preeclampsia, ethanol
withdrawal, renal failure, splenectomy)
~50% of patients with “unexpected” increase of platelet count are found to have a malignancy.
Decreased In
(Thrombocytopenia)
Acquired
Decreased platelet production (e.g., aplastic anemia, myelophthisis, exposure to ionizing radiation, nutritional deficiencies [folate, vitamin B 12, etc.], drug effects
[alcohol, chemotherapeutic agents, etc.])
Infections (e.g., AIDS, SBE, septicemia, typhus, rubella, infectious mononucleosis) may have several mechanisms.
Increased platelet destruction.
wAntiplatelet antibodies (IgG and IgM) may be found in plasma and by flow cytometry, may be detected on platelets in most patients with drug-induced
thrombocytopenia (e.g., heparin, quinidine, procainamide, quinine) (sensitivity = 90%). 15–29% of patients with autoimmune thrombocytopenia have only
platelet-associated IgM. Negative results in plasma and on platelets argues strongly against an immune cause of thrombocytopenia. Platelet-associated IgG may be
seen in ITP, sepsis, aplastic anemia, acute leukemia, SLE, immune vasculitis, drugs.
Drug-induced immune thrombocytopenia (e.g., quinidine, quinine, gold, sulfonamides, penicillins; heparin causes thrombocytopenia in £10% of patients, usually in](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-302-320.jpg)
![Drug effects
Interference with platelet membrane receptors (e.g., amitriptyline, imipramine, doxepin, chlorpromazine, cocaine, lidocaine [Xylocaine], isoproterenol,
propranolol, cephalothin, ampicillin, penicillin, others)
Inhibition of prostaglandin pathways (e.g., aspirin, indomethacin, ibuprofen, phenylbutazone, naproxen, furosemide, verapamil, others)
Inhibition of platelet phosphodiesterase activity (e.g., caffeine, aminophylline, theophylline, papaverine, others)
Unknown mechanisms (e.g., dicumarol, heparin, chlortetracycline, glycerol guaiacolate, others)
PLATELET VOLUME, MEAN
(Limited value when measured by routine automated hematology instruments)
Normal = 7.4–10.4 fL
Use
Indicates uniformity or heterogeneity of size of platelet population.
Study of thrombocytopenic patients
Increased mean platelet volume with thrombocytopenia indicates that thrombopoiesis is stimulated and platelet production is increased.
Normal mean platelet volume with thrombocytopenia indicates impaired thrombopoiesis.
Increased In
Immune thrombocytopenic purpura
Thrombocytopenia due to sepsis (recovery phase)
Myeloproliferative disorders
Massive hemorrhage
Prosthetic heart valve
Splenectomy
Vasculitis
Decreased In
Wiskott-Aldrich syndrome
PROTEIN C, PLASMA
Normal range = 70–130%
Use
Detect hypercoagulable states associated with episodes of venous thrombosis
Decreased In
Hereditary (autosomal dominant) deficiency (heterozygote levels are usually 30–65%; found in screening in 1 in 300 persons; thrombosis is not usual if level >50%).
Establishes the diagnosis of purpura fulminans, which is seen in homozygous infants (usually <1% of normal). Warfarin-induced skin necrosis is almost pathognomonic
for protein C deficiency.
Liver disease
DIC (not diagnostically useful)
Postoperative state
Malignancy
ARDS
Pregnancy
Oral contraceptive use
High loading dose of warfarin causes transient rapid drop in protein C levels.
L-Asparaginase therapy
Decreases with age (~4% per decade).
PROTEIN S, PLASMA
Use
Detect hypercoagulable states associated with episodes of venous thrombosis
Should be assayed whenever protein C is assayed; both are vitamin K–dependent inhibitors of coagulation. Heterozygotes with levels of 30–60% may have episodes
of recurrent thrombosis. Functional rather than immunologic tests are preferred to detect qualitative as well as quantitative deficiency.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-304-320.jpg)
![Reporting
PT should be reported as ratio of patient results to control rather than as percentage.
PT may also be reported as INR (international normalized ratio) only for patients on oral anticoagulants for ³2 wks who have stable PTs and responded appropriately
to the drug. INR = ratio of patient PT to mean of PT reference range for that laboratory raised to the power of the international sensitivity index (index is provided by
the thromboplastin manufacturer). Is intended to take into account differences due to different methods or thromboplastin-instrument combinations in interpretation of
results. Suggested INR range = 2.0–3.0 for standard-dose therapy for treatment or prophylaxis of venous thrombosis or pulmonary or systemic embolus. Suggested
INR range = 2.5–3.5 for high-risk patients with mechanical heart valves.
Note: INR is dependent on instrumentation. Sensitive thromboplastin (low international sensitivity index) leads to undertreatment and insensitive thromboplastin (high
international sensitivity index) leads to overtreatment.
RISTOCETIN COFACTOR ACTIVITY
Use
Differential diagnosis of von Willebrand's disease
Decreased In
Von Willebrand's disease type I
Von Willebrand's disease type IIA
Cirrhosis
THROMBIN TIME
Use
Detects abnormal fibrinogen
Increased In
Fibrinogen levels that are very low (<80 mg/dL) or high (>400 mg/dL)
Interference with polymerization of fibrin
Fibrin degradation products, especially DIC.
High concentrations of monoclonal immunoglobulins (e.g., myeloma, macroglobulinemia) interfere with fibrin monomer polymerization.
Uremia.
Dysfibrinogenemia (abnormal fibrinogen present).
Heparin contamination of specimen is common cause in hospital patients; however, a reptilase test is normal in presence of heparin but prolonged by other causes
listed in previous section.
Antithrombin antibodies
TOURNIQUET TEST
Use
Differential diagnosis of purpura
Positive In
Thrombocytopenic purpuras
Nonthrombocytopenic purpuras
Thrombocytopathies
Scurvy
DISORDERS OF COAGULATION
See Table 11-35.
AFIBRINOGENEMIA, CONGENITAL
(Rare inherited autosomal recessive congenital condition)
See Table 11-34, Table 11-35 Table 11-36.
wPlasma fibrinogen is absent.
BT is often increased (one-third of patients).
PT, aPTT, and thrombin time are abnormal.
Platelet-to-glass adhesiveness is abnormal unless fibrinogen is added.
BERNARD-SOULIER SYNDROME
(Rare autosomal recessive absence or dysfunction of platelet membrane glycoproteins Ib receptor, V, IX [AQ37] that enable platelets to bind vWF)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-306-320.jpg)
![Antibodies develop in ~20% of patients receiving repeated transfusion of factor VIII products, prolonging aPTT and lowering factor VIII activity of normal plasma.
wPrenatal diagnosis during eighth to tenth week of pregnancy by DNA analysis of amniocytes or chorionic villus material or by analysis of fetal blood at 12–14 wks for
VIII:C and VIII:Ag.
Carrier status determination by pedigree analysis and laboratory studies is 95% accurate in ~80% of women.
>75% of patients with severe hemophilia who received multiple doses of factor concentrate before 1985 are HIV positive; many have AIDS. High incidence of viral
hepatitis seropositivity.
FACTOR IX (PLASMA THROMBOPLASTIN COMPONENT) DEFICIENCY (CHRISTMAS DISEASE; HEMOPHILIA B)
(Inherited recessive X-linked deficiency)
In severe cases, increased coagulation time, BT, prothrombin consumption time, and aPTT are found.
Defect is corrected by administration of frozen plasma just as well as by bank blood.
w Factor IX assay
FACTOR X (STUART-PROWER) DEFICIENCY
(Rare autosomal recessive defect resembles factor VII deficiency; heterozygotes show mild or no clinical manifestations)
Increased PT (not corrected by use of viper venom as thromboplastin) is not corrected by administration of vitamin K. Heterozygotes may have only slight increase in
PT.
w Factor X assay
Acquired form may be associated with amyloidosis, coumarin anticoagulant therapy, vitamin K deficiency, liver trauma.
FACTOR XI (PLASMA THROMBOPLASTIN ANTECEDENT) DEFICIENCY
(Inherited autosomal recessive deficiency is usually mild; acquired forms are recognized)
In mild form, coagulation may be normal, prothrombin consumption time is slightly increased.
In severe cases, increased coagulation time, increased prothrombin consumption time.
Postoperative bleeding may not begin until several days after surgery.
w Factor XI assay
FACTOR XII (HAGEMAN FACTOR) DEFICIENCY
Coagulation time and prothrombin consumption time are increased.
Specific factor assay is needed to distinguish from factor XI deficiency.
No hemorrhagic symptoms occur.
FACTOR XIII (FIBRIN-STABILIZING FACTOR) DEFICIENCY
(Inherited autosomal recessive deficiency with severe coagulation defect)
Congenital
Results of all standard clotting tests appear normal.
Patient's fibrin clot is soluble in 5M urea.
Whole blood clot is qualitatively friable.
Acquired Type May Occur In
AML
Liver disease
Association with hypofibrinogenemia in obstetric complications
Presence of circulating inhibitors
GLANZMANN'S THROMBASTHENIA
(Rare autosomal recessive absence or dysfunction of glycoprotein receptor GPIIb/IIIa that enable platelets to bind a family of integrins [to generate large
platelet aggregates], of which fibrinogen is most important; variant forms exist)
See Table 11-36.
Prolonged BT.
Impaired clot retraction. Normal in essential athrombia, in which other laboratory abnormalities are the same.
Normal platelet count and morphology but unusually well dispersed on smear with no clumping.
Normal coagulation time.
wTotally absent primary platelet aggregation induced by ADP, thrombin, collagen, or epinephrine. Decreased maximum response to ristocetin.](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-310-320.jpg)
![wProthrombin consumption tests abnormal but corrected by adding platelet substitute.
HELLP SYNDROME
(hemolysis, elevated liver enzymes, low platelets)
w Diagnostic Criteria
Hemolysis (increased serum bilirubin >1.2 mg/dL, LD >600 U/L, abnormal peripheral blood smear)
Abnormal liver enzymes (serum ALT >79 U/L)
Platelet count <100,000/cu mm
Hemolysis and thrombocytopenia are typically milder than in TTP/hemolytic uremic syndrome.
Bone marrow shows excessive megakaryocytes.
Normal PT, aPTT, fibrinogen, fibrinogen degradation products
Occurs during pregnancy or within 48 hrs of delivery.
HEMORRHAGIC DISEASE OF THE NEWBORN
(Due to lack of vitamin K)
See Table 11-41.
Table 11-41. Comparison of Hemorrhagic Diseases of the Newborn
PT is markedly increased.
PTT is increased.
Coagulation time is increased.
BT is normal; may be slightly increased.
Capillary fragility, prothrombin consumption, and platelet count are normal.
Laboratory findings due to blood loss.
Secondary
Due to a variety of transient defects in clotting; more commonly seen in low-birth-weight premature infants and anoxic or septic neonates.
HEMORRHAGIC DISORDERS, CLASSIFICATION
Vascular abnormalities
Congenital (e.g., hereditary hemorrhagic telangiectasia [Osler-Weber-Rendu disease])
Acquired (see Purpura, Nonthrombocytopenic)
Infection (e.g., bacterial endocarditis, rickettsial infection)
Immunologic (e.g., Schönlein-Henoch disease, allergic purpura, drug sensitivity)
Metabolic (e.g., scurvy, uremia, diabetes mellitus)
Miscellaneous (e.g., neoplasms, amyloidosis, angioma serpiginosum)
Connective tissue abnormalities
Congenital (e.g., Ehlers-Danlos syndrome)
Acquired (e.g., Cushing's syndrome)
Platelet abnormalities (see sections on thrombocytopenic purpura, thrombocythemia, thrombocytopathies)
Most useful tests are platelet count, peripheral smear examination, BT, platelet aggregation, platelet lumi-aggregation (release), platelet IgG and IgM antibodies,
platelet membrane glycoproteins (flow cytometry), cyclo-oxygenase. Platelet factor 4, beta-thromboglobulin, thromboxanes for hyperactive/prethrombotic
platelets.
Plasma coagulation defects
Causing defective thromboplastin formation
Factor VIII deficiency (hemophilia)
Factor IX (plasma thromboplastin component) deficiency (Christmas disease)
Factor XI (plasma thromboplastin antecedent) deficiency](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-311-320.jpg)
![Deficiency of antithrombin III (when concentrate is not available), protein C, protein S, heparin cofactor II
Hypoglobulinemia (rarely)
Plasma exchange for TTP or hemolytic uremic syndrome
Contraindicated as volume expander
Each unit increases any clotting factor by 2–3% in average adult.
Platelet Transfusion
Platelet count >50,000/cu mm: unlikely to be needed; bleeding unlikely due to low count.
Platelet count <5000/cu mm
Spontaneous bleeding is likely except in platelet destruction disorders; prophylactic use is indicated.
Platelet count <10,000/cu mm
Prophylactic with minor hemorrhage; fever
Platelet count <20,000 in patients
Without thrombotic or ITP or posttransfusion purpura or hemolytic uremic syndrome
Prophylactic in leukemia in presence of coagulation disorders, during induction therapy
Before minor surgical procedures
Platelet count <50,000 in patients with
Minor bleeding
Preoperative for a minor procedure
Prematurity
High blast count
Platelet count <90,000 in patients with
Bleed requiring RBC transfusion
Preoperative for a major procedure
Received massive RBC transfusion (>8 U/24 hrs)
BT >10 mins
Received transfusion of >6 RBC unit/case (e.g., open heart surgery)
(Unit of platelets = 5.5 × 1010
cu mm)
VON WILLEBRAND'S DISEASE
(Heterogeneous group of inherited [>20 subtypes] and acquired disorders of vWF with mucocutaneous bleeding due to abnormal vWF quantity or quality.
Most common inherited hemostatic abnormality.)
See Table 11-36 and Table 11-43.
Table 11-43. Types of von Willebrand's Disease (vWD)
Hereditary deficiency (types I and III) or qualitative defect (type II) of a high-molecular-weight plasma protein (vWF) that mediates adherence of platelets to injured
endothelium. All show mild to moderate bleeding except type III, which is severe. Type I: decreased amount of vWF without qualitative abnormality. Type III: vWF
completely or almost completely absent from plasma and platelets. Type II: qualitative abnormalities of vWF due to loss of various multimers. vWF circulates
complexed to (carrier for) factor VIII:c, which also responds as an acute-phase protein. Pseudo–von Willebrand's disease is a rare platelet disorder in which platelet
receptors have marked avidity for vWF, which causes spontaneous clumping, depletes the plasma of vWF, and may cause mild to moderate thrombocytopenia.
Acquired von Willebrand's disease due to formation of autoantibodies (in association with autoimmune and lymphoproliferative disorders), decreased synthesis, or
other mechanisms (e.g., in myeloproliferative, vascular, and congenital heart diseases), or idiopathic.
Difficulty in diagnosis arises from temporal variation in clinical and laboratory findings in an individual patient as well as from patient to patient; because many patients
do not have the classic laboratory findings, a number of clinical variants have been described.
BT is prolonged using a calibrated template; in a few patients, may only be prolonged after administration of 300 mg of aspirin.
aPTT is prolonged.
Platelet adhesiveness to glass beads is decreased. Ristocetin-induced aggregation of platelets is abnormal if ristocetin cofactor activity is <30%; thus may be normal](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-317-320.jpg)
![In analyzing acid-base disorders, several points should be kept in mind:
Determination of pH and blood gases should be performed on arterial blood. Venous blood is useless for judging oxygenation but offers an estimate acid-base
status.
Blood specimens should be packed in ice immediately; delay of even a few minutes causes erroneous results, especially if WBC is high.
Determination of electrolytes, pH, and blood gases ideally should be performed on blood specimens obtained simultaneously, because the acid-base situation is
very labile.
Repeated determinations may often be indicated because of the development of complications, the effect of therapy, and other factors.
Acid-base disorders are often mixed rather than in the pure form usually described in textbooks.
These mixed disorders may represent simultaneously occurring diseases, complications superimposed on the primary condition, or the effect of treatment.
Changes in chronic forms may be notably different from those in the acute forms.
For judging hypoxemia, one must also know the patient's Hb or Hct and whether the patient was breathing room air or oxygen when the specimen was drawn.
Arterial blood gas values cannot be interpreted without clinical information about the patient.
Renal compensation for a respiratory disturbance is slower (3–7 days) but more successful than respiratory compensation for a metabolic disturbance but cannot
completely compensate for pCO2 >65 mm Hg unless another stimulus for HCO3
– retention is present. Respiratory mechanism responds quickly but can only eliminate
sufficient CO2 to balance the most mild metabolic acidosis.
Most laboratories measure pH and pCO2 directly and calculate HCO3
– using the Henderson-Hasselbalch equation:
Arterial pH = 6.1 + log [(HCO3
–) ÷ (0.03 × pCO2)]
where 6.1 is the dissociation constant for CO 2 in aqueous solution and 0.03 is a constant for the solubility of CO 2 in plasma at 37°C.
A normal pH does not ensure the absence of an acid-base disturbance if the pCO2 is not known.
An abnormal HCO3
– means a metabolic rather than a respiratory problem; decreased HCO3
– indicates metabolic acidosis, and increased HCO 3
– indicates metabolic
alkalosis. Respiratory acidosis is associated with a pCO 2 of >45 mm Hg, and respiratory alkalosis is associated with a pCO2 of <35 mm Hg. Thus mixed metabolic and
respiratory acidosis is characterized by low pH, low HCO 3
–, and high pCO2. Mixed metabolic and respiratory alkalosis is characterized by high pH, high HCO 3
–, and
low pCO2.
See Table 12-1, Table 12-2 and Table 12-3.
Table 12-1. Metabolic and Respiratory Acid-Base Changes in Blood
Table 12-2. Illustrative Serum Values in Acid-Base Disturbances
Table 12-3. Illustrative Serum Electrolyte Values in Various Conditions
In severe metabolic acidosis, respiratory compensation is limited by inability to hyperventilate pCO2 to less than ~15 mm Hg; beyond that, small increments of H+
ion
produce disastrous changes in pH and prognosis; thus patients with lung disorders (e.g., COPD, neuromuscular weakness) are very vulnerable because they cannot
compensate by hyperventilation. In metabolic alkalosis, respiratory compensation is limited by CO2 retention, which rarely causes pCO2 levels >50–60 mm Hg
(because increased CO2 and hypoxemia stimulate respiration very strongly); thus pH is not returned to normal.
Base excess is a value that hypothetically “corrects” pH to 7.40 by first adjusting pCO 2 to 40 mm Hg, thereby allowing comparison of resultant HCO3
– with normal](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-321-320.jpg)
![Fig. 12-1. Acid-base map. The values demarcated for each disorder represent a 95% probability range for each pure disorder (N = normal). Coordinates lying outside
these zones suggest mixed acid-base disorders. (Adapted from Goldberg M, et al. Computer-based instruction and diagnosis of acid-base disorders. JAMA
1973;223:269. Copyright 1973 American Medical Association.)
ACID-BASE DISTURBANCES, MIXED
(Must always be interpreted with clinical data and other laboratory findings)
See Table 12-2.
Respiratory Acidosis with Metabolic Acidosis
Examples: Acute pulmonary edema, cardiopulmonary arrest (lactic acidosis due to tissue anoxia and CO 2 retention due to alveolar hypoventilation)
Acidemia may be extreme with
•pH <7.0 (H+
>100 mEq/L).
m• HCO3
– <26 mEq/L. Failure of HCO3– to increase ³3 mEq/L for each 10 mm Hg rise in pCO2 suggests metabolic acidosis with respiratory acidosis.
Mild metabolic acidosis superimposed on chronic hypercapnia causing partial suppression of HCO3
– may be indistinguishable from adaptation to hypercapnia alone.
Metabolic Acidosis with Respiratory Alkalosis
Examples: Rapid correction of severe metabolic acidosis, salicylate intoxication, septicemia due to gram-negative organisms, initial respiratory alkalosis with
subsequent development of metabolic acidosis.
m Primary metabolic acidosis with primary respiratory alkalosis with an increased AG is characteristic of salicylate intoxication in absence of uremia and diabetic
ketoacidosis.
pH may be normal or decreased.
Hypocapnia remains inappropriate to decreased HCO3
– for several hours or more.
Respiratory Acidosis with Metabolic Alkalosis
Examples: Chronic pulmonary disease with CO2 retention in which patient develops metabolic alkalosis due to administration of diuretics, severe vomiting, or sudden
improvement in ventilation (“posthypercapnic” metabolic alkalosis)
m Decreased or absent urine chloride indicates that chloride-responsive metabolic alkalosis is a part of the picture.
m In clinical setting of respiratory acidosis but with normal blood pH and/or HCO 3
– higher than predicted, complicating metabolic alkalosis may be present.
Respiratory Alkalosis with Metabolic Alkalosis
Examples: Hepatic insufficiency with hyperventilation plus administration of diuretics or severe vomiting; metabolic alkalosis with stimulation of ventilation (e.g.,
sepsis, pulmonary embolism, mechanical ventilation) that causes respiratory alkalosis
w Marked alkalemia with decreased pCO2 and increased HCO3
– is diagnostic.
Acute and Chronic Respiratory Acidosis
Examples: Chronic hypercapnia with acute deterioration of pulmonary function causing further rise of pCO 2
m May be suspected when HCO3
– in intermediate range between acute and chronic respiratory acidosis (similar findings in chronic respiratory acidosis with
superimposed metabolic acidosis or acute respiratory acidosis with superimposed metabolic alkalosis)
Coexistence of Metabolic Acidoses of Hyperchloremic Type and Increased AG Type
Examples: Uremia and proximal renal tubular acidosis, lactic acidosis with diarrhea, excessive administration of sodium chloride to patient with organic acidosis
m May be suspected when plasma HCO3
– level is lower than is explained by the increase in anions (e.g., AG = 16 mEq/L and HCO 3
– = 5 mEq/L)
Coexistence of Metabolic Alkalosis and Metabolic Acidosis
Examples: Vomiting causing alkalosis plus bicarbonate-losing diarrhea causing acidosis
m May be suggested by acid-base values that are too normal for clinical picture
ACIDOSIS, LACTIC
Indicates acute hypoperfusion and tissue hypoxia.
m Should be considered in any metabolic acidosis with increased AG (>15 mEq/L).
w Diagnosis is confirmed by exclusion of other causes of metabolic acidosis and serum lactate ³5 mEq/L (upper limit of normal = 1.6 for plasma and 1.4 for whole
blood). Considerable variation in literature in limits of serum lactate and pH to define lactic acidosis.
w Exclusion of other causes by
Normal serum creatinine and BUN. (Increased acetoacetic acid [but not beta-hydroxybutyric acid] causes false increase of creatinine by colorimetric assay.)
Osmolar gap <10 mOsm/L.
Negative nitroprusside reaction. (Nitroprusside test for ketoacidosis measures acetoacetic acid but not beta-hydroxybutyric acid; thus blood ketone test may be](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-323-320.jpg)
![Serum pH and bicarbonate are above those predicted by the pCO2 (by nomogram or Table 12-4).
Hypokalemia is an almost constant feature and is the chief danger in metabolic alkalosis.
Decreased serum chloride is relatively lower than sodium.
BUN may be increased.
Urine pH is >7.0 (£7.9) if potassium depletion is not severe and concomitant sodium deficiency (e.g., vomiting) is not present. With severe hypokalemia (<2.0 mEq/L),
urine may be acid in presence of systemic alkalosis.
m When the urine chloride is low (<10 mEq/L) and the patient responds to chloride treatment, the cause is more likely loss of gastric juice, diuretic therapy, or rapid
relief of chronic hypercapnia. Chloride replacement is completed when urine chloride remains >40 mEq/L. When the urine chloride is high (>20 mEq/L) and the
patient does not respond to sodium chloride treatment, the cause is more likely hyperadrenalism or severe potassium deficiency.
See Table 12-4.
ALKALOSIS, RESPIRATORY
(Decreased pCO2 of <38 mm Hg)
Due To
Hyperventilation
CNS disorders (e.g., infection, tumor, trauma, cerebrovascular accident [CVA])
Salicylate intoxication
Fever
Bacteremia due to gram-negative organisms
Liver disease
Pulmonary disease (e.g., pneumonia, pulmonary emboli, asthma)
Mechanical overventilation
Congestive heart failure
Hypoxia (e.g., decreased barometric pressure, ventilation-perfusion imbalance)
Anxiety-hyperventilation
Laboratory Findings
Acute hypocapnia—usually only a modest decrease in plasma HCO 3
– concentrations and marked alkalosis
Chronic hypocapnia—usually only a slight alkaline pH (not usually >7.55)
ANION GAP CLASSIFICATION
(Calculated as Na – [Cl + HCO3]; typically normal = 8–16 mEq/L; if K is included, normal = 10–20 mEq/L; reference interval varies considerably depending
on instrumentation.)
Use
Identification of cause of metabolic acidosis
Supplement to laboratory quality control along with its components
Increased In
m Increased “unmeasured” anions
Organic (e.g., lactic acidosis, ketoacidosis)
Inorganic (e.g., administration of phosphate, sulfate)
Protein (e.g., transient hyperalbuminemia)
Exogenous (e.g., salicylate, formate, nitrate, penicillin, carbenicillin)
Not completely identified (e.g., hyperosmolar hyperglycemic nonketotic coma, uremia, poisoning by ethylene glycol, methanol, salicylates)
Artifactual
Falsely increased serum sodium
Falsely decreased serum chloride or bicarbonate
Decreased unmeasured cations (e.g., hypokalemia, hypocalcemia, hypomagnesemia)
m When AG >12–14 mEq/L, diabetic ketoacidosis is the most common cause, uremic acidosis is the second most common cause, and drug ingestion (e.g.,
salicylates, methyl alcohol, ethylene glycol, ethyl alcohol) is the third most common cause; lactic acidosis should always be considered when these three causes
are ruled out.
Decreased In
m Decreased unmeasured anion (e.g., hypoalbuminemia is probably most common cause of decreased AG)
m Artifactual
“Hyperchloremia” in bromide intoxication (if chloride determination by colorimetric method)
Hyponatremia due to viscous serum
False decrease in serum sodium; false increase in serum chloride or HCO 3
–
m Increased unmeasured cations
Hyperkalemia, hypercalcemia, hypermagnesemia
Increased proteins in multiple myeloma, paraproteinemias, polyclonal gammopathies (these abnormal proteins are positively charged and lower the AG)](https://image.slidesharecdn.com/wallachinterpretationofdiagnostictests7thed2000-160812064525/85/Wallach-interpretation-of-diagnostic-tests-7th-ed-2000-326-320.jpg)
Wallach interpretation of diagnostic tests 7th ed 2000
- 1. Interpretation of Diagnostic Tests 7th edition (April 15, 2000): by Jacques B. Wallach By Lippincott Williams & Wilkins Publishers By OkDoKeY
- 2. Interpretation of Diagnostic Tests Table of Contents Author Preface Preface to the First Edition Acknowledgments PART I NORMAL VALUES Chapter 1. Introduction to Normal Values (Reference Ranges) Chapter 2. Critical Values PART II SPECIFIC LABORATORY EXAMINATIONS Chapter 3. Core Blood Analytes: Alterations by Diseases Chapter 4. Urine PART III DISEASES OF ORGAN SYSTEMS Chapter 5. Cardiovascular Diseases Chapter 6. Respiratory Diseases Chapter 7. Gastrointestinal Diseases Chapter 8. Hepatobiliary Diseases and Diseases of the Pancreas Chapter 9. Central and Peripheral Nervous System Disorders Chapter 10. Musculoskeletal and Joint Diseases Chapter 11. Hematologic Diseases Chapter 12. Metabolic and Hereditary Disorders Chapter 13. Endocrine Diseases Chapter 14. Genitourinary Diseases Chapter 15. Infectious Diseases Chapter 16. Miscellaneous Diseases Chapter 17. Disorders due to Physical and Chemical Agents Chapter 18. Therapeutic Drug Monitoring and Toxicology Chapter 19. Body Substances Bibliography APPENDICES Appendix A: Abbreviations and Acronyms Appendix B: Conversion Factors between Conventional and Système International Units Appendix C: Summary of Causes of and Diagnostic Tests for Spurious Laboratory Results
- 3. Preface The history is important in the selection of appropriate diagnostic tests and for an estimate of prior prevalence for interpreting the test sensitivity and specificity. Laboratory tests have greater specificity and sensitivity than the physical examination for many disorders. Test selection depends largely on the clinical purpose for testing (e.g., screening, case finding, monitoring the course of disease, following the effects of therapy, determining drug levels or drug effects) and on the patient population being evaluated. Whereas formerly it was common to order a multiphasic panel of blood chemistry and hematology tests, this practice is now discouraged to decrease costs and to avoid the “Ulysses syndrome.” Appropriate diseases for screening should be sufficiently prevalent, life threatening, disabling, or financially burdensome; detectable by tests of sufficient sensitivity and specificity with high predictive value; and susceptible to available therapy that can prevent, ameliorate, or delay the onset of disease or prolong useful life. Common examples of conditions for screening and case finding in asymptomatic persons include cytology for cervical cancer, testing for HIV and other transmissible diseases in blood donors, and for phenylketonuria (PKU) and hypothyroidism in newborns. Laboratory tests are an increasing part of most patient-physician relationships and contribute greatly to the selection of additional diagnostic procedures and, ultimately to diagnosis and treatment. They often precede the history and physical examination. The use of physician office laboratories and increased consolidation of distant reference laboratories diminishes the opportunity for clinicians to consult with local laboratory directors even as there are greater economic constraints and criticisms regarding inappropriate utilization of health resources. Many remarkable advances have occurred in laboratory medicine since the first edition of Interpretation of Diagnostic Tests was published in 1970. A wealth of new laboratory tests has become essential to the modern practice of medicine, and each edition has paralleled these changes by including more recently described disorders and newer tests, which accounts for the increased size of each edition. The number, cost, complexity, sophistication, variety, utility, and availability of laboratory tests continues to grow along with clinicians’ dependence on them. Many diagnoses can only be established, or etiologies confirmed or appropriate therapy selected, by such tests. The size of this medical knowledge database defies and challenges the ability of any individual to use it to its greatest advantage. I have attempted to address these issues in the following ways: 1. Maintaining the organization, format, style, ease of use, nominal cost, thoroughness, and practical utility. 2. Making significant improvements through extensive editing, remodeling, cross-referencing, and book design (e.g., edge tabs) to make the data more readable and more useful. 3. Information about tests and diseases has been extensively updated, including newer technologies such as monoclonal antibodies, DNA probes, polymerase chain reaction, specific hormone assays, immunochemical and cytochemical staining, flow cytometry, cytogenics, and chromosomal studies that have markedly improved our accuracy and diagnostic ability. Outmoded or rarely used tests have been deleted. 4. Additional algorithms and tables may clarify and expedite the patient’s workup. 5. More data on test sensitivity, specificity, and predictive value and more current references have been included. 6. Reorganization includes improved alphabetizing and organizing of the tests and diseases within each chapter and deleting redundancies and repetitions that may have crept in during the previous 25 years, thereby simplifying the reader’s search as well as reducing the size of the extensive index that characterized previous editions. The reader can now find answers more quickly and expeditiously. 7. A symbol is used to mark tests that are diagnostic for a disease (w), and a different icon ( ) is used for those tests that are suggestive or supportive or should arouse suspicion of, but are not diagnostic for, that disease, thus encouraging more cost-effective and immediate diagnosis. Unmarked tests simply let the reader know that such test results may occur and are nonspecific, although they may occasionally provide useful collateral information in the differential diagnosis of an individual problem. 8. The effect of drugs on laboratory tests that appeared in a separate chapter in previous editions has been included with the tests themselves, diminishing the need for the reader to cross-check between chapters and possible redundancy. 9. Electronic versions are available for easier pursuit of information and cross-referencing and ultimately for integration with computerized laboratory test reporting. 10. A more concise pocket version (Handbook of Interpretation of Diagnostic Tests) has been published for those who may need less detail and more portability. 11. This edition continues to mostly use conventional rather than Système International (SI) units because many journals do so and especially because most physicians are more familiar with them; a table for converting units is included in Appendix B. 12. Computerized consolidation of laboratory results brings clinicians closer to the goal of integrating these results and clinical findings with their interpretation and constitutes an increasing unique opportunity in medicine. These modifications should permit this book to continue to meet the needs of students in medicine, dentistry, nursing, laboratory technology, and veterinary medicine, as well as a wide range of health care providers from novices and house officers to seasoned clinicians, laboratorians, and pathologists. Its success is indicated in the use of hundreds of thousands of copies of earlier editions in various languages and countries for 30 years, the many favorable comments received, and the number of authors who have tried to emulate it. Readers are encouraged to continue their suggestions and criticisms. The author’s perspective as a practicing pathologist, laboratory director, clinician, and teacher who personally needs current, concise, and practical diagnostic data without the distraction of other material, such as methodology, technology, physiologic mechanisms, and Medicare code numbers, has informed the preparation of this edition and continues to distinguish it from other laboratory books. J.W.
- 4. Preface to the First Edition Results of laboratory tests may aid in Discovering occult disease Preventing irreparable damage (e.g., phenylketonuria) Early diagnosis after onset of signs or symptoms Differential diagnosis of various possible diseases Determining the stage of the disease Estimating the activity of the disease Detecting the recurrence of disease Monitoring the effect of therapy Genetic counseling in familial conditions Medicolegal problems, such as paternity suits This book is written to help the physician achieve these purposes with the least amount of Duplication of tests Waste of patient’s money Overtaxing of laboratory facilities and personnel Loss of physician’s time Confusion caused by the increasing number, variety, and complexity of tests currently available. Some of these tests may be unrequested but performed as part of routine surveys or hospital admission multitest screening. In order to provide quick reference and maximum availability and usefulness, this handy-sized book features Tabular and graphic style of concise presentation Emphasis on serial time changes in laboratory findings in various stages of disease Omission of rarely performed, irrelevant, esoteric, and outmoded laboratory tests Exclusion of discussion of physiologic mechanisms, metabolic pathways, clinical features, and nonlaboratory aspects of disease Discussion of only the more important diseases that the physician encounters and should be able to diagnose This book is not An encyclopedic compendium of clinical pathology A technical manual A substitute for good clinical judgment and basic knowledge of medicine Deliberately omitted are Technical procedures and directions Photographs and illustrations of anatomic changes (e.g., blood cells, karyo-types, isotope scans) Discussions of quality control Selection of a referral laboratory Performance of laboratory tests in the clinician’s own office Bibliographic references, except for the most general reference texts in medicine, hematology, and clinical pathology and for some recent references to specific conditions The usefulness and need for a book of this style, organization, and contents have been increased by such current trends as The frequent lack of personal assistance, advice, and consultation in large commercial laboratories and hospital departments of clinical pathology, which are often specialized and fragmented as well as impersonal Greater demand for the physician’s time The development of many new tests Faculty and administrators still assume that this essential area of medicine can be learned "intuitively" as it was 20 years ago and that it therefore requires little formal training. This attitude ignores changes in the number and variety of tests now available as well as their increased sophistication and basic value in establishing a diagnosis. The contents of this book are organized to answer the questions most often posed by physicians when they require assistance from the pathologist. There is no other single adequate source of information presented in this fashion. It appears from numerous comments I have received that this book has succeeded in meeting the needs not only of practicing physicians and medical students but also of pathologists, technologists, and other medical personnel. It has been adopted by many schools of nursing and of medical technology, physicians assistant training programs, and medical schools. Such widespread acceptance confirms my original premise in writing this book and is most gratifying. A perusal of the table of contents and index will quickly show the general organization of the material by type of laboratory test or organ system or certain other categories. In order to maintain a concise format, separate chapters have not been organized for such categories as newborn, pediatric, and geriatric periods or for primary psychiatric or dermatologic diseases. A complete index provides maximum access to this information. Obviously these data are not original but have been adapted from many sources over the years. Only the selection, organization, manner of presentation, and emphasis are original. I have formulated this point of view during 40 years as a clinician and pathologist, viewing with pride the important and growing role of the laboratory but deeply regretting its inappropriate utilization. This book was written to improve laboratory utilization by making it simpler for the physician to select and interpret the most useful laboratory tests for his clinical problems. J.W.
- 5. Acknowledgments I thank colleagues in various parts of the world who have shared their clinical and laboratory problems with me and encouraged the continuation of this book. The universal need to convert an ever-expanding mass of raw laboratory data into accessible, cost-effective, clinically usable information continues to be a matter of increasing significance throughout the medical community and a chief concern of mine in producing this book and in other teaching and research efforts. The need for expeditious, unencumbered information has been repeatedly confirmed during teaching of medical students and house officers, in the daily practice of pathology, by discussions with physicians in many countries that I have visited or in which I have worked or taught, and by the translation of this volume into various other languages. I am rewarded by numerous instances of friendship, criticism, kindness, and help and by learning far more than I could include in this small volume. I continue to be gratified and stimulated beyond expectation. My thanks to Executive Editor Rich Winters for his sensible advice and support, to Developmental Editor Michelle LaPlante, to Supervising Editor Mary Ann McLaughlin, and to the other people behind the scenes at Lippincott Williams & Wilkins who were so uniformly helpful; to Production Editor Shannon Garza and staff at Silverchair Science + Communications for their tireless, diligent, and meticulous work on this project; and to Linda Hallinger for her careful indexing. The friendship, love, care, and generosity of my wife, Doris, can never be sufficiently acknowledged.
- 6. Author Jacques Wallach, M.D. Clinical Professor of Pathology, State University of New York Health Science Center at Brooklyn; Attending Pathologist, Kings County Hospital Center, Brooklyn, New York
- 7. BIBLIOGRAPHY Interpretation of Diagnostic Tests BIBLIOGRAPHY Baron EJ, Finegold SM. Bailey & Scott's diagnostic microbiology, 8th ed. St. Louis: Mosby, 1990. Baum GL, Celli BR, Crapo JD, Karlinsky JB, eds. Textbook of pulmonary diseases, 6th ed. Philadelphia: Lippincott–Raven Publishers, 1997. Becker KL, et al., eds. Principles and practice of endocrinology and metabolism, 2nd ed. Philadelphia: JB Lippincott, 1995. Bennett JC, Plum F. Cecil textbook of medicine, 20th ed. Philadelphia: WB Saunders, 1996. Black RM, Alfred HJ, Fan P, Stoff JS. Rose & Black's clinical problems in nephrology. Boston: Little, Brown and Company, 1996. Carey CF, Lee HH, Woeltje KF. The Washington manual of medical therapeutics, 29th ed. Philadelphia: Lippincott–Raven Publishers, 1998. Cotran RS, Kumar V, Robbins SL, Schoen FJ. Robbins pathologic basis of disease, 6th ed. Philadelphia: WB Saunders, 1998. DeGroot LJ, et al., eds. Endocrinology. Philadelphia: WB Saunders, 1989. Edelman CM, Bernstein J, Meadow SR, Spitzer A, Travis LB, eds. Pediatric kidney disease, 2nd ed. Boston: Little, Brown and Company, 1992. Falk SA, ed. Thyroid disease. Endocrinology, surgery, nuclear medicine, and radiotherapy, 2nd ed. Philadelphia: Lippincott–Raven Publishers, 1997. Frank MM, Austen KF, Claman HN, Unanue ER, eds. Samter's immunologic diseases, 5th ed. Boston: Little, Brown and Company, 1995. Gantz NM, Brown RB, Berk SL, Esposito AL, Gleckman RA. Manual of clinical problems in infectious diseases, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999. Greene A, Morgan I. Neonatal and clinical biochemistry. London: ACB Venture Publications, 1993. Greenfield LJ, Mulholland M, Oldham KT, Zelenock GB, Lillemoe KD, eds. Surgery. Scientific principles and practice, 2nd ed. Philadelphia: Lippincott–Raven Publishers, 1997. Handin RI, Lux SE, Stossel TP, eds. Blood. Principle & practice of hematology. Philadelphia: JB Lippincott, 1994. Hurst JW, ed. Criteria for diagnosis. Boston: Butterworth, 1989. Jandl JH. Blood: textbook of hematology, 2nd ed. Boston: Little, Brown and Company, 1996. Kelley WN, ed. Textbook of internal medicine, 3rd ed. Philadelphia: Lippincott–Raven Publishers, 1997. Krisht AF, Tindall GT, eds. Pituitary disorders. Comprehensive management. Baltimore: Lippincott Williams & Wilkins, 1999. Lawlor GL, Fischer TJ, Adelman DC, eds. Manual of allergy and immunology, 3rd ed. Boston: Little, Brown and Company, 1995. Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM, eds. Wintrobe's clinical hematology, 10th ed. Philadelphia: Lippincott Williams & Wilkins, 1999. Mazza JJ, ed. Manual of clinical hematology, 2nd ed. Boston: Little, Brown and Company, 1995. McMillan JA, DeAngelis CD, Feigin RD, Warshaw JB, eds. Oski's pediatrics: principles and practice, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 1999. Nyhan WL, Sakati NA. Diagnostic recognition of genetic disease. Philadelphia: Lea & Febiger, 1987. Robinson SH, Reich PR, eds. Hematology. Pathophysiologic basis for clinical practice, 3rd ed. Boston: Little, Brown and Company, 1993. Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff's diseases of the liver, 8th ed. Philadelphia: Lippincott Williams & Wilkins, 1998. Schrier RW, ed. Renal and electrolyte disorders, 5th ed. Philadelphia: Lippincott Williams & Wilkins, 1997. Schrier RW, Gottschalk CW, eds. Diseases of the kidney, 6th ed. Boston: Little, Brown and Company, 1996. Scott JR, DiSaia PJ, Hammond CB, Spellacy WN, eds. Danforth's obstetrics and gynecology, 8th ed. Philadelphia: Lippincott Williams & Wilkins, 1999. Scriver CR, ed. The metabolic and molecular basis of inherited disease. New York: McGraw-Hill, 1989. Stein JH, ed. Internal medicine, 4th ed. St. Louis: Mosby, 1994. Tietz NW, et al., eds. Clinical guide to laboratory tests, 2nd ed. Philadelphia: WB Saunders, 1995. Trent RJ, ed. Handbook of prenatal diagnosis. New York: Cambridge University Press, 1995. Wallach J. Interpretation of pediatric tests. Boston: Little, Brown and Company, 1983. Yamada T, Alpers DH, Laine L, Owyang C, Powell DW, eds. Textbook of gastroenterology, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 1999.
- 8. CHAPTER 1 INTRODUCTION TO NORMAL VALUES (REFERENCE RANGES) Interpretation of Diagnostic Tests CHAPTER 1 INTRODUCTION TO NORMAL VALUES (REFERENCE RANGES) General Principles References Values GENERAL PRINCIPLES The purpose of all testing (laboratory, radiologic, electrocardiographic [ECG], etc.) is to reduce clinical uncertainty. The degree of reduction varies with the test characteristics and clinical situation. Modern medicine has superseded Voltaire's dictum that “the art of medicine consists of amusing the patient while nature cures the disease.” Many clinicians are still largely unaware of the reasoning process that they pursue in seeking a diagnosis and tend to follow an empirical path that was previously successful or was learned during early training periods by observing their mentors during clinical rounds without appreciating the rationale for selecting, ordering, and interpreting laboratory tests; this is often absorbed in a subliminal, informal, or rote fashion. The need to control health care costs and many recent studies on laboratory test utilization have emphasized the need for a selective approach. Some important principles in utilizing laboratory (and all other) tests are as follows: 1. Under the best of circumstances, no test is perfect (e.g., 100% sensitivity, specificity, predictive value). In any specific case, the results may be misleading. The most sensitive tests are best used to rule out a suspected disease so that the number of false-negative tests is minimal; thus a negative test tends to exclude the disease. The most specific tests are best used to confirm or exclude a suspected disease and minimize the number of false-positive results. Sensitivity and specificity may be markedly altered by the coexistence of other disorders or by complications or sequelae of the primary disease. 2. Choice of tests should be based on the prior probability of the diagnosis being sought, which affects the predictive value of the test. This prior probability is determined by the history, physical examination, and prevalence of the suspected disorder (in that community at that time), which is why history and physical examination should precede ordering of tests. The clinician need not know the exact prior probability of the disease. Estimating this as high, intermediate, or low is usually sufficient. Moderate errors in estimating prior probability have only relatively limited effects on interpretation of the tests. If the prior prevalence is high, a positive result tends to confirm the presence of the disease, but an unexpected negative result is not very useful in ruling out the disease. Conversely, when the prior prevalence is low, a normal result tends to rule out the disease, but an unexpected positive result is not very useful in confirming the disease. (See Table 1-1 and Table 1-2.) Table 1-1. Assuming a Low Prior Probability (10%) (in 1000 Tests, Disease is Present in 100 and Absent in 900) Table 1-2. Assuming a High Prior Probability (90%) (in 1000 Cases Tested, Disease is Present in 900 and Absent in 100) 3. In the majority of laboratory measurements, the combination of short-term physiologic variation and analytic error is sufficient to render the interpretation of single determinations difficult when the concentrations are in the borderline range. Any particular laboratory result may be incorrect for a large variety of reasons, regardless of the high quality of the laboratory; such results should be rechecked. If indicated, a new specimen sample should be submitted with careful confirmation of patient identification, prompt delivery to the laboratory, and immediate processing; in some circumstances, confirmation of test results at another laboratory may be appropriate. 4. Reference ranges vary from one laboratory to another; the user should know what these ranges are for each laboratory used and should also be aware of variations due to age, sex, race, size, physiologic status (e.g., pregnancy, lactation) that apply to the particular patient. These “normal” ranges represent collected statistical data rather than classification of patients as having disease or being healthy and are based on the statistical definition of normal as 95% range of values, whereby 5% of independent tests will be outside this normal range in the absence of disease. This is best illustrated in the use of multitest chemical profiles for screening persons known to be free of disease. The probability of any given test being abnormal is approximately 2% to 5% and the probability of disease if a screening test is abnormal is generally low (0% to 15%). The frequency of abnormal single tests is 1.5% (albumin) to 5.9% (glucose) and up to 16.6% for sodium. Based on statistical expectations, when a panel of 8 tests is performed in a multiphasic health program, 25% of the patients have one or more abnormal results and when the panel includes 20 tests, 55% have one or more test abnormalities. 1 5. Tables of reference values represent statistical data for 95% of the population; values outside of these ranges do not necessarily represent disease. Results may still be within the reference range but be elevated above the patient's baseline, which is why serial testing is important in a number of conditions. For example, in acute myocardial infarction, the increase in serum total creatine kinase (CK) may be abnormal for that patient although the value may be within “normal” range. 6. An individual's test values when measured by a good laboratory tend to remain fairly consistent over a period of years when performed with comparable technology; comparison of results with previous values obtained when the patient was not ill (if available) are often a better reference value than “normal” ranges. 7. Multiple test abnormalities are more likely to be significant than single test abnormalities. When two or more tests for the same disorder are positive, the results reinforce the diagnosis, but when only one test is positive and the other is not positive, the strength of the interpretation is diluted. 8. The greater the degree of abnormality of a test result, the more likely that a confirmed value is clinically significant or represents a real disorder. Thus, an increase ten times the upper reference range is much more likely to be significant compared to a result that is only slightly increased. Most slightly abnormal results are due to preanalytic factors. 9. Characteristic laboratory test profiles that are described in the literature and in this book represent the full-blown picture of the well-developed or far-advanced case, but all abnormal tests may be present simultaneously in only a small fraction (e.g., one-third) of patients with that condition. Even when a test profile
- 9. (combination of tests) is characteristic of a particular disorder, other disorders or groups of conditions may produce exactly the same combination of laboratory test changes. 10. Excessive repetition of tests is wasteful, and the excess burden increases the possibility of laboratory errors. Appropriate intervals between tests should be dictated by the patient's clinical condition. 11. Tests should be performed only if they will alter the patient's diagnosis, prognosis, treatment, or management. Incorrect test values or isolated individual variation in results may cause “Ulysses syndrome” and result in loss of time, money, and peace of mind. 12. Clerical errors are far more likely than technical errors to cause incorrect results. Greatest care should be taken to completely and properly label and identify every specimen, which should always be accompanied by a test requisition form. Busy hospital laboratories receive inordinate numbers of unlabeled, unidentified specimens each day, which are useless, burdensome, and sometimes dangerous. 13. The effect of drugs on laboratory test values must never be overlooked. Test abnormalities may be due to drugs as often as to disease. The clinician should always be aware of what drugs the patient has been taking, including over-the-counter medications, vitamins, iron, and such. Patients often do not tell their physicians about medications they are taking (prescribed by other doctors or by the patients themselves) which may produce false-negative as well as false-positive results. In addition, there is environmental exposure to many drugs and chemicals. The classes of drugs most often involved include the anticoagulants, anticonvulsants, antihypertensives, antiinfectives, oral hypoglycemics, hormones, and psychoactive agents. A number of causative mechanisms may operate, sometimes simultaneously (e.g., interference with the chemical reaction in the testing procedure, damage to a specific organ such as liver or kidney, competition for binding sites, accelerated or retarded formation or excretion of a specific chemical, and such). Often the mechanism of these altered laboratory test values is not known. 14. Laboratory values in the elderly must be interpreted in light of the many factors that affect “normal” values in this group: Altered function due to aging (e.g., diminished renal function). Presence of chronic disease that is more prevalent in older populations and may be asymptomatic or occult. Occurrence of multiple concurrent conditions or diseases, some of which may have additive effects on laboratory results. Use of medications that affect laboratory analytes (e.g., 10% to 30% of elderly persons may be taking diuretics). Homeostasis is not compromised by age alone. Biological variability does not increase simply with age. Values given for age are always in comparison to young adults of the same sex unless otherwise stated. Values given for sex are always in comparison to opposite sex of comparable age. When sex is not specified, it refers to both sexes. 15. The reader must be aware of the effect of artifacts causing spurious values and of factitious disorders especially in the face of discrepant laboratory results. 16. Negative laboratory (or any other type of tests) do not necessarily rule out a clinical diagnosis. REFERENCES VALUES2 Hematology Reference Values Complete blood cell count (CBC) See Table 1-3, Table 1-4, Table 1-5 and Table 1-6 Table 1-3. Reference Ranges for Complete Blood Cell Count at Various Ages Table 1-4. Reference Ranges for White Blood Cell Count (WBC) at Various Ages (Differential Count in Absolute Numbers) Table 1-5. Reference Ranges for Blood Cell Count at Various Fetal Ages Table 1-6. Pediatric Reference Ranges for Lymphocyte Counts
- 10. Table 1-6. Pediatric Reference Ranges for Lymphocyte Counts Carboxyhemoglobin <5% of total Delta-aminolevulinic acid 1.5–7.5 mg/24-hr urine Erythrocyte sedimentation rate (ESR) Westergren Males 0–13 mm in 1 hr Females 0–20 mm in 1 hr Wintrobe Males 0–10 mm in 1 hr Females 0–15 mm in 1 hr Children 0–13 mm in 1 hr Newborns 0–2 mm in 1 hr Erythropoietin (radioimmunoassay [RIA]) Males 17.2 mU/mL (mean) Females 18.8 mU/mL (mean) Ferritin Newborns 25–200 ng/mL 1 mo 200–600 ng/mL 2–5 mos 50–200 ng/mL 6 mos–15 yrs 7–142 ng/mL Adult males 20–300 ng/mL Adult females 15–120 ng/mL Borderline (males or females) 10–20 ng/mL Iron excess >400 ng/mL Folate, erythrocyte <1 yr 74–995 ng/mL 1–11 yrs 96–362 ng/mL ³12 yrs 180–600 ng/mL Folate, serum ³3.5 µg/L Free erythrocyte protoporphyrin (FEP) <100 µg/dL packed red blood cells (RBCs) Glucose-6-phosphate dehydrogenase (G-6-PD) erythrocyte 2–17 yrs 6.4–15.6 U/gm hemoglobin (Hb) ³18 yrs 8.6–18.6 U/gm Hb Haptoglobins Genetic absence in 1% of population Newborns Absent in 90%; 10 mg/dL in 10% Age 1–6 mos Gradual increase to 30 mg/dL 6 mos–17 yrs 40–180 mg/dL Adults 40–270 mg/dL Hemoglobin, plasma ³18 yrs old <15 mg/dL Infants and newborns May be higher Hemoglobin electrophoresis HbA 0–30 days 10–40% 6 mos to adult >95% HbA2 0–30 days <1% 1 yr to adult 1.5–3.0% 3–3.5% (borderline) HbF <2% No abnormal Hb variants Hemoglobin F, RBC HbF remaining in <1% of RBCs Hemosiderin, urine Negative Iron, liver tissue 530–900 µg/gm dry weight Iron, serum Newborns 100–250 µg/dL Infants 40–100 µg/dL Children 50–120 µg/dL Adults Males 65–175 µg/dL Females 50–170 µg/dL Iron, urine 100–300 ng/24 hrs Iron-binding capacity 250–450 µg/dL % saturation 14–50% Leukocyte alkaline phosphatase score 40–100 Lysozyme (muramidase), plasma 0.2–15.8 µg/mL Lysozyme (muramidase), urine <3 mg/24 hrs Marrow sideroblasts ³30% of normoblasts Methemoglobin <3% of total Myoglobin, serum £90 ng/mL Myoglobin, urine 0–2 mg/mL Osmotic fragility of RBC Increased if hemolysis occurs in >0.5% NaCl Decreased if incomplete in 0.30% NaCl Phosphofructokinase, erythrocyte 3.0–6.0 U/gm Hb Plasma iron turnover rate 38 mg/24 hrs (0.47 mg/kg) Pyruvate kinase, erythrocyte 2.0–8.8 U/gm Hb Red blood cell survival time (sodium chromate [51 Cr]) Half-life: 25–35 days Reticulocyte count % 0.5–1.85% of erythrocytes Absolute 29–87 × 109 /L Ringed sideroblasts None Transferrin 240–480 mg/dL Unsaturated vitamin B12–binding capacity 870–1800 pg/mL Urobilinogen, stool 50–300 mg/24 hrs Urobilinogen, urine <4 mg/24 hrs Vitamin B12, serum 190–900 ng/L By seventh decade Decrease to 60–80% Higher in black than in white populations
- 11. Volume (mL/kg body weight) MalesFemales Blood 75 67 RBC 30 24 Plasma 44 43 Blood Coagulation Tests—Reference Values Antithrombin III, plasma Immunologic 17–30 mg/dL Functional 80–120% Bleeding time (Simplate) 3–9.5 mins Clot retraction, qualitative Begins in 30–60 mins; complete within 24 hrs, usually within 6 hrs Coagulation factor assay3 Activity Plasma Levels I (fibrinogen) Males 180–340 mg/dL Females 190–420 mg/dL II (prothrombin) 70–140%* 100 µg/mL V (accelerator globulin) 70–160%* † 10 µg/mL VII (proconvertin-Stuart) 65–170%* † 0.5 µg/mL VIII (anti-hemophilic globulin) 55–145%* 0.1 µg/mL IX 70–140%* † 5 µg/mL X (Stuart factor) 70–140%* † 10 µg/mL XI 65–145%* 5 µg/mL XII (Hageman factor) 60–160%* 30 µg/mL XIII 50–200%* 10 µg/mL Factor VIII–related antigen 45–185% Coagulation factor VIII inhibitor Negative Coagulation time (Lee-White) 6–17 mins (glass tubes) 19–60 mins (siliconized tubes) Euglobulin lysis No lysis in 2 hrs Fibrinogen Males 180–340 mg/dL Females 190–420 mg/dL Fibrinogen split products Negative at >1:4 dilution Positive at >1:8 dilution Fibrinolysins No clot lysis in 24 hrs Lupus anticoagulant (dilute Russell viper venom time [dRVVT]) (plasma [P]) Negative Partial thromboplastin time, activated (aPTT) 25–38 secs Platelet aggregation Full response to adenosine diphosphate, epinephrine, and collagen Platelet antibody, serum Negative Platelet count 140,000–340,000/cu mm (Rees-Ecker) 150,000–350,000/cu mm (Coulter counter) Protein C activity (P) 70–130% Protein C antigen (P) 60–125% Protein S activity, total or free (P) Males 60–130% Females 50–120% Prothrombin time (PT), one stage ±2 secs of control (control should be 11–16 secs) Ristocetin cofactor (P) 45–140% Ristocetin-von Willebrand's factor (vWF) 45–140% Thrombin time (TT) ±5 secs of control vWF antigen, plasma 45–165% Whole blood clot lysis No clot lysis in 24 hrs * Infants may not reach adult level until age 6 mos. † Increased with age in elderly. Blood Chemistries—Reference Values These values will vary, depending on the individual laboratory as well as the methods and instruments used. Each clinician should compare the applicability of these data to his or her own situation. Acetone 0.3–2.0 mg/dL Aldolase 0–2 yrs 3.4–11.8 U/L 2–16 yrs 1.2–8.8 U/L Adults (³17 yrs) 1.7–4.9 U/L Ammonia 9–33 U/L Newborns at term or premature <50 U/L Amylase (total) <18 yrs 0–260 U/L Adults (³18 yrs) 35–115 U/L Apolipoprotein A-I Males 90–155 mg/dL Females 94–172 mg/dL Apolipoprotein B Males 55–100 mg/dL Females 45–110 mg/dL Base, excess Newborns –10 to –2 mEq/L Infants –7 to –1 mEq/L Children –4 to +2 mEq/L Adults –3 to +3 mEq/L Bicarbonate Males Females 1–2 yrs 1–3 yrs 17–25 mEq/L
- 12. 3–4 yrs 4–5 yrs 18–26 mEq/L 4–5 yrs 6–7 yrs 19–27 mEq/L 6–7 yrs 8–9 yrs 20–28 mEq/L ³8* yrs ³10* yrs 21–29 mEq/L * Adult value Bilirubin Total <1 day <5.8 mg/dL 1–2 days <8.2 mg/dL 3–5 days <11.7 mg/dL >1 mo <1.0 mg/dL Direct 1 mo to adult <0.6 mg/dL Calcium Total 1–3 yrs 8.7–9.8 mg/dL 4–11 yrs 8.8–10.1 mg/dL 12–13 yrs 8.8–10.6 mg/dL 14–15 yrs 9.2–10.7 mg/dL >16 yrs 8.9–10.7 mg/dL Males Females Ionized 1–19 yrs 1–17 yrs 4.9–5.5 mg/dL ³20 yrs ³18 yrs 4.75–5.3 mg/dL Carbon dioxide CO2 17–31 mEq/L Partial pressure of carbon dioxide (pCO 2) (whole blood) Adults 32–48 mm Hg Infants 27–41 mm Hg Ceruloplasmin 1–3 yrs 24–46 mg/dL 4–6 yrs 24–42 mg/dL 7–9 yrs 24–40 mg/dL 10–13 yrs 22–36 mg/dL 14–19 yrs 14–34 mg/dL Chloride 96–109 (mEq/L) Cholesterol (Table 1-7) See Lipid Fractionation. Table 1-7. Lipid Fractionation: Desirable Levels for Cholesterol and Triglycerides a Cholinesterase Plasma 7–25 U/mL RBC 0.65–1.3 pH units Complement Total complement 25–110 U C1 esterase inhibitor 8–24 mg/dL C1q complement component 7–15 mg/dL C2 (second component of complement) 50–250% of normal C3 (third component of complement) 70–150 mg/dL C4 (fourth component of complement) 10–30 mg/dL C5 (fifth component of complement) 9–18 mg/dL Copper 75–145 µg/dL Creatine kinase Males 55–170 U/L Females 45–135 U/L Creatine kinase isoenzyme MB <5% (CK-MB) <10 ng/mL (mass) Creatinine <1 wk 0.6–1.1 mg/dL 1–4 wks 0.3–0.7 mg/dL 1–12 mos 0.2–0.4 mg/dL >1 yr 0.2–0.7 mg/dL Males Females 1–2 yrs 1–3 yrs 0.2–0.6 mg/dL 3–4 yrs 4–5 yrs 0.3–0.7 mg/dL 5–9 yrs 6–8 yrs 0.5–0.8 mg/dL 10–11 yrs ³9 yrs 0.6–0.9 mg/dL
- 13. 12–13 yrs 0.6–1.0 mg/dL 14–15 yrs 0.7–1.1 mg/dL ³16 yrs (adult values) 0.8–1.2 mg/dL Cryoglobulins 0 Gamma-glutamyl transferase (GGT) 1–3 yrs 6–19 U/L 4–6 yrs 10–22 U/L 7–9 yrs 13–25 U/L Males Females 10–11 yrs 17–30 U/L 17–28 U/L 12–13 yrs 17–44 U/L 14–25 U/L 14–15 yrs 12–33 U/L 14–26 U/L 16–19 yrs 11–34 U/L 11–28 U/L Glucose (fasting) 60–100 mg/dL (depends on method) Homocysteine, total 5–15 µmol/L Desirable <10 µmol/L Optimal <12 µmol/L Borderline 12–15 µmol/L Moderate hyperhomocystinemia >15–30 µmol/L Intermediate hyperhomocystinemia >30–100 µmol/L Severe hyperhomocystinemia >100 µmol/L Isocitrate dehydrogenase (ICD) 3–85 U/L Lactate 6.3–18.9 mg/dL Lactate dehydrogenase (LD) Newborn 160–1500 U/L Infant 150–360 U/L Child 150–300 U/L Adult 100–250 U/L LD isoenzymes LD-1 17–28% LD-2 30–36% LD-3 19–25% LD-4 10–16% LD-5 6–13% Lead Adults <20 µg/dL £15 yrs <10 µg/dL Leptin <15% body fat in men and <25% in women 1–16 µg/L Leucine aminopeptidase (LAP) Depends on method Lipase 56–239 U/L Lipid fractionation (see Table 1-7 and Table 1-8) Table 1-8. Lipid Fractionation: Desirable Levels for HDL Cholesterol and LDL Cholesterol a Cholesterol esters 60–75% of total Phospholipids 180–320 mg/dL Magnesium 1.7–2.3 mg/dL Myoglobin (serum [S]) £90 ng/mL Osmolality 275–295 mOsm/kg Oxygen Saturation, arterial 96–100% of capacity Tension, partial pressure of oxygen (pO 2), arterial while breathing room air Newborns 60–75 mm Hg <60 yrs >85 mm Hg 60 yrs >80 mm Hg 70 yrs >70 mm Hg 80 yrs >60 mm Hg 90 yrs >50 mm Hg While breathing 100% oxygen >500 mm Hg Oxygen dissociation, P50 (RBCs) 26–30 mm Hg pH, arterial 7.36–7.44 pH, venous 7.32–7.38 Phenylalanine £1 wk 42–124 µmol/L <16 yrs 26–86 µmol/L ³16 yrs 41–68 µmol/L Phosphatase, prostatic acid (PAP) <3.7 ng/mL Phosphatase, alkaline (ALP)
- 14. 1–3 yrs 145–320 U/L 4–6 yrs 150–380 U/L 7–9 yrs 175–420 U/L Males Females 10–11 yrs 135–530 U/L 130–560 U/L 12–13 yrs 200–495 U/L 105–420 U/L 14–15 yrs 130–525 U/L 70–230 U/L 16–19 yrs 65–260 U/L 50–130 U/L Phosphate <5 days 4.6–8.0 mg/dL 1–3 yrs 3.9–6.5 mg/dL 4–6 yrs 3.7–5.4 mg/dL 7–11 yrs 3.7–5.6 mg/dL 12–13 yrs 3.3–5.4 mg/dL 14–15 yrs 2.9–5.4 mg/dL 16–19 yrs 2.8–4.6 mg/dL Potassium 1–15 yrs 3.7–5.0 mEq/L 16–59 yrs 3.6–4.8 mEq/L ³60 yrs 3.9–5.3 mEq/L Prostate-specific antigen (PSA) (S), males4 Normal <4.0 ng/mL Borderline 4–10 ng/mL Values higher in black than in white men; increase with age 40–49 yrs 1.5 ng/mL 50–59 yrs 2.5 ng/mL 60–69 yrs 4.5 ng/mL 70–79 yrs 7.5 ng/mL Proteins, serum Total (gm/dL) Albumin (gm/dL) <5 days 5.4–7.0 2.6–3.6 1–3 yrs 5.9–7.0 3.4–4.2 4–6 yrs 5.9–7.8 3.5–5.2 7–9 yrs 6.2–8.1 3.7–5.6 10–19 yrs 6.3–8.6 3.7–5.6 Globulin (gm/dL) <1 yr 0.4–3.7 1–3 yrs 1.6–3.5 4–9 yrs 1.9–3.4 10–49 yrs 1.9–3.5 Prealbumin (transthyretin) (mg/dL) <5 days 6.0–21.0 1–5 yrs 14.0–30.0 6–9 yrs 15.0–33.0 10–13 yrs 20.0–36.0 14–19 yrs 22.0–45.0 Electrophoresis Albumin 3.1–4.3 gm/dL Globulin Alpha1 0.1–0.3 gm/dL Alpha2 0.6–1.0 gm/dL Beta 0.7–1.4 gm/dL Gamma 0.0–1.6 gm/dL Alpha1-antitrypsin >180 mg/dL Z heterozygotes 79–171 mg/dL Z homozygotes 19–31 mg/dL Immunoglobulins (Ig) IgG (mg/dL) IgA (mg/dL) IgM (mg/dL) 0–4 mos 141–930 5–64 14–142 5–8 mos 250–1190 10–87 24–167 9–11 mos 320–1250 17–94 1–3 yrs 400–1250 1–2 yrs 35–242 (females) 35–200 (males) 2–3 yrs 24–192 41–242 (females) 41–200 (males) 4–6 yrs 560–1307 26–232 7–9 yrs 598–1379 33–258 10–12 yrs 638–1453 45–285 13–15 yrs 680–1531 47–317 16–17 yrs 724–1611 55–377 4–17 yrs 56–242 (females) 47–200 (males) ³18 yrs 700–1500 60–400 60–300 IgE <1 yr 0.0–6.6 U/mL 1–2 yrs 0.0–20.0 U/mL 2–3 yrs 0.1–15.8 U/mL 3–4 yrs 0.0–29.2 U/mL
- 15. 4–5 yrs 0.3–25.0 U/mL 5–6 yrs 0.2–17.6 U/mL 6–7 yrs 0.2–13.1 U/mL 7–8 yrs 0.3–46.1 U/mL 8–9 yrs 1.8–60.1 U/mL 9–10 yrs 3.6–81.0 U/mL 10–11 yrs 8.0–95.0 U/mL 11–12 yrs 1.5–99.7 U/mL 12–13 yrs 3.9–83.5 U/mL 13–16 yrs 3.3–188.0 U/mL IgD 0–14 mg/dL Sodium 135–145 mEq/L Transaminase Aspartate aminotransferase (AST; serum glutamic oxaloacetic transaminase [SGOT]) 1–3 yrs 20–60 U/L 4–6 yrs 15–50 U/L 7–9 yrs 15–40 U/L 10–11 yrs 10–60 U/L Males Females 12–15 yrs 15–40 U/L 10–30 U/L 16–19 yrs 15–45 U/L 5–30 U/L Alanine aminotransferase (ALT; serum glutamic pyruvic transaminase [SGPT]) 1–3 yrs 5–45 U/L 4–6 yrs 10–25 U/L 7–9 yrs 10–35 U/L Males Females 10–11 yrs 10–35 U/L 10–30 U/L 12–13 yrs 10–55 U/L 10–30 U/L 14–15 yrs 10–45 U/L 5–30 U/L 16–19 yrs 10–40 U/L 5–35 U/L Troponin I <1.6 ng/mL Troponin T <0.1 ng/mL Urea nitrogen, blood (BUN) 1–3 yrs 5–17 mg/dL 4–13 yrs 7–17 mg/dL 14–19 yrs 8–21 mg/dL Uric acid 1–3 yrs 1.8–5.0 mg/dL 4–6 yrs 2.2–4.7 mg/dL 7–9 yrs 2.0–5.0 mg/dL Males Females 10–11 yrs 2.3–5.4 mg/dL 3.0–4.7 mg/dL 12–13 yrs 2.7–6.7 mg/dL 3.0–5.8 mg/dL 14–15 yrs 2.4–7.8 mg/dL 3.0–5.8 mg/dL 16–19 yrs 4.0–8.6 mg/dL 3.0–5.9 mg/dL Viscosity (correlates with fibrinogen, high-density lipoprotein [HDL] cholesterol) (viscosimeter) Plasma 1.38±0.08 relative units Serum 1.26±0.08 relative units See Table 1-9. Table 1-9. Reference Blood Values for Fetal Umbilical Blood at 18–40 Wks of Pregnancy (Hitachi 717 Analyzer) Normal Blood and Urine Hormone Levels Adrenocorticotropic hormone (ACTH), plasma £60 pg/mL Aldosterone, serum 0–3 wks 16.5–154 ng/dL 1–11 mos 6.5–86 ng/dL 1–10 yrs (supine) 3.0–39.5 ng/dL 1–10 yrs (upright) 3.5–124 ng/dL ³11 yrs (morning specimen, peripheral vein) 1–21 ng/dL Aldosterone, urine 0–30 days 0.7–11 µg/24 hrs 1–11 mos 0.7–22 µg/24 hrs ³1 yr 2–16 µg/24 hrs Androstenedione, serum Males Females 0–7 yrs 0.1–0.2 ng/mL 0.1–0.3 ng/mL 8–9 yrs 0.1–0.3 ng/mL 0.2–0.5 ng/mL
- 16. 10–11 yrs 0.3–0.7 ng/mL 0.4–1.0 ng/mL 12–13 yrs 0.4–1.0 ng/mL 0.8–1.9 ng/mL 14–17 yrs 0.5–1.4 ng/mL 0.7–2.2 ng/mL ³18 yrs 0.3–3.1 ng/mL 0.2–3.1 ng/mL Angiotensin-converting enzyme (ACE), serum £1 yr 10.9–42.1 U/L 1–2 yrs 9.4–36 U/L 3–4 yrs 7.9–29.8 U/L 5–9 yrs 9.6–35.4 U/L 10–12 yrs 10.0–37.0 U/L 13–16 yrs 9.0–33.4 U/L 17–19 yrs 7.2–26.6 U/L ³20 yrs 6.1–21.1 U/L Calcitonin, plasma Males Females Basal £19 pg/mL <14 pg/mL Calcium infusion (2.4 mg calcium/kg) £190 pg/mL £130 pg/mL Pentagastrin infusion (0.5 µg/kg) £110 pg/mL £30 pg/mL Catecholamine fractionation (free), plasma Supine Standing Norepinephrine 70–750 pg/mL 200–1700 pg/mL Epinephrine £110 pg/mL £140 pg/mL Dopamine <30 pg/mL (any posture) Catecholamine fractionation, urine Epinephrine <1 yr <2.5 µg/24 hrs 1–2 yrs <3.5 µg/24 hrs 2–3 yrs <6.0 µg/24 hrs 4–9 yrs 0.2–10 µg/24 hrs 10–15 yrs 0.5–20 µg/24 hrs ³16 yrs 0–20 µg/24 hrs Norepinephrine <1 yr 0–10 µg/24 hrs 1 yr 1–17 µg/24 hrs 2–3 yrs 4–29 µg/24 hrs 4–6 yrs 8–45 µg/24 hrs 7–9 yrs 13–65 µg/24 hrs ³10 yrs 15–80 µg/24 hrs Dopamine <1 yr <85 µg/24 hrs 1 yr 10–140 µg/24 hrs 2–3 yrs 40–260 µg/24 hrs ³4 yrs 65–400 µg/24 hrs Catecholamine metabolites fractionation, urine Homovanillic acid (HVA), urine <1 yr <35 µg/mg creatinine >1 yr <23 µg/mg creatinine 2–4 yrs <13.5 µg/mg creatinine 5–9 yrs <9 µg/mg creatinine 10–14 yrs <12 µg/mg creatinine Adults <8 mg/24 hrs Metanephrines, urine Vanillylmandelic acid (VMA), urine <1.3 mg/24 hrs <1 yr <27 µg/mg creatinine 1 yr <18 µg/mg creatinine 2–4 yrs <13 µg/mg creatinine 5–9 yrs <8.5 µg/mg creatinine 10–14 yrs <7 µg/mg creatinine 15–18 yrs <5 µg/mg creatinine Adults <9 mg/24 hrs Chorionic gonadotropins, beta-subunit, serum Females <5 U/L Postmenopausal females <9 U/L Males <2.5 U/L Cerebrospinal fluid (CSF) £1.5 U/L Cortisol (for general screening), a.m.: 7–25 µg/dL plasma p.m.: 2–14 µg/dL Cortisol, free, urine 24–108 µg/24 hrs Deoxycorticosteroids (for metyrapone test), plasma a.m.: 0–5 µg/dL p.m.: 0–3 µg/dL Dehydroepiandrosterone sulfate (DHEA-S), serum Males Females 0–30 days (premature) (full-term) 0.25–10.0 µg/mL 0.25–10.0 µg/mL 0.25–2.0 µg/mL 0.25–2.0 µg/mL 1–16 yrs <0.5 µg/mL <0.5 µg/mL ³17 yrs <6.0 µg/mL <3.0 µg/mL Estradiol, serum Children <10 pg/mL Adult males 10–50 pg/mL Premenopausal adult females 30–400 pg/mL Postmenopausal females <30 pg/mL Estrogen and progesterone receptor assays, tissue Negative <3 fmol/mg cytosol protein Borderline 3–9 fmol/mg cytosol protein
- 17. Positive ³10 fmol/mg cytosol protein Follicle-stimulating hormone (FSH), serum Males Females Prepuberty <2 U/L <2 U/L Adult 1–10 U/L Follicular 1–10 U/L Midcycle 6–30 U/L Luteal 1–8 U/L Postmenopausal 20–100 U/L Follicle-stimulating hormone, urine Males Females Prepuberty <0.5 U/24 hrs <0.7 U/24 hrs Adult 7–10 U/24 hrs Not midcycle 0.7–10 U/24 hrs Postmenopausal >10 U/24 hrs Gastrin, serum £200 pg/mL Growth hormone, serum Males Females £5 ng/mL £10 ng/mL 5-Hydroxyindole acetic acid (5-HIAA), urine £6 mg/24 hrs 17-Hydroxyprogesterone, serum Males <220 ng/dL Prepubertal <110 ng/dL Females Follicular phase <80 ng/dL Luteal phase <285 ng/dL Postmenopausal <51 ng/dL Prepubertal <100 ng/dL Newborns <630 ng/dL Insulin, serum <20 µU/mL Borderline 21–25 µU/mL 17-Ketogenic steroids (17-KGS), urine Adult males 4–14 mg/24 hrs Adult females 2–12 mg/24 hrs Children, 0–10 yrs 0.1–4 mg/24 hrs 11–14 yrs 2–9 mg/24 hrs 17-Ketosteroids (17-KS), urine Adult males 6–21 mg/24 hrs Adult females 4–17 mg/24 hrs Children, 0–10 yrs 11–14 yrs 0.1–3 mg/24 hrs 2–7 mg/24 hrs 17-KS, fractionation, urine See Table 1-10 Table 1-10. 17-Ketosteroids (Fractionation), Urine (mg/24 hrs) Luteinizing hormone (LH), serum Prepuberty males <0.5 U/L Adult males 1–10 U/L Prepuberty females <0.2 U/L Adult females, follicular 1–20 U/L Adult females, midcycle 25–100 U/L Postmenopausal females 20–100 U/L Luteinizing hormone, urine Prepuberty males <0.8 U/24 hrs Adult males 0.2–5.0 U/24 hrs Prepuberty females <0.8 U/24 hrs Adult females, nonmidcycle 0.5–5.0 U/24 hrs Postmenopausal females >5.0 U/24 hrs Parathyroid hormone (PTH), serum (intact + N-terminal PTH) 1.0–5.0 pmol/L Pregnanetriol, urine Males Females 0–5 yrs <0.1 mg/24 hrs <0.1 mg/24 hrs 6–9 yrs <0.3 mg/24 hrs <0.3 mg/24 hrs 10–15 yrs 0.2–0.6 mg/24 hrs 0.1–0.6 mg/24 hrs >16 yrs 0.2–2.0 mg/24 hrs 0.0–1.4 mg/24 hrs Progesterone, serum Males Females 0–1 yr 0.87–3.37 ng/mL 0.87–3.37 ng/mL 2–9 yrs 0.12–0.14 ng/mL 0.20–0.24 ng/mL Postpuberty <1.0 ng/mL Increasing values Follicular phase £0.7 ng/mL Luteal phase 2.0–20.0 ng/mL Prolactin, serum Males 0–20 ng/mL Females 0–23 ng/mL
- 18. Renin activity (peripheral vein), plasma (PRA) Na-depleted, upright 18–39 yrs 2.9–24.0 ng/mL/hr >40 yrs 2.9–10.8 ng/mL/hr Na-replete, upright 18–39 yrs £0.6–4.3 ng/mL/hr ³40 yrs £0.6–3.0 ng/mL/hr Sex hormone–binding globulin, serum Adult males 10–80 nmol/L Adult nonpregnant females 20–130 nmol/L Somatomedin-C, plasma Age (yrs) Males Females 0–5 0–103 ng/mL 0–112 ng/mL 6–8 2–118 ng/mL 5–128 ng/mL 9–10 15–148 ng/mL 24–158 ng/mL 11–13 55–216 ng/mL 65–226 ng/mL 14–15 114–232 ng/mL 124–242 ng/mL 16–17 84–221 ng/mL 94–231 ng/mL 18–19 56–177 ng/mL 66–186 ng/mL 20–24 75–142 ng/mL 64–131 ng/mL 25–29 65–131 ng/mL 55–121 ng/mL 30–34 58–122 ng/mL 47–112 ng/mL 35–39 51–115 ng/mL 40–104 ng/mL 40–44 46–109 ng/mL 35–98 ng/mL 45–49 43–104 ng/mL 32–93 ng/mL ³50 40–100 ng/mL 29–90 ng/mL Testosterone, serum Total Free % Males 300–1200 ng/dL 9–30 ng/dL 2.0–4.8% Females 20–80 ng/dL 0.3–1.9 ng/dL 0.9–3.8% Thyroid function indicators See Table 1-11 Table 1-11. Thyroid Function Indicators by Age (Serum Concentration)a Thyroid microsomal and thyroglobulin antibodies <1:100 Vasoactive intestinal polypeptide (VIP), plasma <75 µg/mL Normal Values for Serologic Tests for Infectious Agents Amebiasis (Entamoeba histolytica) No invasive disease <1:32 Borderline <1:32–1:64 Active or recent infection ³128 Current infection >1:256 Aspergillosis Negative Blastomycosis Negative (positive in <50% of cases) Brucellosis <1:80 Candidosis Negative (positive in 25% of normal persons) Chlamydia IgG <1:10 Chlamydia antigen (endocervix, male urine, male urethra) Negative Cold agglutinin titer <1:16 Cryptococcosis antigen, serum or CSF Negative Cryptosporidium antigen, feces Negative Cysticercosis, serum Negative Cytomegalovirus (CMV)* IgG Negative (<15 U/mL) IgM Negative Echinococcosis Negative at 1:128 Epstein-Barr virus Epstein-Barr virus Heterophil Heterophil Hepatitis Hepatitis Herpes simplex, serum or CSF IgG <1:5 IgM <1:10 Polymerase chain reaction (PCR), CSF Negative Histoplasmosis, serum or CSF Negative Influenza A or B* <1:10 IgG or IgM
- 19. Lyme disease (Borrelia burgdorferi) Lyme disease (Borrelia burgdorferi) Monospot screen Negative Mumps* IgG <1:5 IgM <1:10 Murine typhus IgG £1:32 Mycoplasma pneumoniae IgG or IgM <1:10 Respiratory syncytial virus (RSV) IgG <1:10 IgM <1:10 RSV antigen, nasopharynx Negative Q fever* Not infected <1:10 Previous infection ³1:10 Recent or active infection ³1:160 Rocky Mountain spotted fever* IgG £1:32 Rubella IgG >1:10 confirms immunity IgM Negative Rubeola, serum or CSF IgG <1:5 IgM <1:10 Scrub typhus £1:40 St. Louis encephalitis* <1:10 Sporotrichosis <1:80 Streptococcal ASO Anti-DNase-B Preschool children £85 U £60 U School-age children £170 U £170 U Adults £85 U £85 U Syphilis serology Toxocara canis antibody Negative Toxoplasmosis IgG No previous infection (except eye) <1:16 Prevalent in general population 1:16–1:256 Suggests recent infection >1:256 Active infection ³1:1024 IgM Adults ³1:64 = active infection Children Any titer is significant Trichinosis Negative Tularemia <1:40 Varicella IgG <1:10 IgM <1:10 nonimmune 1:10 borderline immunity 1:40 immune * Presence of IgM antibodies or ³ fourfold rise in IgG titer between acute- and convalescent-phase sera drawn within 30 days of each other indicates recent infection. Generally, presence of IgG indicates past exposure and possible immunity. Congenital infections require serial sera from both mother and infant. Passively acquired antibodies in infant will decay in 2–3 mos. Antibody levels that are unchanged or increased in 2–3 mos indicate active infection. Absence of antibody in mother rules out congenital infection in infant. Normal Blood Antibody Levels Acetylcholine (ACh) Receptor-binding antibodies £0.02 nmol/L Receptor-blocking antibodies <25% blockade of ACh receptors Receptor-modulating antibodies <20% loss of ACh receptors Antiglomerular basement membrane antibody Negative Antinuclear antibodies (ANA) Negative Antimitochondrial antibodies Negative Antibodies to Scl 70 antigen Negative Antibodies to Jo 1 antigen Negative Anti–double-stranded DNA (dsDNA) antibodies Negative <70 U Borderline 70–200 U Positive >200 U Antiextractable nuclear antigens (anti-RNP, anti-Sm, anti-SSB, anti-SSA) Negative Antineutrophil cytoplasmic antibodies (ANCA)(c-ANCA and p-ANCA) Negative Granulocyte antibodies Negative Human leukocyte antigen (HLA) B27 Present in Whites: 6–8% Blacks: 3–4% Asians: 1% Intrinsic factor blocking antibody Negative Parietal cell antibodies Negative Rheumatoid factor (RF) Latex agglutination Negative Rate nephelometry Nonreactive 0–39 U/mL Weakly reactive 40–79 U/mL Reactive ³80 U/mL
- 20. Smooth muscle antibody Negative Striated muscle antibodies <1:60 Normal Blood Levels for Metabolic Diseases U = urine S = serum P = plasma B = whole blood F = skin fibroblasts L = leukocytes RBC = erythrocytes St = stool Acid mucopolysaccharides (U) <14 yrs old Age dependent Adult £13.3 µg glucuronic acid/mg creatinine Alpha1-antitrypsin (S) 126–226 mg/dL Alpha-fucosidase (F) (L) Compare with controls 0.49–1.76 U/gm cellular protein Alpha-galactosidase (S) 0.016–0.2 U/L (Fabry's disease) (F) 0.24–1.10 U/gm cellular protein (L) 0.60–3.63 U/1010 cells Alpha-glucosidase (F) 0.13–1.84 U/gm protein Alpha-L-iduronidase (F) 0.44–1.04 U/gm cellular protein (Hurler's, Scheie's syndromes) (L) 0.17–0.54 U/1010 cells Alpha-mannosidase (F) 0.71–5.92 U/gm cellular protein (mannosidosis) (L) 1.50–3.33 U/1010 cells Alpha-N-acetylglucosaminidase (S) 0.09–0.58 U/L (Sanfilippo type B) (F) 0.076–0.291 U/gm cellular protein Arylsulfatase A (mucolipidosis, (F) 2.28–15.74 U/gm cellular protein types II and III) (L) ³2.5 U/1010 cells (U) >1 U/L Arylsulfatase B (F) 1.6–14.9 U/gm cellular protein Beta-galactosidase (Gm1 (F) 4.7–19.1 U/gm cellular protein gangliosidosis, Morquio's syndrome) (L) 1.01–6.52 U/1010 cells Beta-glucosidase (Gaucher's (F) 3.80–8.70 U/gm cellular protein disease) (L) 0.08–0.35 U/1010 cells Beta-glucuronidase (mucopoly-saccharidosis VII) (F) 0.34–1.24 U/gm cellular protein Carbohydrate (U) Negative Cystine (U) <1 mo 64–451 µmol/gm creatine 1–5 mos 66–375 µmol/gm creatine 6–11 mos 70–316 µmol/gm creatine 1–2 yrs 53–244 µmol/gm creatine 3–15 yrs 11–53 µmol/gm creatine ³16 yrs 28–115 µmol/gm creatine Fatty acid profile of serum lipids Linoleate ³25% of fatty acids in serum lipids Arachidonate ³6% of fatty acids in serum lipids Palmitate 18–26% of fatty acids in serum lipids Phytanate £0.3% of fatty acids in serum lipids (>0.5% suggests Refsum's disease; 0.3–0.5% borderline) Free fatty acids (S) 239–843 µEq/L Galactose (U) Not detectable Galactose 1-phosphate (RBC) Nongalactosemic 5–49 µg/gm Hb Galactosemic (galactose-restricted diet) 80–125 µg/gm Hb Galactosemic (unrestricted diet) >125 µg/gm Hb Galactose 1-phosphate uridyltransferase (galactosemia) (B) 18.5–28.5 U/gm Hb Galactokinase (B) <2 yrs old 20–80 mU/gm Hb ³2 yrs old 12–40 mU/gm Hb Galactosylceramide-beta-galactosidase (Krabbe's disease, globoid cell leukodystrophy) (F) (L) 10.3–89.7 mU/gm cellular protein >21.5 mU/gm cellular protein Glucose-6-phosphate dehydrogenase (B) 2–17 yrs old 6.4–15.6 U/gm Hb >18 yrs old 8.6–18.6 U/gm Hb Glucose phosphate isomerase (B) 49–81 U/gm Hb Hexosaminidase (³5 yrs old) (Tay-Sachs disease, GM2 gangliosidosis) Total (S) 10.4–23.8 U/L Hexosaminidase A Normal 1.23–2.59 U/L; 56–80% of total Indeterminate 1.16–1.22 U/L; 50–55% of total Carrier 0.58–1.15 U/L; <50% of total Total (L) 16.4–36.2 U/gm cellular protein Hexosaminidase A 63–75% of total Total (F) 92–184.5 U/gm cellular protein Hexosaminidase A 41–65% of total Homogentisic acid (U) Negative Hydroxyproline, free (24 hr U) <1.3 mg/24 hrs Hydroxyproline, total (24 hr U) <5 yrs old 100–400 µg/mg creatinine
- 21. 5–12 yrs 100–150 µg/mg creatinine Females ³19 yrs 0.4–2.9 mg/2 hr specimen Males ³19 yrs 0.4–5.0 mg/2 hr specimen 35S Mucopolysaccharide (I, II, III, VI, VII) (F) Normal or abnormal turnover Phenylalanine (P) £1 wk of age 0.69–2.0 mg/dL (42–124 µmol/L) <16 yrs old 0.43–1.4 mg/dL (26–86 µmol/L) >16 yrs old 0.68–1.1 mg/dL (41–68 µmol/L) Phytanate (phytanic acid) (S) <0.3% = normal 0.3–0.5% = borderline >0.5% suggests Refsum's disease Porphyrins, total (RBC) 16–60 µg/dL packed cells Uro (octacarboxylic) £2 µg/dL Hepatocarboxylic £1 µg/dL Hexacarboxylic £1 µg/dL Pentacarboxylic £1 µg/dL Copro (tetracarboxylic) £2 µg/dL Porphyrins, total (P) £1 µg/dL Fractionation £1 µg/dL for any fraction Porphyrins (St) Coproporphyrin £200 µg/24 hrs Protoporphyrin £1500 µg/24 hrs Uroporphyrin £1000 µg/24 hrs Porphyrins, fractionation Uro (octacarboxylic) (U) Males £46 µg/24 hrs Females £22 µg/24 hrs Hepatocarboxylic Males £13 µg/24 hrs Females £9 µg/24 hrs Hexacarboxylic Males £5 µg/24 hrs Females £4 µg/24 hrs Pentacarboxylic Males £4 µg/24 hrs Females £3 µg/24 hrs Copro (tetracarboxylic) Males £96 µg/24 hrs Females £60 µg/24 hrs Porphobilinogen Normal: £1.5 mg/24 hrs Marginal: 1.5–2.0 mg/24 hrs Excess: >2.0 mg/24 hrs Protoporphyrins (RBC) Free 1–10 µg/dL packed RBCs Zinc-protoporphyrin 10–38 µg/dL packed RBCs Sphingomyelinase (Niemann-Pick disease) (F) 1.53–7.18 U/gm cellular protein Tyrosine (P) £1 wk 0.6–2.2 mg/dL (33–122 µmol/L) <16 yrs 0.47–2.0 mg/dL (26–110 µmol/L) >16 yrs 0.8–1.3 mg/dL (45–74 µmol/L) Uroporphyrinogen synthase (RBC) Males 7.9–14.7 nM/sec/L Females 8.0–16.8 nM/sec/L Marginal values 6.0–8.0 nM/sec/L are suggestive but indeterminate Values <6.0 nM/sec/L are definite for acute, intermittent porphyria Vitamins See Chapter 12 1 Friedman GD, Golberg M, Ahuja JN, Siegelaub AB, Bassis ML, Collen MI. Biochemical screening tests: effect of panel size on medical care. Arch Int Med 1972;129:91. 2Burritt ME, Slockbower JM, Forsman RW, Offord KP, Bergstralh EJ, Smithson WA. Pediatric reference intervals for 19 biologic variables in healthy children. Mayo Clin Proc 1990;65:329. Leavelle DE, ed. Mayo Medical Laboratories 1995 test catalog. Rochester, MN: Mayo Medical Laboratories, 1995. Lockitch G, Halstead AC, Quigley G, MacCallum C. Age- and sex-specific pediatric reference intervals—various analytes. Clin Chem 1988;34:1618. Kratz A, Lewandrowski KB. Case records of the Massachusetts General Hospital. Normal reference laboratory values. N Engl J Med 1998;339:1063. Soldin SJ, Hicks JM, eds. Pediatric reference ranges. Washington: AACC Press, 1995. Tietz NW, Shuey DF, Wekstein DR. Laboratory values in fit aging individuals—sexagenarians through centenarians. Clin Chem 1992;38:1167. Green A, Morgan I. Neonatology and clinical biochemistry. London: CB Venture Publications, 1993. 3 Roberts HR, Lozier J. New perspectives on the coagulation cascade. Hosp Pract 1992;27:99. 4 Anderson JR, et al. Age-specific reference ranges for serum prostate-specific antigen. Urology 1995;46:54.
- 22. CHAPTER 2 CRITICAL VALUES Interpretation of Diagnostic Tests CHAPTER 2 CRITICAL VALUES Hematology Blood Chemistry Cerebrospinal Fluid Microbiology Urinalysis Serology Therapeutic Drugs These values may indicate the need for prompt clinical intervention. Any sudden changes may also be critical. Also called action values or automatic call back values. Values will vary according to the laboratory performing the tests as well as patient age and other factors. HEMATOLOGY Low High Hct (packed cell volume) <20 vol% >60 vol% Hb <7 gm/dL >20 gm/dL Platelet count (adult) <40,000/cu mm >1,000,000/cu mm Platelet count (pediatric) <20,000/cu mm >1,000,000/cu mm aPTT None >78 secs PT None >30 secs or >3× control level Positive test for fibrin split products, protamine sulfate, high heparin level Fibrinogen <100 mg/dL >700 mg/dL WBC <2000/cu mm >30,000/cu mm Presence of blast cells, sickle cells New diagnosis of leukemia, sickle cell anemia, aplastic crisis BLOOD CHEMISTRY Low High Ammonia None >40 µmol/L Amylase None >200 U/L Arterial pCO2 <20 mm Hg >70 mm Hg Arterial pH <7.2 U >7.6 U Arterial pO2 (adults) <40 mm Hg None Arterial pO2 (newborns) <37 mm Hg (standard deviation [SD] = 7) 92 mm Hg (SD = 12) Bicarbonate <10 mEq/L >40 mEq/L Bilirubin, total (newborns) None >15 mg/dL Calcium <6 mg/dL >13 mg/dL Carbon dioxide <10 mEq/L >40 mEq/L Cardiac troponin (cTn) Cardiac troponin T (cTnT) None >0.1 µg/L Cardiac troponin I (cTnI) None >1.6 µg/L Chloride <80 mEq/L >115 mEq/L CK None >3–5× upper limit of normal (ULN) CK-MB None >5% or ³10 µg/L Creatinine (except dialysis patients) None >5.0 mg/dL Glucose <40 mg/dL >450 mg/dL Glucose (newborns) <30 mg/dL >300 mg/dL Magnesium <1.0 mg/dL >4.7 mg/dL Phosphorus <1 mg/dL None Potassium <2.8 mEq/L >6.2 mEq/L Potassium (newborns) <2.5 mEq/L >8.0 mEq/L Sodium <120 mEq/L >160 mEq/L BUN (except dialysis patients) 2 mg/dL >80 mg/dL CEREBROSPINAL FLUID Low High Glucose <80% of blood level Protein, total None >45 mg/dL Positive bacterial stain (e.g., Gram, acid-fast), antigen detection, culture, or India ink preparation WBC in CSF None >10/cu mm Presence of malignant cells or blasts or any other body fluid MICROBIOLOGY Positive blood culture Positive Gram stain or culture from any body fluid (e.g., pleural, peritoneal, joint) Positive acid-fast stain or culture from any site Positive culture or isolate for Corynebacterium diphtheriae, Cryptococcus neoformans, Bordetella pertussis, Neisseria gonorrhoeae (only nongenital sites), dimorphic fungi (Histoplasma, Coccidioides, Blastomyces, Paracoccidioides) Presence of blood parasites (e.g., malaria organisms, Babesia, microfilaria) Positive antigen detection (e.g., Cryptococcus, group B streptococci, Haemophilus influenzae type B, Neisseria meningitidis, Streptococcus pneumoniae) Stool culture positive for Salmonella, Shigella, Campylobacter, Vibrio, or Yersinia
- 23. URINALYSIS Strongly positive test for glucose and ketone Presence of reducing sugars in infants Presence of pathological crystals (urate, cysteine, leucine, tyrosine) SEROLOGY Incompatible cross match Positive direct and indirect antiglobulin (Coombs') test on routine specimens Positive direct antiglobulin (Coombs') test on cord blood Titers of significant RBC alloantibodies during pregnancy Transfusion reaction workup showing incompatible unit of transfused blood Failure to call within 72 hrs for Rh Ig after possible or known exposure to Rh-positive RBCs Positive confirmed test for hepatitis, syphilis, acquired immunodeficiency syndrome (AIDS) Increased blood antibody levels for infectious agents. THERAPEUTIC DRUGS Blood Levels Acetaminophen >150 µg/mL Carbamazepine >20 µg/mL Chloramphenicol >50 µg/mL (peak) Digitoxin >35 ng/mL Digoxin >2.5 ng/mL Ethosuximide >200 µg/mL Gentamicin >12 µg/mL Imipramine >400 ng/mL Lidocaine >9 µg/mL Lithium >2 mEq/L Phenobarbital >60 µg/mL Phenytoin >40 µg/mL Primidone >24 µg/mL Quinidine >10 µg/mL Salicylate >700 µg/mL Theophylline >25 µg/mL Tobramycin >12 µg/mL (peak) See Chapter 18, Therapeutic Drug Monitoring and Toxicology, for toxic levels of various therapeutic drugs and toxic substances. In addition, the physician is promptly notified of any of the following: Serum glucose, fasting >130 mg/dL Serum glucose, random >250 mg/dL Serum cholesterol >300 mg/dL Serum total protein >9.0 mg/dL Blood lead Increased Urinalysis Pus, blood, or protein ³2+ Urine colony count/culture >50,000 colonies/mL of single organism Respiratory culture Heavy growth of pathogen Peripheral blood smear Atypical lymphocytes, plasma cells Some data from Emmancipator K. Critical values. ASCP practice parameter. Am J Clin Pathol 1997;108:247.
- 24. CHAPTER 3 CORE BLOOD ANALYTES: ALTERATIONS BY DISEASES Interpretation of Diagnostic Tests CHAPTER 3 CORE BLOOD ANALYTES: ALTERATIONS BY DISEASES Alanine Aminotransferase (ALT; Serum Glutamic-Pyruvic Transaminase [SGPT]) Alkaline Phosphatase (ALP) Ammonia Antistreptococcal Antibody Titers (ASOT) Apolipoproteins Aspartate Aminotransferase (AST; Serum Glutamic-Oxaloacetic Transaminase [SGOT]) AST/ALT (SGOT/SGPT) Ratio Autohemagglutination, Cold Bilirubin Blood Urea Nitrogen (BUN)/Creatinine Ratio Calcium, Ionized Calcium, Total Chloride Cholesterol, High-Density Lipoprotein (HDL) Cholesterol, Low-Density Lipoprotein (LDL) Cholesterol, Triglycerides Complement C-Reactive Protein (CRP) Creatine Creatine Kinase (CK), Total Creatine Kinase (CK) Isoenzymes Creatinine Erythrocyte Sedimentation Rate (ESR) 5'-Nucleotidase (5'-N) Gamma-Glutamyl Transferase (GGT) Glucose Immunoglobulin A (IgA) Immunoglobulin D (IgD) Immunoglobulin E (IgE) Immunoglobulin G (IgG) Immunoglobulin M (IgM) Immunologic Tests Inflammatory Reactants, Acute Lactate Dehydrogenase (LD) Lactate Dehydrogenase Isoenzymes Leucine Aminopeptidase (LAP) Magnesium (Mg) Osmolality Osmolal Gap >10 Due to Phosphorus Plasma, Discolored Potassium Pregnancy Test Protein Gammopathies Protein, Total Protein Separation (Immunodiffusion, Immunofixation, Electrophoresis) Sodium Urea Nitrogen (BUN) Uric Acid Vitamin D ALANINE AMINOTRANSFERASE (ALT; SERUM GLUTAMIC-PYRUVIC TRANSAMINASE [SGPT]) Use Differential diagnosis of diseases of hepatobiliary system and pancreas Repeat testing to establish chronicity of viral hepatitis Generally parallels but lower than AST in alcohol-related diseases Increased In See serum AST Obesity (not AST; modest increase to 1–3× ULN) Severe preeclampsia (both) Rapidly progressing acute lymphoblastic leukemia (both) Levels in females ~75% of those in males Decreased In GU tract infection Malignancy Pyridoxal phosphate deficiency states (e.g., malnutrition, pregnancy, alcoholic liver disease) Others Albumin (Generally parallels total protein except when total protein changes are due to gamma globulins) Use Marker of disorders of protein metabolism (e.g., nutritional, decreased synthesis, increased loss) Increased In Dehydration (relative increase) Intravenous (IV) albumin infusions Decreased In Inadequate intake (e.g., malnutrition)
- 25. Decreased absorption (e.g., malabsorption syndromes) Increased need (e.g., hyperthyroidism, pregnancy) Impaired synthesis (e.g., liver diseases, chronic infection, hereditary analbuminemia) Increased breakdown (e.g., neoplasms, infection, trauma) Increased loss (e.g., edema, ascites, burns, hemorrhage, nephrotic syndrome, protein-losing enteropathy) Dilutional states (e.g., IV fluids, SIADH, psychogenic diabetes/water intoxication) Congenital deficiency ALKALINE PHOSPHATASE (ALP) (See also Table 13-7.) Use Diagnosis of causes and monitoring of course of cholestasis (e.g., neoplasm, drugs) Diagnosis of various bone disorders (e.g., Paget's disease, osteogenic sarcoma) Interferences Intravenous injection of albumin; sometimes marked increase (e.g., 10× normal level) lasting for several days (placental origin); total parenteral nutrition (TPN) Decreased by collection of blood in EDTA, fluoride, or oxalate anticoagulant Increased (£30%) by standing at room or refrigerator temperature Increased In Bone origin—increased deposition of calcium Hyperparathyroidism. Paget's disease (osteitis deformans) (highest reported values 10–20× normal). Marked elevation in absence of liver disease is most suggestive of Paget's disease of bone or metastatic carcinoma from prostate. Increase in cases of metastases to bone is marked only in prostate carcinoma. Osteoblastic bone tumors (osteogenic sarcoma, metastatic carcinoma). Osteogenesis imperfecta (due to healing fractures). Familial osteoectasia. Osteomalacia, rickets. Polyostotic fibrous dysplasia. Osteomyelitis. Late pregnancy; reverts to normal level by 20th day postpartum. Children. Administration of ergosterol. Hyperthyroidism. Transient hyperphosphatasemia of infancy. Hodgkin's disease. Healing of extensive fractures (slightly). Liver disease—any obstruction of biliary system (e.g., stone, carcinoma, primary biliary cirrhosis); is a sensitive indicator of intra- or extrahepatic cholestasis. Whenever the ALP is elevated, a simultaneous elevation of 5'-NT establishes biliary disease as the cause of the elevated ALP. If the 5'-NT is not increased, the cause of the elevated ALP must be found elsewhere, e.g., bone disease. Nodules in liver (metastatic or primary tumor, abscess, cyst, parasite, tuberculosis [TB], sarcoid); is a sensitive indicator of a hepatic infiltrate. Increase >2× upper limit of normal in patients with primary breast or lung tumor with osteolytic metastases is more likely due to liver than bone metastases. Liver infiltrates (e.g., amyloid or leukemia). Cholangiolar obstruction in hepatitis (e.g., infectious, toxic). Hepatic congestion due to heart disease. Adverse reaction to therapeutic drug (e.g., chlorpropamide) (progressive elevation of serum ALP may be first indication that drug therapy should be halted); may be 2–20× normal. Increased synthesis of ALP in liver. Diabetes mellitus—44% of diabetic patients have 40% increase of ALP. Parenteral hyperalimentation of glucose. Liver diseases with increased ALP. <3–4× increase lacks specificity and may be present in all forms of liver disease. 2× increase: acute hepatitis (viral, toxic, alcoholic), acute fatty liver, cirrhosis. 5× increase: infectious mononucleosis, postnecrotic cirrhosis. 10× increase: carcinoma of head of pancreas, choledocholithiasis, drug chole-static hepatitis. 15–20× increase: primary biliary cirrhosis, primary or metastatic carcinoma. Chronic therapeutic use of anticonvulsant drugs (e.g., phenobarbital, phenytoin) Hodgkin's disease. Placental origin—appears 16th–20th wk of normal pregnancy, increases progressively to 2× normal up to onset of labor, disappears 3–6 days after delivery of placenta. May be increased during complications of pregnancy (e.g., hypertension, preeclampsia, eclampsia, threatened abortion) but difficult to interpret without serial determinations. Lower in diabetic than in nondiabetic pregnancy. Intestinal origin—is a component in ~25% of normal sera; increases 2 hrs after eating in persons with blood type B or O who are secretors of H blood group. Has been reported to be increased in cirrhosis, various ulcerative diseases of GI tract, severe malabsorption, chronic hemodialysis, acute infarction of intestine. Benign familial hyperphosphatasemia.
- 26. Ectopic production by neoplasm (Regan isoenzyme) without involvement of liver or bone (e.g., Hodgkin's disease, cancer of lung, breast, colon, or pancreas; highest incidence in ovary and cervical cancer) Vascular endothelium origin—some patients with myocardial, pulmonary, renal (one-third of cases), or splenic infarction, usually after 7 days during phase of organization Hyperphosphatasia (liver and bone isoenzymes) Hyperthyroidism (liver and bone isoenzymes). Increased ALP alone in a chemistry profile, especially with a decreased serum cholesterol and lymphocytosis, should suggest excess thyroid medication or hyperthyroidism. Primary hypophosphatemia (often increased) ALP isoenzyme determinations are not widely used clinically; heat inactivation may be more useful to distinguish bone from liver source of increased ALP. Extremely (90%) heat labile: bone, vascular endothelium, reticuloendothelial system. Extremely (90%) heat stable: placenta, neoplasms. Intermediate (60–80%) heat stable: liver, intestine. Also differentiate by chemical inhibition (e.g., L-phenylalanine) or use serum LAP. Children—mostly bone; little or no liver or intestine. Adults—liver with little or no bone or intestine; after age 50, increasing amounts of bone. Normal In Inherited metabolic diseases (Dubin-Johnson, Rotor's, Gilbert, Crigler-Najjar syndromes; types I to V glycogenoses, mucopolysaccharidoses; increase in Wilson's disease and hemochromatosis related to hepatic fibrosis) Consumption of alcohol by healthy persons (in contrast to GGT); may be normal even in alcoholic hepatitis. In acute icteric viral hepatitis, increase is <2× normal in 90% of cases, but when ALP is high and serum bilirubin is normal, infectious mononucleosis should be ruled out as cause of hepatitis. Decreased In Excess vitamin D ingestion Milk-alkali (Burnett's) syndrome Congenital hypophosphatasia Achondroplasia Hypothyroidism, cretinism Pernicious anemia (PA) in one-third of patients Celiac disease Malnutrition Scurvy Zinc deficiency Magnesium deficiency Postmenopausal women with osteoporosis taking estrogen replacement therapy Therapeutic agents (e.g., corticosteroids, trifluoperazine, antilipemic agents, some hyperalimentation) Cardiac surgery with cardiopulmonary bypass pump AMMONIA Use Increased in some inherited metabolic disorders, especially ornithine carbamoyltransferase deficiency, citrullinemia, argininosuccinic aciduria. Should be measured in cases of unexplained lethargy and vomiting, encephalopathy, or in any newborn with unexplained neurological deterioration. Not useful to assess degree of dysfunction; e.g., in Reye's syndrome, hepatic function improves and ammonia level falls even in patients who finally die of this. Increased In Certain inborn errors of metabolism (see Chapter 12) Transient hyperammonemia in newborn; unknown etiology; may be life-threatening in first 48 hrs. Moribund children—moderate increases (£300 µmol/L) without being diagnostic of a specific disease. May occur in any patient with severe liver disease (e.g., acute hepatic necrosis, terminal cirrhosis, hepatectomy). Increased in most cases of hepatic coma but correlates poorly with degree of encephalopathy. In cirrhosis, blood ammonia may be increased after portacaval anastomosis. GU tract infection with distention and stasis Sodium valproate therapy
- 27. Decreased In Hyperornithinemia (deficiency of ornithine aminotransaminase activity) with gyrate atrophy of choroid and retina ANTISTREPTOCOCCAL ANTIBODY TITERS (ASOT) Use Individual determinations depend on various factors (e.g., duration and severity of infection, antigenicity) and are of limited clinical value. Serial determinations are most desirable; a 4× increase in ASOT confirms immunologic response to streptococcal organisms. A high or rising titer is indicative only of current or recent streptococcal infection. Direct diagnostic value in Scarlet fever Erysipelas Streptococcal pharyngitis and tonsillitis Indirect diagnostic value in Rheumatic fever Glomerulonephritis Detection of subclinical streptococcal infection Differential diagnosis of joint pains of rheumatic fever and rheumatoid arthritis (RA) Increased In Antibody appears as early as 1 wk after infection; titer rises rapidly by 3–4 wks and then declines quickly; may remain elevated for months. Even in severe streptococcal infection, ASOT will be increased in only 70–80% of patients. Conditions Usual ASO Titer (Todd Units) Normal persons 12–166 Active rheumatic fever 500–5000 Inactive rheumatic fever 12–250 RA 12–250 Acute GN 500–5000 Streptococcal URI 100–333 Collagen diseases 12–250 False positives are associated with TB, liver disease (e.g., active viral hepatitis), bacterial contamination. ASOT is increased in only 30–40% of patients with streptococcal pyoderma and 50% of patients with poststreptococcal GN; DNase antibodies are the most sensitive indicators of these conditions. DNase B titers may also be helpful in diagnosis of delayed sequelae of Sydenham's chorea because they are detectable for several months. Other streptococcal antigens may be tested Antistreptococcal hyaluronidase (significant titer >128) Antideoxyribonuclease (DNase B) (significant titer >10) Interferences Latex agglutination method may give false positive in markedly lipemic or contaminated specimens. APOLIPOPROTEINS Apolipoprotein A-I Use Decreased level is associated with increased risk of coronary heart disease (CHD). Increased In Familial hyperalphalipoproteinemia Pregnancy Estrogen therapy Alcohol consumption Exercise Decreased In Tangier disease “Fish-eye” disease Familial hypoalphalipoproteinemia
- 28. Familial lecithin-cholesterol acyltransferase deficiency Type I and type V hyperlipoproteinemia Diabetes mellitus Cholestasis Hemodialysis Infection Drugs (e.g., diuretics, beta-blockers, androgenic steroids, glucocorticoids, cyclosporine) Apolipoprotein A-II Increased In Alcohol consumption Decreased In Tangier disease Cholestasis Cigarette smoking Apolipoprotein A-IV Increased In Postprandial lipemia Decreased In Abetalipoproteinemia Chronic pancreatitis Malabsorption Obstructive jaundice Acute hepatitis Total parenteral nutrition Apolipoprotein (a) Use Increased risk of CHD with serum levels >0.03 gm/L Increased In Pregnancy Patients who have had acute myocardial infarction (AMI) Decreased In Drugs (e.g., nicotinic acid, neomycin, anabolic steroids) Apolipoprotein B-48 Normally absent during fasting Increased In Hyperlipoproteinemia (types I, V) Apoprotein (apo) E deficiency Decreased In Liver disease Hypo- and abetalipoproteinemia Malabsorption Apolipoprotein B-100 Use
- 29. Increased levels are associated with increased risk of CHD. Increased In Hyperlipoproteinemia (types IIa, IIb, IV, V) Familial hyperapobetalipoproteinemia Nephrotic syndrome Pregnancy Biliary obstruction Hemodialysis Cigarette smoking Drugs (e.g., diuretics, beta-blockers, cyclosporine, glucocorticoids) Decreased In Hypo- and abetalipoproteinemia Type I hyperlipoproteinemia (hyperchylomicronemia) Liver disease Exercise Infections Drugs (e.g., cholesterol-lowering drugs, estrogens) Apolipoprotein C-1 Increased In Hyperlipoproteinemia (types I, III, IV, V) Decreased In Tangier disease Apolipoprotein C-II Increased In Hyperlipoproteinemia (types I, III, IV, V) Decreased In Tangier disease Hypoalphalipoproteinemia Apo C-II deficiency Nephrotic syndrome Apolipoprotein C-III Use With combined hereditary apo A-I and apo C-III deficiency increased risk of premature CHD. Increased In Hyperlipoproteinemia (types III, IV, V) Decreased In Tangier disease Combined with hereditary deficiency apo A-I Apolipoprotein E Increased In Hyperlipoproteinemia (types I, III, IV, V) Pregnancy Cholestasis
- 30. Multiple sclerosis in remission Drugs (e.g., dexamethasone) Decreased In Drugs (e.g., ACTH) ASPARTATE AMINOTRANSFERASE (AST; SERUM GLUTAMIC-OXALOACETIC TRANSAMINASE [SGOT]) Use Differential diagnosis of diseases of hepatobiliary system and pancreas Formerly surrogate test for screening blood donors for hepatitis Interferences Increase due to hemolysis, lipemia Increase due to calcium dust in air (e.g., due to construction in laboratory) Increased due to enzyme activation during test Therapy with oxacillin, ampicillin, opiates, erythromycin Decreased (because of increased serum lactate–consuming enzyme during test) Diabetic ketoacidosis Beriberi Severe liver disease Chronic hemodialysis (reason unknown) Uremia—proportional to BUN level (reason unknown) Increased In Liver diseases (see Chapter 8) Active necrosis of parenchymal cells is suggested by extremely high levels. Acute viral hepatitis shows greatest increases; may be 20× to 100×. Rapid rise and decline suggests extrahepatic biliary disease. Administration of opiates to patients with diseased biliary tract or previous cholecystectomy causes increase in LD and especially AST. AST increases by 2–4 hrs, peaks in 5–8 hrs; increase may persist for 24 hrs; elevation may be 2.5–65× normal. Congestion, e.g., heart failure, cirrhosis, biliary obstruction, primary or metastatic cancer, granulomas, hepatic ischemia. Eclampsia. Hepatotoxic drugs and chemicals (e.g., carbon tetrachloride). Musculoskeletal disorders (see Chapter 10), including trauma, surgery, and IM injections Myoglobinuria Acute myocardial infarction Others Acute pancreatitis Intestinal injury (e.g., surgery, infarction) Local irradiation injury Pulmonary infarction (relatively slight increase) Cerebral infarction (increased in following week in 50% of patients) Cerebral neoplasms (occasionally) Renal infarction (occasionally) Drugs (e.g., heparin therapy, salicylates, opiates, tetracycline, chlorpromazine [Thorazine], isoniazid) Burns Heat exhaustion Mushroom poisoning Lead poisoning (not useful for screening) Hemolytic anemia Marked Increase (>3000 U/L) In Acute hypotension (e.g., AMI, sepsis, post–cardiac surgery) Toxic liver injury (e.g., drugs) Viral hepatitis Liver trauma Liver metastases Rhabdomyolysis Decreased In Azotemia
- 31. Chronic renal dialysis Pyridoxal phosphate deficiency states (e.g., malnutrition, pregnancy, alcoholic liver disease) Normal In Angina pectoris Coronary insufficiency Pericarditis Congestive heart failure without liver damage Varies <10 U/day in the same person. AST/ALT (SGOT/SGPT) RATIO (Normal = 0.7–1.4 depending on methodology.) Use Differential diagnosis of diseases of hepatobiliary system and pancreas Increased In Drug hepatotoxicity (>2.0) Alcoholic hepatitis (>2.0 is highly suggestive; may be £6.0) Cirrhosis (1.4–2.0) Intrahepatic cholestasis (>1.5) Hepatocellular carcinoma Chronic hepatitis (slightly increased; 1.3) Decreased In Acute hepatitis due to virus, drugs, toxins (with AST increased 3–10× upper limit of normal) (usually £0.65; ratio 0.3–0.6 is said to be a good prognostic sign but higher ratio of 1.2–1.6 is a poor prognostic sign) Extrahepatic cholestasis (normal or slightly decreased; 0.8) 1 AUTOHEMAGGLUTINATION, COLD Use Primary atypical (Mycoplasma) pneumonia (30–90% of patients): titer ³1:14–1:224. Not ruled out by negative titer. Increased In Atypical hemolytic anemia Paroxysmal hemoglobinuria Raynaud's disease Cirrhosis of the liver Trypanosomiasis Malaria Infectious mononucleosis Adenovirus infections Influenza Psittacosis Mumps Measles Scarlet fever Rheumatic fever Some cases of lymphoma BILIRUBIN
- 32. See Chapter 8, Hepatobiliary Diseases and Diseases of the Pancreas. Use Differential diagnosis of diseases of hepatobiliary system and pancreas and other causes of jaundice. Jaundice becomes apparent clinically at ³2.5 mg/dL. Interferences Exposure to either white or ultraviolet light decreases total and indirect bilirubin 2% to >20%. Fasting for 48 hrs produces a mean increase of 240% in healthy persons and 194% in those with hepatic dysfunction. Increased Direct (Conjugated) Bilirubin In Hereditary disorders (e.g., Dubin-Johnson syndrome, Rotor's syndrome) Hepatic cellular damage. Increased conjugated bilirubin may be associated with normal total bilirubin in up to one-third of patients with liver diseases. Viral Toxic Alcohol related Drug related Methodologic interference Evelyn-Malloy (dextran, novobiocin) Diazo reaction (ethoxazene, histidine, indican, phenazopyridine, rifampin, theophylline, tyrosine) SMA 12/60 (aminophenol, ascorbic acid, epinephrine, isoproterenol, levodopa, methyldopa, phenelzine) Spectrophotometric methods (drugs that cause lipemia) Other effects (e.g., toxic, cholestasis) Biliary duct obstruction Extrahepatic Intrahepatic Infiltrations, space-occupying lesions, e.g., Metastatic tumor Abscess Granulomas Amyloidosis Direct bilirubin 20–40% of total: more suggestive of hepatic than posthepatic jaundice 40–60% of total: occurs in either hepatic or posthepatic jaundice >50% of total: more suggestive of posthepatic than hepatic jaundice Total serum bilirubin >40 mg/dL indicates hepatocellular rather than extrahepatic obstruction. Increased Unconjugated (Indirect) Bilirubin (Conjugated <20% of Total) Increased bilirubin production Hemolytic diseases (e.g., hemoglobinopathies, RBC enzyme deficiencies, disseminated intravascular coagulation [DIC], autoimmune hemolysis) Ineffective erythropoiesis (e.g., PA) Blood transfusions Hematomas Hereditary disorders (e.g., Gilbert's disease, Crigler-Najjar syndrome) Drugs (e.g., causing hemolysis) Decreased In Drugs (e.g., barbiturates) Interferences Presence of hemoglobin Exposure to sunlight or fluorescent light Decreased In Ingestion of certain drugs (e.g., barbiturates) BLOOD UREA NITROGEN (BUN)/CREATININE RATIO (See also Table 15-3.) Normal range for healthy person on normal diet = 12–20; ratio for most individuals is 12–16. Because of considerable variability, should be used only as a rough
- 33. guide. Use Differentiate pre- and postrenal azotemia from renal azotemia Increased Ratio (>20:1) with Normal Creatinine In Prerenal azotemia (BUN rises without increase in creatinine) (e.g., heart failure, salt depletion, dehydration, blood loss) due to decreased glomerular filtration rate Catabolic states with increased tissue breakdown GI hemorrhage. It has been reported that ratio ³36 distinguishes upper from lower GI hemorrhage in patients with negative gastric aspirate. High protein intake Impaired renal function plus Excess protein intake or production or tissue breakdown (e.g., GI bleeding, thyrotoxicosis, infection, Cushing's syndrome, high-protein diet, surgery, burns, cachexia, high fever) Urine reabsorption (e.g., ureterocolostomy) Reduced muscle mass (subnormal creatinine production) Certain drugs (e.g., tetracycline, glucocorticoids) Increased Ratio (>20:1) with Elevated Creatinine In Postrenal azotemia (BUN rises disproportionately more than creatinine) (e.g., obstructive uropathy) Prerenal azotemia superimposed on renal disease Decreased Ratio (<10:1) with Decreased BUN In Acute tubular necrosis Low protein diet, starvation, severe liver disease, and other causes of decreased urea synthesis Repeated dialysis (urea rather than creatinine diffuses out of extracellular fluid) Inherited hyperammonemias (urea is virtually absent in blood) SIADH (due to tubular secretion of urea) Pregnancy Decreased Ratio (<10:1) with Increased Creatinine In Phenacemide therapy (accelerates conversion of creatine to creatinine) Rhabdomyolysis (releases muscle creatinine) Muscular patients who develop renal failure Inappropriate Ratio Diabetic ketoacidosis (acetoacetate causes false increase in creatinine with certain methodologies, resulting in normal ratio when dehydration should produce an increased BUN/creatinine ratio) Cephalosporin therapy (interferes with creatinine measurement) CALCIUM, IONIZED See Calcium, Total. Use In patients with hypo- or hypercalcemia with borderline serum calcium and altered serum proteins ~50% of calcium is ionized; 40–45% is bound to albumin; 5–10% is bound to other anions (e.g., sulfate, phosphate, lactate, citrate); only ionized fraction is physiologically active. Total calcium values may be deceiving because they may be unchanged even if ionized calcium values are changed; e.g., increased blood pH increases protein-bound calcium and decreases ionized calcium, and parathyroid hormone has opposite effect ( blood pH should always be performed with ionized calcium, which is increased in acidosis and decreased in alkalosis). However, in critically ill patients, elevated total serum calcium usually indicates ionized hypercalcemia, and a normal total serum calcium is evidence against ionized hypocalcemia. Ionized calcium is the preferred measurement rather than total calcium because it is physiologically active and can be rapidly measured, which may be essential in certain situations (e.g., liver transplantation, rapid or large transfusion of citrated blood that makes interpretation of total calcium nearly impossible). Life-threatening complications are frequent when serum ionized calcium is <2 mg/dL (<0.50 mmol/L). With multiple blood transfusions, ionized calcium <3 mg/dL (<0.95 mmol/L) may be an indication to administer calcium. Reference ranges for ionized calcium vary with method and type of sample preparation (e.g., brand of heparin used) and should be determined by each laboratory. Sample ranges (mmol/L) are: Age Values Adult 1.15–1.35 1 yr to adult 1.29–1.31 5 days 1.24–1.44
- 34. 3 days 1.16–1.36 1 day 1.11–1.31 Interferences Hypo- or hypermagnesemia; patients respond to serum magnesium that becomes normal but not to calcium therapy. Serum magnesium should always be measured in any patient with hypocalcemia. Increase of ions to which calcium is bound Phosphate (e.g., phosphorus administration in treatment of diabetic ketoacidosis, chemotherapy causing tumor lysis syndrome, rhabdomyolysis) Bicarbonate Citrate (e.g., during blood transfusion) Radiographic contrast media containing calcium chelators (edetate, citrate) Increased In Normal total serum calcium associated with hypoalbuminemia may indicate ionized hypercalcemia. ~25% of patients with hyperparathyroidism have normal total but increased ionized calcium levels. Decreased In Hyperventilation (e.g., to control increased intracranial pressure) (total serum calcium may be normal) Administration of bicarbonate to control metabolic acidosis Increased serum free fatty acids (increase calcium binding to albumin) due to Certain drugs (e.g., heparin, intravenous lipids, epinephrine, norepinephrine, isoproterenol, alcohol) Severe stress (e.g., acute pancreatitis, diabetic ketoacidosis, sepsis, AMI) Hemodialysis Hypoparathyroidism (primary, secondary) Vitamin D deficiency Toxic shock syndrome Fat embolism Hypokalemia protects patient from hypocalcemic tetany; correction of hypokalemia without correction of hypocalcemia may provoke tetany. CALCIUM, TOTAL See Fig. 13-6 and Table 13-8. Use Diagnosis of parathyroid dysfunction, hypercalcemia of malignancy. 90% of cases of hypercalcemia are due to hyperparathyroidism, neoplasms, or granulomatous diseases. Hypercalcemia of sarcoidosis, adrenal insufficiency, and hyperthyroidism tend to be found in clinically evident disease. Blood calcium should be monitored in renal failure, effects of various drugs, acute pancreatitis, postoperative thyroidectomy, and parathyroidectomy. Interferences Increased by Elevated serum protein Dehydration Venous stasis during blood collection by prolonged application of tourniquet Use of cork-stoppered test tubes Hyponatremia (<120 mEq/L), which increases protein-bound fraction of calcium thereby slightly increasing the total calcium (opposite effect in hypernatremia) Decreased by Hypomagnesemia (e.g., due to cisplatin chemotherapy) Hyperphosphatemia (e.g., due to laxatives, phosphate enemas, chemotherapy for leukemia or lymphoma, rhabdomyolysis). Hypoalbuminemia Hemodilution Total serum protein and albumin should always be measured simultaneously for proper interpretation of serum calcium levels, because 0.8 mg of calcium is bound to 1.0 gm of albumin in serum; to correct, add 0.8 mg/dL for every 1.0 g/dL that serum albumin falls below 4.0 g/dL; binding to globulin affects total calcium only if globulin is >6 gm/dL. Increased In Hyperparathyroidism Primary Secondary Acute and chronic renal failure Post–renal transplant Osteomalacia with malabsorption Aluminum-associated osteomalacia
- 35. Malignant tumors (especially breast, lung, kidney; 2% of patients with Hodgkin's or non-Hodgkin's lymphoma) Direct bone metastases (up to 30% of these patients) (e.g., breast cancer, Hodgkin's and non-Hodgkin's lymphoma, leukemia, pancreatic cancer, lung cancer) Osteoclastic activating factor (e.g., multiple myeloma, Burkitt's lymphoma; may be markedly increased in adult T-cell [HTLV] lymphoma) Humoral hypercalcemia of malignancy (parathyroid hormone–related protein [PTHrP]) Ectopic production of 1,25-dihydroxyvitamin D3 (e.g., Hodgkin's and non-Hodgkin's lymphoma) Effect of drugs Vitamin D intoxication Milk-alkali (Burnett's) syndrome Diuretic use (thiazide and chlorthalidone rarely increase serum calcium >1.0 mg/dL) Use of therapeutic agents (estrogens, androgens, progestins, tamoxifen, lithium) Others (e.g., vitamin A intoxication, thyroid hormone use, parenteral nutrition) Chronic renal failure Other endocrine conditions Hyperthyroidism (in 20–40% of patients; usually <14 mg/dL) Hypothyroidism in some patients, Cushing's syndrome, adrenal insufficiency acromegaly, pheochromocytoma, vasoactive intestinal polypeptide hormone–producing tumor Multiple endocrine neoplasia (MEN) syndrome Granulomatous disease (1,25-dihydroxyvitamin D excess) (e.g., sarcoidosis, TB, leprosy, mycoses, berylliosis, silicone granulomas) Acute osteoporosis (e.g., immobilization of young patients or in Paget's disease) Polyuric phase of acute renal failure Miscellaneous Familial hypocalciuric hypercalcemia Rhabdomyolysis causing acute renal failure Porphyria Dehydration with hyperproteinemia Hypophosphatasia Idiopathic hypercalcemia of infancy Decreased In Hypoparathyroidism Surgical Idiopathic Infiltration of parathyroids (e.g., sarcoidosis, amyloidosis, hemochromatosis, tumor) Congenital (DiGeorge syndrome) Pseudohypoparathyroidism Malabsorption of calcium and vitamin D Obstructive jaundice Chronic renal disease with uremia and phosphate retention; Fanconi's syndrome; renal tubular acidosis Acute pancreatitis with extensive fat necrosis Insufficient calcium, phosphorus, and vitamin D ingestion Bone disease (osteomalacia, rickets) Starvation Late pregnancy Use of certain drugs Cancer chemotherapy drugs (e.g., cisplatin, mithramycin, cytosine arabinoside) Fluoride intoxication Antibiotics (e.g., gentamicin, pentamidine, ketoconazole) Chronic therapeutic use of anticonvulsant drugs (e.g., phenobarbital, phenytoin) Loop-active diuretics Calcitonin Multiple citrated blood transfusions Neonates born of complicated pregnancies Hyperbilirubinemia Respiratory distress, asphyxia Cerebral injuries Infants of diabetic mothers Prematurity Maternal hypoparathyroidism Hypomagnesemia Malignant disease
- 36. Toxic shock syndrome Rhabdomyolysis Tumor lysis syndrome Temporary hypocalcemia after subtotal thyroidectomy in >40% of patients; >20% are symptomatic. Concomitant hypokalemia is not infrequent in hypercalcemia. Concomitant dehydration is almost always present because hypercalcemia causes nephrogenic diabetes insipidus. CHLORIDE Use With sodium, potassium, and carbon dioxide to assess electrolyte, acid-base, and water balance. Usually changes in same direction as sodium except in metabolic acidosis with bicarbonate depletion and metabolic alkalosis with bicarbonate excess when serum sodium levels may be normal. Interferences Hyperlipidemia (artifactual change; see Sodium) Increased In Metabolic acidosis associated with prolonged diarrhea with loss of NaHCO 3 Renal tubular diseases with decreased excretion of H+ and decreased reabsorption of HCO3 – (“hyperchloremic metabolic acidosis”) Respiratory alkalosis (e.g., hyperventilation, severe central nervous system [CNS] damage) Drugs Excessive administration of certain drugs (e.g., NH4Cl, IV saline, salicylate intoxication; acetazolamide therapy) False (methodological) increase due to bromides or other halogens Retention of salt and water (e.g., corticosteroids, guanethidine, phenylbutazone) Some cases of hyperparathyroidism Diabetes insipidus, dehydration Sodium loss > chloride loss (e.g., diarrhea, intestinal fistulas) Ureterosigmoidostomy Decreased In Prolonged vomiting or suction (loss of HCl) Metabolic acidoses with accumulation of organic anions (see Anion Gap Classification) Chronic respiratory acidosis Salt-losing renal diseases Adrenocortical insufficiency Primary aldosteronism Expansion of extracellular fluid (e.g., SIADH, hyponatremia, water intoxication, congestive heart failure) Burns Drugs Alkalosis (e.g., bicarbonates, aldosterone, corticosteroids) Diuretic effect (e.g., ethacrynic acid, furosemide, thiazides) Other loss (e.g., chronic laxative abuse) CHOLESTEROL, HIGH-DENSITY LIPOPROTEIN (HDL) CHOLESTEROL, LOW-DENSITY LIPOPROTEIN (LDL) CHOLESTEROL, TRIGLYCERIDES See Disorders of Lipid Metabolism. COMPLEMENT Use Evaluate role of complement in immune disorders. Determine if deficiency is acquired or genetic. Normal In Renal diseases IgG-IgA nephropathy (Berger's disease)
- 37. Idiopathic rapidly progressive GN Anti–glomerular basement membrane disease Immune-complex disease Negative immunofluorescence findings Systemic diseases Polyarteritis nodosa Hypersensitivity vasculitis Wegener's granulomatosis Schönlein-Henoch purpura Goodpasture's syndrome Visceral abscess Decreased In (Acquired) Common diseases associated with arthritis Active SLE, particularly associated with renal disease Prodromal hepatitis B virus (HBV) hepatitis Essential mixed cryoglobulinemia Sjögren's syndrome Serum sickness Short bowel syndrome Common diseases associated with vasculitis Rheumatoid vasculitis Essential mixed cryoglobulinemia Sjögren's syndrome Hypocomplementemic vasculitis Wegener's granulomatosis Common diseases associated with nephritis % of Cases in Which Occurs Acute poststreptococcal GN Transient (3–8 wks) decline in C3 Membranoproliferative GN Type I (“classic” membranopro-liferative GN) 50–80% Type II (“dense deposit disease”) SLE 80–90%; C3 often remains depressed Focal 75% Diffuse 90% Subacute bacterial endocarditis (SBE) 90% Cryoglobulinemia 85% “Shunt” nephritis 90% Serum sickness Atheromatous emboli Decreased In (Inherited) Deficient Complement SLE C1qINH, C1q, C1r, C1s, C2, C4, C5, C8 Hereditary angioedema C1qINH Familial Mediterranean fever C5aINH Urticarial vasculitis C3 GN C1r, C2 Severe combined immunodeficiency C1q X-linked hypogammaglobulinemia C1q Recurrent infections C3, C3bINH Recurrent neisserial infections C5, C6, C7, C8 Increased In Inflammatory conditions that increase acute-phase reactants Use of Individual Complement Levels CH50 detects activation of classic pathway; measures functional activity of C1 through C9; is useful for screening because a normal result indicates classic complement pathway is functionally intact. Decrease indicates 50–80% of normal amounts have been depleted. Detects all inborn and most acquired complement deficiencies. AH50 measures only activity of alternative pathway. C3 is useful for screening for activation of classic and alternate complement pathways. May be increased in subacute inflammation, biliary obstruction, nephrotic syndrome, corticosteroid therapy. May be decreased in immune complex disease (especially lupus nephritis), acute poststreptococcal GN, hypercatabolism (especially C3b inactivator deficiency), massive necrosis and tissue injury, sepsis, viremia, hereditary deficiency, infancy. C3 or CH50 may be useful for monitoring disease activity in SLE but usefulness may vary from case to case. C4 may be decreased in immune complex disease (especially lupus nephritis), hereditary angioneurotic edema, hereditary deficiency, acute GN, infancy, or when classic pathway is activated. Decreased C3 and C4 indicate initiation of classic activation pathway and activation of functional unit (e.g., active viral hepatitis, immune complex formation). Normal C3 with decreased C4 suggests C4 deficiency (e.g., hereditary angioedema, malaria, some SLE patients). Normal C4 and decreased C3 suggests congenital C3 deficiency or deficiency of C3b inactivator, or activation of functional unit by alternate pathway (e.g., gram-negative toxemia).
- 38. Normal C3 and C4 with decreased C50 indicates isolated deficiency of another complement component and further testing is indicated. C2 may be decreased in immune complex disease (especially lupus nephritis), hereditary angioedema, hereditary deficiency, infancy. C1 esterase inhibitor deficiency is characteristic of hereditary angioedema. In heterozygote, C1 inhibitor is substantially decreased. Patients have low CH100, C4, and C2 during attacks. C1q can be very low in acquired angioedema, severe combined immunodeficiency, and X-linked hypogammaglobulinemia. May be decreased in SLE, infancy. Absence of or marked decrease in any of the components of complement will cause absence of or marked decrease in the total hemolytic complement assay, but mild to moderate decrease of an individual component of complement may not alter this total. Deficiency of early classic pathway components (C1q, C1r, C1s, C2, C4) Serum shows absence of hemolytic complement activity. The affected component is absent or decreased on immunochemical testing. Opsonic activity and generation of chemotactic activity are defective. Infections are not a problem (because alternative pathway is intact). Symptoms due to collagen vascular disorders (e.g., nephritis, arthritis). Deficiency of C3 and C5 Serum shows absence of hemolytic complement activity. C3 or C5 is absent or decreased in serum. Defective opsonic capacity and chemotactic activity. Severe recurrent infections (e.g., pneumonia, sepsis, otitis media, chronic diarrhea). Often responds to fresh plasma. Deficiency of late classic pathway components (C6, C7, C8) Serum shows absence of hemolytic complement activity. Normal opsonization and generation of chemotactic factor. Total absence of individual component. Recurrent systemic infection due to Neisseria gonorrhoeae or Neisseria meningitidis. C-REACTIVE PROTEIN (CRP) (An acute-phase reactant; quantitative test is superior; normal value <8 mg/dL) Use Inflammatory disorders for monitoring course and effect of therapy: In any acute inflammatory change, CRP shows an earlier (begins in 4–6 hrs), more intense increase rise than ESR; with recovery, disappearance of CRP precedes the return to normal of ESR. CRP disappears when inflammatory process is suppressed by steroids or salicylates. Generally parallels ESR but is not influenced by anemia, polycythemia, spherocytosis, macrocytosis, congestive heart failure, hypergammaglobulinemia in which ESR is increased. Most useful as indicator of activity in a rheumatic disease (e.g., RA, rheumatic fever). Infection: Indicate presence of infection (30–35 mg/dL in 80–85% of acute bacterial infections and <20 mg/dL in viral infections, but not useful to differentiate bacterial from viral infections). Normal value is useful to exclude infection. Monitor recovery from infection (spontaneous or due to therapy). Diagnose postoperative and intercurrent infection: After surgery, CRP begins to increase in 4–6 hrs to peak in 48–72 hrs (usually 25–35 mg/dL), begins to decrease after third day to normal by fifth to seventh day. Should have baseline preoperative value; serial pattern is different with complicating infection or tissue necrosis. Leukemia: Fever, blast crisis, or cytotoxic drugs cause only modest elevation of CRP, but intercurrent infection stimulates significantly higher CRP levels and measurement is particularly useful to monitor response to antibiotic therapy. Not useful to differentiate graft-versus-host disease from infection after marrow transplant. Increased In Inflammatory disorders: RA, rheumatic fever, seronegative arthritides (e.g., Reiter's syndrome), vasculitis syndromes (e.g., hypersensitivity vasculitis). Inflammatory bowel disease: Significantly higher in Crohn's disease than in ulcerative colitis and corresponds to relapse, remission, and response to therapy in Crohn's disease. Chronic inflammatory diseases: Usually <8.0 mg/dL; if >10.0 mg/dL, superimposed infection should be ruled out. Tissue injury or necrosis: AMI: CRP appears within 24–48 hrs, peaks at 72 hrs, and becomes negative after 7 days; correlates with peak CK-MB levels, but CRP peak occurs 1–3 days later. Failure of CRP to return to normal indicates tissue damage in heart or elsewhere. Absent CRP increase raises question of a significant infarct in prior 2–10 days. May be increased in unstable angina but not by angina in absence of tissue necrosis. Ischemia or infarction of other tissues. Rejection of kidney or marrow transplant but not of heart transplant. Malignant (but not benign) tumors, especially breast, lung, GI tract; >10 mg/dL in one-third of cases. May be a useful tumor marker because a high CRP is often present when CEA and other tumor markers are not increased. After surgery: CRP increases within 4–6 hrs to peak at 48–72 hrs (usually at 25–35 mg/dL). Begins to decrease after third postoperative day and returns to normal by fifth to seventh day; failure to fall is more sensitive indicator of complications (e.g., infection, pulmonary infarction) than WBC, ESR, temperature, pulse rate. Burns, trauma. Infections:
- 39. Highest levels are found in acute bacterial infections (>30 mg/dL) but <20 mg/dL in acute viral infections. Lower in viral compared to bacterial infection but may be very high in both. CSF CRP has been reported specific to differentiate bacterial from viral meningitis. Infections in various sites (e.g., newborns; GU, GI, and biliary tracts, pelvic inflammatory disease [PID], CNS) or due to other organisms (e.g., parasites, fungi). In premature rupture of membranes, CRP >12.5 mg/dL in cord blood strongly suggests chorioamnionitis. Increased CRP in seriously ill neonate is indication for immediate vigorous antibiotic therapy. In children younger than 6 yrs with meningitis, CRP >20 mg/dL after 12 hrs (50 mg/dL in older patients) suggests bacterial rather than viral cause. Not Increased In Autoimmune diseases (e.g., SLE, mixed connective tissue disease, dermatomyositis, scleroderma): Little or no increase unless infection is present. Pregnancy Strenuous exercise Angina Cerebrovascular accident Seizures Asthma Common cold Rejection of heart transplant CREATINE Use Is rarely used clinically. Increased In High dietary intake (meat) Destruction of muscle Hyperthyroidism (this diagnosis almost excluded by normal serum creatine) Active RA Testosterone therapy Decreased In Not clinically significant Drugs (e.g., TMP/SMX, cimetidine, cefoxitin) Interferences Artifactual decrease in diabetic ketoacidosis CREATINE KINASE (CK), TOTAL Use Marker for injury or diseases of cardiac with good specificity Measurement of choice for striated muscle disorders (see Chapter 10) Increased In Necrosis or inflammation of cardiac muscle Disorders listed under CK-MB (CK index usually >2.5%) Necrosis, inflammation or acute atrophy of striated muscle (see Chapter 10) Disorders listed under CK-MB (CK index usually <2.5%) Muscular dystrophy Myotonic dystrophy Amyotrophic lateral sclerosis (>40% of cases) Polymyositis (70% of cases; average 20× ULN) Thermal and electrical burns (values usually higher than in AMI) Rhabdomyolysis (especially with trauma and severe exertion); marked increase may be 1000× ULN Severe or prolonged exercise as in marathon running (begins 3 hrs after start of exercise; peaks after 8–16 hrs; usually normal by 48 hrs); smaller increases in well-conditioned athletes Status epilepticus Parturition and frequently the last few weeks of pregnancy Malignant hyperthermia Hypothermia Familial hypokalemic periodic paralysis
- 40. McArdle's disease Drugs and chemicals Cocaine Alcohol Emetine (ipecac) (e.g., bulimia) Toxic chemicals (benzene ring compounds [e.g., xylene] depolarize surface membrane and leach out low-molecular-weight enzymes, producing very high levels of total CK [100% MM] with increased LD 3–5× normal) Half of patients with extensive brain infarction. Maximum levels in 3 days; increase may not appear before 2 days; levels usually less than in AMI and remain increased for longer time; return to normal within 14 days; high mortality associated with levels >300 IU. Elevated serum CK in brain infarction may obscure diagnosis of concomitant AMI. Some persons with large muscle mass (£2× normal) (e.g., football players) Slight Increase Occasionally In IM injections. Variable increase after IM injection to 2–6× normal level. Returns to normal 48 hrs after cessation of injections. Rarely affects CK-MB, LD-1, AST. Muscle spasms or convulsions in children Moderate hemolysis Normal In Pulmonary infarction Renal infarction Liver disease Biliary obstruction Some muscle disorders Thyrotoxicosis myopathy Steroid myopathy Muscle atrophy of neurologic origin (e.g., old poliomyelitis, polyneuritis) PA Most malignancies Scleroderma Acrosclerosis Discoid lupus erythematosus Decreased In Decreased muscle mass (e.g., old age, malnutrition, alcoholism) RA (approximately two-thirds of patients) Untreated hyperthyroidism Cushing's disease Connective tissue disease not associated with decreased physical activity Pregnancy level (8th to 12th wk) is said to be ~75% of nonpregnancy level Various drugs (e.g., phenothiazine, prednisone, estrogens, tamoxifen, ethanol), toxins, and insecticides (e.g., aldrin, dieldrin) Metastatic tumor in liver Multiple organ failure Intensive care unit patients with severe infection or septicemia CREATINE KINASE (CK) ISOENZYMES Use CK-MB is the most widely used early marker for myocardial injury. CK-MB Increased In Necrosis of cardiac muscle (CK index >2.5%; in all other causes, CK index usually <2.5%) AMI. Cardiac contusion. After thoracic/open heart surgery, values return to baseline in 24–48 hrs. AMI is difficult to diagnose in first 24 postoperative hrs. Resuscitation for cardiac arrest may increase CK and CK-MB in ~50% of patients with peak at 24 hrs due to defibrillation (>400 J) and chest compression but CK-MB/CK total ratio may not be increased even with AMI. Percutaneous transluminal coronary angioplasty.
- 41. Myocarditis. Prolonged supraventricular tachycardia. Cardiomyopathies (e.g., hypothyroid, alcohol). Collagen diseases involving the myocardium. Coronary angiography (transient). Necrosis, inflammation, or acute atrophy of striated muscle Exercise myopathy; slight to significant increases in 14–100% of persons after extreme exercise (e.g., marathons); smaller increases in well-conditioned athletes Skeletal muscle trauma with rhabdomyolysis, myoglobinuria Skeletal muscle diseases (e.g., myositis, muscular dystrophies, polymyositis, collagen vascular diseases [especially SLE]) Familial hypokalemic periodic paralysis Electrical and thermal burns and trauma (~50% of patients; but not supported by LD-1 > LD-2) Drugs (e.g., alcohol, cocaine, halothane [malignant hyperthermia], ipecac) Endocrine disorders (e.g., hypoparathyroidism, acromegaly, diabetic ketoacidosis; hypothyroidism—total CK 4–8× ULN in 60–80% of cases; becomes normal within 6 wks of initiating replacement therapy) Some infections Viral (e.g., HIV, Epstein-Barr virus [EBV], influenza, picornaviruses, coxsackievirus, echoviruses, adenoviruses) Bacterial (e.g., Staphylococcus, Streptococcus, Clostridium, Borrelia) Rocky Mountain spotted fever Fungal Parasitic (e.g., trichinosis, toxoplasmosis, schistosomiasis, cysticercosis) Other conditions Malignant hyperthermia; hypothermia Reye's syndrome Peripartum period for first day beginning within 30 mins Acute cholecystitis Hyperthyroidism and chronic renal failure may cause persistent increase, although the proportion of CK-MB remains low Acute exacerbation of obstructive lung disease Drugs (e.g., aspirin, tranquilizers) Carbon monoxide poisoning Some neoplasms (see Tumor Markers) For example, prostate, breast. Increase in 90% of patients after cryotherapy for prostate carcinoma with peak at 16 hrs to ~5× upper limit of normal value; similar increase in total CK. % Activity Distribution of CK Isoenzymes in Tissue CK-MM CK-MB CK-BB Skeletal muscle 99 1 0 Myocardium 77 22 1 Brain 4 0 96 CK-MB >15–20% should raise the possibility of an atypical macro CK-MB. CK-MB Not Increased In Angina pectoris, coronary insufficiency, exercise testing for coronary artery disease, or pericarditis; an increase implies some necrosis of cardiac muscle even if a discrete infarct is not identified. After cardiopulmonary bypass, cardiac catheterization (including Swan-Ganz), cardiac pacemaker implantation, and coronary arteriography unless myocardium has been injured by catheter IM injections (total CK may be slightly increased) Seizures (total CK may be markedly increased) Brain infarction or injury (total CK may be increased) CK-BB Isoenzyme Use Is rarely encountered clinically. CK-BB May Be Increased In Malignant hyperthermia, uremia, brain infarction or anoxia, Reye's syndrome, necrosis of intestine, various metastatic neoplasms (especially prostate), biliary atresia Atypical Macro Isoenzyme (High-molecular-mass complex of a CK isoenzyme and immunoglobulin, most often CK-BB and monoclonal IgG and a kappa light chain) May cause falsely high or low CK-MB results (depending on type of assay), resulting in an incorrect diagnosis of myocardial infarction or delayed recognition of a real myocardial infarction. Discovered in <2% of all CK isoenzyme electrophoresis studies. Type 1 Type 2 Electrophoretic location Between CK-MM and CK-MB Cathode side of CK-MM Prevalence (%) 0.43 1.30 Associated disorders Myositis Malignancy Autoimmune disease
- 42. CREATININE Use Diagnosis of renal insufficiency. Serum creatinine is a more specific and sensitive indicator of renal disease than BUN. Use of simultaneous BUN and creatinine determinations provides more information in conditions listed in next section. Increased In Diet Ingestion of creatinine (roast meat) Muscle disease Gigantism Acromegaly Prerenal azotemia (see BUN) Postrenal azotemia (see BUN) Impaired kidney function; 50% loss of renal function is needed to increase serum creatinine from 1.0 to 2.0 mg/dL; therefore not sensitive to mild to moderate renal injury. Decreased In Pregnancy—normal value is 0.4–0.6 mg/dL. >0.8 mg/dL is abnormal and should alert clinician to further diagnostic evaluation. Interferences (Depending on methodology) Artifactual decrease by Marked increase of serum bilirubin Enzymatic reaction (glucose >100 mg/dL) Artifactual increase due to Reducing alkaline picrate (e.g., glucose, ascorbate, uric acid). Ketoacidosis may substantially increase serum creatinine results with alkaline picrate reaction. Formation of colored complexes (e.g., acetoacetate, pyruvate, other ketoacids, certain cephalosporins). Enzymatic reaction (flucytosine [5-fluorocytosine] may increase serum creatinine £0.6 mg/dL). Other methodologic interference (e.g., ascorbic acid, PSP, L-dopa, para-aminohippurate). ERYTHROCYTE SEDIMENTATION RATE (ESR) See Table 3-1. Table 3-1. Changes in Erythrocyte Sedimentation Rate Use mIndicates presence and intensity of an inflammatory process; never diagnostic of a specific disease. Changes are more significant than a single abnormal occurrence. Detect occult disease (e.g., screening program), but a normal ESR does not exclude malignancy or other serious disease. Monitor the course of or response to treatment of certain diseases (e.g., temporal arteritis, polymyalgia rheumatica, acute rheumatic fever, RA, SLE, Hodgkin's disease, TB, bacterial endocarditis). ESR is normal in 5% of patients with RA or SLE. wConfirm or exclude a diagnosis (a normal ESR virtually excludes diagnosis of temporal arteritis or polymyalgia rheumatica; >50 mm/hr in 90% of these patients). Rarely may assist in differential diagnosis (e.g., acute myocardial infarction versus angina pectoris; early acute appendicitis versus ruptured ectopic pregnancy or acute pelvic inflammatory disease; RA versus osteoarthritis; acute versus quiescent gout). ESR is said to be useful to differentiate iron deficiency anemia (ESR normal) from anemia of acute or chronic disease alone or combined with iron deficiency, in which ESR is almost always increased. Rarely (6 in 10,000) useful for screening of asymptomatic persons after history and physical examination. Unexplained increase with no detectable disease occurs in <3% of cases.
- 43. mHyperviscosity syndrome should be suspected in patients with hyperproteinemia (e.g., multiple myeloma, Waldenström's macroglobulinemia) with rouleaux formation but no increase of ESR. mExtreme elevation of ESR is found particularly in association with malignancy (most frequently malignant lymphoma, carcinomas of colon and breast), hematologic diseases (most frequently myeloma), collagen diseases (e.g., RA, SLE), renal diseases (especially with azotemia), drug fever, and other conditions (e.g., cirrhosis). In patients with cancer, ESR >100 mm/hr indicates metastases. Other causes of ESR >100 mm/hr are severe infections (osteomyelitis, SBE), giant cell arteritis, polymyalgia rheumatica, renal diseases. Interferences That Increase ESR Macrocytosis Hypercholesterolemia Increased fibrinogen, gamma or beta globulins Technical factors (e.g., tilted ESR tube, high room temperature) Drugs (e.g., dextran, methyldopa, methysergide, penicillamine, theophylline, trifluperidol, vitamin A) Interferences That Decrease ESR Polycythemia, vera or secondary Abnormal RBCs, especially sickle cells; hereditary spherocytosis; acanthocytosis Microcytosis (e.g., HbC disease) Hypofibrinogenemia (e.g., DIC, massive hepatic necrosis) High WBC count Technical factors (e.g., short ESR tube, low room temperature, delay in test performance >2 hrs, clotted blood sample, excess anticoagulation) Drugs (e.g., quinine [therapeutic], salicylates [therapeutic], drugs that cause a high glucose level, high doses of adrenal steroids) Increased In Chronic inflammatory diseases, especially collagen and vascular diseases Postoperative (may be increased for up to 1 mo), postpartum Decreased In Congestive heart failure Cachexia High doses of adrenal steroids Factors That Do Not Affect ESR Body temperature Recent meal Aspirin Nonsteroidal anti-inflammatory drugs Formula for normal range Westergren ESR: 5'-NUCLEOTIDASE (5'-N) Use Is rarely used. May aid in differential diagnosis of hepatobiliary disease during pregnancy. Increased Only In Obstructive type os hepatobiliary disease. May be an early indication of liver metastases in the cancer patient, especially if jaundice is absent. Normal In Pregnancy and postpartum period (in contrast to serum LAP and ALP).
- 44. GAMMA-GLUTAMYL TRANSFERASE (GGT) Use In liver disease, generally parallels changes in serum ALP. Sensitive indicator of occult alcoholism Diagnosis of liver disease in presence of bone disease or pregnancy, or in childhood; serum ALP and LAP increased but not GGT. Increased In Liver disease—generally parallels changes in serum ALP, LAP, and 5'-nucleotidase but is more sensitive. Acute hepatitis. Elevation is less marked than that of other liver enzymes, but it is the last to return to normal and therefore is useful to indicate recovery. Chronic active hepatitis. Increased (average >7× ULN) more than in acute hepatitis. More elevated than AST and ALT. In dormant stage, may be the only enzyme elevated. In alcoholic hepatitis, average increase is >3.5× ULN. Cirrhosis. In inactive cases, average values are lower (4× ULN) than in chronic hepatitis. Increase >10–20 times in cirrhotic patients suggests superimposed primary carcinoma of the liver (average increase >21× ULN). Primary biliary cirrhosis. Elevation is marked: average >13× ULN. Fatty liver. Elevation parallels that of AST and ALT but is greater. Obstructive jaundice. Increase is faster and greater than that of serum ALP and LAP. Average increase >5× ULN. Liver metastases. Parallels ALP; elevation precedes positive liver scans. Average increase >14× ULN. Cholestasis. In mechanical and viral cholestasis, GGT and LAP are about equally increased, but in drug-induced cholestasis, GGT is much more increased than LAP. Average increase >6× ULN. Children. Much more increased in biliary atresia than in neonatal hepatitis (300 U/L is useful differentiating level). Children with alpha 1-antitrypsin deficiency have higher levels than other patients with biliary atresia. Pancreatitis: Always elevated in acute pancreatitis. In chronic pancreatitis is increased when involvement of the biliary tract or active inflammation is present. Acute myocardial infarction. Increased in 50% of patients. Elevation begins on fourth to fifth day, reaches maximum at 8–12 days. With shock or acute right heart failure, may have early peak within 48 hrs, with rapid decline followed by later rise. Heavy use of alcohol: Is the most sensitive indicator and a good screening test for alcoholism, because elevation exceeds that of other commonly assayed liver enzymes. Various drugs (e.g., barbiturates, phenytoin, tricyclic antidepressants, acetaminophen) Some cases of carcinoma of prostate Neoplasms, even in absence of liver metastases; especially malignant melanoma, carcinoma of breast and lung; highest levels in hypernephroma Other conditions (e.g., gross obesity [slight increase], renal disease, cardiac disease, postoperative state) Normal In Pregnancy (in contrast to serum ALP, LAP) and children older than 3 mos; therefore may aid in differential diagnosis of hepatobiliary disease occurring during pregnancy and childhood. Patients with bone disease or with increased bone growth (children and adolescents); therefore useful in distinguishing bone disease from liver disease as a cause of increased serum ALP. Renal failure Strenuous exercise GLUCOSE Use Diagnosis of diabetes mellitus (defined by World Health Organization as unequivocal increase of fasting serum [or plasma] glucose ³126 mg/dL on more than one occasion or any glucose level ³200 mg/dL) Control of diabetes mellitus Diagnosis of hypoglycemia May Be Increased In Diabetes mellitus, including Hemochromatosis Cushing's syndrome (with insulin-resistant diabetes) Acromegaly and gigantism (with insulin-resistant diabetes in early stages; hypopituitarism later) Increased circulating epinephrine Adrenalin injection Pheochromocytoma Stress (e.g., emotion, burns, shock, anesthesia) Acute pancreatitis Chronic pancreatitis (some patients)
- 45. Wernicke's encephalopathy (vitamin B 1 deficiency) Some CNS lesions (subarachnoid hemorrhage, convulsive states) Effect of drugs (e.g., corticosteroids, estrogens, alcohol, phenytoin, thiazides, propran olol, vitamin A [chronic hypervitaminosis]) May Be Decreased In Pancreatic disorders Islet cell tumor, hyperplasia Pancreatitis Glucagon deficiency Extrapancreatic tumors Carcinoma of adrenal gland Carcinoma of stomach Fibrosarcoma Other Hepatic disease Diffuse severe disease (e.g., poisoning, hepatitis, cirrhosis, primary or metastatic tumor) Endocrine disorders Hypopituitarism* Addison's disease Hypothyroidism Adrenal medulla unresponsiveness Early diabetes mellitus Functional disturbances Postgastrectomy Gastroenterostomy Autonomic nervous system disorders Pediatric anomalies Prematurity* Infant of diabetic mother* Ketotic hypoglycemia Zetterstrom's syndrome Idiopathic leucine sensitivity Spontaneous hypoglycemia in infants Enzyme diseases von Gierke's disease* Galactosemia* Fructose intolerance* Amino acid and organic acid defects* Methylmalonic acidemia* Glutaric acidemia, type II* Maple syrup urine disease* 3-hydroxy, 3-methyl glutaric acidemia* Fatty acid metabolism defects* Acyl coenzyme A dehydrogenase defects* Carnitine deficiencies* Other Exogenous insulin (factitious) Oral hypoglycemic medications (factitious) Leucine sensitivity Malnutrition Hypothalamic lesions Alcoholism * May cause neonatal hypoglycemia. Interferences Blood samples in which serum is not separated from blood cells will show glucose values decreasing at rate of 3–5%/hr at room temperature. Most glucose strips and meters quantify whole blood glucose, whereas most laboratories use plasma or serum, which reads 10–15% higher. Postprandial capillary glucose is £36 mg/dL higher than venous glucose at peak of 1 hr postprandial; usually returns to negligible difference with fasting level within 4 hrs but in ~15% of patients may still be >20 mg/dL difference. Considerable imprecision is found between glucose meters from the same manufacturer and between different types of meters.
- 46. Only fresh capillary blood should be used with some reflectance meters; low oxygen content (e.g., venous blood, altitudes >3000 m) gives falsely increased values. Reflectance meter value of ~160 mg/dL on capillary blood corresponds to venous plasma level of ~135 mg/dL in most cases. Whole blood glucose value multiplied by 0.94 = plasma concentration. IMMUNOGLOBULIN A (IgA) Increased In (in relation to other immunoglobulins) Gamma-A myeloma (M component) Cirrhosis of liver Chronic infections RA with high titers of RF SLE (some patients) Sarcoidosis (some patients) Wiskott-Aldrich syndrome Other Decreased In (Alone) Healthy persons (1 in 700) Hereditary telangiectasia (80% of patients) Type III dysgammaglobulinemia Malabsorption (some patients) SLE (occasionally) Cirrhosis of liver (occasionally) Still's disease (occasionally) Recurrent otitis media (occasionally) Non-IgA myeloma Waldenström's macroglobulinemia Acquired immunodeficiency Decreased In (Combined with Other Immunoglobulin Decreases) Agammaglobulinemia Acquired Primary Secondary (e.g., multiple myeloma, leukemia, nephrotic syndrome, protein-losing enteropathy) Congenital Hereditary thymic aplasia Type I dysgammaglobulinemia (decreased IgG and IgA and increased IgM) Type II dysgammaglobulinemia (absent IgA and IgM and normal levels of IgG) Infancy, early childhood IMMUNOGLOBULIN D (IgD) Use Diagnosis of rare IgD myelomas (greatly increased) Increased In Chronic infection (moderately) Autoimmune disease Decreased In Hereditary deficiencies Acquired immunodeficiency
- 47. Non-IgD myeloma Infancy, early childhood IMMUNOGLOBULIN E (IgE) Use Diagnosis of E-myeloma Indicates various parasitic or allergic diseases. A normal serum IgE level excludes the diagnosis of bronchopulmonary aspergillosis. Increased In Atopic diseases Exogenous asthma in ~60% of patients Hay fever in ~30% of patients Atopic eczema Influenced by type of allergen, duration of stimulation, presence of symptoms, hyposensitization treatment. Parasitic diseases (e.g., ascariasis, visceral larva migrans, hookworm disease, schistosomiasis, Echinococcus infection) Normal or Low In Asthma Decreased In Hereditary deficiencies Acquired immunodeficiency Ataxia-telangiectasia Non-IgE myeloma IMMUNOGLOBULIN G (IgG) Use Diagnosis of IgG myeloma Diagnosis of hereditary and acquired IgG immunodeficiencies Increased In Sarcoidosis Chronic liver disease (e.g., cirrhosis) Autoimmune diseases Parasitic diseases Chronic infection Decreased In Protein-losing syndromes Pregnancy Non-IgG myeloma Waldenström's macroglobulinemia IMMUNOGLOBULIN M (IgM) Use Diagnosis of hereditary and acquired IgM immunodeficiencies Diagnosis of Waldenström's macroglobulinemia Increased In Liver disease Chronic infections Decreased In
- 48. Protein-losing syndromes Non-IgM myeloma Infancy, early childhood IMMUNOLOGIC TESTS See Table 3-2. Table 3-2. Immunologic Tests INFLAMMATORY REACTANTS, ACUTE Acute-phase reactants in serum (except CRP) are not used to detect inflammation, but recognizing this cause of increase is important when they are used in testing for other conditions (e.g., ceruloplasmin). CRP can increase up to 1000% in severe tissue injury. Fibrinogen usually increases by 200–400%. Alpha1-antitrypsin increases by 200–400%. Haptoglobin increases by 200–400%. Ferritin usually increases by 50%. Ceruloplasmin. Alpha1-acid glycoprotein. Serum complement usually increases by 50%. Total WBC, neutrophils, and bands ESR LACTATE DEHYDROGENASE (LD) Use Replaced by cardiac troponins as late marker for AMI. May be a useful marker of disease activity in cryptogenic fibrosing alveolitis and extrinsic allergic alveolitis. Marker for hemolysis, in vivo (e.g., hemolytic anemias) or in vitro (artifactual) LD is a very nonspecific test. Interferences Artifactual hemolysis (e.g., poor venipuncture, failure to separate clot from serum, heating of blood) Increased In Cardiac diseases AMI. AMI with congestive heart failure. May show increase of LD-1 and LD-5. Congestive heart failure alone. LD isoenzymes are normal or LD-5 is increased due to liver congestion. Coronary insufficiency may show mild elevation; flipped LD is less likely. Insertion of intracardiac prosthetic valves consistently causes chronic hemolysis with increase of total LD and of LD-1 and LD-2. This is also often present before surgery in patients with severe hemodynamic abnormalities of cardiac valves. Cardiovascular surgery. LD is increased to £2 times normal without cardiopulmonary bypass and returns to normal in 3–4 days; with extracorporeal circulation, it may increase to £4–6 times normal; increase is more marked when transfused blood is older. Increases have been described in acute myocarditis and rheumatic fever. Liver diseases Cirrhosis, obstructive jaundice, acute viral hepatitis show moderate increases. Hepatitis. Most marked increase is of LD-5, which occurs during prodromal stage and is greatest at time of onset of jaundice; total LD is also increased in 50% of the cases. LD increase is isomorphic in infectious mononucleosis ALT/LD or AST/LD ratio ³1.5 within 24 hrs of admission favors acute hepatitis over acetaminophen or ischemic injury. Acute and subacute hepatic necrosis. LD-5 is also increased with other causes of liver damage (e.g., chlorpromazine hepatitis, carbon tetrachloride poisoning, exacerbation of cirrhosis, biliary obstruction) even when total LD is normal. Metastatic carcinoma to liver may show marked increases. LD-4/LD-5 ratio <1.05 has been reported to favor diagnosis of hepatocellular carcinoma, whereas ratio >1.05 favors liver metastases in >90% of cases.2 If liver disease is suspected but total LD is very high and isoenzyme pattern is isomorphic, rule out cancer. Liver disease, per se, does not produce marked increase of total LD or LD-5.
- 49. Various inborn metabolic disorders affecting liver (e.g., hemochromatosis, Dubin-Johnson syndrome, hepatolenticular degeneration, Gaucher's disease, McArdle's disease). Hematologic diseases Untreated PA and folic acid deficiency show some of the greatest increases, chiefly in LD-1, which is >LD-2 (flipped), especially with Hb <8 gm/dL. Increased in all hemolytic anemias, which can probably be ruled out if LD-1 and LD-2 are not increased in an anemic patient. Normal in aplastic anemia and iron-deficiency anemia, even when anemia is very severe. Diseases of lung Pulmonary embolus and infarction—pattern of moderately increased LD with increased LD-3 and normal AST 24–48 hrs after onset of chest pain (see Lactate Dehydrogenase Isoenzymes section). Sarcoidosis. Malignant tumors Increased in ~50% of patients with various solid carcinomas, especially in advanced stages. In patients with cancer, a higher LD level generally indicates a poorer prognosis. Whenever the total LD is increased and the isoenzyme pattern is nonspecific or cannot be explained by obvious clinical findings (e.g., myocardial infarction, hemolytic anemia), cancer should always be ruled out. Moderately increased in ~60% of patients with lymphomas and lymphocytic leukemias and ~90% of patients with acute leukemia; degree of increase is not correlated with level of WBC; relatively low levels in lymphatic type of leukemia. Increased in 95% of patients with chronic myelogenous leukemia, especially LD-3. (See also Chapter 11, Hematologic Diseases.) Diseases of muscle Marked increase of LD-5 is likely due to anoxic injury of striated muscle. Electrical and thermal burns and trauma. Marked increase of total LD (about the same as in myocardial infarction) and LD-5. Renal diseases Renal cortical infarction may mimic pattern of AMI. Rule out renal infarction if LD-1 (>LD-2) is increased in the absence of AMI or anemia; increased LD is out of proportion to AST and ALP levels. May be slightly increased (LD-4 and LD-5) in nephrotic syndrome. LD-1 and LD-2 may be increased in nephritis. Miscellaneous conditions (may be related to hemolysis, involvement of liver, striated muscle, heart, etc.) Various infectious and parasitic diseases Hypothyroidism, subacute thyroiditis Collagen vascular diseases Acute pancreatitis Intestinal obstruction Sarcoidosis Various CNS conditions (e.g., bacterial meningitis, cerebral hemorrhage or thrombosis) Drugs Decreased In X-ray irradiation LACTATE DEHYDROGENASE ISOENZYMES % Activity Distribution of LD Isoenzymes in Tissue LD-1 LD-2 LD-3 LD-4 LD-5 Heart 60 30 5 3 2 Liver 0.2 0.8 1 4 94 Kidney 28 34 21 11 6 Cerebrum 28 32 19 16 5 Skeletal muscle 3 4 8 9 76 Lung 10 18 28 23 21 Spleen 5 15 31 31 18 RBCs 40 30 15 10 5 Skin 0 0 4 17 79 Use To delineate tissue source of elevated serum total LD. Interpretation of this test must be correlated with clinical status of the patient. Do serial determinations to obtain maximum information. Condition LD Isoenzyme Increased AMI LD-1 > LD-2 Acute renal cortical infarction LD-1 > LD-2 PA LD-1 Sickle cell crisis LD-1 and LD-2 Electrical and thermal burn, trauma LD-5 Mother carrying erythroblastotic child LD-4 and LD-5 AMI with acute congestion of liver LD-1 and LD-5 Early hepatitis LD-5 (may become normal even when ALT is still rising) Malignant lymphoma LD-3 and LD-4 (may even increase LD-2) (reflects effect of chemotherapy) Active chronic granulocytic leukemia LD-3 increased in >90% of cases but normal during remission Carcinoma of prostate LD-5; LD-5:LD-1 ratio >1 Dermatomyositis LD-5 SLE LD-3 and LD-4 Collagen disorders LD-2, LD-3, and LD-4 Pulmonary embolus and infarction LD-2, LD-3, and LD-4 Pulmonary embolus with acute cor pulmonale causing acute congestion of liver LD-3 and LD-5 Congestive heart failure LD-2, LD-3, and LD-4 Viral infections LD-2, LD-3, and LD-4 Various neoplasms LD-2, LD-3, and LD-4 Strenuous physical activity LD-4 and LD-5
- 50. CNS malignant neoplasms LD-5 Abnormally migrating macroenzymes (circulating complexes of LD with IgA or IgG immunoglobulins) may be found in some autoimmune conditions, cancer, and some miscellaneous conditions but not useful for diagnosis. Increased total LD with normal distribution of isoenzymes may be seen in AMI, arteriosclerotic heart disease with chronic heart failure, and various combinations of acute and chronic diseases (this may represent a general stress reaction). Approximately 50% of patients with malignant tumors have altered LD patterns. This change often is nonspecific and of no diagnostic value. Solid tumors, especially of germ cell origin, may increase LD-1. In megaloblastic anemia, hemolysis, renal cortical infarction, and cancer in some patients the isoenzyme pattern may mimic that of AMI, but the time to peak value and the increase help to differentiate. LEUCINE AMINOPEPTIDASE (LAP) Use Is rarely used. Parallels serum ALP except that LAP is usually normal in the presence of bone disease or malabsorption syndrome. LAP is a more sensitive indicator of choledocholithiasis and of liver metastases in anicteric patients. When serum LAP is increased, urine LAP is almost always increased; but when urine LAP is increased, serum LAP may have already returned to normal. MAGNESIUM (Mg) Use Diagnose and monitor hypo- and hypermagnesemia, especially in renal failure or GI disorders Increased In Iatrogenic (usual cause, most often with acute or chronic renal failure) Antacids containing magnesium Enemas containing magnesium Laxative and cathartic abuse Parenteral nutrition Magnesium for eclampsia or premature labor Lithium carbonate intoxication Renal failure (when glomerular filtration rate [GFR] approaches 30 mL/min); in chronic renal failure, hypermagnesemia is inversely related to residual renal function. Increase is rarely observed with normal renal function. Diabetic coma before treatment Hypothyroidism Addison's disease and after adrenalectomy Controlled diabetes mellitus in older patients Accidental ingestion of large amount of sea water Signs Approximate Serum Levels in Adults Neuromuscular depression, hypotension >4–6 mg/dL Difficulty in urination >5 mg/dL CNS depression 6–8 mg/dL Nausea, vomiting, cutaneous flushing 6 mg/dL Hyporeflexia, drowsiness 8 mg/dL Coma 12–17 mg/dL ECG changes >10 mg/dL Complete heart block 30 mg/dL Cardiac arrest 34–40 mg/dL Decreased In (Almost always due to GI or renal disturbance) GI disease Malabsorption (e.g., sprue, small bowel resection, biliary and intestinal fistulas, abdominal irradiation, celiac disease and other causes of steatorrhea; familial magnesium malabsorption) Abnormal loss of GI fluids (chronic ulcerative colitis, Crohn's disease, villous adenoma, carcinoma of colon, laxative abuse, prolonged aspiration of GI tract contents, vomiting, etc.) Renal disease (>2 mEq/day in urine during hypomagnesemia indicates excessive renal loss) Chronic GN Chronic pyelonephritis Renal tubular acidosis Diuretic phase of acute tubular necrosis Postobstructive diuresis Drug injury Diuretics (e.g., furosemide, thiazides, ethacrynic acid)
- 51. Antibiotics (e.g., gentamicin, tobramycin, carbenicillin, ticarcillin, amphotericin B, aminoglycosides) Digitalis (in 20% of patients taking digitalis) Antineoplastic (e.g., cisplatin) Cyclosporine Tubular losses due to ions or nutrients Hypercalcemia Diuresis due to glucose, urea, or mannitol Phosphate depletion Extracellular fluid volume expansion Primary renal magnesium wasting Nutritional Prolonged parenteral fluid administration without magnesium (usually >3 wks) Acute alcoholism and alcoholic cirrhosis Starvation with metabolic acidosis Kwashiorkor, protein-calorie malnutrition Endocrine Hyperthyroidism Aldosteronism (primary and secondary) Hyperparathyroidism and other causes of hypercalcemia Hypoparathyroidism Diabetes mellitus (in 25–75% of patients) Metabolic Excessive lactation Third trimester of pregnancy Insulin treatment of diabetic coma Other Toxemia of pregnancy or eclampsia Lytic tumors of bone Active Paget's disease of bone due to increased uptake by bone Acute pancreatitis Transfusion of citrated blood Severe burns Sweating Sepsis Hypothermia Magnesium deficiency frequently coexists with other electrolyte abnormalities. Magnesium deficiency may cause apparently unexplained hypocalcemia and hypokalemia; the patients may have neurologic and GI symptoms (see Calcium, Total). In ~90% of patients, high or low serum magnesium levels are not clinically recognized; therefore routine inclusion of magnesium with electrolyte measurements has been suggested. Digitalis sensitivity and toxicity frequently occur with hypomagnesemia. Ionized magnesium may be decreased despite increased or normal total magnesium. Because deficiency can exist with normal or borderline serum magnesium levels, 24-hr urine testing may be indicated by frequent concomitant disorders. 24-hr urine level <25 mg suggests magnesium deficiency (in absence of conditions or agents that promote magnesium excretion). If due to renal loss, urine magnesium should be >3.65–6.00/day. If <2.4 mg/day, collect 24-hr urine during IV of 72 mg of MgCl. 60–80% of load is excreted by patients with normal magnesium stores. <50% suggests nonrenal magnesium depletion. OSMOLALITY Use Diagnosis of nonketotic hyperglycemic coma Monitoring of fluid and electrolyte balance Determine serum water deviation from normal for evaluation of hyponatremia (see Causes of Hyponatremia, Fig. 13-27). Urine and plasma osmolality are more useful to diagnose state of hydration than changes in Hct, serum proteins, and BUN, which are more dependent on other factors than hydration. Increased In Hyperglycemia Diabetic ketoacidosis. (Osmolality should be determined routinely in grossly unbalanced diabetic patients.) Nonketotic hyperglycemic coma Hypernatremia with dehydration Diarrhea, vomiting, fever, hyperventilation, inadequate water intake Diabetes insipidus—central Nephrogenic diabetes insipidus—congenital or acquired (e.g., hypercalcemia, hypokalemia, chronic renal disease, sickle cell disease, effect of some drugs)
- 52. Osmotic diuresis—hyperglycemia, administration of urea or mannitol Hypernatremia with normal hydration—due to hypothalamic disorders Insensitivity of osmoreceptors (essential hypernatremia)—water loading does not return serum osmolality to normal; chlorpropamide may lower serum sodium toward normal Defect in thirst (hypodipsia)—forced water intake returns serum osmolality to normal Hypernatremia with overhydration—iatrogenic or accidental (e.g., infants given feedings with high sodium concentrations or given NaHCO 3 for respiratory distress or cardiopulmonary arrest) Alcohol ingestion is the most common cause of hyperosmolar state and of coexisting coma and hyperosmolar state. Decreased In (Equivalent to Hyponatremia) Hyponatremia with hypovolemia (urine sodium is usually >20 mEq/L) Adrenal insufficiency (e.g., salt-losing form of congenital adrenal hyperplasia, congenital adrenal hypoplasia, hemorrhage into adrenals, inadequate replacement of corticosteroids, inappropriate tapering of steroids) Renal losses (e.g., osmotic diuresis, proximal renal tubular acidosis, salt-losing nephropathies, usually tubulointerstitial diseases such as GU tract obstruction, pyelonephritis, medullary cystic disease, polycystic kidneys) GI tract loss (e.g., vomiting, diarrhea) Other losses (e.g., burns, peritonitis, pancreatitis) Hyponatremia with normal volume or hypervolemia (dilutional syndromes) Congestive heart failure, cirrhosis, nephrotic syndrome SIADH Formulas for calculation or prediction of serum osmolality: Osmolal Gap Difference between measured and calculated values; <10 in healthy persons. Use Osmolal gap has been used to estimate the blood alcohol. Because serum osmolality increases 22 mOsm/kg for every 100 mg/dL of ethanol : OSMOLAL GAP >10 DUE TO Decreased serum water content Hyperlipidemia (serum will appear lipemic) Hyperproteinemia (total protein >10 gm/dL) Additional low-molecular-weight substances are in serum (measured osmolality will be >300 mOsm/kg water): Ethanol. (An especially large osmolal gap with a low or only moderately elevated ethanol level should raise the possibility of another low-molecular-weight toxin [e.g., methanol].) Methanol. Isopropyl alcohol. Mannitol. (Osmolal gap can be used to detect accumulation of infused mannitol in serum.) Ethylene glycol, acetone, paraldehyde result in relatively small osmolal gaps even at lethal levels. Severe illness, especially shock, acidosis (lactic, diabetic, alcoholic), renal failure Laboratory analytic error Random error from all measurements could add or subtract £15 mOsm/kg. Use of incorrect blood collection tubes. PHOSPHORUS See Fig. 3-1. Fig. 3-1. Algorithm for hyperphosphatemia. (PTH = parathyroid hormone.)
- 53. Use Monitor blood phosphorus level in renal and GI disorders, effect of drugs Increased In Most causes of hypocalcemia except vitamin D deficiency, in which it is usually decreased. Acute or chronic renal failure (most common cause) with decreased GFR Increased tubular reabsorption of phosphate Hypoparathyroidism Idiopathic Surgical Radiation induced Secondary hyperparathyroidism (renal rickets) Pseudohypoparathyroidism Other endocrine disorders Addison's disease Acromegaly Hyperthyroidism Sickle cell anemia Increased cellular release of phosphate Neoplasms (e.g., myelogenous leukemia) Excessive breakdown of tissue (e.g., chemotherapy for neoplasms, rhabdomyolysis, malignant hyperthermia, lactic acidosis, acute yellow atrophy) Bone disease Healing fractures Multiple myeloma (some patients) Paget's disease (some patients) Osteolytic metastatic tumor in bone (some patients) Childhood Increased phosphate load Exogenous phosphate (e.g., oral or IV) Phosphate enemas, laxatives, or infusions Excess vitamin D intake IV therapy for hypophosphatemia or hypercalcemia Milk-alkali (Burnett's) syndrome (some patients) Massive blood transfusions Hemolysis of blood Miscellaneous High intestinal obstruction Sarcoidosis (some patients) Decreased In Renal or intestinal loss (>100 mg/day in urine during hypophosphatemia indicates excessive renal loss) Administration of diuretics Renal tubular defects (Fanconi syndrome; isolated hypophosphatemia due to drugs, neoplasia, X-linked, etc.) Primary hyperparathyroidism Idiopathic hypercalciuria Hypokalemia Hypomagnesemia Dialysis Primary hypophosphatemia Idiopathic hypercalciuria Acute gout Decreased intestinal absorption Malabsorption Vitamin D deficiency and/or resistance, osteomalacia Malnutrition, vomiting, diarrhea Administration of phosphate-binding antacids* Intracellular shift of phosphate Alcoholism* Diabetes mellitus* Acidosis (especially diabetic ketoacidosis) Hyperalimentation* Nutritional recovery syndrome* (rapid refeeding after prolonged starvation) Administration of IV glucose (e.g., recovery after severe burns, hyperalimentation) Alkalosis, respiratory (e.g., gram-negative bacteremia) or metabolic Salicylate poisoning Administration of anabolic steroids, androgens, epinephrine, glucagon, insulin Cushing's syndrome (some patients)
- 54. Prolonged hypothermia (e.g., open heart surgery) Sepsis Often more than one mechanism is operative, usually associated with prior phosphorus depletion. * Indicates conditions that may be associated with severe hypophosphatemia (<1 mg/dL). PLASMA, DISCOLORED (Differentiated by spectrophotometric analysis of plasma) Due To Total bilirubin (causes of jaundice) Lipemia Free hemoglobin (hemolysis) Ceruloplasmin (green color) Excess drugs, medications, diet, e.g.: Suntanning agents (orange-pink color due to canthaxanthin) Carotenoids Bacterial contamination Diseases POTASSIUM See Table 3-3, Fig. 3-2 and Fig. 3-3. Table 3-3. Urine and Blood Changes in Electrolytes, pH, and Volume in Various Conditions Fig. 3-2. Algorithm for hyperkalemia. (D = decreased; I = increased; N = normal; ACTH = adrenocorticotropic hormone; Ald = aldosterone; PRA = plasma renin activity.) a Potassium-sparing diuretics, administration of potassium (e.g. blood transfusions, salt substitutes, potassium penicillin). b Pseudohyperkalemia = WBC > 100,000/cu mm or platelet count > 1,000,000/cu mm (serum potassium > plasma potassium). Fig. 3-3. Algorithm for hypokalemia.
- 55. Use Diagnosis and monitoring of hyper- and hypokalemia in various conditions (e.g., treatment of diabetic coma, renal failure, severe fluid and electrolyte loss, effect of certain drugs) Diagnosis of familial hyperkalemic periodic paralysis and hypokalemic paralysis Increased In Potassium Retention Glomerular filtration rate <3–5 mL/min Oliguria due to any condition (e.g., renal failure) Chronic nonoliguric renal failure associated with dehydration, obstruction, trauma, or excess potassium Drugs Renal toxicity (e.g., amphotericin B, methicillin, tetracycline) Glomerular filtration rate >20 mL/min Decreased (aldosterone) mineralocorticoid activity Addison's disease Hypofunction of renin-angiotensin-aldosterone system Hyporeninemic hypoaldosteronism with renal insufficiency (GFR 25–75 mL/minute) Various drugs (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], angio-tensin-converting enzyme inhibitors, cyclosporine, pentamidine) Decreased aldosterone production Pseudohypoaldosteronism Aldosterone antagonist drugs (e.g., spironolactone, captopril, heparin) Inhibition of tubular secretion of potassium Drugs (e.g., spironolactone, triamterene, amiloride) Hyperkalemic type of distal renal tubular acidosis (e.g., sickle cell disease, obstructive uropathy) Mineralocorticoid-resistant syndromes (increased renin and aldosterone may be low in those marked with * ) Primary tubular disorders Hereditary Acquired (e.g., SLE, amyloidosis, sickle cell nephropathy, * obstructive uropathy,* renal allograft transplant, chloride shift) Potassium Redistribution Familial hyperkalemic periodic paralysis (Gamstorp's disease, adynamia episodica hereditaria) Acute acidosis (especially hyperchloremic metabolic acidosis; less with respiratory acidosis; little with metabolic acidosis due to organic acids) (e.g., diabetic ketoacidosis, lactic acidosis, acute renal failure, acute respiratory acidosis) Decreased insulin Beta-adrenergic blockade Drugs (e.g., succinylcholine, great excess of digitalis, arginine infusion) Use of hypertonic solutions (e.g., saline, mannitol) Intravascular hemolysis (e.g., transfusion reaction, hemolytic anemia), rhabdomyolysis Rapid cellular release (e.g., crush injury, chemotherapy for leukemia or lymphoma, burns, major surgery) Increased Supply of Potassium Laboratory artifacts (e.g., hemolysis during venipuncture, conditions associated with thrombocytosis [>1,000,000/cu mm] or leukocytosis [>100,000/cu mm], incomplete separation of serum and clot) Potassium value can be elevated ~15% in slight hemolysis (Hb £50 mg/dL); elevated ~30–50% in moderate hemolysis (Hb >100 mg/dL). Thus potassium status can be assessed with slight hemolysis but not with moderate hemolysis. Prolonged tourniquet use and hand exercise when drawing blood Excess dietary intake or rapid potassium infusion Drugs (e.g., those with high potassium content [1 million U of penicillin G potassium contains 1.7 mEq of potassium]) Urinary Diversion Ureteral implants into jejunum In neonates—dehydration, hemolysis (e.g., cephalohematoma, intracranial hemorrhage, bruising, exchange transfusion), acute renal failure, congenital adrenal hyperplasia, adrenocortical insufficiency Decreased In See Table 12-3 and Fig. 3-3. (Each 1 mEq/L decrease of serum potassium reflects a total deficit of <200–400 mEq; serum potassium <2 mEq/L may reflect total deficit >1000 mEq.) Excess Renal Excretion Osmotic diuresis of hyperglycemia (e.g., uncontrolled diabetes)
- 56. Nephropathies Renal tubular acidosis (proximal and especially distal) Bartter's syndrome Liddle's syndrome Magnesium depletion due to any cause Renal vascular disease, malignant hypertension, vasculitis Renin-secreting tumors Endocrine Hyperaldosteronism (primary, secondary) Cushing's syndrome, especially due to ectopic ACTH production Congenital adrenal hyperplasia Hyperthyroidism (especially in Asian persons) Drugs Diuretics (e.g., thiazides, ethacrynic acid, furosemide) Mineralocorticoids (e.g., fludrocortisone) High-dose glucocorticoids High-dose antibiotics (e.g., penicillin, nafcillin, ampicillin, carbenicillin) Substances with mineralocorticoid effect (e.g., glycyrrhizic acid [ licorice], carbenoxolone, gossypol) Drugs associated with magnesium depletion (e.g., aminoglycosides, cisplatin, amphotericin B, foscarnet) Acute myelogenous, monomyeloblastic or lymphoblastic leukemia Nonrenal Causes of Excess Potassium Loss Gastrointestinal Vomiting Diarrhea (e.g., infections, malabsorption, radiation) Drugs (e.g., laxatives [phenolphthalein], enemas, cancer therapy) Neoplasms (e.g., villous adenoma of colon, pancreatic vipoma that produces vasoactive intestinal polypeptide >200 pg/mL, Zollinger-Ellison [Z-E] syndrome) Excessive spitting (sustained expectoration of all saliva in neurotic persons and to induce weight loss in professional wrestlers) Skin Excessive sweating Cystic fibrosis Extensive burns Draining wounds Cellular shifts Respiratory alkalosis Classic periodic paralysis Insulin use Use of certain drugs (e.g., bronchodilators, decongestants) Accidental ingestion of barium compounds Treatment of severe megaloblastic anemia with vitamin B12 or folic acid Physiologic causes (e.g., in highly trained athletes) Diet Severe eating disorders (e.g., anorexia nervosa, bulimia) Dietary deficiency Delirium tremens In neonates—asphyxia, alkalosis, renal tubular acidosis, iatrogenic causes (glucose and insulin administration), diuretic use Major causes of hypokalemia with hypertension: Diuretic drugs (e.g., thiazides) Primary aldosteronism Secondary aldosteronism (renovascular disease, renin-producing tumors) Cushing's syndrome Malignant hypertension Renal tubular acidosis PREGNANCY TEST (Immunoassay detection of human chorionic gonadotropin [hCG] in blood) (See also Urinary Chorionic Gonadotropins, Serum Human Chorionic Gonadotropin) Use (Positive In) Pregnancy. Test becomes positive as early as 4 days after expected date of menstruation; it is >95% reliable by 10th–14th day. Ectopic pregnancy. Hydatidiform mole, choriocarcinoma. Test negative one or more times in >60% of these patients and negative at all times in >20% of patients, for whom more sensitive methods (e.g., radioimmunoassay) should be used. Quantitative titers should be performed for diagnosis and for following the clinical course of patients with these conditions.
- 57. Interferences False-negative results may occur with dilute urine or in cases of missed abortion, dead fetus syndrome, ectopic pregnancy. False-positive results may occur in Bacterial contamination or protein or blood in urine or in patients on methadone therapy Marijuana smokers Postorchiectomy patients (secondary to decreased testosterone) With the latex agglutination type of test, only urine should be used if patient has RA. Leukocyte alkaline phosphatase scoring has also been used as a pregnancy test. PROTEIN GAMMOPATHIES Use Identify hereditary and acquired immunodeficiencies Identify monoclonal gammopathies (increases) and associated disorders (concomitant hyperproteinemia is very frequent; see Table 3-4, Table 3-5) Table 3-4. Changes in Serum Immunoproteins in Various Conditions Table 3-5. Serum Immunoglobulin Changes in Various Diseases Monoclonal Increase In Classification of monoclonal gammopathies Polyclonal Gammopathy with Hyperproteinemia Collagen diseases (e.g., SLE, RA, scleroderma) Liver disease (e.g., chronic hepatitis, cirrhosis) Chronic infection (e.g., chronic bronchitis and bronchiectasis, lung abscess, TB, osteomyelitis, SBE, infectious mononucleosis, malaria, leishmaniasis, trypanosomiasis) Miscellaneous (e.g., sarcoidosis, malignant lymphoma, acute myeloid and monocytic leukemia, diabetes mellitus) Idiopathic (family of patients with SLE) PROTEIN, TOTAL See Table 3-6.
- 58. Table 3-6. Serum Protein Electrophoretic Patterns in Various Diseases * Use Screening for nutritional deficiencies and gammopathies Increased In Hypergammaglobulinemias (mono- or polyclonal; see following sections) Hypovolemic states Decreased In Nutritional deficiency, e.g., Malabsorption Kwashiorkor Marasmus Decreased or ineffective protein synthesis, e.g., Severe liver disease Agammaglobulinemia Increased loss Renal (e.g., nephrotic syndrome) GI disease (e.g., protein-losing enteropathies, surgical resection) Severe skin disease (e.g., burns, pemphigus vulgaris, eczema) Blood loss, plasmapheresis Increased catabolism, e.g., Fever Inflammation Hyperthyroidism Malignancy Chronic diseases Dilutional, e.g., IV fluid administration SIADH Water intoxication PROTEIN SEPARATION (IMMUNODIFFUSION, IMMUNOFIXATION, ELECTROPHORESIS) Use Diagnosis of Specific Diseases Multiple myeloma Waldenström's macroglobulinemia Hypogammaglobulinemia Agammaglobulinemia Agamma-A-globulinemia Analbuminemia Bisalbuminemia Afibrinogenemia Atransferrinemia Alpha1-antitrypsin variant Cirrhosis Acute-phase reactant Other Changes Nonspecific changes in serum proteins Protein pattern changes in urine, cerebrospinal fluid, peritoneal fluid, etc. SODIUM See Fig. 13-27 and Fig. 13-28; Table 3-3. Use Diagnosis and treatment of dehydration and overhydration. Changes in serum sodium most often reflect changes in water balance rather than sodium balance. If patient has not received large load of sodium, hypernatremia suggests need for water and values <130 mEq/L suggest overhydration. Determinations of blood sodium and potassium levels are not useful in diagnosis or in estimating net ion losses but are performed to monitor changes in sodium and potassium during therapy. Interference
- 59. Hyperglycemia—serum sodium decreases 1.7 mEq/L for every increase of serum glucose of 100 mg/dL). Hyperlipidemia and hyperproteinemia cause spurious results only with flame photometric technique but not with specific ion electrode techniques for measuring sodium. UREA NITROGEN (BUN) Use Diagnosis of renal insufficiency Correlates with uremic symptoms better than serum creatinine. A low BUN of 6–8 mg/dL is frequently associated with states of overhydration. A BUN of 10–20 mg/dL almost always indicates normal glomerular function. A BUN of 50–150 mg/dL implies serious impairment of renal function. Markedly increased BUN (150–250 mg/dL) is virtually conclusive evidence of severely impaired glomerular function. In chronic renal disease, BUN correlates better with symptoms of uremia than does the serum creatinine. Evidence of hemorrhage into GI tract Assessment of patients requiring nutritional support for excess catabolism (e.g., burns, cancer) Increased In Impaired kidney function (see Creatinine) Prerenal azotemia—any cause of reduced renal blood flow Congestive heart failure Salt and water depletion (vomiting, diarrhea, diuresis, sweating) Shock Postrenal azotemia—any obstruction of urinary tract (increased BUN/creatinine ratio) Increased protein catabolism (serum creatinine remains normal) Hemorrhage into GI tract Acute myocardial infarction Stress Methodologic interference Nesslerization (chloral hydrate, chloramphenicol, ammonium salts) Berthelot (aminophenol, asparagine, ammonium salts) Fearon (acetohexamide, sulfonylureas) Decreased In Diuresis (e.g., with overhydration, often associated with low protein catabolism) Severe liver damage (liver failure) Drugs Poisoning Hepatitis Other Increased utilization of protein for synthesis Late pregnancy Infancy Acromegaly Malnutrition Anabolic hormones Diet Low protein and high carbohydrate IV feedings only Impaired absorption (celiac disease) Malnutrition Nephrotic syndrome (some patients) SIADH Inherited hyperammonemias (urea is virtually absent in blood) Methodologic interference Berthelot (chloramphenicol, streptomycin)
- 60. URIC ACID Levels are very labile and show day-to-day and seasonal variation in same person; also increased by emotional stress, total fasting, increased body weight. Use Monitor treatment of gout. Monitor chemotherapeutic treatment of neoplasms to avoid renal urate deposition with possible renal failure. Increased In Renal failure (does not correlate with severity of kidney damage; urea and creatinine should be used) Gout 25% of relatives of patients with gout Asymptomatic hyperuricemia (e.g., incidental finding with no evidence of gout; clinical significance is not known but people so afflicted should be rechecked periodically for gout). The higher the level of serum uric acid, the greater the likelihood of an attack of acute gouty arthritis. Increased destruction of nucleoproteins Leukemia, multiple myeloma Polycythemia Lymphoma, especially postirradiation Other disseminated neoplasms Cancer chemotherapy (e.g., nitrogen mustards, vincristine, mercaptopurine, prednisone) Hemolytic anemia Sickle cell anemia Resolving pneumonia Toxemia of pregnancy (serial determinations to follow therapeutic response and estimate prognosis) Psoriasis (one-third of patients) Drugs Small doses of salicylates (<4 gm/day) Intoxications (e.g., barbiturates, methyl alcohol, ammonia, carbon monoxide); some patients with alcoholism Decreased renal clearance or tubular secretion (e.g., various diuretics: thiazides, furosemide, ethacrynic acid) Nephrotoxic effect (e.g., mitomycin C) Other effects (e.g., levodopa, phenytoin sodium) Methodologic interference (e.g., ascorbic acid, levodopa, methyldopa) Metabolic acidosis Diet High-protein weight reduction diet Excess nucleoprotein (e.g., sweetbreads, liver) may increase level £1 mg/dL. Alcohol consumption Miscellaneous von Gierke's disease Lead poisoning Lesch-Nyhan syndrome Maple syrup urine disease Down syndrome Polycystic kidney disease Calcinosis universalis and circumscripta Hypoparathyroidism Primary hyperparathyroidism Hypothyroidism Sarcoidosis Chronic berylliosis Arteriosclerosis and hypertension (serum uric acid is increased in 80% of patients with elevated serum triglycerides) Certain population groups (e.g., Blackfoot and Pima, Filipinos, New Zealand Maoris) Most common causes in hospitalized men are azotemia, metabolic acidosis, diuretics, gout, myelolymphoproliferative disorders, other drugs, unknown causes. (“It is difficult to justify therapy in asymptomatic persons with hyperuricemia to prevent gouty arthritis, uric acid stones, urate nephropathy or risk of cardiovascular disease.”3 ) Decreased In Drugs ACTH Uricosuric drugs (e.g., high doses of salicylates, probenecid, cortisone, allopurinol, coumarins) Various other drugs (radiographic contrast agents, glyceryl guaiacolate, estrogens, phenothiazines, indomethacin) Wilson's disease Fanconi's syndrome Acromegaly (some patients)
- 61. Celiac disease (slightly) PA in relapse (some patients) Xanthinuria Neoplasms (occasional cases) (e.g., carcinomas, Hodgkin's disease) Healthy adults with isolated defect in tubular transport of uric acid (Dalmatian dog mutation) Decreased in ~5% of hospitalized patients; most common causes are postoperative state (GI surgery, coronary artery bypass), diabetes mellitus, various drugs, SIADH in association with hyponatremia. Unchanged In Colchicine administration VITAMIN D Use Diagnosis of rickets and vitamin D toxicity Differential diagnosis of hypercalcemias Serum/Urine Calcium Increased 1,25-dihydroxy-vitamin D 25-hydroxy-vitamin D Hyperparathyroidism N N, I Conditions associated with parathyroid hormone–related protein (PTHrP) N D Lymphoma N D, I Granulomatous conditions (e.g., sarcoidosis) N I Idiopathic hypercalciuria N N, I Osteoporosis N N, I Vitamin D and 25-hydroxy-vitamin D intoxication I N 1,25-dihydroxy-vitamin D and dihydrotachysterol intoxication N I Serum Calcium Decreased 1,25-dihydroxy-vitamin D 25-hydroxy-vitamin D Hypoparathyroidism N D, N Pseudohypoparathyroidism N D, N Vitamin D deficiency D D, N, I Vitamin D-dependent rickets Type I N D Type II N I Severe liver disease D D, N Nephrotic syndrome D D, N Renal failure N D Hyperphosphatemia N D Hypomagnesemia N D, N Serum Calcium Normal 1,25-dihydroxy-vitamin D 25-hydroxy-vitamin D Pregnancy, lactation N I Growing children N I Elderly D, N D, N, I Summertime N N Wintertime D N Increased latitude D N I = increased; D = decreased; N = normal. 1 Reg R Aminotransferases in disease. Clin Lab Med 1989;9:667. 2 Castaldo G, et al. Serum LD isoenzyme 4/5 ratio discriminates between hepatocellular and secondary liver neoplasms. Clin Chem 1991;37:1419. 3 Duffy WB, et al. Management of asymptomatic hyperuricemia. JAMA 1981;246:2215–2216.
- 62. CHAPTER 4 URINE Interpretation of Diagnostic Tests CHAPTER 4 URINE Normal Values Bacteriuria Bilirubinuria Calciuria Chyluria Color, Abnormal Creatine Creatinine Crystalluria Cytology Diagnostic Indices Electrolytes Eosinophiluria Ferric Chloride Test Gonadotropins, Chorionic Hematuria Hematuria, Benign Familial or Recurrent Hemoglobinuria Hemosiderinuria Ketonuria Lipuria Melanogenuria Myoglobinuria Odors (of Urine and Other Body Fluids) Porphyrinuria Proteinuria Reducing Substances Renal Antigens Excretion Renal Enzyme Excretion Specific Gravity Uric Acid/Creatinine Ratio Urobilinogenuria Volume Other Procedures NORMAL VALUES Addis count (no longer performed) RBC £1,000,000/24 hrs Casts £100,000/24 hrs WBC + epithelial cells £ 2,000,000/24 hrs Calcium <150 mg/24 hrs on low-calcium (Bauer-Aub) diet Chloride 140–250 mEq/L Coproporphyrin 50–300 µg/24 hrs; 0–75 µg/24 hrs in children weighing <80 lb Creatine <100 mg/24 hrs (<6% of creatinine); higher in children (<1 yr: may = creatinine; older children: £30% of creatine) and during pregnancy (£12% of creatinine) Creatinine Males 19–26 mg/kg of body weight/24 hrs Females 14–21 mg/kg of body weight/24 hrs Cystine or cysteine 0 Delta-aminolevulinic acid 1.5–7.5 mg/24 hrs Glucose Qualitative = 0£0.3 gm/24 hrs Hemoglobin and myoglobin 0 Homogentisic acid 0 Ketones Qualitative = 0 Lead <0.08 µg/mL or 120 µg/24 hrs Microscopic examination £1–2 RBC, WBC, epithelial cells/high-power field (HPF); occasional hyaline cast/low-power field (LPF) Osmolality 500–1200 mOsm/L Oxalate Males £55 mg/24 hrs Females £50 mg/24 hrs pH 4.6–8.0 (average = 6.0), depending on diet; >9 indicates old specimen Phenylpyruvic acid 0 Phosphorus 1 gm/24 hrs (average), depending on diet Porphobilinogen 0–2 mg/24 hrs Protein Qualitative = 0 0–0.1 gm/24 hrs Specific gravity 1.003–1.030 Total solids 30–70 gm/L (average = 50). To estimate, multiply last two figures of specific gravity by 2.66 (Long's coefficient). Uric acid £750 mg/24 hrs Urobilinogen 0–4 mg/24 hrs Uroporphyrin 0 Volume Adults 600–2500 mL/24 hrs (average = 1200) Night volume usually <700 mL with specific gravity <1.018 or osmolality >825 mOsm/kg of body weight in children Ratio of night to day volume 1:2–1:4 Infants Premature 1–3 mL/kg/hr Full-term 15–60 mL/24 hrs 2 wks 250–400 mL/24 hrs 8 wks 250–400 mL/24 hrs 1 yr 500–600 mL/24 hrs BACTERIURIA See Chapter 14. BILIRUBINURIA See Chapter 8.
- 63. CALCIURIA Use Diagnosis of hypercalciuria causing renal calculi. Increased In Hyperparathyroidism Idiopathic hypercalciuria High-calcium diet Excess milk intake Immobilization (especially in children) Lytic bone lesions Metastatic tumor Multiple myeloma Osteoporosis (primary or secondary to hyperthyroidism, Cushing's syndrome, acromegaly) Drugs Diuretics (e.g., ammonium chloride, mercurials) Androgens, anabolic steroids Cholestyramine Dihydrotachysterol, vitamin D, parathyroid injections Viomycin Fanconi's syndrome Glucocorticoid excess due to any cause Paget's disease Renal tubular acidosis Rapidly progressive osteoporosis Sarcoidosis Decreased In Hypoparathyroidism Rickets, osteomalacia Familial hypocalciuric (benign) hypercalcemia Steatorrhea Renal failure Metastatic carcinoma of prostate Drugs (e.g., sodium phytate, thiazides) Hypercalciuria without Hypercalcemia Due To Idiopathic hypercalciuria Sarcoidosis Glucocorticoid excess due to any cause Hyperthyroidism Rapidly progressive bone diseases (Paget's disease, immobilization, malignant tumors) Renal tubular acidosis Medullary sponge kidney Furosemide administration CHYLURIA Use Diagnosis of injury or obstruction of lymphochylous system of chest or abdomen
- 64. Due To Obstruction of the lymphochylous system, usually filariasis. Microfilariae appear in the urine for 6 wks after acute infection then disappear, unless endemic. Trauma to chest or abdomen Abdominal tumors or lymph node enlargement Milky urine is due to chylomicrons recognized as fat globules by microscopy (this is almost entirely neutral fat). Protein is normal or low. Hematuria is common. Specific gravity is low, and reaction is acid. A test meal of milk and cream may cause chyluria in 1–4 hrs. Laboratory findings due to pyelonephritis that is often present. COLOR, ABNORMAL1 Red (“red” often includes colors from pink to red-brown) No specific test (chlorzoxazone, ethoxazene, oxamniquine, phenothiazines, rifampin) Acid urine only (phenolphthalein) Red-orange No specific test (butazopyridine, chlorzoxazone, ethoxazene, mannose, oxamniquine, phenothiazines, rifampin) Alkaline urine only (phenindione) Acid urine only (phenolphthalein) Red or pink No specific test (aminopyrine, aniline dyes, antipyrine, doxorubicin, fuscin, ibuprofen, phenacetin, phenothiazines, phensuximide, phenytoin) Acid urine only (beets, blackberries, anisindione) Alkaline urine only (anthraquinone laxatives, rhubarb, santonin, phenolsulfonphthalein, sulfobromophthalein sodium [Bromsulphalein]; eosin produces green fluorescence) Darkens on standing (porphyrins) Presence of urates and bile On contact with hypochlorite bleach (toilet bowl cleaner) (aminosalicylic acid) Centrifuged specimen shows RBC in base (blood) Purple Alkaline urine only (phenolphthalein) Darkens on standing (porphyrins; fluoresces with ultraviolet light) No specific test (chlorzoxazone) Red-brown Acid urine only (methemoglobin, metronidazole, anisindione) ( Fig. 4-1) Fig. 4-1. Algorithm for red or brown urine. (GU = genitourinary; Hb = hemoglobin; RBC = red blood cell.) Alkaline urine only (anthraquinone laxatives, levodopa, methyldopa, parahydroxyphenylpyruvic acid, phenazopyridine) Positive o-toludine test for blood Centrifuged urine shows RBC in base if blood; centrifuged blood shows pink supernatant plasma if Hb but clear plasma if myoglobin. Green in reflected light (antipyrine) Orange with addition of HCl (phenazopyridine) No specific test (chloroquine, deferoxamine, ethoxazene, ibuprofen, iron sorbitex, pamaquine, phenacetin, phenothiazines, phensuximide, phenytoin, trinitrophenol) Brown-black Darkens on standing (homogentisic acid, melanin, melanogen, nitrobenzene, parahydroxyphenylpyruvic acid [alkaline urine only], phenol, cresol, naphthol) Does not darken on standing Ferric chloride test Color fades (Argyrol) Blue-green (homogentisic acid) Black (melanin or melanogen) Nitroprusside test is red with melanin, black with melanogen. Yellow-brown Darkens on standing in acid urine (anthraquinone laxatives, rhubarb) Positive test for bile (bilirubin, urobilin) No specific test (niridazole, nitrofurantoin, pamaquine, primaquine, sulfamethoxazole)
- 65. Yellow Acid urine only (quinacrine, santonin) Alkaline urine only (beets) Positive test for bile (bilirubin, urobilin) No specific test (fluorescein dye, phenacetin, riboflavin, trinitrophenol) Yellow-orange Alkaline urine only (anisindione, sulfasalazine) Positive test for bile (bilirubin, urobilin) Color increases with HCl (phenazopyridine) Ether soluble (carrots, vitamin A) High specific gravity (dehydration) No specific test (aminopyrine, warfarin) Yellow-green or brown-green Darkens on standing (cresol, phenol [Chloraseptic], methocarbamol [Robaxin], resorcinol) Positive test for bile (biliverdin) Blue-green Darkens on standing (methocarbamol, resorcinol) Blue fluorescence in acid urine (triamterene) Bacteriuria, pyuria (Pseudomonas infection [rare]) Decolorizes with alkali (indigo-carmine dye) Positive Obermayer's test (indican) No specific test (chlorophyll breath mints [Clorets], Evans blue dye, guaiacol, magnesium salicylate [Doan's Pills], methylene blue, thymol [Listerine]) Biliverdin due to oxidation of bilirubin in poorly preserved specimens. Gives negative diazo tests for bilirubin (Ictotest), but oxidative tests (Harrison spot test) may still be positive. Milky Lipuria, chyluria (ether soluble) Many polymorphonuclear neutrophils (PMNs) (microscopic examination) White cloud is due to excessive oxalic acid and glycolic acid in urine; occurs in oxalosis (primary hyperoxaluria). Colorless Specific gravity High (diabetes mellitus with glycosuria; positive test for glucose) Low (diabetes insipidus, recent fluid intake) Variable (diuretics, ethyl alcohol, hypercalcemia) Clear to deep yellow Normal (due to urochrome pigment) Blue diaper syndrome results from indigo blue in urine due to familial metabolic defect in tryptophan absorption associated with idiopathic hypercalcemia and nephrocalcinosis. Red diaper syndrome is due to a nonpathogenic chromobacterium (Serratia marcescens) that produces a red pigment when grown aerobically at 25–30°C. Darkening of urine on standing, alkalinization, or oxygenation is nonspecific and may be due to Melanogen, Hb, indican, urobilinogen, porphyrins, phenols, salicylate metabolites (e.g., gentisic acid), homogentisic acid (due to alkaptonuria), administration of metronidazole hydrochloride (Flagyl). In acid pH, urine may not darken for hours (e.g., tyrosinosis). Sickle cell crises produce a characteristic dark-brown color independent of volume or specific gravity that becomes darker on standing or on exposure to sunlight due to increase in porphyrins. CREATINE Increased In Physiologic states Childhood growth Pregnancy Puerperium (2 wks) Starvation Raw meat diet Increased formation Myopathy Amyotonia congenita Muscular dystrophy Poliomyelitis Myasthenia gravis Crush injury Acute paroxysmal myoglobinuria Endocrine diseases Hyperthyroidism Addison's disease Cushing's syndrome Acromegaly Diabetes mellitus
- 66. Eunuchoidism Therapy with ACTH, cortisone, or desoxycorticosterone acetate Increased breakdown Infections Burns Fractures Leukemia SLE Decreased In Hypothyroidism CREATININE Use Determine urine concentration of various substances when 24-hr urine cannot be obtained. Detect artifactual dilution of urine in drug abuse testing. In healthy young men on meat-free diet, can be used to calculate muscle mass 2 : Total muscle mass (kg) = creatinine (gm) excreted/24 hrs × 21.8 CRYSTALLURIA Disorder Substance Massive hepatic necrosis (acute yellow atrophy), tyrosinemia, tyrosinosis Tyrosine Cystinuria, cystinosis Cystine Fanconi's syndrome Leucine Hyperoxaluria, oxalosis Calcium oxalate Lesch-Nyhan syndrome Uric acid Orotic aciduria Orotic acid Xanthinuria Xanthine CYTOLOGY Use Screen persons exposed to urothelial or bladder carcinogens Detect urothelial dysplasia and carcinomas (see Chapter 14) Monitor effects of radiation or chemotherapy Detect nonbacterial infections (parasitic, fungal, viral) Characterize cells with inclusions Characterize inflammatory conditions Confirm abnormal routine urinalysis microscopy findings Flow cytometry and DNA analysis are used for diagnosis, prognosis, and monitoring of therapy but not for screening. DIAGNOSTIC INDICES See Table 14-12. ELECTROLYTES Use Diagnosis of causes of hyponatremia (see Table 13-27.) and hypokalemia Identify suspected disorders of adrenal cortex Aid diagnosis of causes of acute renal failure ( Table 14-12. and Table 4-1) Table 4-1. Urine Electrolytes in Various Metabolic Conditions
- 67. Interferences Value may be limited due to failure to obtain 24-hr excretion levels rather than random samples or administration of diuretics. EOSINOPHILURIA3 (Refers to >1% of urinary leukocytes as eosinophils; should be performed using Hansel's rather than Wright's stain) Use May be useful to distinguish acute interstitial nephritis from acute tubular necrosis, in which it is absent. Due To Acute interstitial nephritis (drug induced); sensitivity = 60–90%, specificity >85%, positive predictive value ~50%, negative predictive value 98%. Acute GN (rapidly progressive; acute including poststreptococcal) IgA nephropathy (Henoch-Schönlein purpura) Chronic pyelonephritis Acute rejection of renal allograft Obstructive uropathy Prostatitis Eosinophilic cystitis Schistosoma hematobium infestation Bladder cancer Cholesterol embolization to kidney FERRIC CHLORIDE TEST (Primarily used as screening test for phenylketonuria) Positive In Phenistix color Phenylketonuria (unreliable for diagnosis) Gray-green Tyrosinuria (transient elevation in newborns) Green Maple syrup urine disease Negative Alkaptonuria Negative Histidinemia Blue-gray to green Tyrosinosis Green (fades quickly) Oasthouse urine disease — Bilirubin — Lactic acidosis Gray Melanin — Methionine malabsorption — Pyruvic acid Yellow Xanthurenic acid Negative Acetoacetic acid Negative Drugs Para–aminosalicylic acid Purple Phenothiazines Purple Salicylates Purple A positive test should always be followed by other tests (e.g., chromatography of blood and urine) to rule out genetic metabolic disorders. GONADOTROPINS, CHORIONIC (See also Pregnancy Test, Human Chorionic Gonadotropin, Serum.) Increased In Normal pregnancy (secreted first by trophoblastic cells of conceptus and later by placenta). Becomes positive as early as 4 days after expected date of menstruation; it is >95% reliable by 10th–14th day. Human chorionic gonadotropin (hCG) increases to peak at 60th–70th day, then drops progressively. Hydatidiform mole, choriocarcinoma. Test negative one or more times in >60% and negative at all times in >20% of these patients, for whom more sensitive methods should be used. Quantitative titers should be performed for diagnosis and for following the clinical course of patients with these conditions. Serum is preferred test. False Positive Due To Drugs Chlorpromazine (frog, rabbit, immunologic) Phenothiazines (frog, rabbit, immunologic) Promethazine (Gravindex) Methadone
- 68. Bacterial contamination Protein or blood in urine False Negative Due To Drugs Promethazine (DAP test) Dilute urine Missed abortion Dead fetus syndrome Ectopic pregnancy With the latex agglutination type of text, only urine should be used if patient has RA. Normal In Nonpregnant state Fetal death HEMATURIA Use Screening and diagnosis of disorders of genitourinary tract ( Fig. 4-2). Fig. 4-2. Algorithm for diagnosis of microhematuria. (ANA = antinuclear antibodies; ASOT = antistreptolysin-O titer.) Screening for excess anticoagulation medication. Interpretation <3% of normal persons have ³3 RBCs/HPF or >1000 RBCs/mL (no easy conversion formula between these two methods). Abnormal range is >3 RBCs/HPF. Hematuria found in 18% of persons after very strenuous exercise. Centrifuged fresh urine sediment should be examined under high dry magnification. Urine does not show any red color at <5,000,000 RBCs/mL. Dipsticks (orthotolidine or peroxidase) detect heme peroxidase activity in RBCs, Hb, or myoglobin with reported sensitivity of 91–100% and specificity of 65–99%; may miss 10% of patients with microscopic hematuria. Orthotolidine test strips are sensitive to 3–10 RBCs/HPF. Are more reliable in hypotonic urine (lyses RBCs) than hypertonic urine. For detection of hematuria, specificity = 65–99% compared to microscopy; positive predictive value for significant disease = 0–2% and for possibly significant disease = 6–58%. Dipsticks exposed to air (uncapped bottles) for a week or more may give false-negative results for blood. In microscopic hematuria, number of RBCs is not related to the significance of the causative lesion. Presence of blood clots virtually rules out glomerular origin of blood. Large thick clots suggest bladder origin; small stringy clots suggest upper tract. Wright's stain or phase microscopy in urine sediment is said to show distortion with crenation and uneven Hb distribution of RBCs (dysmorphic) of glomerular origin; if >80% are similar to RBCs in peripheral blood (eumorphic), the source is likely to be distal to glomeruli. Dysmorphic changes are much more apt to be found with urine osmolality >700 mOsm/kg (equivalent to specific gravity 1.017) or pH <7. With an automated RBC counter that produces size distribution curves, urine RBC size distribution has been reported less than that of venous RBCs in GN and either greater than that of venous RBCs (nonglomerular) or both (mixed) types in lower GU tract lesions. Immunocytochemical staining (against human Tamm-Horsfall protein) is positive in >80% of RBCs of renal origin and <13.1% of RBCs of nonrenal origin. RBC casts or Hb casts indicates blood is of glomerular origin, but their absence does not rule out glomerular disease. Gross hematuria that is initial suggests origin in urethra distal to urogenital diaphragm; terminal suggests origin in bladder neck or prostatic urethra; total suggests origin in bladder proper or upper urinary tract. Proteinuria may occur with gross hematuria. In nonglomerular hematuria, sufficient proteinuria to produce 2+ dipstick requires equivalent of 25 mL of blood/L urine (if Hct is normal), which would cause gross hematuria; in glomerular hematuria, proteins filter through glomerulus out of proportion to RBCs. Therefore microscopic hematuria with 2+ protein on dipstick favors glomerular origin; one exception is in papillary necrosis, which may show 2+ proteinuria with nonglomerular type of RBCs. Pyuria or WBC casts suggest inflammation or infection of GU tract. Persistent or intermittent hematuria should always be evaluated; one episode of microscopic hematuria usually does not require full evaluation (may be due to viral infection, mild trauma, exercise, etc.).
- 69. Routine screening of all adults is not recommended. Interferences False positive Vaginal bleeding Factitious Bacteriuria (due to catalase production by gram-negative bacteria and Staphylococcus sp. whose action on dipsticks is similar to that of Hb peroxidase) Red diaper syndrome Drugs (e.g., rifampin, phenolphthalein, iodides, bromides, copper, oxidizing agents, permanganate) Foods (e.g., beets, blackberries, rhubarb) Pigmenturia (porphyria, hemoglobinuria, myoglobinuria) Oxidizing contaminants (e.g., bacterial peroxidases, povidone, hypochlorite) False negative Reducing agents (e.g., high doses of ascorbic acid [vitamin C]) pH <5.1 Nonglomerular Hematuria Due To Trauma Hemoglobinopathies (especially sickle cell trait and Hb sickle cell disease) Hypercalciuria Polycystic disease GU tract tumors, infections Some Causes of Hematuria in Adults4 Gross (%) Microscopic (%) GU tract cancer 22.5 5.1 Kidney 3.6 0.5 Prostate 2.4 0.5 Ureter 0.8 0.2 Bladder 15 4 Other lesions GU tract infection 33 4.3 Calculi 11 5 Benign prostatic hypertrophy 13 13 Renal 2.2 Systemic (e.g., hemophilia, thrombocytopenia, dicumarol overdose) 1 No source found 8.4 43 Hematuria in Children Due To Glomerular Acute postinfectious GN Membranoproliferative GN IgG-IgA nephropathy (Berger's disease) Hereditary nephritis SLE Henoch-Schönlein purpura Benign familial hematuria Benign recurrent hematuria Nonglomerular Polycystic kidneys Renal tumors Renal TB Vascular abnormalities (e.g., renal hemangioma, essential hematuria) Hematologic conditions (e.g., sickle cell trait, coagulation disorders) Hydronephrosis
- 70. GU tract infection, foreign body, calculi, etc. (usually symptomatic) HEMATURIA, BENIGN FAMILIAL OR RECURRENT Asymptomatic hematuria without proteinuria Other laboratory and clinical findings are normal. Renal biopsy is normal on light microscopy, electron microscopy, and immunofluorescence. Other family members may also have asymptomatic hematuria. Should gradually clear spontaneously; annual screening for other abnormalities should be performed until condition clears. HEMOGLOBINURIA Renal threshold is 100–140 mg/dL plasma. Use Confirms hemolyzed blood in urine from either GU tract or intravascular cause. Due To Hematuria (due to any cause) with hemolysis in urine Infarction of kidney Intravascular hemolysis due to Parasites (e.g., malaria, Oroya fever due to Bartonella bacilliformis) Infection (e.g., Clostridia, Escherichia coli bacteremia due to transfused blood) Antibodies (e.g., transfusion reactions, acquired hemolytic anemia, paroxysmal cold hemoglobinuria, paroxysmal nocturnal hemoglobinuria) DIC Inherited hemolytic disorders (e.g., sickle cell disease, thalassemias, G-6-PD deficiency, pyruvate kinase deficiency, hereditary spherocytosis) Fava bean sensitivity Mechanical causes (e.g., prosthetic heart valve) Hypotonicity (e.g., transurethral prostatectomy with irrigation of bladder with water, hemodialysis accidents) Chemicals (e.g., naphthalene, sulfonamides) Thermal burns injuring RBCs Strenuous exercise and march hemoglobinuria Interferences False-positive (Occultest) results may occur in the presence of pus, iodides, bromides. Serum is pink due to free Hb but clear due to myoglobin. HEMOSIDERINURIA Centrifuged specimen of random urine incubated for 10 mins with Prussian blue stain shows blue granules. Granules are located in cells, but if these have disintegrated, free granules may be predominant. Normal—absent Use Present in intravascular hemolysis even when hemoglobinuria is absent (e.g., paroxysmal nocturnal hemoglobinuria). KETONURIA (Ketone bodies [acetone, beta-hydroxybutyric acid, acetoacetic acid] appear in urine.) Use Screen for ketoacidosis, especially in diabetes mellitus when blood is not immediately available Confirm fasting in testing for insulinoma Interferences (reagent strips) False positive Drugs (e.g., levodopa) False negative Volatilization of acetone Breakdown of acetoacetic acid Occurs In Metabolic conditions
- 71. Diabetes mellitus Renal glycosuria Glycogen storage disease Dietary conditions Starvation High-fat diets Increased metabolic requirements Hyperthyroidism Fever Pregnancy and lactation Other LIPURIA Lipids in the urine include all fractions. Double refractile (cholesterol) bodies can be seen. Protein content is high. Use Rarely used. May Occur In Hyperlipidemia due to Nephrotic syndrome Severe diabetes mellitus Severe eclampsia Extensive trauma with bone fractures Phosphorus poisoning Carbon monoxide poisoning MELANOGENURIA Use In some patients with malignant melanoma, when the urine is exposed to air for several hours, colorless melanogens are oxidized to melanin, and urine becomes deep brown and later black. Melanogenuria occurs in 25% of patients with malignant melanoma; it is said to be more frequent with extensive liver metastasis. It is not useful for judging completeness of removal or early recurrence. Is also said to occur in some patients with Addison's disease or hemochromatosis and in intestinal obstruction in black persons. Confirmatory tests Ferric chloride test Thormählen's test Ehrlich's test None of these is consistently more reliable or sensitive than observation of urine for darkening. Interferences Beware of false-positive red-brown or purple suspension due to salicylates. MYOGLOBINURIA Renal threshold is 20 mg/dL plasma. Use Indicates recent necrosis of skeletal or cardiac muscle. Interpretation Diagnosis based on w Positive benzidine or o-toluidine test of urine, which contains few or no RBCs when urine is red or brown. This is the simplest and most practical initial test. Tests may be positive even when urine is normal in color. Serum is clear (not pink) unless renal failure is present, in contrast to hemoglobinemia. Serum haptoglobin is normal (in contrast to hemoglobinemia). Serum enzymes of muscle origin (e.g., CK) are increased.
- 72. w Identification of myoglobin in urine by various means. Immunodiffusion is most sensitive and specific. Ultracentrifugation and electrophoresis lack specificity. Spectrophotometry shows similar peaks for myoglobin and hemoglobin. Precipitation by ammonium sulfate may give false-negative results. Hereditary Phosphorylase deficiency (McArdle's syndrome) Metabolic defects (e.g., associated with muscular dystrophy) Sporadic Ischemic (e.g., arterial occlusion) (in AMI, levels >5 mg/mL occur within 1–2 hrs and precede ECG and serum CK and CK-MB changes). Has 100% sensitivity but is less specific than CK-MB elevation. Crush syndrome. Exertional (e.g., exercise, some cases of march hemoglobinuria, electric shock, convulsions, and seizures). Metabolic myoglobinuria (e.g., Haff disease, alcoholism, sea snake bite, carbon monoxide poisoning, diabetic acidosis, hypokalemia, malignant hyperpyrexia, systemic infection, barbiturate poisoning). £50% of patients with progressive muscle disease (e.g., dermatomyositis, polymyositis, SLE, others) in active stage. Various drugs and chemicals, especially illicit (e.g., cocaine, heroin, methadone, amphetamines, diazepam, etc.). ODORS (OF URINE AND OTHER BODY FLUIDS) Use Clue to various metabolic disorders. Condition Odor Maple syrup urine disease Maple syrup, burned sugar Oasthouse disease, methionine malabsorption Brewery, oasthouse Methylmalonic, propionic, isovaleric, and butyric/hexanoic acidemia Sweaty feet Tyrosinemia Cabbage, fish Trimethylaminuria Stale fish Hypermethioninemia Rancid butter, rotten cabbage Phenylketonuria Musty, mousy Ketosis Sweet Cystinuria, homocystinuria Sulfurous PORPHYRINURIA (Due mainly to coproporphyrin) Use Porphyrias (see Chapter 12) Lead poisoning Cirrhosis Infectious hepatitis Passive in newborn of mother with porphyria; lasts for several days. PROTEINURIA See Table 14-2 and Fig. 4-3. Fig. 4-3. Algorithm for diagnosis of proteinuria. (ANA = antinuclear antibodies; ASOT = antistreptolysin-O titer; SBE = subacute bacterial endocarditis; HBV = hepatitis B virus; UTI = uninary tract infection.) See Microalbuminuria. Use Detection of various renal disorders and Bence Jones proteinuria. Interpretation Found in 1–9% of cases on routine screening. Refers to protein excretion >150 mg/day in adults and >100 mg/day in children <10 yrs or >140 mg/m 2 /day. Significant proteinuria is >300 mg/day in adults. >1000
- 73. mg/day makes a diagnosis of renal parenchymal disease very likely. >2000 mg/day in adults or >40 mg/m 2 in children usually indicates glomerular etiology. >3500 mg/day or protein/creatinine ratio >3.5 points to a nephrotic syndrome. When a 24-hr urine specimen cannot be reliably collected, a spot urine for urine protein/creatinine ratio (especially after first morning specimen and before bedtime and if renal function is not severely impaired) often correlate well. Normal value is <0.2 for adults, 0.5 for age 6–24 months, 0.2–0.25 for child >24 months. Low-grade proteinuria = 0.2–1.0. Moderate proteinuria = 1.0–5.0. Value >5 is typical of nephrosis. Dipstick is sensitive to ~30 mg/dL of protein; 1+ = 100 mg/dL; 2+ = 300 mg/dL; 4+ = 1000 mg/dL; may be falsely negative with predominantly low-molecular-weight or nonalbumin proteins. Positive dipstick should always be followed by sulfosalicylic acid test, which is sensitive to 5–10 mg/dL of protein; may be falsely negative with very alkaline or dilute urine; may be falsely positive due to certain drugs (e.g., radiographic contrast media, high doses of penicillin, chlorpromazine, tolbutamide, sulfa drugs). When sulfosalicylic acid test shows a significantly higher concentration than the dipstick in an adult, Bence Jones proteinuria should be ruled out. Association with hematuria indicates high likelihood of disease. For detection of proteinuria, sensitivity and specificity = 95–99%; positive predictive value for renal disease = 0–1.4% (in young populations). Urine electrophoresis Glomerular Selective: primarily albumin (>80%) and transferrin (mild renal injury due to dibetes mellitus, immune complex disease, minimal change disease) Nonselective: pattern resembles serum. Primary and secondary glomerulonephropathies (diabetes mellitus, amyloidosis, collagen diseases, dysglobulinemia, HUS). Tubular: principally alpha1, alpha2, beta, and gamma globulins; albumin is not marked. Most often seen in chronic pyelonephritis, interstitial tubular nephritis, congenital tubular nephropathies, polycystic kidneys, hypercalciuria, acute tubular necrosis due to ischemia or drugs. Mixed glomerular-tubular: advanced renal disease involving entire nephron (e.g., chronic renal failure, chronic pyelonephritis) Dysglobulinemias (see Chapter 11; e.g., multiple myeloma, macroglobulinemia, heavy chain diseases) Due To Orthostatic (postural) w First morning urine before arising shows high specific gravity but no protein (protein/creatinine ratio <0.1). Protein appears only after person is upright; usually <1.5 gm/day (protein/creatinine ratio usually 0.1–1.3). Urine microscopy is normal. Is usually considered benign and slowly disappears with time but is still present in 50% of persons 10 yrs later. Progressive renal insufficiency does not occur. Occurs in 15% of apparently healthy young men and 3% of otherwise healthy persons and some patients with resolving acute pyelonephritis or GN. Renal biopsy, electron microscopy, and immunofluorescent stains show pathologic changes in some patients. Transient Commonly found in routine urinalysis of asymptomatic healthy children and young adults initially but not subsequently. Progressive renal disease is not present. Functional occurs in 10% of hospital medical patients; associated with high fever, congestive heart failure, hypertension, stress, exposure to cold, strenuous exercise, seizures. Usually <2 gm/day; disappears with recovery from precipitating cause. Progressive renal disease is not present. Persistent Glomerular (composed of large proteins, e.g., albumin, alpha 1-antitrypsin, transferrin) Idiopathic (e.g., membranoproliferative GN, membranous glomerulopathy, minimal change disease, focal segmental glomerulosclerosis, amyloidosis) Secondary Infection (e.g., poststreptococcal, hepatitis B, bacterial endocarditis, malaria, infectious mononucleosis, pyelonephritis, etc.) Vascular (e.g., thrombosis of inferior vena cava or renal vein, renal artery stenosis) Drugs (e.g., nonsteroidal antiinflammatory drugs, heroin, gold, captopril, penicillamine) Autoimmune (e.g., SLE, RA, dermatomyositis, polyarteritis, Goodpasture's syndrome, Henoch-Schönlein purpura, ulcerative colitis) Neoplasia Hereditary and metabolic (e.g., polycystic kidney disease, diabetes mellitus, Fabry's disease, Alport's syndrome of progressive interstitial nephritis and nerve deafness) Decreased tubular reabsorption (composed of low-molecular-weight proteins [e.g., alpha and beta microglobulins, free Ig light chains, retinol-binding protein, lysozyme; usually <1.5 gm/day]) Acquired Drugs (e.g., phenacetin, aminoglycoside, cephalosporins, cyclosporine, high-dose analgesics, lithium, methicillin, etc.) Heavy metals (e.g., lead, mercury, cadmium) Sarcoidosis Acute tubular necrosis Interstitial nephritis Renal tubular acidosis Acute and chronic pyelonephritis Renal graft rejection Balkan nephropathy Congenital (e.g., Fanconi's syndrome, oculo-cerebral-renal syndrome) Hereditary (e.g., Wilson's disease, sickle cell disease, medullary cystic disease, oxalosis, cystinosis) Increased plasma levels of normal or abnormal proteins (e.g., Bence Jones proteins, myoglobin, lysozyme in monocytic or myelocytic leukemias) Common causes of low-grade proteinuria (<1 gm/24 hrs) Kimmelstiel-Wilson syndrome Idiopathic low-grade proteinuria–normal history and physical examination, renal function, and urine sediment with no hematuria. Nephrosclerosis Polycystic kidney disease Medullary cystic disease Chronic obstruction of urinary tract Chronic interstitial nephritis (e.g., analgesic abuse, uric acid, oxalate, hypercalcemia, hypokalemia, lead, cadmium) Interferences False Positive Dipstick Sulfosalicylic Acid
- 74. Gross hematuria* + + Highly concentrated urine + + Highly alkaline urine (pH >8) (e.g., GU tract infection with urea-splitting bacteria) + – Antiseptic contamination (e.g., benzalkonium, chlorhexidine) + – Phenazopyridine + – Radiopaque contrast media – + Tolbutamide metabolites – + High levels of cephalosporin or penicillin analogs – + Sulfonamide metabolites – + *Protein excretion >500 mg/m2 /day is significant. With microscopic hematuria, any amount more than an occasional trace of protein is abnormal. False Negative Very dilute urine Bence Jones Proteinuria Use Detection of various gammopathies 80% of tests are true positive due to Myeloma (70% of all positive tests) Cryoglobulinemia Waldenström's macroglobulinemia Primary amyloidosis Adult Fanconi's syndrome Hyperparathyroidism Benign monoclonal gammopathy Approximately 20% of tests are false positive (i.e., urine electrophoresis does not show a spike, and immunoelectrophoresis does not show a monoclonal light chain) due to Connective tissue disease (e.g., RA, SLE, scleroderma, polymyositis, Wegener's granulomatosis) Chronic renal insufficiency Lymphoma and leukemia Metastatic carcinoma of lung, GI, or GU tracts High doses of penicillin and aminosalicylic acid Presence of radiographic contrast media Positive test for Bence Jones proteinuria by heat test should always be confirmed by electrophoresis and immunoelectrophoresis/immunofiltration of concentrated urine. Heat test is not reliable and should not be used for diagnosis. Dipstick test for albumin does not detect Bence Jones protein. Beta2-Microglobulin Normal <1 mg/day by enzyme-linked immunosorbent assay (ELISA) or RIA. Use Detection of various renal disorders Increased In Tubular disease (>50 mg/day) Heavy metal poisoning (e.g., mercury, cadmium, cisplatin) Drug toxicity (e.g., aminoglycosides, cyclosporine) Hereditary (e.g., Fanconi's syndrome, Wilson's disease, cystinosis) Pyelonephritis Renal allograft rejection Others (e.g., nephrocalcinosis) Also increased due to increased production in hepatitis, sarcoidosis, Crohn's disease, vasculitis, and certain malignancies, which prevents diagnostic utility. Interferences Need 24-hr timed collection Unstable at room temperature, with acid urine, and in presence of pyuria Differentiation Precipitated by 5% Sulfosalicylic Acid On boiling, precipitate remains On boiling, precipitate disappears Albumin Bence Jones protein Globulin A “proteose” Pseudo–Bence Jones protein Precipitated at 40–60°C Resuspend precipitate in normal urine and equal volume 5% sulfosalicylic acid and boil: Precipitate dissolves: Bence Jones protein Precipitate does not dissolve: Pseudo–Bence Jones protein
- 75. Now replaced by electrophoretic and immunologic procedures. Globulin (Predominantly) Rather than Albumin Multiple myeloma Macroglobulinemia Primary amyloidosis Adult Fanconi's syndrome (some patients) Postrenal Proteinuria Primarily associated with epithelial tumors of bladder or renal pelvis Degree of proteinuria related to size and invasiveness; generally <1 gm/day (similar to pyelonephritis) and includes IgM Renal Diseases in Which Proteinuria May Be Absent Congenital abnormalities Renal artery stenosis Obstruction of GU tract Pyelonephritis Stone Tumor Polycystic kidneys Hypokalemic nephropathy Hypercalcemic nephropathy Prerenal azotemia Retinol-Binding Protein Use Detection of various renal disorders Increased In Proximal tubular dysfunction. Correlates with beta 2-microglobulin excretion but not affected by acid urine. More sensitive than N-acetyl-beta-D-glucosaminidase excretion. May show false negative due to low serum level in vitamin A deficiency. REDUCING SUBSTANCES Use Screening for diabetes mellitus (not recommended as primary screening modality due to poor sensitivity) Interferences (Reagent Strips) False positive Strips exposed to air (uncapped bottles) for a week or more Peroxidase contamination Oxidizing agents False negative (found in >1% of routine urine analyses in hospital) Ascorbic acid >25 mg/dL Drugs (e.g., aspirin) Specific gravity >1.020 High pH Due To Glycosuria Hyperglycemia Endocrine (e.g., diabetes mellitus, pituitary, adrenal, thyroid disease) Nonendocrine (e.g., liver, CNS diseases) Administration of hormones (e.g., ACTH, corticosteroids, thyroid, epinephrine) or drugs (e.g., morphine, anesthetic drugs, tranquilizers) Renal Tubular origin (serum glucose <180 mg/dL; oral and IV glucose tolerance test [GTT] are normal; ketosis is absent) Fanconi's syndrome Toxic renal tubular disease (e.g., due to lead, mercury, degraded tetracycline) Inflammatory renal disease (e.g., acute GN, nephrosis) Glomerular due to increased GFR without tubular damage
- 76. Idiopathic Melituria (5% of cases of melituria in the general population are due to renal glycosuria [incidence = 1:100,000], pentosuria [incidence = 1:50,000], essential fructosuria [incidence = 1:120,000]) Hereditary (e.g., galactose, fructose, pentose, lactose) Galactose (classic and variant forms of galactosemia). Galactosuria (in galactosemia) shows a positive urine reaction with Clinitest but negative with Clinistix and Tes-Tape. Fructose (fructosemia, essential fructosuria, hereditary fructose intolerance) Lactose (lactase deficiency, lactose intolerance) Phenolic compounds (phenylketonuria, tyrosinosis) Xylulose (pentosuria) Neonatal (e.g., physiologic lactosuria, sepsis, gastroenteritis, hepatitis) Lactosuria during lactation Xylose (excessive ingestion of fruit) Non–sugar-reducing substances (e.g., ascorbic acid, glucuronic acid, homogentisic acid, salicylates) RENAL ANTIGENS EXCRETION (Derived from proximal tubule brush borders) Low levels in healthy persons May Be Useful To Distinguish cases of prerenal azotemia and glomerular disease (with low levels) from increased levels in acute renal failure due to proximal tubular disease Follow course of renal transplant patients Distinguish pyelonephritis from cystitis RENAL ENZYME EXCRETION Lactate Dehydrogenase (LD) Increased In Carcinoma of kidney, bladder, and prostate in a high proportion of cases; may be useful for detection of asymptomatic lesions or screening of susceptible population groups and differential diagnosis of renal cysts Other renal diseases Active GN, SLE with nephritis, nephrotic syndrome, acute tubular necrosis, diabetic nephrosclerosis, malignant nephrosclerosis, renal infarction Active pyelonephritis (25% of patients), cystitis, and other inflammations Instrumentation of the GU tract (especially cystoscopy with retrograde pyelography); transient increase is <1 wk AMI and other conditions with considerably increased serum levels Normal In Benign nephrosclerosis Pyelonephritis (most patients) Obstructive uropathy Renal stones Polycystic kidneys Renal cysts The test is not useful in routine screening for malignancy of kidney, renal pelvis, and bladder because increased levels suggest GU tract disease but do not indicate its nature. Increased values usually precede clinical symptoms. Precautions 8-hr overnight urine collection, clean voided to prevent bacterial and menstrual contamination. Refrigerate until analysis is begun. Specimen must be dialyzed to remove inhibitors in urine. Urinalysis should be performed first, because false-positive LD may occur if there are >10 bacteria/HPF or if RBCs or hemolyzed blood is present. L-Alanine Aminopeptidase (Derived from proximal tubule brush borders) Normal is 1500–3700 mU/24 hrs in women and 2000–6000 mU/24 hrs in men. Affected by diuresis and circadian rhythm but not by proteinuria or bacteriuria. Increased by all types of proximal tubular injury and other renal diseases (e.g., glomerular disease, tumors); consequently, test too sensitive and nonspecific. N-Acetyl-Beta-D-glucosaminidase (Derived from proximal tubule lysozymes) Increased in many types of renal disease causing low specificity; therefore not clinically useful.
- 77. Correlates with degree of albuminuria. Lysozyme Increased in acute monocytic and myelomonocytic leukemias. SPECIFIC GRAVITY Increased In Proteinuria Glucosuria Sucrosuria Radiographic contrast medium (frequently 1.040–1.050) Mannitol Dextran Diuretics Antibiotics Detergent Temperature Urinometer readings should be corrected by adding or subtracting 0.001 to specific gravity reading for each 3°C above or below calibration temperature, respectively. Subtract 0.003 for each 1 gm/dL of protein and 0.004 for each 1 gm/dL of glucose from temperature-compensated specific gravity. For reagent strips, add 0.005 if pH >6.5. Specific gravity compares mass of a solution to that of an equal volume of water (i.e., it is related to but not an exact measure of number of solute particles); osmolality measures the exact number of solute particles and is a constant weight/weight relationship. Osmolarity is 1 Osm of nonelectrolyte in 1 L of water and varies with the volume-expanding effect of the dissolved substance and the proportional effect of temperature on the fluid volume. Osmolality is the preferred unit of measure. Decreased volume of concentrated urine (specific gravity >1.030 and osmolality >500 mOsm/kg) is diagnostic of prerenal azotemia. Urine/plasma osmolality ratio is more accurate than urine osmolality or specific gravity to distinguish prerenal azotemia (with increased ratio) from acute tubular necrosis (with decreased ratio that is rarely >1.5). See also Urine Concentration and Dilution Tests . URIC ACID/CREATININE RATIO Ratio >1.0 in most patients with acute renal failure due to hyperuricemia but lower in other causes of acute renal failure. UROBILINOGENURIA Use Rarely useful instead of blood direct and indirect bilirubin. Quantitative determination is not as useful as simple qualitative test. Interferences False-positive dipstick Increased pH Some drugs (e.g., procaine, 5-HIAA, sulfonamides) Increased In Increased hemolysis (e.g., hemolytic anemias) Hemorrhage into tissues (e.g., pulmonary infarction, severe bruises) Hepatic parenchymal cell damage (e.g., cirrhosis, acute hepatitis in early and recovery stages) Cholangitis Absent In Complete biliary obstruction VOLUME Anuria (Excretion <100 mL/24 hrs)
- 78. Due To Bilateral complete urinary tract obstruction Acute cortical necrosis Necrotizing GN Certain causes of acute tubular necrosis Acute Oliguria (Excretion usually <400 mL/24 hrs or ~20 mL/hr; <15–20 mL/kg/24 hrs in children) Due To See Acute Renal Failure. Prerenal causes Postrenal causes Renal causes Glomerular: urine protein >2+ (>1.5 gm/24 hrs), RBCs, RBC casts Tubulointerstitial: urine protein £2+ (£1.5 gm/24 hrs), WBCs, WBC casts Polyuria (Normal or increased urine excretion in presence of increasing serum creatinine and BUN) Due To Diabetic ketoacidosis Partial obstruction of urinary tract with impaired urinary concentration function Some types of acute tubular necrosis (e.g., due to aminoglycosides) OTHER PROCEDURES Urine findings in various diseases: see Table 14-2. See also specific tests on urine in various chapters (e.g., Chapter 7, Gastrointestinal Diseases; Chapter 11, Hematologic Diseases; Chapter 12, Metabolic and Hereditary Diseases; Chapter 13, Endocrine Diseases). 1 Raymond JR, Yarger WE. Abnormal urine color: differential diagnosis. South Med J 1988;81:837. 2Wang Z-M, Gallagher D, Nelson ME, et al. Total-body skeletal muscle mass: evaluation of 24-h urinary creatinine excretion by computerized axial tomography. Am J Clin Nutr 1996;63:863. 3 Corwin HL, Bray BA, Haber MH. The detection and interpretation of urinary eosinophils. Arch Pathol Lab Med 1989;113:1256. 4Sutton JM. Evaluation of hematuria in adults. JAMA1990;263;2475.
- 79. CHAPTER 5 CARDIOVASCULAR DISEASES Interpretation of Diagnostic Tests CHAPTER 5 CARDIOVASCULAR DISEASES Arrhythmias Arteriovenous Fistulas, Angiomatous, Congenital Behçet's Syndrome Churg-Strauss Syndrome (Allergic Granulomatosis and Angiitis) Cor Pulmonale Coronary Heart Disease (CHD) Endocarditis, Bacterial Giant Cell Arteritis (GCA) Heart Failure Hypertension Kawasaki Syndrome (Mucocutaneous Lymph Node Syndrome) Löffler's Parietal Fibroplastic Endocarditis Myocardial Contusion Myocardial Infarction, Acute (AMI) Myocarditis, Viral Myxoma of Left Atrium Pericardial Effusion, Chronic Pericarditis, Acute Phlebothrombosis Polyarteritis Nodosa Prosthetic Heart Valves Rheumatic Fever, Acute Shock Systemic Capillary Leak Syndrome Takayasu's Syndrome (Arteritis) Thromboangiitis Obliterans (Buerger's Disease) Thrombophlebitis, Septic Transplant Rejection (Acute) of Heart Valvular Heart Disease Vasculitis, Classification Wegener's Granulomatosis ARRHYTHMIAS Metabolic abnormalities should always be ruled out before performing Holter monitor studies or committing to long-term antiarrhythmic therapy (e.g., hypokalemia, hypomagnesemia, anemia, hypoxemia, hypo- or hyperthyroidism). ARTERIOVENOUS FISTULAS, ANGIOMATOUS, CONGENITAL Platelet count may be decreased. BEHÇET'S SYNDROME (Systemic vasculitis involving arteries and veins characterized by triad of recurrent aphthous ulcers of mouth and genitalia, and relapsing panuveitis.) No definitive laboratory tests Laboratory findings due to involvement of various organ systems, e.g., Large vessel occlusion (e.g., aneurysms, arthritis, meningitis) Skin lesions CHURG-STRAUSS SYNDROME (ALLERGIC GRANULOMATOSIS AND ANGIITIS) w Biopsy showing granulocytes around an arteriole and venule establishes the diagnosis. 1 ESR is high. WBC count is increased. Eosinophilia is usual and seems to correlate with disease activity. Serum IgE is often increased. p-ANCA is found in £60% of patients. c-ANCA is rare. COR PULMONALE Secondary polycythemia Increased blood CO2 when cor pulmonale is secondary to chest deformities or pulmonary emphysema Laboratory findings of the primary lung disease (e.g., chronic bronchitis and emphysema, multiple small pulmonary emboli, pulmonary schistosomiasis) CORONARY HEART DISEASE (CHD) Increased risk factors Increased serum total and LDL cholesterol, decreased HDL cholesterol and various ratios (see Chapter 12). Recent reports suggest that apo A-I and apo B may be better discriminators of CHD than cholesterol, and low ratio of apo A-I to apo B may be best predictor. (Variation in methodology and lack of interlaboratory standardization makes this difficult to evaluate at present.) Atherogenic index (combination of ratio of LDL to HDL × apo B with ratio of apo B to apo A-I) = Increased serum homocysteine >15.9 µmol/L (normal = 5–15 µmol/L) triples risk of AMI. Each increase of 5 µmol/L increases risk equivalent to increased cholesterol of 20 mg/dL. Increase may be due to vitamin B deficiency or genetic deficiency of methylene-tetrahydrofolate reductase enzyme. Increased in end-stage renal disease dialysis patients and in hypothyroidism, certain drug therapies (e.g., methotrexate [transient], phenytoin and carbamazepine [mild], theophylline, nitrous oxide), cigarette smoking. Low plasma vitamin B12 and folate levels are each independent risk factors for coronary artery disease. Increased serum triglyceride level is a risk factor but may not be independent of other factors. Clinical evidence of CHD or atherosclerosis in patient <age 40, family history of premature CHD, hypertension, male gender, smoking. Syndrome X: insulin resistance, low HDL level, high level of very low density lipoproteins (VLDLs) and triglycerides.
- 80. Various abnormalities of blood clotting mechanisms (e.g., fibrinogen, factor VII, antithrombin III, phospholipid antibodies, protein C, protein S). Lipoprotein electrophoresis (see Table 13-6) shows a specific abnormal pattern in <2% of Americans (usually types II, IV). Chief purpose of test is to identify rare familial disorders (I, III, V) to anticipate problems in children. Lipoprotein electrophoresis may be indicated if serum triglyceride level is >300 mg/dL, fasting serum is lipemic, or hyperglycemia, significant glycosuria, impaired glucose tolerance, or increased serum uric acid (>8.5 mg/dL) is present. Perform laboratory tests to rule out diabetes mellitus, liver disease, nephrotic syndrome, dysproteinemias, hypothyroidism. ENDOCARDITIS, BACTERIAL w Blood culture is positive in 80–90% of patients. Streptococcus viridans causes 40–50% of cases; Staphylococcus aureus, 15–20%; Streptococcus pneumoniae, 5%; and Enterococcus, 5–10%. Other causes may be gram-negative bacteria (~10% of cases; e.g., Escherichia coli, Pseudomonas aeruginosa, Klebsiella, Proteus) and fungi (e.g., Candida, Histoplasma, Cryptococcus). Bartonella has been reported to cause 3% of cases, which may be culture negative. w In drug addicts, S. aureus causes 50–60% of cases and ~80% of tricuspid infections; gram-negative bacteria cause 10–15% of cases; cases due to polymicrobial and unusual organisms appear to be increasing. £75% of patients may be HIV positive. w Proper blood cultures require adequate volume of blood, at least five cultures taken during a period of several days with temperature of 101°F or more (preferably when highest), anaerobic as well as aerobic growth, variety of enriched media, prompt incubation, prolonged observation (growth is usual in 1–4 days but may require 2–3 wks). Beware of negative culture due to recent antibiotic therapy. Beware of transient bacteremia after dental procedures, tonsillectomy, etc., which does not represent bacterial endocarditis (in these cases, streptococci usually grow only in fluid media; in bacterial endocarditis, many colonies also occur on solid media). Blood culture is also negative in bacterial endocarditis due to Rickettsia burnetii, but phase 1 complement fixation test is positive. w Positive blood cultures may be more difficult to obtain in prosthetic valve endocarditis (due to unusual and fastidious organisms), right-sided endocarditis, uremia, and long-standing endocarditis. A single positive culture must be interpreted with extreme caution. Aside from the exceptions noted in this paragraph, the diagnosis should be based on two or more cultures positive for the same organism. Serum bactericidal test measures ability of serial dilutions of patient's serum to sterilize a standardized inoculum of patient's infecting organisms; it is sometimes useful to demonstrate inadequate antibiotic levels or to avoid unnecessary drug toxicity. Progressive normochromic normocytic anemia is a characteristic feature; in 10% of patients, Hb level is <7 gm/dL. Rarely there is a hemolytic anemia with a positive Coombs' test. Serum iron is decreased. Bone marrow contains abundant hemosiderin. WBC is normal in ~50% of patients and elevated £15,000/cu mm in the rest, with 65–86% neutrophils. Higher WBC indicates presence of a complication (e.g., cerebral, pulmonary). Occasionally leukopenia is present. Monocytosis may be pronounced. Large macrophages may occur in peripheral blood. Platelet count is usually normal, but occasionally it is decreased; rarely purpura occurs. Serum proteins are altered, with an increase in gamma globulin; therefore positive ESR and tests for cryoglobulins, RF, etc., are found. Often a direct correlation is seen between ESR and course and severity of disease. Hematuria (usually microscopic) occurs at some stage in many patients due to glomerulitis, renal infarct, or focal embolic GN. Albuminuria is almost invariably present, even without these complications. Renal insufficiency with azotemia and fixed specific gravity is infrequent now. Nephrotic syndrome is rare. CSF findings in various complications, meningitis, brain abscess Laboratory findings due to underlying or predisposing diseases or complications Rheumatic heart disease. Congenital heart disease. Infection of genitourinary system. Congestive heart failure. Bacterial endocarditis occurs in £4% of patients with prosthetic valves. Other. GIANT CELL ARTERITIS (GCA) (Systemic panarteritis of medium-sized elastic arteries) w Biopsy of involved segment of temporal artery is diagnostic, 1 but negative biopsy does not exclude GCA because of skip lesions. Therefore, surgeon should remove at least 20 mm of artery, paraffin sections of which must be examined at multiple levels. Biopsy findings remain positive for at least 7–14 days after onset of therapy. m Classic triad of increased ESR (³50 mm/hr),1 anemia, increased serum ALP is strongly suggestive of GCA. Mild to moderate normocytic normochromic anemia is present in 20–50% of cases and is rough indicator of degree of inflammation. ESR is markedly increased in virtually all patients (97%); average Westergren = 107. A normal ESR excludes the diagnosis when little clinical evidence exists for temporal arteritis. CRP test has equal sensitivity. Serum ALP is slightly increased in ~25% of patients. WBC is usually normal or slightly increased with shift to the left. Platelet count may be nonspecifically increased. Serum protein electrophoresis may show increased gamma globulins. Rouleaux may occur. Serum CK is normal. Laboratory findings reflect specific organ involvement. Kidney (e.g., GN). CNS (e.g., intracerebral artery involvement, which may cause increased CSF protein; stroke; mononeuritis of brachial plexus). Heart and great vessels (e.g., myocardial infarction, aortic dissection, Raynaud's disease). Mild liver function abnormalities in 20–35% of patients.
- 81. SIADH. Microangiopathic hemolytic anemia. Polymyalgia rheumatica is presenting symptom in one-third of patients and ultimately develops in 50–90% of cases. HEART FAILURE Renal changes: Slight albuminuria (<1 gm/day) is common. Isolated RBCs and WBCs, hyaline, and (sometimes) granular casts. Urine is concentrated, with specific gravity >1.020. Phenolsulfonphthalein (PSP) excretion and urea clearance are usually depressed. Moderate azotemia (BUN usually <60 mg/dL) is evident with severe oliguria; may increase with vigorous diuresis. (Primary renal disease is indicated by proportionate increase in serum creatinine and low specific gravity of urine despite oliguria.) Oliguria is a characteristic feature of right-sided failure. ESR may be decreased because of decreased serum fibrinogen. Plasma volume is increased. Serum albumin and total protein are decreased, with increased gamma globulin. Hct is slightly decreased, but RBC mass may be increased. Plasma sodium and chloride tend to fall but may be normal before treatment. Urine sodium is decreased. Total body sodium is markedly increased and potassium is decreased. Plasma potassium is usually normal or slightly increased (because of shift from intracellular location); it may be somewhat reduced with hypochloremic alkalosis due to some diuretics. Liver function changes. Laboratory findings due to underlying disease (e.g., rheumatic fever, viral myocarditis, bacterial endocarditis, chronic severe anemia, hypertension, hyperthyroidism, Hurler's syndrome). Acidosis (reduced blood pH) occurs when renal insufficiency is associated or CO 2 retention exists due to pulmonary insufficiency, low plasma sodium, or ammonium chloride toxicity. Alkalosis (increased blood pH) occurs in uncomplicated heart failure itself, in hyperventilation, in alveolar-capillary block due to associated pulmonary fibrosis, after mercurial diuresis that causes hypochloremic alkalosis, or because of potassium depletion. Alkalosis (with normal or increased blood pH) showing increased plasma bicarbonate and moderately increased pCO 2 after acute correction of respiratory acidosis is due to CO2 retention when there is chloride deficit and usually decreased potassium. HYPERTENSION (Present in 18% of adults in the United States) Systolic hypertension Hyperthyroidism Chronic anemia with hemoglobin <7 gm/dL Arteriovenous fistulas—advanced Paget's disease of bone; pulmonary arteriovenous varix Beriberi Diastolic hypertension Hypothyroidism Systolic and diastolic hypertension Essential (primary) hypertension (causes >90% of cases of hypertension). Secondary hypertension (causes <10% of cases of hypertension). Laboratory findings due to the primary disease. These conditions are often unsuspected and should always be ruled out, because many of them represent curable causes of hypertension. Due To Endocrine diseases Adrenal Pheochromocytoma (<0.64% of cases of hypertension) Aldosteronism (<1% of cases of hypertension) Cushing's syndrome Congenital adrenal hyperplasia ( CAH;) Pituitary disease Signs of hyperadrenal function Acromegaly Hyperthyroidism Hyperparathyroidism Renal diseases Vascular (4% of cases of hypertension) Renal artery stenosis (usually due to atheromatous plaque in elderly patients and to fibromuscular hyperplasia in younger patients) (0.18% of cases of hypertension) Nephrosclerosis Embolism Arteriovenous fistula Aneurysm Aortitis or coarctation of aorta with renal ischemia Parenchymal
- 82. Glomerulonephritis Pyelonephritis Polycystic kidneys Kimmelstiel-Wilson syndrome Amyloidosis Collagen diseases Renin-producing renal tumor (Wilms' tumor; renal hemangiopericytoma) Miscellaneous Urinary tract obstructions Central nervous system diseases Cerebrovascular accident Brain tumors Poliomyelitis Other Toxemia of pregnancy Polycythemia Acute porphyria Drugs, toxins Oral contraceptives, tricyclic antidepressants Lead, alcohol Licorice ingestion In children <18 yrs of age Renal disease 61–78% Cardiovascular disease (e.g., coarctation of aorta) 13–15% Endocrine (e.g., mineralocorticoid excess, pheochromocytoma, hyperthyroidism, hypercalcemia) 6–9% Miscellaneous (e.g., induced by traction, after GU tract surgery, associated with sleep apnea) 2–7% Essential 1–16% In neonates and young infants Most common Renal artery thrombosis after umbilical artery catheterization Coarctation of aorta Congenital renal disease Renal artery stenosis Less common Bronchopulmonary dysplasia Patent ductus arteriosus Intraventricular hemorrhage Laboratory findings indicating the functional renal status (e.g., urinalysis, BUN, creatinine, uric acid, serum electrolytes, PSP, creatinine clearance, radioisotope scan of kidneys, renal biopsy). The higher the uric acid in uncomplicated essential hypertension, the less the renal blood flow and the higher the renal vascular resistance. Laboratory findings due to complications of hypertension (e.g., congestive heart failure, uremia, cerebral hemorrhage, myocardial infarction) Laboratory findings due to administration of some antihypertensive drugs Oral diuretics (e.g., benzothiadiazines) Increased incidence of hyperuricemia (to 65–75% of hypertensive patients from incidence of 25–35% in untreated hypertensive patients) Hypokalemia Hyperglycemia or aggravation of preexisting diabetes mellitus Less commonly, bone marrow depression, aggravation of renal or hepatic insufficiency by electrolyte imbalance, cholestatic hepatitis, toxic pancreatitis Hydralazine Long-term dosage of >200 mg/day may produce syndrome not distinguishable from SLE. Usually regresses after drug is discontinued. Antinuclear antibody may be found in £50% of asymptomatic patients. Methyldopa £20% of patients may have positive results on direct Coombs' test, but relatively few have hemolytic anemia. When drug is discontinued, Coombs' test may remain positive for months but anemia usually reverses promptly. Abnormal liver function tests indicate hepatocellular damage without jaundice associated with febrile influenza-like syndrome. RA and SLE tests may occasionally be positive (see Chapter 17). Rarely, granulocytopenia or thrombocytopenia may occur. Monoamine oxidase inhibitors (e.g., pargyline hydrochloride) Wide range of toxic reactions, most serious of which are Blood dyscrasias Hepatocellular necrosis Diazoxide Sodium and fluid retention Hyperglycemia (usually mild and manageable by insulin or oral hypoglycemic agents) When hypertension is associated with decreased serum potassium, rule out Primary aldosteronism Pseudoaldosteronism (due to excessive ingestion of licorice) Secondary aldosteronism (e.g., malignant hypertension) Hypokalemia due to diuretic administration Potassium loss due to renal disease
- 83. Cushing's syndrome KAWASAKI SYNDROME (MUCOCUTANEOUS LYMPH NODE SYNDROME) (Variant of childhood polyarteritis of unknown etiology, with high incidence of cardiac complications; diagnosis is based on clinical criteria) w Diagnosis is confirmed by histologic examination of coronary artery (same as in poly- arteritis nodosa). w Laboratory changes due to acute myocardial infarction Acute phase reactants are increased (e.g., ESR, CRP, alpha-1-antitrypsin); usually return to normal after 6–8 wks. Leukocytosis (20,000–30,000/cu mm) with shift to left during first week; lymphocytosis thereafter; peaks at end of second week; this is a hallmark of the illness. Anemia occurs in ~50% of patients; reaches nadir about end of second week; improves during recovery. CSF shows increased mononuclear cells with normal protein and sugar. Increased mononuclear cells in urine; dipstick negative. Increased WBC (predominantly PMNs) in joint fluid in patients with arthritis. LÖFFLER'S PARIETAL FIBROPLASTIC ENDOCARDITIS m Eosinophilia £70%; may be absent at first but appears sooner or later. WBC frequently increased. Laboratory findings due to frequent Mural thrombi in heart and embolization of spleen and lung Mitral and tricuspid regurgitation MYOCARDIAL CONTUSION (90% due to motor vehicle accident) w Increased serum CK-MB (>3%) alone in 15% of cases; combined with ECG changes in 20% of cases; ECG changes alone in 65% of cases w Increased serum cardiac troponin I (cTnI) implies some myocardial necrosis and differentiates increased CK-MB due to skeletal muscle damage. Specificity = 90% but sensitivity = only 30% and positive predictive value = only 16%. Cardiac troponin T (cTnT) may be increased due to muscle necrosis. MYOCARDIAL INFARCTION, ACUTE (AMI) See Fig. 5-1, Fig. 5-2, Table 5-1, Table 5-2 and Table 5-3. Fig. 5-1. Algorithm for diagnosis of acute myocardial infarction. Fig. 5-2. Serial serum cardiac markers after acute myocardial infarction.
- 84. Table 5-1. Summary of Increased Serum Marker Levels After Acute Myocardial Infarction (AMI) Table 5-2. Interpretation of Markers for Diagnosis of Acute Myocardial Infarction (AMI) Table 5-3. Characteristics of Serum Markers for Myocardial Damage Includes the whole spectrum of acute coronary syndromes, from silent ischemia, unstable angina, and “non–Q wave” infarction, to typical AMI. w Diagnostic Criteria for AMI Two of the following three findings: History of ischemic chest discomfort for ³30 mins Characteristic evolution of ECG changes Typical rise and fall of cardiac enzymes. Blood should be drawn promptly after onset of symptoms. Repeat determinations should be made at appropriate intervals (e.g., 4, 8, and 12 hrs) and also if symptoms recur or new signs or symptoms develop. Changes may indicate extension or additional myocardial infarction (MI) or other complications (e.g., pulmonary infarction). Use of Laboratory Determinations For diagnosis when ECG changes are nondiagnostic (occurs in ~50% of AMI patients) on admission to emergency room (e.g., masked by bundle branch block or Wolff-Parkinson-White syndrome) or may not reveal intramural or posterior or lateral infarcts. False-positive ECG occurs in >10–20% of cases. For differential diagnosis of chest pain. To follow the course of the patient with AMI. To estimate prognosis (e.g., marked elevation of serum enzyme [4–5× normal] correlates with increased incidence of ventricular arrhythmia, shock, and heart failure, and with higher mortality). For noninvasive assessment of coronary reperfusion after thrombolytic therapy. Utility of each enzyme depends on time of specimen's collection after onset of AMI. Combination of markers (e.g., serum myoglobin, CK-MB, cTn) and (ratios of) serial changes are most effective because of uncertainty as to actual duration of myocardial damage. Serum Total Creatine Kinase (CK) Use Replaced by serum cTn, CK-MB, myoglobin in various combinations. May allow early diagnosis because increased levels appear 3–6 hrs after onset and persist £48 hrs. Sensitive indicator because of large amplitude of change (6–12× normal). Interpretation Serial total CK has sensitivity of 98% early in course of MI but false-positive rate of 15% due to many causes of increased CK. Returns to normal by third day; a poorer prognosis is suggested if the increase lasts more than 3–4 days. Reinfarction is indicated by an elevated level after the fifth day after previous return to normal. Useful in differential diagnosis of chest pain due to diseases often associated with MI or difficult to distinguish from MI. Serial Serum CK-MB Concentrations Use Present gold standard for diagnosis within 24 hrs of onset of symptoms. Detect reinfarction or extension of MI after 72 hrs. Document reperfusion after thrombolytic therapy. Interpretation
- 85. w· In AMI, CK-MB usually is evident at 4–8 hrs, peaks at 15–24 hrs (mean peak = 16× normal), with sensitivity and specificity each >97% within the first 48 hrs. By 72 hrs, two-thirds of patients still show some increase in CK-MB. More frequent sampling (every 6 hrs) is more likely to identify a peak value. False-negative results may be due to sampling timing (e.g., only once in 24 hrs or sampling <4 hrs or >72 hrs after AMI). w· Diagnosis of AMI is usually confirmed by 8–12 hrs, and sampling beyond 24 hrs is usually not needed except to detect early reinfarction (especially in patients receiving thrombolytic therapy). w· Diagnosis of AMI should not be based on only a single enzyme value. One criterion for AMI is serial CK-MB measurements 4 hrs apart that show ³50% increase with at least one sample greater than upper reference value. w· In ~5% of AMI patients (especially in older age groups) a peak CK-MB may be the only abnormality, with total CK and CK-MB still within reference ranges. This is because normal serum total CK values decline with decreased muscle mass (e.g., with age and sedentary or bedridden status). Rapid return to normal makes CK-MB a poor marker >72 hrs after symptoms. Increased CK-MB with normal total CK may indicate non–Q wave AMI. MB index (CK-MB/total CK) should be calculated; normal <2.5. For example, with extreme skeletal muscle injury (e.g., trauma, perioperative condition), total CK may be >4000 U/L and CK-MB may be £40 U/L. CK-MB should be reported in units as well as percentage, because if injury of both cardiac and skeletal muscle (e.g., perioperative AMI) is present, CK-MB percentage may not appear increased. CK-MB mass immunoassays (preferred method) at 0, 3, and 6 hrs can measure small but significant serial changes that may still be within the normal range. CK-MB mass ³10 µg/L indicates AMI. Serum CK-MB can now be measured directly in the emergency room with or without total CK, cTn, and myoglobin. Thrombolytic therapy should be given within 4–6 hrs of the acute event, at which time CK-MB may not yet be increased. CK-MB, cTn, and myoglobin measured initially and at 60 and/or 90 mins after thrombolytic therapy can document failed reperfusion.2 60 min 90 min Sensitivity Specificity Sensitivity Specificity CK-MB (1.5) 33% 85% (5) 82% 66% (5) 93% 60% (10) 91% 49% cTnT (1.5) 70% 65% (5) 82% 67% (5) 97% 43% (10) 95% 58% Myoglobin (1.5) 42% 89% (5) 84% 73% (5) 92% 59% (10) 88% 65% Numbers in parentheses are ratios of marker values after thrombolytic therapy to pretreatment values. CK and CK-MB May Also Be Increased In Diagnostic value of CK-MB and total CK are diminished after cardiac surgery. A diagnosis of AMI cannot be made until >12–24 hrs after cardiac surgery; typically AMI patients have higher peak values of CK, CK-MB, and myoglobin; patients without AMI have earlier peaks that return to base values more rapidly. Increases common after angioplasty of coronary arteries; may indicate reperfusion. Cardiac trauma and contusions, electrical injury, and inflammatory myocarditis may produce enzyme changes that cannot be distinguished from those due to AMI. CK-MB and total CK can be increased with long-term exercise and in chronic disease. No significant increase after pacemaker implantation or electrical cardioversion. If CK-MB is >20% or persists >48–72 hrs, consider atypical CK-MB. Other causes of CK and CK-MB changes are noted. In one protocol the criteria for AMI are an increasing (above reference range) and then decreasing CK total and CK-MB in serial specimens drawn on admission and at 8- or 12-hr intervals; this is considered almost pathognomonic in patients in whom AMI is strongly suspected; no blood need be collected after 48 hrs in patients with uneventful course. CK-MB in pericardial fluid may be helpful for postmortem diagnosis of AMI. Increased Serum Cardiac Troponins T and I Use Increased cTn implies some myocardial necrosis (e.g., anoxia, contusion, inflammation) even without ECG changes. Replace LD testing for late diagnosis of AMI. May replace CK-MB as gold standard. Risk stratification in patients with chest pain. Sensitive marker for minor myocardial injury in unstable angina without AMI. Patients with chest pain, normal CK-MB, nondiagnostic ECG, and detectable cTn have greater risk of later coronary events. Diagnosis of perioperative AMI when CK-MB may be increased by skeletal muscle injury. Serial measurements to assess reperfusion after thrombolytic therapy. Peak cTn after reperfusion is related to infarct size. Serial values may be indicator of cardiac allograft rejection. Interpretation w· cTn is about as sensitive as CK-MB during first 48 hrs after AMI; sensitivity = 33% from 0 to 2 hrs, 50% from 2 to 4 hrs, 75% from 4 to 8 hrs, and approaches 100% from 8 hrs after onset of chest pain. >85% concordance with CK-MB. Specificity approaches 100%. High sensitivity for 6 days; may remain increased for ~7–10 days. With rapid ELISA for cTnT, AMI was present in 1% of cases with cTnT <0.1 µg/L 28% of cases with cTnT 0.1–0.19 µg/L 88% of cases with cTnT 0.2–0.29 µg/L 100% of cases with cTnT >4.0 µg/L3 cTnT may be increased in some patients with skeletal muscle injury, myotonic dystrophy, and chronic renal failure. cTnI is not increased by skeletal muscle injury, which makes it more highly specific for myocardial injury; may be detected in some patients with renal failure. Normal values exclude myocardial necrosis in patients with increased CK of skeletal muscle origin (e.g., after arduous physical exercise). Not increased by uncomplicated coronary angioplasty or electrical cardioversion. Not increased by pulmonary or orthopedic surgery. Long duration of increase provides a longer diagnostic window than with CK-MB but may make it difficult to recognize reinfarction. cTnI increases ~4–6 hrs after AMI and remains increased for £7 days. Rapid (20 mins) test kit using whole blood is now available. Comparative Sensitivity4 Time after symptom onset in AMI Rapid cTnI CK-MB mass CK-MB activity 3.5±2.7 hrs 60% 48% 36% 4 hrs later 98% 91% 61% Unstable angina 38% 4% 2% Serum Myoglobin Use
- 86. Earliest marker for AMI w Interpretation Increased within 1–3 hrs in >85% of AMI patients, peaks in ~8–12 hrs (may peak within 1 hr) to ~10× upper reference limit, and becomes normal in ~24–36 hrs or less; reperfusion causes peak 4–6 hrs earlier. May precede release of CK-MB by 2–5 hrs. Sensitivity >95% within 6 hrs of onset of symptoms. Myoglobinuria often occurs. Disadvantages Two or three blood samples should be drawn at ~1-hr intervals (myoglobin may be released in multiple short bursts). Wide normal range (6–90 ng/mL). Low specificity for AMI (may also be increased in renal failure, shock, open heart surgery, and skeletal muscle damage or exhaustive exercise, or in patients and carriers of progressive muscular dystrophy, but not by cardioversion, cardiac catheterization, or congestive heart failure). Values are usually much higher in patients with uremia and muscle trauma than in those with AMI. CK Isoforms CK-MB and CK-MM are sequentially converted in the serum by a carboxypeptidase (CK-MM®MM-3®MM-2®MM-1; CK-MB®MB-2®MB-1). Interpretation w· CK-MM and CK-MB isoforms parallel CK-MB but rise and peak earlier. MB-2/MB-1 and MM-3/MM-1 isoform ratios appear to be the most useful, but methodology for rapid turnaround time is not widely available. Because serum MM-3 is normally so low, its release from damaged cardiac muscle is readily evident. Diagnostic MM isoform changes are independent of amount of tissue damage, whereas total CK activity depends on infarct size. MM-3/MM-1 isoform ratio shows a large change because MM-1 is continually cleared from the blood. Ratio is ~1.3 in controls but >14 in AMI patients (1.0 is a useful cutoff value). MB-2 >1.0 U/L and MB-2/MB-1 ratio >1.5 (normal ratio = 1) is specific for AMI within 4–8 hrs of infarct. Ratio is >1.5 within 2–4 hrs in >50% of cases, within 4–6 hrs in 92%, and by 8 hrs in 100%. MB-2/MB-1 ratio £1.0 by 4–6 hrs or normal CK-MB by 10 hrs rules out AMI in 95% of cases. MM-3 and MM-3/MM-1 ratio also increase 2 hrs after intense brief exercise and in marathon runners. CK-MB subforms may also be increased in severe skeletal muscle damage (e.g., rhabdomyolysis) and muscular dystrophy. Isoform ratios return to normal by 24 hrs in most patients. Glycogen Phosphorylase BB Use More sensitive early marker for AMI and unstable angina within 4 hrs after onset of pain than is CK-MB, cTnT, or myoglobin Sensitive marker of perioperative myocardial injury in coronary artery bypass surgery Interpretation Returns to normal within 24–36 hrs. Not widely available. Additional studies are needed. Also being investigated are serum cardiac myosin heavy and light chains, fatty acid–binding protein, alpha-actin, calcitonin gene-related peptide. Serum Lactate Dehydrogenase (LD) Use Replaced by cTn. Prolonged elevation lasting 10–14 days was formerly used for late diagnosis. Interpretation Increases in 10–12 hrs, peaks in 48–72 hrs (~3× normal). Increased CK-MB and LD-1/LD-2 ratio >1 (“flipped” LD) both within 48 hrs (not necessarily at the same time) is virtually diagnostic of AMI. Increased total LD with flipped LD may also occur in acute renal infarction, hemolysis (e.g., hemolytic anemia, pernicious anemia, prosthetic heart valves), some muscle disorders (e.g., polymyositis, muscular dystrophies, rhabdomyolysis), pregnancy, some neoplasms (e.g., small cell of lung, prostate, testicular germ cell); LD >2000 U suggests a poorer prognosis. Serum Aspartate Aminotransferase (AST) Use Replaced by other enzymes in diagnosis of AMI. Interpretation AST is increased in >95% of the patients when blood is drawn at the appropriate time. Increase appears within 6–8 hrs, peaks in 24 hrs; level usually returns to normal in 4–6 days. Peak level is usually ~200 U (5× normal). Value >300 U and a more prolonged increase suggest a poorer prognosis. Reinfarction is indicated by a rise that follows a return to normal. Serum ALT is usually not increased unless there is liver damage due to congestive heart failure, drug therapy, etc. Serum ALP (from vascular endothelium) is increased during reparative phase (4–10 days after onset). Serum GGT is also increased. Leukocytosis is almost invariable; commonly detected by second day but may occur as early as 2 hrs. WBC is usually 12,000–15,000; £20,000 is not rare; sometimes it is very high. Usually 75–90% PMNs with only a slight shift to the left. Leukocytosis is likely to develop before fever. ESR is increased, usually by second or third day (may begin within a few hrs); peak rate is in 4–5 days, persists for 2–6 mos. ESR is sometimes more sensitive than
- 87. WBC, as increase may occur before fever and persists after temperature and WBC have returned to normal. Degree of ESR increase does not correlate with severity or prognosis. CRP is usually normal in unstable angina patients who have a normal cTnT (<0.1 µg/L). Peak CRP correlates with peak CK-MB. Blood lactate is increased; sensitivity = 55%, specificity = 96% in patients presenting with acute chest pain. Glycosuria and hyperglycemia occur in £50% of patients. Glucose tolerance is decreased. Laboratory findings due to underlying coronary heart disease. Laboratory findings due to sequelae (e.g., congestive heart failure). MYOCARDITIS, VIRAL (Routine autopsy incidence of 1.2–3.5%) Due To Coxsackievirus B (causes most cases in United States) and coxsackievirus A, echovirus, poliomyelitis, influenza A and B, cytomegalovirus (CMV), EBV, adenovirus, rubeola, mumps, rubella, variola, vaccinia, varicella-zoster virus (VZV), rabies, lymphocytic choriomeningitis, chikungunya, dengue, yellow fever w Serologic tests for viral antigen, IgM antibody, or changed titer using acute and convalescent paired sera w Endomyocardial biopsy of right ventricular muscle showing >5 lymphocytes/HPF and degeneration of muscle fibers has become major diagnostic tool to establish diagnosis of myocarditis and rules out other lesions (e.g., sarcoidosis). Increased serum markers of myocardial damage is common only in early stages cTn sensitivity = 53%, specificity = 93% CK-MB and CK total <10% sensitivity Increased acute phase reactants (e.g., ESR, CRP, mild to moderate leukocytosis) MYXOMA OF LEFT ATRIUM m Anemia that is hemolytic in type and mechanical in origin (due to local turbulence of blood) should be sought and may be severe. Bizarre poikilocytes may be seen in blood smear. Reticulocyte count may be increased. Other findings may reflect effects of hemolysis or compensatory erythroid hyperplasia. The anemia is recognized in ~50% of patients with this tumor. Increased serum LD reflects hemolysis. Serum gamma globulin is increased in ~50% of patients. IgG may be increased. Increased ESR is a reflection of abnormal serum proteins. Platelet count may be decreased (possibly the cause here also is mechanical) with resultant findings due to thrombocytopenia. Negative blood cultures differentiate this tumor from bacterial endocarditis. Occasionally WBC is increased, and CRP may be positive. Laboratory findings due to complications Emboli to various organs (increased AST may reflect many small emboli to striated muscle) Congestive heart failure These findings are reported much less frequently in myxoma of the right atrium, which is more likely to be accompanied by secondary polycythemia than by anemia. PERICARDIAL EFFUSION, CHRONIC See Table 6-2 on body fluids. Laboratory findings due to underlying disease (e.g., TB, myxedema, metastatic tumor, uremia, SLE). Rarely due to severe anemia, scleroderma, polyarteritis nodosa, Wegener's granulomatosis, RA, irradiation therapy, mycotic or viral infections, primary tumor of heart, African endomyocardial fibrosis, idiopathic causes. PERICARDITIS, ACUTE Laboratory Findings Due to Primary Disease Active rheumatic fever (40% of patients) Bacterial infection (20% of patients) Other infections (e.g., viral [especially coxsackievirus B], rickettsial, parasitic, mycobacterial, fungal) Viruses are most common infectious causes. Uremia (11% of patients) Benign nonspecific pericarditis (10% of patients) Neoplasms (3.5% of patients) Collagen disease (e.g., SLE, polyarteritis nodosa) (2% of patients)
- 88. Acute myocardial infarction, postcardiac injury syndrome Trauma Myxedema Others (e.g., hypersensitivity, unknown origin or in association with various syndromes) WBC is usually increased in proportion to fever; normal or low in viral disease and tuberculous pericarditis; markedly increased in suppurative bacterial pericarditis Examination of aspirated pericardial fluid (see Table 6-1) PHLEBOTHROMBOSIS Tests indicate recent extensive clotting of any origin (e.g., postoperative status). D-dimer test (see Pulmonary Embolism and Infarction). Staphylococcal clumping test measures breakdown products of fibrin in serum; these indicate the presence of a clot that has begun to dissolve. Sensitivity = 88%, specificity = 66% using venography as gold standard. Serial dilution protamine sulfate test measures the presence of a fibrin monomer that is one of the polymerization products of fibrinogen. It is less sensitive than the staphylococcal clumping test but indicates clotting earlier. Laboratory findings of pulmonary infarction should be sought as evidence of embolization. POLYARTERITIS NODOSA w Tissue biopsy is basis for diagnosis Findings on biopsy of small or medium-sized artery. Findings in random skin and muscle biopsy are confirmatory in 25% of patients; most useful when taken from area of tenderness; if no symptoms are present, pectoralis major is the most useful site. Testicular biopsy is useful when local symptoms are present. Lymph node and liver biopsies are usually not helpful. Renal biopsy is not specific; often shows glomerular disease. Increased BUN or creatinine; uremia occurs in 15% of patients. Hepatitis B surface antigen (HBsAg) is present in 20–40% of adult patients. p-ANCA is positive in 70% of patients; rarely reflects disease activity. Increased WBC (£40,000/cu mm) and PMNs. A rise in eosinophils takes place in 25% of patients and is sometimes very marked; it usually occurs in patients with pulmonary manifestations. ESR and CRP are increased. Mild anemia is frequent; it may be hemolytic anemia with positive Coombs' test. Urine is frequently abnormal. Albuminuria (60% of patients) Hematuria (40% of patients) “Telescoping” of sediment (variety of cellular and noncellular casts) Serum globulins are increased. Abnormal serum proteins occasionally occur. Biological false-positive test for syphilis, circulating anticoagulants, cryoglobulins, macroglobulins, etc., occurs. Laboratory findings due to organ involvement by arteritis may be present (e.g., GU, pulmonary, GI, neurologic in >75% of patients). PROSTHETIC HEART VALVES Complications Hemolysis—increased serum LD, decreased haptoglobin, reticulocytosis are usual. Severe hemolytic anemia is uncommon and suggests leakage due to partial dehiscence of valve or infection. Prosthetic valve infection Early (<60 days after valve replacement)—usually due to Staphylococcus epidermidis, S. aureus, gram-negative bacteria, diphtheroids, fungi; occasionally due to Mycobacteria and Legionella. 30–80% mortality. Late (>60 days postoperatively)—usually due to streptococci. S. epidermidis is common up to 12 mos after surgery. 20–40% mortality. w· Blood culture positive in >90% of patients unless received antibiotic therapy, infection involves fastidious organism (e.g., HACEK [Haemophilus-Actinobacillus-Cardiobacterium -Eikenella-Kingella]), or identification requires special technique (e.g., Rickettsia, fungi, mycobacteria, Legionella). Surgery is indicated if blood culture is positive after 5 days of appropriate antimicrobial therapy or infection is recurrent. Infection with organisms other than Streptococcus usually require valve replacement. Complications of anticoagulant therapy RHEUMATIC FEVER, ACUTE5 w Increased serum cTn implies some myocardial necrosis due to myocarditis. w Laboratory confirmation of preceding group A streptococcal infection
- 89. Increased titer of antistreptococcal antibodies Positive throat culture for group A Streptococcus and recent scarlet fever Serologic tests—see below w Serologic titers: one of the following is elevated in 95% of patients with acute rheumatic fever; if all are normal, a diagnosis of rheumatic fever is less likely. ASOT increase indicates recent group A Streptococcus pharyngitis within the last 2 mos. Increased titer develops only after the second week and reaches a peak in 4–6 wks. Increasing titer is more significant than a single determination. Titer is usually >250 U; more significant if >400–500 U. A normal titer helps to rule out clinically doubtful rheumatic fever. Sometimes ASOT is not increased even when other titers are increased. Height of titer is not related to severity; rate of fall is not related to course of disease. Anti–DNase B assay should also be performed because >15% of patients with acute rheumatic fever do not have an increased ASOT. This assay is superior to ASOT in detecting antibodies after group A streptococcal skin infections and is less prone to false-positive reactions; longer period of reactivity is helpful in patients with isolated chorea or carditis, who may have a long latent period before manifesting rheumatic fever during which ASOT may have returned to normal. Antihyaluronidase titer of 1000–1500 U follows recent group A streptococcal disease and £4000 U with rheumatic fever. Average titer is higher in early rheumatic fever than in subsiding or inactive rheumatic fever or nonrheumatic streptococcal disease or nonstreptococcal infections. Antihyaluronidase titer is increased as often as ASOT and antifibrinolysin titer. Antifibrinolysin (antistreptokinase) titer is increased in rheumatic fever and in recent hemolytic streptococcus infections. w Acute phase reactants (ESR, CRP, increased WBC) are minor manifestations. ESR increase is a sensitive test of rheumatic activity; ESR returns to normal after adequate treatment with ACTH or salicylates. It may remain increased after WBC becomes normal. It is said to become normal with onset of congestive heart failure even in the presence of rheumatic activity. It is normal in uncomplicated chorea alone. CRP parallels ESR. WBC may be normal but usually is increased (10,000–16,000/cu mm) with shift to the left; increase may persist for weeks after fever subsides. Count may decrease with salicylate and ACTH therapy. Serum proteins are altered, with decreased serum albumin and increased alpha 2 and gamma globulins. (Streptococcus group A infections do not increase alpha2 globulin.) Fibrinogen is increased. Anemia (Hb usually 8–12 gm/dL) is common; gradually improves as activity subsides; microcytic type. Anemia may be related to increased plasma volume that occurs in early phase of acute rheumatic fever. Urine: A slight febrile albuminuria is present. Often mild abnormality of protein, casts, RBCs, WBCs indicates mild focal nephritis. Concomitant GN appears in £2.5% of cases. Blood cultures are usually negative. Occasional positive culture is found in 5% of patients (bacteria usually grow only in fluid media, not on solid media), in contrast to bacterial endocarditis. Throat culture is often negative for group A streptococci. Serum AST may be increased, but ALT is normal unless the patient has cardiac failure with liver damage. Determine clinical activity—follow ESR, CRP, and WBC. Return to normal should be seen in 6–12 wks in 80–90% of patients; it may take £6 mos. Normal findings do not prove inactivity if patient is receiving hormone therapy. When therapy is stopped after findings have been suppressed for 6–8 wks, a mild rebound may be seen for 2–3 days followed by a return to normal. Relapse after cessation of therapy occurs within 1–8 wks. SHOCK Leukocytosis is common, especially with hemorrhage. Leukopenia may be present when shock is severe, as in gram-negative bacteremia. Circulating eosinophils are decreased. Hemoconcentration (e.g., dehydration, burns) or hemodilution (e.g., hemorrhage, crush injuries, and skeletal trauma) takes place. Acidosis appears when shock is well developed, with increased blood lactate, low serum sodium, low CO 2-combining power with decreased alkaline reserve. Blood pH is usually relatively normal but may be decreased. BUN and creatinine may be increased. Serum potassium may be increased. Hyperglycemia occurs early. Urine examination Volume: Normovolemic patients have output ³50 mL/hr; cause should be investigated if <25–30 mL/hr. In hypovolemia, normal kidney may lower 24-hr urine output to 300–400 mL. Specific gravity: >1.020 with low urine output suggests patient is fluid depleted. <1.010 with low urine output suggests renal insufficiency. Specific gravity depends on weight rather than concentration of solutes; therefore it is more affected than osmolarity by high-molecular-weight substances such as urea, albumin, and glucose. Osmolarity: Hypovolemia is suggested by high urine osmolarity and urine-plasma osmolarity ratio of ³1:2. Renal failure is suggested by low urine osmolarity with oliguria and urine/plasma osmolarity ratio of £1:1. SYSTEMIC CAPILLARY LEAK SYNDROME6 (Very rare recurring idiopathic disorder in adults with sudden transient extravasation of <70% of plasma; very high morbidity and mortality; hypotension is part of triad) Hemoconcentration (e.g., leukocytosis; Hb may be ~25 gm/dL) Hypoalbuminemia Monoclonal gammopathy (especially IgG with kappa or lambda light chain) without evidence of multiple myeloma is often present. Some patients may progress to multiple myeloma.
- 90. Laboratory findings due to complications (e.g., rhabdomyolysis, acute tubular necrosis, pleural/pericardial effusion) TAKAYASU'S SYNDROME (ARTERITIS) Increased ESR in ~75% of cases during active disease but normal in only one-half during remission WBC usually normal Serum proteins abnormal with increased gamma globulins (mostly composed of IgM) Female patients have a continuous high level of urinary total estrogens (rather than the usual rise during luteal phase after a low excretion during follicular phase). Laboratory tests not useful for diagnosis or to guide management. w Diagnosis is established by characteristic arteriographic changes or histologic examination. THROMBOANGIITIS OBLITERANS (BUERGER'S DISEASE) (Vascular inflammation and occlusion of intermediate-sized arteries and veins of extremities) Laboratory tests are usually normal. THROMBOPHLEBITIS, SEPTIC Laboratory findings due to associated septicemia Increased WBC (often >20,000/cu mm) with marked shift to left and toxic changes in neutrophils. DIC may be present. Respiratory alkalosis due to ventilation-perfusion abnormalities with hypoxia. Significant acidosis indicates shock. Azotemia. Positive blood culture (S. aureus is most frequent organism; others are Klebsiella, Pseudomonas aeruginosa, enterococci, Candida). Laboratory findings due to complications (e.g., septic pulmonary infarction) Laboratory findings due to underlying disease TRANSPLANT REJECTION (ACUTE) OF HEART w Endocardial biopsy to determine acute rejection and follow effects of therapy has no substitute. Increasing ESR and WBC Increased isoenzyme LD-1 as amount (>100 IU) and percentage (35%) of total LD during first 4 wks after surgery These findings are reversed with effective immunosuppressive therapy. Total LD continues to be increased even when LD-1 becomes normal. Chronic rejection is accelerated coronary artery atherosclerosis. VALVULAR HEART DISEASE Laboratory findings due to associated or underlying or predisposing disease (e.g., syphilis, rheumatic fever, carcinoid syndrome, genetic disease of mucopolysaccharide metabolism, congenital defects) Laboratory findings due to complications (e.g., heart failure, bacterial endocarditis, embolic phenomena) VASCULITIS, CLASSIFICATION By Etiology Primary Polyarteritis nodosa Wegener's granulomatosis Giant cell arteritis Hypersensitivity vasculitis Secondary Infections Bacteria (e.g., septicemia due to Gonococcus or Staphylococcus) Mycobacteria Viruses (e.g., CMV, HBV) Rickettsia (e.g., Rocky Mountain spotted fever) Spirochetes (e.g., syphilis, Lyme disease) Associated with malignancy (e.g., multiple myeloma, lymphomas) Connective tissue diseases RA SLE Sjögren's syndrome Diseases that may simulate vasculitis (e.g., ergotamine toxicity, cholesterol embolization, atrial myxoma) By Size of Involved Vessel (Noninfectious Vasculitis)
- 91. Large vessel Takayasu's arteritis Giant cell (temporal) arteritis Medium-sized vessel Polyarteritis nodosa Kawasaki's disease Primary granulomatous CNS vasculitis Small vessel ANCA-associated vasculitis Wegener's granulomatosis Churg-Strauss syndrome Drug induced Microscopic polyangiitis Immune complex–type vasculitis Henoch-Schönlein purpura Cryoglobulinemia Rheumatoid vasculitis SLE Sjögren's syndrome Goodpasture's syndrome Behçet's disease Drug induced Serum sickness Paraneoplastic vasculitis (lymphoproliferative, myeloproliferative, carcinoma) Inflammatory bowel disease WEGENER'S GRANULOMATOSIS7 (Necrotizing granulomatous vasculitis affecting respiratory tract; disseminated form shows renal involvement) w Diagnosis is established by biopsy of affected tissue with cultures and special stains that exclude mycobacterial and fungal infection. Antineutrophil Cytoplasmic Antibodies (ANCA) Use Aid in diagnosis and classification of various vasculitis-associated and autoimmune disorders. Interpretation w c-ANCA (anti-proteinase 3; coarse diffuse cytoplasmic pattern) is highly specific (>90%) for active Wegener's granulomatosis. Sensitivity >90% in systemic vasculitic phase, ~65% in predominantly granulomatous disease of respiratory tract, ~30% during complete remission. Height of ELISA titer does not correlate with disease activity; high titer may persist during remission for years. Also occasionally found in other vasculitides (polyarteritis nodosa, microscopic polyangiitis [e.g., lung, idiopathic crescentic and pauci-immune GN], Churg-Strauss vasculitis). p-ANCA (against various proteins [e.g., myeloperoxidase, elastase, lysozyme], perinuclear pattern) occurs only with fixation in alcohol, not formalin. Positive result should be confirmed by ELISA. Has poor specificity and 20–60% sensitivity in a variety of autoimmune diseases (microscopic polyangiitis, Churg-Strauss vasculitis, SLE, inflammatory bowel disease, Goodpasture's syndrome, Sjögren's syndrome, idiopathic GN, chronic infection). However, pulmonary small vessel vasculitis is strongly linked with myeloperoxidase antibodies. Both p-ANCA and c-ANCA may be found in non–immune mediated polyarteritis and other vasculitides. Atypical pattern (neither c-ANCA or p-ANCA; unknown target antigens) has poor specificity and unknown sensitivity in various conditions (e.g., HIV infection, endocarditis, cystic fibrosis, Felty's syndrome, Kawasaki syndrome, ulcerative colitis, Crohn's disease). Laboratory findings reflecting specific organ involvement Kidneys—renal disease in ~80% of cases. Hematuria (>5 RBCs/HPF), proteinuria, azotemia. Nephrosis or chronic nephritis may occur. Most patients develop renal insufficiency. Biopsy most frequently shows focal necrotizing GN with crescent formation; coarse granular pattern with immunofluorescent staining. Biopsy is important to define extent of disease. CNS. Respiratory tract. Heart. Nonspecific laboratory findings Normochromic anemia, thrombocytosis, and mild leukocytosis occur in 30–40% of patients; eosinophilia may occur but is not a feature. Leukopenia or thrombocytopenia occur only during cytotoxic therapy. ESR is increased in 90% of cases, often to very high levels; CRP level correlates with disease activity even better than ESR. Serum globulins (IgG and IgA) are increased in up to 50% of cases. Serum C3 and C4 complement levels may be increased. RF may be present in low titer in two-thirds of cases. ANA is negative. Laboratory findings due to secondary infection (usually staphylococcal) of sinus, mucosal, pulmonary lesions. Laboratory findings due to therapy (e.g., bladder cancer and sterility due to cyclophosphamide therapy). 1 Included in American College of Rheumatology 1990 criteria for classification of vasculitis. Arthritis Rheum 1990;33:1068.
- 92. 2 Stewart JT, et al. Early noninvasive identification of failed reperfusion after intravenous thrombolytic therapy in acute myocardial infarction. J Am Coll Cardiol 1998;31:1499. 3 Gerhardt W, et al. An improved rapid troponin T test with a decreased detection limit: a multicentre study of the analytical and clinical performance in suspected myocardial damage. Scand J Clin Lab Invest 1997;57:549. 4Heeschen C, et al. Analytical performance and clinical application of new rapid bedside assay for the detection of serum cardiac troponin I. Clin Chem 1998;44:1925. 5 Special Writing Group, Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Guidelines for the diagnosis of rheumatic fever: Jones Criteria, 1992 update. JAMA 1992;268:2069. 6Tahirkheli NK, Greipp PR. Treatment of the systemic capillary leak syndrome with terbutaline and theophylline. Ann Intern Med 1999;130:905. 7 Included in American College of Rheumatology 1990 criteria for classification of vasculitis. Arthritis Rheum 1990;33:1068.
- 93. CHAPTER 6 RESPIRATORY DISEASES Interpretation of Diagnostic Tests CHAPTER 6 RESPIRATORY DISEASES Bronchoscopy and Bronchoalveolar Lavage (BAL) Gases, Blood Lymph Node (Scalene) Biopsy Pleural Needle Biopsy (Closed Chest) Sputum Thoracoscopy/Open Lung Biopsy Abscess, Lung Adult Respiratory Distress Syndrome (ARDS) Asthma, Bronchial Bronchiectasis Bronchitis, Acute Bronchitis, Chronic Carcinoma, Bronchogenic Croup (Epiglottitis, Laryngotracheitis) Dysplasia, Bronchopulmonary Emphysema, Obstructive Goodpasture's Syndrome Hantavirus Pulmonary Syndrome Hernia, Diaphragmatic Histiocytosis X Interstitial Pneumonitis, Diffuse Larynx Diseases Legionnaires' Disease Nasopharyngitis, Acute Neonatal Respiratory Distress Syndrome (RDS) Pleural Effusion Pneumoconiosis Pneumonia Pneumonia, Lipid Pulmonary Alveolar Proteinosis Pulmonary Embolism and Infarction Sinusitis, Acute LABORATORY TESTS FOR RESPIRATORY SYSTEM DISEASE BRONCHOSCOPY AND BRONCHOALVEOLAR LAVAGE (BAL)1 (Saline lavage of lung subsegment via fiberoptic bronchoscope) Use For biopsy of endobronchial tumor in which obstruction may cause secondary pneumonia with effusion but still a resectable tumor To obtain bronchial washings for Diagnosis of nonresectable tumors that may be treated with radiation (e.g., oat cell carcinoma, Hodgkin's disease), metastatic tumors, peripheral lesions that cannot be reached by bronchoscope. Diagnosis of pulmonary infection, especially when sputum examination is not diagnostic. Quantitative bacterial culture and cytocentrifugation for staining slides provides overall diagnostic accuracy of 79% for pulmonary infection. Negative predictive value = 94%. Giemsa stain Healthy persons show <3% neutrophils, 8–18% lymphocytes, 80–89% alveolar macrophages. >10% neutrophils: indicates acute inflammation (e.g., bacterial infection, including Legionella, acute respiratory distress syndrome [ARDS], drug reaction). >1% squamous epithelial cells: indicates that a positive culture may reflect saliva contamination. >80% macrophages: common in pulmonary hemorrhage. Aspergillosis is the only infection associated with significant alveolar hemorrhage, which may also be found in >10% of patients with hematologic malignancies. >30% lymphocytes: may indicate hypersensitivity pneumonitis (often up to 50—60% with more cytoplasm and large irregular nucleus). >10% neutrophils and >3% eosinophils: characteristic of idiopathic pulmonary fibrosis; alveolar macrophages predominate. Lymphocyte percentage may be increased. >105 colony-forming bacteria/mL indicates bacterial infection if <1% squamous epithelial cells are present on Giemsa stain. Gram stain Many bacteria suggests bacterial infection if there are <1% squamous epithelial cells, especially if culture shows >10 4 bacteria/mL. No bacteria suggests that bacterial infection is unlikely but Legionella should be ruled out with direct fluorescent antibody (DFA) test if Giemsa stain shows increased neutrophils. Combined with methenamine silver or Pap stain, 94% sensitivity for diagnosis of Pneumocystis infection; increased to 100% when BAL is combined with transbronchial biopsy. Acid-fast stain: positive result may indicate Mycobacterium tuberculosis or Mycobacterium avium-intracellulare infection. Toluidine blue stain: may show Pneumocystis carinii cysts in Pneumocystis pneumonia or Aspergillus hyphae in immunocompromised host with invasive aspergillosis. Prussian blue–nuclear red stain: strongly positive result indicates severe alveolar hemorrhage; moderately positive indicates some hemorrhage; absent indicates no evidence of alveolar hemorrhage. DFA stain for Legionella, herpes simplex virus (HSV) I and II (stains bronchial epithelial cells and macrophages), and CMV (stains mononuclear cells) may indicate infection with corresponding organism. Pap stain: atypical cytology may be due to cytotoxic drugs, radiation therapy, viral infection (intranuclear inclusions of herpesvirus or CMV), tumor. Oil red O stain: shows many large intracellular fat droplets in one-third to two-thirds of cells in some patients with fat embolism due to bone fractures but in <3% of patients without embolism. GASES, BLOOD See Chapter 12. Decreased pO2 (Anoxemia) Hypoventilation (e.g., chronic airflow obstruction): due to increased alveolar CO 2, which displaces O2
- 94. Alveolar hypoxia (e.g., high altitude, gaseous inhalation) Pulmonary diffusion abnormalities (e.g., interstitial lung disease): supplemental O 2 usually improves pO2 Right-to-left shunt: supplemental O2 has no effect; requires positive end-expiratory pressure Congenital anomalies of heart and great vessels Acquired (e.g., ARDS) Ventilation-perfusion mismatch: supplemental O2 usually improves pO2 Airflow obstruction (e.g., chronic obstructive pulmonary disease [COPD], asthma) Interstitial inflammation (e.g., pneumonia, sarcoidosis) Vascular obstruction (e.g., pulmonary embolism) Decreased venous oxygenation (e.g., anemia) Increased pCO2 (Hypercapnia) Decreased ventilation Airway obstruction Drug overdose Metabolic disorders (e.g., myxedema, hypokalemia) Neurologic disorders (e.g., Guillain-Barré syndrome, multiple sclerosis) Muscle disorders (e.g., muscular dystrophy, polymyositis) Chest wall abnormalities (e.g., scoliosis) Increased dead space in lungs (perfusion decreased more than ventilation decreased) Lung diseases (e.g., COPD, asthma, pulmonary fibrosis, mucoviscidosis) Chest wall changes affecting lung parenchyma (e.g., scoliosis) Increased production (e.g., sepsis, fever, seizures, excess carbohydrate loads) LYMPH NODE (SCALENE) BIOPSY (Biopsy of scalene fat pad even without palpable lymph nodes) Positive in 15% of bronchogenic carcinoma cases. May also be positive in various granulomatous diseases (e.g., TB, sarcoidosis, pneumoconiosis). PLEURAL NEEDLE BIOPSY (CLOSED CHEST) (Whenever cannot diagnose otherwise) Positive for tumor in ~6% of malignant mesothelioma cases and ~60% of other cases of malignancy. Positive for tubercles in two-thirds of cases on first biopsy with increased yield on second and third biopsies; therefore repeat biopsy if suspicious clinically. Can also culture biopsy material for TB. Fluid culture alone establishes diagnosis of TB in 25% of cases. SPUTUM Color in various conditions • Rusty Lobar pneumonia • Anchovy paste (dark brown) Amebic liver abscess rupture into bronchus • Red currant jelly Klebsiella pneumoniae • Red (pigment, not blood) Serratia marcescens; rifampin overdose • Black Bacteroides melaninogenicus pneumonia; anthracosilicosis • Green (with WBCs, sweet odor) Pseudomonas infection • Milky Bronchioalveolar carcinoma • Yellow (without WBCs) Jaundice Smears and cultures for infections (e.g., pneumonias, TB, fungi) must be adequate samples of sputum showing ciliated cells, macrophages; neutrophils (usually >25/LPF in good specimen) if acute inflammation is present unless patient is neutropenic; monobacterial population if due to bacterial infection; acute inflammation without a definite bacterial pattern may be due to Legionella or RSV or influenza viruses. Must be promptly refrigerated Saliva contamination may show squamous epithelial cells (>19/LPF = poor specimen; 11–19/LPF = fair specimen; <10/LPF = good specimen), extracellular strands of streptococci, clumps of anaerobic Actinomyces, candidal budding yeasts with pseudohyphae. For possible anaerobic aspiration, fine needle aspiration (FNA) or alveolar lavage is needed. Cytology for carcinoma Positive in 40% on first sample Positive in 70% with three samples Positive in 85% with five samples False-positive in <1% Cytology in bronchogenic carcinoma Positive in 67–85% of squamous cell carcinoma Positive in 64–70% of small-cell undifferentiated carcinoma Positive in 55% of adenocarcinoma THORACOSCOPY/OPEN LUNG BIOPSY Use
- 95. Diagnosis of pleural malignancy Accuracy = 96%; sensitivity = 91%, specificity = 100%; negative predictive value = 93% 2 Diagnosis of pulmonary infection or neoplasm when BAL is not diagnostic RESPIRATORY DISEASES ABSCESS, LUNG w Sputum: marked increase; abundant, foul, purulent; may be bloody; contains elastic fibers. Gram stain is diagnostic—sheets of PMNs with a bewildering variety of organisms. Bacterial cultures (including tubercle bacilli)—anaerobic as well as aerobic; rule out amebas, parasites. Cytologic examination for malignant cells. Blood culture: may be positive in acute stage. Increased WBC in acute stages (15,000–30,000/cu mm) Increased ESR Normochromic normocytic anemia in chronic stage Albuminuria is frequent. Findings of underlying disease—especially bronchogenic carcinoma; also drug addiction, postabortion state, coccidioidomycosis, amebic abscess, TB, alcoholism ADULT RESPIRATORY DISTRESS SYNDROME (ARDS) Defined As3 Ratio of pO2 (partial pressure arterial O 2)/FiO2 (fraction inspired O2 concentration) £ 200 regardless of positive end-expiratory pressure. This ratio correlates with patient's outcome. In acute lung injury (change in lung function) this ratio is £ 300. Bilateral pulmonary infiltrates on frontal radiography Pulmonary wedge pressure £ 18 mm Hg or no evidence of increased left atrial pressure Preceding or associated event (e.g., sepsis [most common], aspiration, infection, pneumonia, pancreatitis, shock, fat emboli, trauma, DIC, etc.; more than one cause is often present). Infection is more likely due to gram-negative than gram-positive organisms. Occurs in 23% of cases of gram-negative bacteremia. Static pulmonary compliance <50 mL/cm H2O that markedly reduces vital capacity, total lung capacity, functional residual capacity. Initially there is respiratory alkalosis and varying degrees of hypoxemia resistant to supplementary O 2; then profound anoxemia with pO2 <50 mm Hg on room air. BAL shows increased PMNs (£ 80%). Eosinophilia occurs occasionally. Opportunistic organisms may be found if presents as ARDS. ASTHMA, BRONCHIAL Earliest change is decreased pCO2 with respiratory alkalosis with normal pO2. Then pO2 decreases before pCO2 increases. With severe episode Hyperventilation causes decreased pCO2 in early stages (may be <35 mm Hg). Rapid deterioration of patient's condition may be associated with precipitous fall in pO2 and rise in pCO 2 (>40 mm Hg). pO2 <60 mm Hg may indicate severe attack or presence of complication. Normal pCO2 suggests that the patient is tiring. Acidemia and increased pCO2 suggest impending respiratory failure. Mixed metabolic and respiratory acidosis occurs. When patient requires hospitalization, arterial blood gases should be measured frequently to assess status. Eosinophilia may be present. Sputum is white and mucoid without blood or pus (unless infection is present). Eosinophils, crystals (Curschmann's spirals), and mucus casts of bronchioles may be found. Laboratory findings due to underlying diseases that may be primary and that should be ruled out, especially polyarteritis nodosa, parasitic infestation, bronchial carcinoid, drug reaction (especially to aspirin), poisoning (especially by cholinergic drugs and pesticides), hypogammaglobulinemia. BRONCHIECTASIS WBC usually normal unless pneumonitis is present. Mild to moderate normocytic normochromic anemia with chronic severe infection Sputum abundant and mucopurulent (often contains blood); sweetish smell Sputum bacterial smears and cultures
- 96. Laboratory findings due to complications (pneumonia, pulmonary hemorrhage, brain abscess, sepsis, cor pulmonale) Rule out cystic fibrosis of the pancreas and hypogammaglobulinemia or agammaglobulinemia. BRONCHITIS, ACUTE Due To Viruses (e.g., rhinovirus, coronavirus, adenovirus, influenza) cause most cases. Mycoplasma pneumoniae, Chlamydia pneumoniae, Bordetella pertussis, Legionella spp. WBC and ESR may be increased. BRONCHITIS, CHRONIC WBC and ESR normal or increased Eosinophil count increased if there is allergic basis or component Smears and cultures of sputum and bronchoscopic secretions Laboratory findings due to associated or coexisting diseases (e.g., emphysema, bronchiectasis) Acute exacerbations are most commonly due to Viruses M. pneumoniae Haemophilus influenzae S. pneumoniae Moraxella (Branhamella) catarrhalis CARCINOMA, BRONCHOGENIC w Cytologic examination of sputum for malignant cells—positive in 40% of patients on first sample, in 70% with three samples, in 85% with five samples. False-positive tests are <1%. w Sputum cytology gives highest positive yield with squamous cell carcinoma (67–85%), intermediate with small cell undifferentiated carcinoma (64–70%), lowest with adenocarcinoma (55%). w Biopsy of scalene lymph nodes for metastases to indicate inoperable status—positive in 15% of patients w Biopsy of bronchus, pleura, lung, metastatic sites in appropriate cases w Cytology of pleural effusion w Needle biopsy of pleura is positive in 58% of cases with malignant effusion; indicates inoperable status. w Transthoracic needle aspiration provides definitive cytologic diagnosis of cancer in 80—90% of cases; useful when other methods (e.g., sputum cytology, bronchoscopy) fail to provide a microscopic diagnosis. w Cancer cells in bone marrow and rarely in peripheral blood m Biochemical tumor markers Serum CEA is increased in one-third to two-thirds of patients with all four types of lung cancer. Principal uses are to monitor response to therapy and to correlate with staging. Values <5 ng/mL correlate with survival over 3 yrs compared to values >5 ng/mL. Values >10 ng/mL correlate with higher incidence of extensive disease and extrathoracic metastases. A fall to normal suggests complete tumor removal. A fall to still elevated values may indicate residual tumor. An elevated unchanged value suggests residual progressive disease. A value that falls and then rises during chemotherapy suggests that resistance to drugs has occurred. Serum neuron-specific enolase may be increased in 79–87% of patients with small cell cancer and in 10% of those with non–small cell cancer and nonmalignant lung diseases. Pretreatment level correlates with stage of small cell cancer. May be used to monitor disease progression; falls in response to therapy and becomes normal in complete remission but not useful for initial screening or detecting early recurrence. Paraneoplastic syndromes Endocrine and metabolic (primarily due to small cell cancer) ACTH (Cushing's syndrome) is most commonly produced ectopic hormone (50% of patients with small cell cancer) Hypercalcemia occurs in >12% of patients (mostly in epidermoid carcinoma); correlates with large tumor mass that is often incurable and quickly fatal. (See Humoral Hypercalcemia of Malignancy.) Serotonin production by carcinoid of bronchus. SIADH occurs in 11% of patients with small cell cancer. Prolactin usually due to anaplastic tumors. Gonadotropin production predominantly with large cell carcinoma Renal tubular dysfunction with glycosuria and aminoaciduria Hyponatremia due to massive bronchorrhea in bronchoalveolar cell carcinoma Others (e.g., melanocyte-stimulating hormone, vasoactive intestinal peptides) Coagulopathies, e.g., DIC Migratory thrombophlebitis Chronic hemorrhagic diathesis Neuromuscular syndromes (most commonly with small cell cancer), e.g., Myasthenia Encephalomyelitis—antineuronal antibodies and small cell cancer associated with limbic encephalitis Cutaneous, e.g., Dermatomyositis Acanthosis nigricans Syndromes due to metastases (e.g., liver metastases with functional hepatic changes, Addison's disease, diabetes insipidus) Findings of complicating conditions (e.g., pneumonitis, atelectasis, lung abscess) Normochromic, normocytic anemia in <10% of patients
- 97. CROUP (EPIGLOTTITIS, LARYNGOTRACHEITIS) Group B H. influenzae causes >90% of cases of epiglottitis; other bacteria include beta-hemolytic streptococci and pneumococci. Cultures, smears, and tests for specific causative agents Blood cultures should be taken at the same time as throat cultures. Neutrophilic leukocytosis is present. Clinical picture in infectious mononucleosis or diphtheria may resemble epiglottitis. Laryngotracheitis is usually viral (especially parainfluenza) but rarely bacterial in origin. DYSPLASIA, BRONCHOPULMONARY Usually seen in infants recovering from respiratory distress syndrome (RDS) in whom endotracheal tube and intermittent positive pressure ventilation have been used for >24 hrs. Stage I (first days of life)—severe RDS is present. Stage II (late in first week)—clinical improvement but not asymptomatic Stage III (second week of life)—clinical deterioration, increasing hypoxemia, hypercapnia, acidosis, diffuse radiographic changes in lungs Stage IV (after 1 mo of age)—chronic healing phase with further radiographic changes. 25% die, usually due to pneumonia. Symptoms usually resolve by 2 yrs but abnormal pulmonary function tests and right ventricular hypertrophy may persist for several years. EMPHYSEMA, OBSTRUCTIVE Laboratory findings of underlying disease that may be primary (e.g., pneumoconiosis, TB, sarcoidosis, kyphoscoliosis, marked obesity, fibrocystic disease of pancreas, alpha-1-antitrypsin deficiency) Laboratory findings of associated conditions, especially duodenal ulcer Laboratory findings due to decreased lung ventilation pO2 decreased and pCO2 increased Ultimate development of respiratory acidosis Secondary polycythemia Cor pulmonale GOODPASTURE'S SYNDROME (Alveolar hemorrhage and GN [usually rapidly progressive] associated with antibody against pulmonary alveolar and glomerular basement membranes) Proteinuria and RBCs and RBC casts in urine Renal function may deteriorate rapidly or renal manifestations may be mild. w Renal biopsy may show characteristic linear immunofluorescent deposits of IgG and often complement and focal or diffuse proliferative GN. w Serum may show antiglomerular basement membrane IgG antibodies by enzyme immunoassay (EIA). Titer may not correlate with severity of pulmonary or renal disease. Eosinophilia absent and iron-deficiency anemia more marked than in idiopathic pulmonary hemosiderosis Sputum or BAL showing hemosiderin-laden macrophages may be a clue to occult pulmonary hemorrhage. Other causes of combined pulmonary hemorrhage and GN are Wegener's granulomatosis Hypersensitivity vasculitis SLE Polyarteritis nodosa Endocarditis Mixed cryoglobulinemia Allergic angiitis and granulomatosis (Churg-Strauss syndrome) Behçet's syndrome Henoch-Schönlein purpura Pulmonary-renal reactions due to drugs (e.g., penicillamine) HANTAVIRUS PULMONARY SYNDROME HERNIA, DIAPHRAGMATIC Microcytic anemia (due to blood loss) may be present. Stool may be positive for blood. HISTIOCYTOSIS X w Diagnosis is established by open lung biopsy. Pulmonary disorder is the major manifestation of this disease; bone involvement in minority of cases with lung disease. Pleural effusion is rare.
- 98. BAL shows increase in total number of cells; 2–20% Langerhans' cells, small numbers of eosinophils, neutrophils, and lymphocytes, and 70% macrophages. Most adults do not have positive gallium citrate 67 ( 67 Ga) scans. Mild decrease in pO2, which falls with exercise INTERSTITIAL PNEUMONITIS, DIFFUSE Serum LD is increased. LARYNX DISEASES w Culture and smears for specific organisms (e.g., tubercle bacilli, fungi) w Biopsy for diagnosis of visible lesions (e.g., leukoplakia, carcinoma) May be due to any respiratory viruses. LEGIONNAIRES' DISEASE See Chapter 15. NASOPHARYNGITIS, ACUTE Due To Bacteria (e.g., Group A beta-hemolytic streptococci [causes 10–30% of cases seen by doctors], H. influenzae, M. pneumoniae, etc.). (Mere presence of staphylococci, pneumococci, alpha- and beta-hemolytic streptococci [other than groups A, C, and G] in throat culture does not establish them as cause of pharyngitis and does not warrant antibiotic treatment.) Virus (e.g., EBV, CMV, adenovirus, RSV, HSV, coxsackievirus) M. pneumoniae C. pneumoniae (formerly TWAR agent) Fungus, allergy, foreign body, trauma, neoplasm Idiopathic (no cause is identified in ~50% of cases) Microscopic Examination of Stained Nasal Smear m Large numbers of eosinophils suggest allergy. Does not correlate with blood eosinophilia. Eosinophils and neutrophils suggest chronic allergy with superimposed infection. m Large numbers of neutrophils suggest infection. m Gram stain and culture of pharyngeal exudate may show significant pathogen. NEONATAL RESPIRATORY DISTRESS SYNDROME (RDS) Hypoxemia Hypercapnia and acidosis in severe cases pO2 is maintained between 50–70 mm Hg to minimize retinal damage. Laboratory findings due to complications (e.g., hypoglycemia, hypocalcemia, acidosis, anemia) PLEURAL EFFUSION See Fig. 6-1, Table 6-1, Table 6-2 and Table 6-3. Fig. 6-1. Algorithm for pleural effusion.
- 99. Table 6-1. Pleural Fluid Findings in Various Clinical Conditions Table 6-2. Comparison of “Typical”a Findings in Transudates and Exudatesb Table 6-3. Comparison of Tumor Markers in Various Pleural Effusions Normal Values Specific gravity 1.010–1.026 Total protein Albumin 0.3–4.1 gm/dL Globulin 50–70% Fibrinogen 30–45% pH 6.8–7.6 The underlying cause of an effusion is usually determined by first classifying the fluid as an exudate or a transudate. A transudate does not usually require additional testing but exudates always do. Transudate Congestive heart failure (causes 15% of cases)—acute diuresis can result in pseudoexudate Cirrhosis with ascites (pleural effusion in ~5% of these cases)—rare without ascites Nephrotic syndrome Early (acute) atelectasis Pulmonary embolism (some cases) Superior vena cava obstruction Hypoalbuminemia Peritoneal dialysis—occurs within 48 hrs of initiating dialysis Early mediastinal malignancy Misplaced subclavian catheter Myxedema (rare cause) Constrictive pericarditis—effusion is bilateral Urinothorax—due to ipsilateral GU tract obstruction Exudate
- 100. Pneumonia, malignancy, pulmonary embolism, and GI conditions (especially pancreatitis and abdominal surgery, which cause 90% of all exudates) Infection (causes 25% of cases) Bacterial pneumonia Parapneumonic effusion (empyema) TB Abscess (subphrenic, liver, spleen) Viral, mycoplasmal, rickettsial Parasitic (ameba, hydatid cyst, filaria) Fungal effusion (Coccidioides, Cryptococcus, Histoplasma, Blastomyces, Aspergillus; in immunocompromised host, Aspergillus, Candida, Mucor) Pulmonary embolism/infarction Neoplasms (metastatic carcinoma, especially breast, ovary, lung; lymphoma, leukemia, mesothelioma, pleural endometriosis) (causes 42% of cases) Trauma (penetrating or blunt) Hemothorax, chylothorax, empyema, associated with rupture of diaphragm Immunologic mechanisms Rheumatoid pleurisy (5% of cases) SLE After myocardial infarction or cardiac surgery Other collagen vascular diseases occasionally cause effusions (e.g., Wegener's granulomatosis, Sjögren's syndrome, familial Mediterranean fever, Churg-Strauss syndrome, mixed connective tissue disease) Vasculitis Hepatitis Sarcoidosis (rare cause; may also be transudate) Familial recurrent polyserositis Drug reaction (e.g., nitrofurantoin hypersensitivity, methysergide) Chemical mechanisms Uremic Pancreatic (pleural effusion occurs in ~10% of these cases) Esophageal rupture (high salivary amylase and pH <7.30 that approaches 6.00 in 48–72 hrs) Subphrenic abscess Lymphatic abnormality Irradiation Milroy's disease Yellow nail syndrome (rare condition of generalized hypoplasia of lymphatic vessels) Injury Asbestosis Altered pleural mechanics Late (chronic) atelectasis Trapped lung Endocrine Hypothyroidism Movement of fluid from abdomen to pleural space Meigs' syndrome (protein and specific gravity are often at transudate-exudate border but usually not transudate) Urinothorax Cancer Pancreatitis, pancreatic pseudocyst Unknown (~15% of all exudates) Cirrhosis, pulmonary infarct, trauma, and connective tissue diseases comprise ~9% of all cases. Exudates That Can Present as Transudates Pulmonary embolism (>20% of cases)—due to atelectasis Hypothyroidism—due to myxedema heart disease Malignancy—due to complications (e.g., atelectasis, lymphatic obstruction) Sarcoidosis—stage II and III Pleural fluid analysis results in definitive diagnosis in ~25% and a probable diagnosis in another 50% of patients; may help to rule out a suspected diagnosis in 30%. Location Typically left-sided—ruptured esophagus, acute pancreatitis, RA. Pericardial disease is left-sided or bilateral; rarely exclusively right-sided. Typically right-sided or bilateral—congestive heart failure (if only on left, consider that right pleural space may be obliterated or patient has another process, e.g.,
- 101. pulmonary infarction). Typically right-sided—rupture of amebic liver abscess. Gross Appearance Clear, straw-colored fluid is typical of transudate. Cloudy, opaque appearance indicates more cell components. Bloody fluid suggests malignancy, pulmonary infarct, trauma, postcardiotomy syndrome; also uremia, asbestosis, pleural endometriosis. Bloody fluid from traumatic thoracentesis should clot within several minutes, but blood present more than several hours has become defibrinated and does not form a good clot. Nonuniform color during aspiration and absence of hemosiderin-laden macrophages and some crenated RBCs also suggest traumatic aspiration. Chylous (milky) fluid is usually due to trauma (e.g., auto accident, postoperative) but may be obstruction of duct (e.g., especially lymphoma; metastatic carcinoma, granulomas). Pleural fluid triglyceride >110 mg/dL or triglyceride pleural fluid to serum ratio >2 occurs only in chylous effusion (seen especially within a few hours after eating). After centrifugation, supernatant is white due to chylomicrons, which also stain with Sudan III. Equivocal triglyceride levels (60–110 mg/dL) may require a lipoprotein electrophoresis of fluid to demonstrate chylomicrons diagnostic of chylothorax. Triglyceride <50 mg/dL excludes chylothorax. “Pseudochylous” in chronic inflammatory conditions (e.g., rheumatoid pleurisy, TB, chronic pneumothorax therapy for TB) due to either cholesterol crystals (rhomboid shaped) in sediment or lipid-containing inclusions in leukocytes. Distinguish from chylous effusions by microscopy. Fluid may have lustrous sheen. White fluid suggests chylothorax, cholesterol effusion, or empyema. Black fluid suggests Aspergillus niger infection. Greenish fluid suggests biliopleural fistula. Purulent fluid indicates infection. Anchovy (dark red-brown) color is seen in amebiasis, old blood. Anchovy paste in ruptured amebic liver abscess; amebas found in <10%. Turbid and greenish yellow fluid is classical for rheumatoid effusion. Turbidity may be due to lipids or increased WBCs; after centrifugation, a clear supernatant indicates WBCs as cause; white supernatant is due to chylomicrons. Very viscous (clear or bloody) fluid is characteristic of mesothelioma. Debris in fluid suggests rheumatoid pleurisy; food particles indicate esophageal rupture. Color of enteral tube food or central venous line infusion due to tube or catheter entering pleural space. Odor Putrid due to anaerobic empyema Ammonia due to urinothroax Protein, Albumin, Lactate Dehydrogenase See Table 6-2. When exudate criteria are met by LD but not by protein, consider malignancy and parapneumonic effusions. Very high pleural fluid LD (>1000 U/L) occurs in empyema, rheumatoid pleurisy, paragonimiasis; sometimes with malignancy; rarely with TB. Glucose Same concentration as serum in transudate Usually normal but 30–55 mg/dL or pleural fluid to serum ratio <0.5 and pH <7.30 may be found in TB, malignancy, SLE; also esophageal rupture; lowest levels may occur in empyema and RA. Therefore, only helpful if very low level (e.g., <30). 0–10 mg/dL highly suspicious for RA (see Rheumatoid Effusion). pH Low pH (<7.30) always means exudate, especially empyema, malignancy, rheumatoid pleurisy, SLE, TB, esophageal rupture. Esophageal rupture is only cause of pH close to 6.0; collagen vascular disease is only other cause of pH <7.0. pH <7.10 in parapneumonic effusion indicates need for tube drainage. In malignant effusion, pH <7.30 is associated with short survival time, poorer prognosis, and increased positive yield with cytology and pleural biopsy; tends to correlate with pleural fluid glucose <60 mg/dL. Amylase Increased (pleural fluid to serum ratio >1.0 and may be >5 or pleural fluid greater than upper limit of normal for serum) Acute pancreatitis—may be normal early with increase over time. Pancreatic pseudocyst—always increased, may be >100,000 U/L. Also perforated peptic ulcer, necrosis of small intestine (e.g., mesenteric vascular occlusion); 10% of cases of metastatic cancer and esophageal rupture. Isoenzyme studies Pancreatic type amylase is found in acute pancreatitis and pancreatic pseudocyst. Salivary type amylase is found in esophageal rupture and occasionally in carcinoma of ovary or lung or salivary gland tumor. Should be determined in undiagnosed left pleural effusions. Other Chemical Determinations
- 102. w Cholesterol <55 mg/dL is said to be found in transudates and >55 mg/dL in exudates. w CEA >10 ng/mL has specificity of >95% and sensitivity of 54–100% for lung cancer, 83% for breast cancer, 100% for GI tract cancers. May also be increased in empyema and parapneumonic effusions. w C125 tumor antigen (CA-125;) has sensitivity of 71% and specificity of 99% for non-mucinous epithelial ovarian carcinoma. Combined CEA and CA-125 have sensitivity for detection of malignant effusions due to carcinomas of lung, breast, GI tract, and ovary of 75–100% and specificity of 98%. May indicate primary site when the source is unknown or cytology is negative ( Table 6-3). Other tumor markers have been suggested for diagnosis of cancer, but value not established (e.g., acid phosphatase in prostatic cancer, hyaluronic acid in mesothelioma, beta 2-microglobulin, etc.) Acid mucopolysaccharides (especially hyaluronic acid) may be increased (>120 µg/mL) in mesotheliomas. Immune complexes (measured by Raji cell, C1q component of C, RIA, etc.) are often found in exudates due to collagen vascular diseases (SLE, RA). RA latex agglutination tests show frequent false-positives and should not be ordered. Occasionally latex agglutination for bacterial antigens is useful. Gas-liquid chromatography has been reported to show butyric, isobutyric, propionic, and isovaleric acids in anaerobic acute bacterial infection and increased lactic and acetic acid levels in aerobic infections. Cell Count Total WBC count is almost never diagnostic. >10,000/cu mm indicates inflammation, most commonly with pneumonia, pulmonary infarct, pancreatitis, postcardiotomy syndrome. >50,000/cu mm is typical only in parapneumonic effusions, usually empyema. Chronic exudates (e.g., malignancy and TB) are usually <5000/cu mm. Transudates are usually <1000/cu mm. 5000–6000 RBCs/cu mm needed to give red appearance to pleural fluid Can be caused by needle trauma producing 2 mL of blood in 1000 mL of pleural fluid. >100,000 RBCs/cu mm is grossly hemorrhagic and suggests malignancy, pulmonary infarct, or trauma but occasionally seen in congestive heart failure alone. Hemothorax (pleural fluid to venous Hct ratio >2) suggests trauma, bleeding from a vessel, bleeding disorder, or malignancy but may be seen in same conditions as above. Smears Wright's stain differentiates PMNs from mononuclear cells; cannot differentiate lymphocytes from monocytes. Mononuclear cells predominate in transudates and chronic exudates (lymphoma, carcinoma, TB, rheumatoid conditions, uremia). >50% is seen in two-thirds of cases due to cancer. >85–90% suggests TB, lymphoma, sarcoidosis, rheumatoid causes. PMNs predominate in early inflammatory effusions (e.g., pneumonia, pulmonary infarct, pancreatitis, subphrenic abscess). After several days, mesothelial cells, macrophages, lymphocytes may predominate. Large mesothelial cells >5% are said to rule out TB (must differentiate from macrophages). Lymphocytes >85% suggests TB, lymphoma, sarcoidosis, chronic rheumatoid pleurisy, yellow nail syndrome, chylothorax. 50–75% in >50% of cases of carcinoma. Eosinophils in pleural fluid (>10% of total WBCs) is not diagnostically significant. May mean blood or air in pleural space (e.g., pneumothorax [most common], repeated thoracenteses, traumatic hemothorax). It also is said to be associated with asbestosis, pulmonary infarction, polyarteritis nodosa. Parasitic disease (e.g., paragonimiasis, hydatid disease, amebiasis, ascariasis). Fungal disease (e.g., histoplasmosis, coccidioidomycosis). Drug-related (e.g., nitrofurantoin, bromocriptine, dantrolene). Idiopathic effusion (in approximately one-third of cases; may be due to occult pulmonary embolism or asbestosis). Uncommon with malignant effusions. Rare with TB. Not usually accompanied by striking blood eosinophilia. Many diseases associated with blood eosinophilia infrequently cause pleural effusion eosinophilia. Basophils >10% only in leukemic involvement of pleura. Occasionally lupus erythematosus (LE) cells make the diagnosis of SLE. Gram stain for early diagnosis of bacterial infection. Acid-fast smears are positive in 20% of tuberculous pleurisy. Culture is often positive in empyema but not in parapneumonic effusions. w Bacterial antigens may detect H. influenzae type b, Streptococcus pneumoniae, several types of Neisseria meningitidis. Useful when viable organisms cannot be recovered (e.g., due to prior antibiotic therapy). w Cytology Positive in 60% of malignancies on first tap, 80% by third tap. Therefore should repeat taps with cytologic examinations if cancer is suspected. Is more sensitive than needle biopsy. Combined with needle biopsy, increases sensitivity by <10%. 4 (See Carcinoma, Bronchogenic.) High yield with adenocarcinoma, low yield with Hodgkin's disease. Rheumatoid effusions: cytologic triad of slender elongated and round giant multinucleated macrophages and necrotic background material with characteristically low
- 103. glucose is said to be pathognomonic. Mesothelial cells are nearly always absent. Flow cytometry assay for DNA aneuploidy and staining with monoclonal antibodies (e.g., CEA, cytokeratin) to distinguish malignant mesothelioma, metastatic tumor, and reactive mesothelial cells can be performed (note: some malignant cells may be diploid). Pleural Fluid Findings in Various Clinical Conditions See Fig. 6-1. Tuberculosis High protein content—almost always >4.0 gm/dL Increased lymphocytes w Acid-fast smears are positive in <20%, and culture is positive in ~67% of cases; culture combined with histologic examination establishes the diagnosis in 95% of cases. w Needle biopsy can be performed without hesitation. Large mesothelial cells >5% are said to rule out TB (must differentiate from macrophages). TB often presents as effusion, especially in youth; pulmonary disease may be absent; risk of active pulmonary TB within 5 yrs is 60%. Malignancy Can cause effusion by metastasis to pleura, causing exudate-type fluid, or by metastasis to lymph nodes, obstructing lymph drainage and giving transudate-type fluid. Low pH and glucose indicate a poor prognosis with short survival time. Characteristic effusion is moderate to massive, frequently hemorrhagic, with moderate WBC count with predominance of mononuclear cells; however, only half of malignant effusions have RBC >10,000/cu mm. w Cytology establishes the diagnosis in ~50% of patients. w Combined cytology and pleural biopsy give positive results in 90%. w In some instances of suspected lymphoma with negative conventional test results, flow cytometric analysis of pleural fluid showing a monoclonal lymphocyte population can establish the diagnosis. Mucopolysaccharide level may be increased (normal <17 mg/dL) in mesothelioma. Lung and breast cancer and lymphoma cause 75% of malignant effusions; in 6%, no primary tumor is found. Pleural or ascitic effusion occurs in 20–30% of patients with malignant lymphoma. CEA, CA-125—see Table 6-3. Pulmonary Infarct Effusion occurs in 50% of patients with pulmonary infarct; is bloody in one-third to two-thirds of patients; often no characteristic diagnostic findings occur. Small volume, serous or bloody, predominance of PMNs, may show many mesothelial cells; this “typical pattern” is seen in only 25% of cases. Congestive Heart Failure Is predominantly right-sided or bilateral. If unilateral or left-sided in patients with congestive heart failure, rule out pulmonary infarct. Pneumonias Parapneumonic effusions (exudate type of effusion associated with lung abscess, bronchiectasis; ~5% of bacterial pneumonias). Aerobic gram-negative organisms (Klebsiella, Escherichia coli, Pseudomonas) are associated with a high incidence of exudates (with 5000–40,000/cu mm, high protein, normal glucose, normal pH) and resolve with antibiotic therapy. Nonpurulent fluid with positive Gram stain or positive blood culture or low pH suggests that effusion will become or behave like empyema. S. pneumoniae causes parapneumonic effusions in 50% of cases, especially with positive blood culture. Staphylococcus aureus has effusion in 90% of infants, 50% of adults; usually widespread bronchopneumonia. Streptococcus pyogenes has effusion in 90% of cases; massive effusion, greenish color. Haemophilus influenzae has effusion in 50–75% of cases. Viral or Mycoplasma pneumonia—pleural effusions develop in 20% of cases. Legionnaires' disease—pleural effusion occurs in up to 50% of patients; may be bilateral. P. carinii pneumonia cases often have pleural effusion to serum LD ratio >1.0 and pleural effusion to serum protein ratio <0.5. pH <7.0 and glucose <40 mg/dL indicate need for closed chest tube drainage even without grossly purulent fluid. pH of 7.0–7.2 is questionable indication and should be repeated in 24 hrs, but tube drainage is favored if pleural fluid LD >1000 U/L. Tube drainage is also indicated if fluid is grossly purulent or Gram stain or culture is positive. Normal pH is alkaline and may approach 7.6. Empyema Usually WBCs >50,000/cu mm, low glucose, and low pH. Suspect clinically when effusion develops during adequate antibiotic therapy.
- 104. In Proteus mirabilis empyema, high ammonia level may cause a pH ~8.0. Rheumatoid Effusion See Table 6-4. Table 6-4. Comparison of Pleural Fluid in Rheumatoid Arthritis and Systemic Lupus Erythematosus (SLE) Found in ~70% of RA patients at autopsy. m Exudate is frequently turbid and may be milky. Classic picture is cloudy greenish fluid with 0 glucose level. Level is <50 mg/dL in 80% and <25 mg/dL in 66% of patients; is the most useful finding clinically. Failure of level to increase during IV glucose infusion distinguishes RA from other causes. Nonpurulent, nonmalignant effusions not due to TB or RA almost always have glucose level >60 mg/dL. RF may be present but may also be found in other effusions (e.g., TB, cancer, bacterial pneumonia). RF titer ³1:320 or equal to or greater than serum level suggests rheumatoid pleurisy. RA cells may be found (see Cytology). Cytologic examination for malignant cells and smears and cultures for bacteria, tubercle bacilli, and fungi are negative. w Needle biopsy usually shows nonspecific chronic inflammation but may show characteristic rheumatoid nodule microscopically. One-third of cases have parenchymal lung disease (e.g., interstitial fibrosis). Other laboratory findings of RA are found. Protein level is >3 gm/dL. Increased LD (usually higher than in serum) is commonly found in other chronic pleural effusions and is not useful in differential diagnosis. Systemic Lupus Erythematosus w • LE cells are specific for SLE but test has poor sensitivity. m • ANA titer ³160 or pleural fluid to serum ratio >1.0 is suggestive but not diagnostic. PNEUMOCONIOSIS w Biopsy of lung, scalene lymph node—histologic, chemical, spectrographic, and radiographic diffraction studies, electron microscopy (e.g., silicosis, berylliosis; also metastatic tumor, sarcoidosis, TB, fungus infection) Bacterial smears and cultures of sputum (especially for tubercle bacilli) should be done. Cytologic examination of sputum and bronchoscopic secretions for malignant cells, especially squamous cell carcinoma of bronchus and mesothelioma of pleura Asbestos bodies sometimes occur in sputum after exposure to asbestos dust even without clinical disease. Acute beryllium disease may show occasional transient hypergammaglobulinemia. Chronic beryllium disease Secondary polycythemia Increased serum gamma globulin Increased urine calcium Increased beryllium in urine long after beryllium exposure has ended Increased WBC if associated infection Secondary polycythemia or anemia Silicosis Associated conditions £25% have mycobacterial infections, half of which are nontuberculous. Increased incidence of nocardiosis, cryptococcosis, sporotrichosis. 10% have connective tissue diseases (e.g., progressive systemic sclerosis, RA, SLE). Increased incidence of ANA, RF, hypergammaglobulinemia. ACE increased in one-third of patients. PNEUMONIA
- 105. See Table 6-5. Table 6-5. Opportunistic Pulmonary Infections Due To Bacteria S. pneumoniae causes 60–70% of bacterial pneumonia in patients requiring hospitalization. May cause ~25% of hospital-acquired cases of pneumonia. Blood culture positive in 25% of untreated cases during first 3–4 days. Staphylococcus causes <1% of all acute bacterial pneumonia with onset outside the hospital but more frequent after outbreaks of influenza; may be secondary to measles, mucoviscidosis, prolonged antibiotic therapy, debilitating diseases (e.g., leukemia, collagen diseases). Frequent cause of nosocomial pneumonia. Bacteremia in <20% of patients. H. influenzae is important in 6- to 24-mo age group; rare in adults except for middle-aged men with chronic lung disease and/or alcoholism and patients with immunodeficiency (HIV, multiple myeloma, chronic lymphocytic leukemia [CLL]). Can mimic pneumococcal pneumonia; may be isolated with S. pneumoniae. Gram-negative bacilli (e.g., K. pneumoniae, enterobacteria, E. coli, P. mirabilis, Pseudomonas aeruginosa) are common causes of hospital-acquired pneumonia but unlikely outside the hospital. K. pneumoniae causes 1% of primary bacterial pneumonias, especially in alcoholic patients and patients with upper lobe pneumonia; tenacious red-brown sputum is typical. Tubercle bacilli Legionella pneumophila M. pneumoniae—most common in young adult male population (e.g., armed forces camps) C. pneumoniae, Chlamydia psittaci Others (e.g., streptococcosis, tularemia, plague) See Table 6-5. Viruses Influenza, parainfluenza, adenoviruses, RSV, echovirus, coxsackievirus, reovirus, CMV, viruses of exanthems, herpes simplex, hantavirus Rickettsiae Q fever is most common in endemic areas; typhus. Fungi P. carinii, Histoplasma, and Coccidioides in particular; Blastomyces, Aspergillus. Protozoans Toxoplasma Underlying Condition Organism Obstructive cancer S. pneumoniae, H. influenzae, M. catarrhalis, anaerobes Alcoholism S. pneumoniae, H. influenzae, Klebsiella spp., Legionella spp., anaerobes, M. tuberculosis HIV infection S. pneumoniae, H. influenzae, S. aureus, gram-negative bacilli, P. carinii, M. tuberculosis and MAI (mycobacterium avium-intracellulare), Toxoplasma gondii, Cryptococcus, Nocardia, CMV, histoplasmosis, Coccidioides immitis, Legionella, M. catarrhalis, Rhodococcus equi Atypical pneumonia M. pneumoniae, C. psittaci, C. pneumoniae, Coxiella bur-netii, Francisella tularensis, many viruses Laboratory Findings WBC is frequently normal or slightly increased in nonbacterial pneumonias; considerable increase in WBC is more common in bacterial pneumonia. In severe bacterial pneumonia, WBC may be very high or low or normal. Because individual variation is considerable, it has limited value in distinguishing bacterial and nonbacterial pneumonia. Urine protein, WBCs, hyaline and granular casts in small amounts are common. Ketones may occur with severe infection. Check for glucose to rule out underlying diabetes mellitus. w Sputum reveals abundant WBCs in bacterial pneumonias. Gram stain shows abundant organisms in bacterial pneumonias (e.g., Pneumococcus, Staphylococcus). Culture sputum for appropriate bacteria. Sputum that contains many organisms and WBCs on smear but no pathogens on aerobic culture may indicate aspiration pneumonia. Sputum is not appropriate for anaerobic culture.
- 106. w In all cases of pneumonia, blood culture and sputum culture and smear for Gram stain should be performed before antibiotic therapy is started. Optimum specimen of sputum shows >25 PMNs and £5 squamous epithelial cells/LPF (10× magnification), but >10 PMNs and <25 epithelial cells may be considered acceptable sputum specimen. >25 epithelial cells indicate unsatisfactory specimen from oropharynx which should not be submitted for culture. If good sputum specimen is obtained, further diagnostic microbiological tests are usually not performed. Nasopharyngeal aspirate may identify S. pneumoniae with few false positives but S. aureus and gram-negative bacilli often represent false-positive findings. In H. influenzae pneumonia, sputum culture is negative in >50% of patients with positive cultures from blood, pleural fluid, or lung tissue, and may be present in the sputum in the absence of disease. w Transtracheal aspiration (puncture of cricothyroid membrane) generally yields a faster, more accurate diagnosis. w Protected brush bronchoscopy and BAL have high sensitivity. w Diagnostic lung puncture to determine specific causative agent as a guide to antibiotic therapy may be indicated in critically ill children. w Open lung biopsy is gold standard with 97% accuracy but 10% complication rate. For pleural effusions that are aspirated, Gram stain and culture should also be performed. w Respiratory pathogens isolated from blood, pleural fluid, or transtracheal aspirate (except in patients with chronic bronchitis) or identified by bacterial polysaccharide antigen in urine may be considered the definite causal agent. w Urine testing for capsular antigen from S. pneumoniae or type B H. influenzae by latex agglutination may be helpful. Positive in ~90% of bacteremic pneumococcal pneumonias and 40% of nonbacteremic pneumonias. May be particularly useful when antibiotic therapy has already begun. Acute phase serum should be stored at onset. If causal diagnosis is not established, a convalescent phase serum should be taken. A 4× increase in antibody titer establishes the causal diagnosis (e.g., L. pneumophila, Chlamydia spp., respiratory viruses [including influenza and RSV]), M. pneumoniae. Serologic tests to determine whether pneumonia is due to Histoplasma, Coccidioides, etc. PNEUMONIA, LIPID m Sputum shows fat-containing macrophages that stain with Sudan. They may be present only intermittently; therefore, examine sputum more than once. PULMONARY ALVEOLAR PROTEINOSIS (Rare disease characterized by amorphous, lipid-rich, proteinaceous material in alveoli) m PAS–positive material appears in sputum. m PSP dye injected intravenously is excreted in sputum for long periods of time. BAL fluid contains increased total protein, albumin, phospholipids, and CEA. w Recently antibodies to surfactant protein A (ELISA assay) in sputum and BAL have been reported to be highly specific. m Serum CEA is increased and correlates with BAL findings. Reflects severity of disease and decreases with response to treatment. m Routine laboratory test findings are nonspecific. Serum LD increases when protein accumulates in lungs and becomes normal when infiltrate resolves; correlates with serum CEA. Decreased arterial O2. Secondary polycythemia may occur. w Diagnosis usually requires open lung biopsy. Electron microscopy shows many lamellar bodies. Laboratory findings due to superinfection. PULMONARY EMBOLISM AND INFARCTION No laboratory test is diagnostic. <10% of emboli lead to infarction Measurement of arterial blood gases (obtained when patient is breathing room air) is the most sensitive and specific laboratory test. m • pO2 <80 mm Hg in 88% of cases but normal pO2 does not rule out pulmonary embolus. In appropriate clinical setting, pO 2 <88 mm Hg (even with a normal chest radiograph) is indication for lung scans and search for deep vein thromboses. pO 2 >90 mm Hg with a normal chest radiograph suggests a different diagnosis. Normal complete lung scans exclude the diagnosis. • Hypocapnia and slightly elevated pH. Increased WBC in 50% of patients but is rarely >15,000/cu mm (whereas in acute bacterial pneumonia is often >20,000/cu mm). Increased ESR Triad of increased LD and bilirubin with normal AST is found in only 15% of cases. Serum enzymes differ from those in acute myocardial infarction. Increased serum LD (due to isoenzymes LD-2 and LD-3) in 80% of patients rises on first day, peaks on second, normal by tenth day. Serum AST is usually normal or only slightly increased. cTn not increased. Serum indirect bilirubin is increased (as early as fourth day) to ~5 mg/dL in 20% of cases. Pleural effusion may occur. w Plasma D-dimer (ELISA or Latex Agglutination Kits)
- 107. Use Detects lysis of fibrin clot only, whereas fibrinogen degradation products test detects lysis of both fibrin clot and fibrinogen (see Chapter 11). At appropriate cutoff level, has >80% sensitivity but only ~30% specificity. Negative predictive value >90%; normal test useful in excluding pulmonary embolism in patients with low pretest probability. Value less than cutoff level (which varies with assay kit) obviates need for pulmonary angiography. Increased In Deep venous thrombosis DIC with fibrinolysis Renal, liver, or cardiac failure Major injury or surgery Inflammation (e.g., arthritis, cellulitis), infection (e.g., pneumonia) Thrombolytic therapy Measurements of serum CK, LD, and fibrin products are not indicated routinely as they do not have sufficient sensitivity or specificity to be of diagnostic value. Increased serum ALP (heat labile derived from vascular endothelium) during reparative phase 4–10 days after onset. Serum GGT may similarly increased. Pleural effusion occurs in one-half of patients; bloody in one-third to two-thirds of cases; typical pattern in only one-fourth of cases. These laboratory findings depend on the size and duration of the infarction, and the tests must be performed at the appropriate time to detect abnormalities . Laboratory findings due to predisposing conditions, e.g., Malignant tumors. Pregnancy. Use of estrogens. Hypercoagulable conditions, e.g., Polycythemia vera Dysfibrinogenemias Protein C or S deficiency Antithrombin III deficiency Splenectomy with thrombocytosis See discussion of fat embolism and phlebothrombosis of leg veins. SINUSITIS, ACUTE Due To Often precipitated by obstruction due to viral URI, allergy, foreign body. S. pneumoniae and H. influenzae cause >50% of cases; also anaerobes, S. aureus, S. pyogenes (group A). M. catarrhalis causes ~20% of cases in children Viruses cause ~10–20% of cases P. aeruginosa and H. influenzae are predominant organisms in cystic fibrosis patients. Mucor spp., Aspergillus spp. should be ruled out in patients with diabetes or acute leukemia and in renal transplant recipients. Anaerobes (e.g., streptococci, Bacteroides spp.) occur in ~50% of cases of chronic sinusitis. Needle aspiration of sinus is required for determination of organism. Culture of nose, throat, and nasopharynx specimens do not correlate well. Mucosal biopsy may be indicated if aspirate is not diagnostic in unresponsive patient with acute infection. 1 Kahn FW, Jones JM. Bronchoalveolar lavage in the rapid diagnosis of lung disease. Lab Manage June 1986:31. 2 Menzies R, Charbonneau M. Thoracoscopy for the diagnosis of pleural disease. Ann Intern Med 1991;114:271. 3Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818. 4 Prakesh UBS, Reiman HM. Comparison of needle biopsy with cytologic analysis for the evaluation of pleural effusion: Analysis of 414 cases. Mayo Clin Proc 1985;60:158.
- 108. CHAPTER 7 GASTROINTESTINAL DISEASES Interpretation of Diagnostic Tests CHAPTER 7 GASTROINTESTINAL DISEASES Bentiromide Biopsy, Colon Biopsy, Small Intestine D-Xylose Tolerance Test Gastric Analysis Gastrin, Serum Insulin Test Meal Stool, Laboratory Examination Anticoagulant Therapy, Gastrointestinal Complications Appendicitis, Acute Ascites Celiac Disease (Gluten-Sensitive Enteropathy, Nontropical Sprue, Idiopathic Steatorrhea) Chloridorrhea, Congenital Colitis, Collagenous Colitis, Pseudomembranous Colitis, Ulcerative, Chronic Nonspecific Colon, Carcinoma Diarrhea, Acute Diarrhea, Chronic Diverticula of Jejunum, Multiple Diverticulitis, Acute Dumping Syndrome Duodenal Ulcer, Chronic Enteritis, Regional (Crohn's Disease) Enterocolitis, Acute Membranous Enterocolitis, Necrotizing, in Infancy Enteropathy, Protein-Losing Esophagus, Carcinoma Esophagus, Infections Esophagus, Spontaneous Perforation Esophagus Involvement due to Primary Systemic Diseases Gallstone Ileus Gastric Adenomatous Polyp Gastric Carcinoma Gastric Leiomyoma, Leiomyosarcoma, Malignant Lymphoma Gastric Peptic Ulcer Gastritis, Benign Giant Hypertrophic (Ménétrier's Disease) Gastritis, Chronic Gastroenteritis, Eosinophilic Gastrointestinal Diseases, Genetic Gastrointestinal Tract: Conditions with No Useful Laboratory Findings Hemorrhage, Gastrointestinal Hernia, Diaphragmatic Hirschsprung's Disease (Aganglionic Megacolon) Infections of Gastrointestinal Tract Inflammatory Disorders of the Intestine Intestinal Obstruction Lymphangiectasia, Intestinal Malabsorption Mallory-Weiss Syndrome Meckel's Diverticulum Megacolon, Toxic Peritonitis, Acute Plummer-Vinson Syndrome Polyposis (Gastrointestinal), Hereditary Proctitis, Acute Sprue, Tropical Systemic Diseases, Gastrointestinal Manifestations Systemic Diseases, Oral Manifestations Systemic Manifestations in Some Gastrointestinal Diseases Tumors of Small Intestine Vascular Occlusion, Mesenteric Villous Adenoma of Rectum Whipples Disease (Intestinal Lipodystrophy) LABORATORY TESTS OF GASTROINTESTINAL FUNCTION BENTIROMIDE Bentiromide (Chymex), 500 mg taken orally after overnight fast, is acted on by pancreatic chymotrypsin, releasing para-aminobenzoic acid, which is measured in a 6-hr urine sample (normal value is >50%) and (in some procedures) 1- to 2-hr serum sample. Sensitivity of 6-hr test is £100% in severe chronic pancreatitis (with steatorrhea) and 40–50% in mild to moderate chronic pancreatitis (without steatorrhea). Use Initial test gauges pancreatic exocrine activity to rule out pancreatic disease in patients with chronic diarrhea, weight loss, or steatorrhea. In conjunction with D-xylose tolerance test for differentiation of pancreatic exocrine insufficiency from intestinal mucosal disease. Interference False-negatives may occur due to drugs (e.g., thiazides, chloramphenicol, sulfonamides, acetaminophen, phenacetin, sunscreens, procaine anesthetics) and certain foods (prunes, cranberries). Decreased In Renal insufficiency, diabetes mellitus gastric emptying, severe liver disease, or gut mucosal disease (malabsorption such as celiac sprue) BIOPSY, COLON Rectal biopsy is particularly useful in diagnosis of Cancer of colon Polyps of colon Secondary amyloidosis Amebic ulceration Schistosomiasis (even when no lesions are visible) Hirschsprung's disease Ulcerative colitis BIOPSY, SMALL INTESTINE Use Verifies mucosal lesions or establishes the diagnosis of various causes of malabsorption.
- 109. Confirms deficiency of various enzymes in intestinal mucosal cells (e.g., lactase deficiency). Diagnosis of neoplasms of small intestine Differential diagnosis of some cases of diarrhea Differential diagnosis of some nutritional deficiencies Monitoring of intestinal allografts Biopsy is diagnostic (diffuse lesion, diagnostic histology): Whipple's disease Agammaglobulinemia Abetalipoproteinemia (see acanthotic RBCs, steatorrhea, failure of beta-lipoprotein manufacture, neurologic findings ) Celiac sprue (becomes normal after dietary gluten withdrawal and abnormal after challenge) Mycobacterium avium-intracellulare infection Biopsy may or may not be of specific diagnostic value (patchy lesions, diagnostic histology): Amyloidosis Intestinal lymphangiectasia Malignant lymphoma of small bowel Eosinophilic gastroenteritis Regional enteritis Systemic mastocytosis Hypogammaglobulinemia and dysgammaglobulinemia Parasitic infestations (giardiasis, coccidiosis, strongyloidiasis, capillariasis) Biopsy may be abnormal but not diagnostic (diffuse lesions; histology not diagnostic): Celiac sprue Tropical sprue Severe prolonged folate and vitamin B12 deficiency Z-E syndrome Stasis with intraluminal bacterial overgrowth Drug-induced lesions (neomycin, antimetabolites) Malnutrition Bacterial overgrowth of small bowel Graft-versus-host reaction Viral enteritis Biopsy may be abnormal but not diagnostic (patchy lesions; histology abnormal but not diagnostic): Acute radiation enteritis Dermatitis herpetiformis enteropathy Biopsy is normal: Cirrhosis Pancreatic exocrine insufficiency Postgastrectomy malabsorption without intestinal mucosal disease Functional bowel disease (irritable colon, nonspecific diarrhea) Biopsy taken using radiographic localization, prompt fixation of tissue, proper orientation of tissue for histologic sectioning, and serial sectioning of specimen are all necessary for proper interpretation. Multiple biopsies may be necessary for patchy lesions. D-XYLOSE TOLERANCE TEST Normal: With 25 gm D-xylose dose, 30–52 mg/dL in blood at 2 hrs or ~25% in urine in 5 hrs. Up to age 9 yrs, use 5 gm dose and 1-hr serum sample; urine collection is not reliable. Normal 1-hr blood level ³25 mg/dL, ³20 mg/dL in children £9 yrs, ³15 mg/dL in infants. Reference ranges may vary between laboratories. Use Follow response to gluten-free diet Replaced by biopsy except in diseases with patchy distribution of lesions Screening for intestinal malabsorption. Chief value was to distinguish proximal small intestinal malabsorption due to impaired transport across diseased mucosa, in which values are decreased, from pancreatic steatorrhea (impaired digestion in lumen), in which values are normal. Urine test has poor sensitivity in mild mucosal disease. False-positive and false-negative rates of 20–30% Decreased In Steatorrhea due to proximal small intestinal malabsorption (e.g., sprue, some cases of Giardia lamblia infestation, bacterial overgrowth, viral gastroenteritis; may not be useful in adult celiac disease) Decreased glomerular filtration, e.g., Elderly persons Myxedema Ascites Increased portal pressure Renal insufficiency Delayed gastric emptying
- 110. Vomiting Dehydration Drugs (e.g., NSAIDs) Normal In Steatorrhea due to pancreatic disease Postgastrectomy state Malnutrition GASTRIC ANALYSIS Use Determine status of acid secretion in hypergastrinemia patients being treated for gastrinoma. Determine if patients who have undergone surgery for ulcer disease and who have complications are secreting acid. Interpretation 1-hr basal acid <2 mEq Normal, gastric ulcer, or carcinoma 2–5 mEq Normal, gastric or duodenal ulcer >5 mEq Duodenal ulcer >20 mEq Z-E (Zollinger-Ellison) syndrome 1 hr after stimulation by pentagastrin 0 mEq Achlorhydria, gastritis, gastric carcinoma 1–20 mEq Normal, gastric ulcer, or carcinoma 20–35 mEq Duodenal ulcer 35–60 mEq Duodenal ulcer, high normal, Z-E syndrome >60 mEq Z-E syndrome Ratio of basal acid to poststimulation outputs 20% Normal, gastric ulcer, or carcinoma 20–40% Gastric or duodenal ulcer 40–60% Duodenal ulcer, Z-E syndrome >60% Z-E syndrome Achlorhydria1 Chronic atrophic gastritis (serum gastrin is frequently increased) PA 100% of patients Vitiligo 20–25% Alopecia areata 6% RA 10–20% Thyrotoxicosis 10% Gastric carcinoma (50% of patients) even after pentagastrin stimulation. Hypochlorhydria occurs in 25%, hydrochloric acid is normal in 25%, hyperchlorhydria is rare in patients with gastric carcinoma. Gastric ulcer Common Adenomatous polyps of stomach 85% of patients Ménétrier's disease 75% Chronic renal failure 13% (usually normal; occasionally increased) Iatrogenic Postvagotomy, postantrectomy >90% Measure acid output after IV insulin to demonstrate adequacy of vagotomy (see Insulin Test Meal). Medical (e.g., potent H2 receptor antagonists, substituted benzimidazoles) >80% Occurs in normal persons: 4% of children, increasing to 30% of adults older than age 60 years. True achlorhydria excludes duodenal ulcer. Hyperchlorhydria and Hypersecretion2 Duodenal ulcer 40–45% Z-E syndrome 100% Twelve-hour night secretion shows acid of >100 mEq/L and volume >1500 mL. Basal secretion is >60% of secretion caused by histamine or betazole stimulation. Hyperplasia/hyperfunction of antral gastrin cells >90% (unusual condition with marked hyperchlorhydria, severe peptic ulceration, moderately increased fasting serum gastrin with exaggerated postprandial increase [>200% above fasting levels], no gastrin-secreting tumors) Hypertrophic hypersecretory gastropathy 100% Massive resection of small intestine (transient) 50% Systemic mastocytosis Rare When basal serum gastrin level is equivocal, serum gastrin level should be measured after stimulation with infusion of secretin or calcium. GASTRIN, SERUM
- 111. Normal levels: 0 to £200 pg/mL serum Elevated levels: >500 pg/mL Condition Serum Gastrin Serum Gastrin After Intragastric Administration of 0.1 N HCl Peptic ulcer without Z-E syndrome Normal range — Z-E syndrome Very high No change PA High level may approach that in Z-E syndrome Marked decrease Secretin infusion (IV of 2 U/kg body weight) with blood specimens drawn before and at intervals. Secretin test is preferred first test because of greater sensitivity and simplicity. Normal persons and patients with duodenal ulcer show no increase in serum gastrin. Patients with Z-E syndrome show increased serum gastrin that usually peaks in 45–60 mins (usually >400 pg/mL). With fasting gastrin <1000 pg/mL, sensitivity = 85% for an increased serum gastrin >200 pg/mL. With other causes of hypergastrinemia associated with hyperchlorhydria (e.g., retained antrum syndrome, gastric outlet obstruction, small bowel resection, renal insufficiency), serum gastrin is unchanged or decreases. Calcium infusion (IV calcium gluconate, 5 mg/kg body weight/hr for 3 hrs) with preinfusion blood specimen compared to specimens every 30 mins for up to 4 hrs. Recommended when secretin test is negative in patients in whom Z-E syndrome is suspected. Normal patients and those with ordinary duodenal ulcer show minimal serum gastrin response to calcium. Patients with antral G cell hyperfunction may or may not show serum gastrin increase >400 pg/mL. Patients with Z-E syndrome show increase in serum gastrin >400 pg/mL in 2–3 hrs (sensitivity = 43% for an increase of 395 pg/mL in serum gastrin). Positive in one-third of patients with a negative secretin test. 3 Indications for measurement of serum gastrin and gastric analysis include Atypical peptic ulcer of stomach, duodenum, or proximal jejunum, especially if multiple, in unusual location, poorly responsive to therapy, or multiple, with rapid onset, or showing severe recurrence after adequate therapy Unexplained chronic diarrhea or steatorrhea with or without peptic ulcer Peptic ulcer disease with associated endocrine conditions (see Multiple Endocrine Neoplasia) Serum gastrin levels are indicated with any of the following: Basal acid secretion >10 mEq/hr in patients with intact stomachs. Ratio of basal to poststimulation output >40% in patients with intact stomachs. All patients with recurrent ulceration after surgery for duodenal ulcer. All patients with duodenal ulcer for whom elective gastric surgery is planned. Patients with peptic ulcer associated with severe esophagitis or prominent gastric or duodenal folds or hypercalcemia or extensive family history of peptic ulcer disease. Measurement for screening of all peptic ulcer patients would not be practical or cost effective. Increased Serum Gastrin without Gastric Acid Hypersecretion Atrophic gastritis, especially when associated with circulating parietal cell antibodies PA in ~75% of patients Some cases of carcinoma of body of stomach, a reflection of the atrophic gastritis that is present Gastric acid inhibitor therapy After vagotomy Increased Serum Gastrin with Gastric Acid Hypersecretion Z-E syndrome Hyperplasia of antral gastrin cells Isolated retained antrum (a condition of gastric acid hypersecretion and recurrent ulceration after antrectomy and gastrojejunostomy that occurs when the duodenal stump contains antral mucosa) Increased Serum Gastrin with Gastric Acid Normal or Slight Hypersecretion RA Diabetes mellitus Pheochromocytoma Vitiligo Chronic renal failure with serum creatinine >3 mg/dL; occurs in 50% of patients. Pyloric obstruction with gastric distention Short-bowel syndrome due to massive resection or extensive regional enteritis Incomplete vagotomy INSULIN TEST MEAL
- 112. Aspirate gastric fluid and measure gastric acid every 15 mins for 2 hrs after IV administration of sufficient insulin (usually 15–20 U) to produce blood sugar <50 mg/dL. Use Differentiate causes of hypergastrinemia (see Table 13-14) Supplanted by other tests; formerly used to Aid in distinguishing benign and malignant gastric ulcers Aid in diagnosis of PA Evaluate patients with ulcer dyspepsia but normal radiographs Interpretation Normal: Increased free HCl due to hypoglycemia. Successful vagotomy produces achlorhydria. STOOL, LABORATORY EXAMINATION Normal Values Bulk 100–200 gm Water Up to 75% Total osmolality 200–250 mOsm pH 7.0–7.5 (may be acid with high lactose intake) Nitrogen <2.5 gm/day Potassium 5–20 mEq/kg Sodium 10–20 mEq/kg Magnesium <200 mEq/kg Coproporphyrin 400–1000 mg/24 hrs Trypsin 20–950 U/gm Urobilinogen 50–300 mg/24 hrs Microscopic Examination RBCs absent Epithelial cells present (increased with GI tract irritation); absence of epithelial cells in meconium of newborn may aid in diagnosis of intestinal obstruction in the newborn. Few WBCs present (increased with GI tract inflammation). Crystals of calcium oxalate, fatty acid, and triple phosphate commonly present. Hematoidin crystals sometimes found after GI tract hemorrhage. Charcot-Leyden crystals sometimes found in parasitic infestation (especially amebiasis). Some undigested vegetable fibers and muscle fibers sometimes found normally. Neutral fat globules (stained with Sudan), normal 0–2+ Color Changes Normal: brown Clay color (gray-white): biliary obstruction Tarry: >100 mL of blood in upper GI tract Red: blood in large intestine or undigested beets or tomatoes Black: blood Silver: combination of jaundice and blood (cancer of ampulla of Vater) Various colors: depending on diet Due to Drugs Resulting Color Alkaline antacids and aluminum salts White discoloration or speckling Anticoagulants (excess) Due to bleeding Anthraquinones Brown staining Bismuth salts Black Charcoal Black Diathiazine Green to blue Indomethacin Green (due to biliverdin) Iron salts Black Mercurous chloride Green Phenazopyridine Orange-red Phenolphthalein Red Phenbutazone and oxyphenbutazone Black (due to bleeding) Pyrvinium pamoate Red Rhubarb Yellow
- 113. Salicylates Due to bleeding Santonin Yellow Senna Yellow to brown Tetracyclines in syrup (due to glucosamine) Red Occult Blood Use Screening for asymptomatic ulcerated lesions of GI tract, especially carcinoma of the colon and large adenomas, is generally recommended now. Interpretation Kits (e.g., Hemoccult cards) use guaiac; detect blood losses of ~20 mL/day; "normal" amount of blood lost in stool daily is <2 mL/day or 2 mg Hb/gm of stool, but sensitivity is only 20% at this level and 90% at Hb concentration >25 mg/gram of stool. ~50% of colon cancers shed enough blood to produce a positive test. Hemoccult gives 1—3% false-positives even with strict protocol for stool collection. Sensitivity of Hemoccult and HemoQuant is only ~20—30% for colorectal cancer and ~13% for polyps; most of these lesions are missed.4 Benzidine reaction is too sensitive; yields too many false-positive results. Guaiac test yields too many false-negative results. In various screening programs, 2—6% of participants have positive tests; of these, carcinoma is found in 5—10% and adenoma in 20—40%. Sensitivity = 81% for left colon cancer, 47% for colon and cecum cancer, 45% for rectal cancer. ~90% of positives are false-positives. Adenomas <2 cm in size are less likely to bleed. Upper GI tract bleeding is less likely than lower GI tract bleeding to cause a positive test. Long-distance running is associated with positive guaiac test in up to 23% of runners. Recommendations for testing Test two areas from each of three consecutive stool samples. Test all samples within 7 days of collection. Rehydration of slide before development is controversial. Use of fecal sample obtained during digital rectal examination is not recommended. For 3 days before test, avoid large doses of aspirin (>325 mg/day) and other NSAIDs, ascorbic acid (false-negative may occur with >500 mg/day), oral iron, red meat, poultry, fish, and certain fruits and vegetables that contain catalases and peroxidases (e.g., cucumbers, horseradish, cauliflower), especially if slides are rehydrated. Even one positive result is considered a positive test even without dietary restriction. 5,6 Other tests for occult blood Quantitative HemoQuant test kit (uses fluorescence to assay stool-derived porphyrins) doubles sensitivity of guaiac tests; may be affected by red meat and aspirin (for up to 4 days) but not by other substances mentioned above. Manual test performed in a laboratory requires 90 mins (<2 mg/gm is normal; >4 mg/gm is increased; 2–4 mg/gm is borderline). Immunochemical tests (e.g., HemeSelect) specifically detect human hemoglobin, do not require diet or chemical restrictions (do not react with animal heme or foods), are stable for up to 30 days, detect ~0.3 mg Hb/gm of stool whereas 5–10× this amount is required to cause a positive guaiac test. Samples from upper GI tract should not be tested for blood using urine dipsticks or stool occult blood test kits (low pH may cause false-negative and oral drug use false-positive results).7,8 51 CR TEST FOR BLEEDING Tag 10 mL of the patient's blood with 200 µCi of 51 Cr, and administer it IV. Collect daily stool specimens for radioactivity measurement and also measure simultaneous blood samples. Use Measure GI blood loss in ulcerative diseases (e.g., ulcerative colitis, regional enteritis, peptic ulcer). Interpretation Radioactivity in the stool establishes GI blood loss. Comparison with radioactivity measurements of 1 mL of blood indicates the amount of blood loss. Electrolytes Sodium Chloride Potassium (mEq/24 hrs) (mEq/24 hrs) (mEq/24 hrs) Normal* 7.8±2.0 3.2±0.7 18.2±2.5 Idiopathic proctocolitis 22.3 19.8 Normal Ileostomy 30 19.0 4.1 Cholera Increased Increased *Average values for eight healthy individuals. Variable but considerably lower than simultaneous concentrations in serum. Normal calcium »170;0.6 gm/24 hrs Fat See Malabsorption. Osmotic Gap (Osmotic gap = measured osmolality minus 2 × [Na + K] or 290 mOsm/kg H2O minus 2 × [Na + K]) Increased In Osmotic diarrhea See Factitious Disorders.
- 114. Stool Findings Possible Diagnosis Osmotic gap <50 mOsm/kg H2O and Na >90 mEq/L Secretory diarrhea or osmotic diarrhea due to Na 2SO4 or Na2PO4* Osmotic gap >100 mOsm/kg H2O and Na <60 mEq/L Osmotic diarrhea; if fasting does not return stool volume to normal, consider factitious Mg ingestion † Osmolality >375 mOsm/kg H2O and Na <60 mEq/L Possible contamination with concentrated urine Osmolality <200–250 mOsm/kg H2O Possible contamination with dilute urine or water. Stool osmolality considerably lower than plasma osmolality; useful only if <250 mOsm/kg. *Stool sulfate and phosphate increased; chloride <20 mEq/L. †Mg usually >50 and often >100 mmol/L; normal during fasting is <10 mmol/L; normal on regular diet is 10–45 mmol/L. Other Procedures Alkalinization of stool to pH of 10 turns stool blue due to phenolphthalein in certain laxatives. Useful in cases of laxative abuse. Examination for ova and parasites Trypsin digestion (see Cystic Fibrosis of Pancreas) See Malabsorption. Urobilinogen (Normal = 50–300 mg/24 hrs; 100–400 Ehrlich units/100 gm) Increased In Hemolytic anemias Decreased In Complete biliary obstruction Severe liver disease Oral antibiotic therapy altering intestinal bacterial flora Decreased hemoglobin turnover (e.g., aplastic anemia, cachexia) Latex Agglutination Test Kit for Leukocytes (Detects fecal lactoferrin, a marker protein for fecal leukocytes; uses frozen or fresh stool.) Use Detection of bowel inflammation not evident by endoscopy or radiographic studies Interpretation In one study, a stool dilution of 1:50 had a negative predictive value of 94% for the presence of invasive enteropathogens. Positive and negative predictive values of 93% and 88% compared to stool microscopy for leukocytes are reported. At 1:200 dilution, sensitivity is <70%; therefore if test is negative when infectious diarrhea must be ruled out with considerable certainty (e.g., in immunocompromised patient), stool should be cultured. Leukocytes labeled with 111 indium have been used as quantitative index of fecal leukocyte loss in research laboratory. Microscopic Examination of Diarrheal Stools for Leukocytes Primarily PMNs—any number of PMNs found in less than two-thirds of cases Shigellosis: 70% have >5 PMNs/oil immersion field Salmonellosis: 30% have >5 PMNs/oil immersion field Campylobacter infection: 30% have >5 PMNs/oil immersion field Rotavirus infection: 11% have >5 PMNs/oil immersion field Invasive Escherichia coli colitis Yersinia infection Ulcerative colitis Clostridium difficile infection (pseudomembranous colitis) Primarily mononuclear leukocytes Typhoid Leukocytes absent Cholera Noninvasive E. coli diarrhea Other bacterial toxins (e.g., Staphylococcus, Clostridium perfringens) Viral diarrheas Parasitic infestations (e.g., Giardia lamblia, Entamoeba histolytica, Dientamoeba fragilis) Drug effects DISEASES OF THE GASTROINTESTINAL TRACT ANTICOAGULANT THERAPY, GASTROINTESTINAL COMPLICATIONS Hemorrhage into gastrointestinal tract occurs in 3–4% of patients on anticoagulant therapy; may be spontaneous or secondary to unsuspected disease (e.g., peptic
- 115. ulcer, carcinoma, diverticula, hemorrhoids). Occasionally hemorrhage occurs into the wall of the intestine with secondary ileus. PT may be in the therapeutic range or, more commonly, is increased. Coumarin drug action is potentiated by administration of aspirin, antibiotics, phenylbutazone, and thyroxine and T-tube drainage of the common bile duct, especially if pancreatic disease is present. Hypersensitivity to phenindione may cause hepatitis or steatorrhea. Stool is positive for occult blood. APPENDICITIS, ACUTE Increased WBC (12,000–14,000/cu mm) with shift to the left in acute catarrhal stage; higher and more rapid rise with suppuration or perforation ESR may be normal during first 24 hrs. CRP <2.5 mg/dL 12 hrs after onset of symptoms has been said to exclude acute appendicitis. Later—laboratory findings due to complications (e.g., dehydration, abscess formation, perforation with peritonitis) ASCITES (See also Pleural Effusion, for differential diagnosis of effusions.) Chronic liver disease: To differentiate ascites due to malignancy from that due to chronic liver disease Albumin gradient (= serum albumin minus ascitic fluid albumin) reflects portal pressure (replaces terms transudate and exudate). Almost always ³1.1 in cirrhosis (most common cause), alcoholic hepatitis, massive liver metastases, fulminant hepatic failure, portal vein thrombosis, Budd-Chiari syndrome, cardiac ascites, acute fatty liver of pregnancy, myxedema, mixed (e.g., cirrhosis with peritoneal TB). May be falsely low if serum albumin <1.1 gm/dL or patient in shock. May be falsely high with chylous ascites (lipid interferes with albumin assay). <1.1 gm/dL in >90% of cases of peritoneal carcinomatosis (most common cause) or TB, pancreatic or biliary ascites, nephrotic syndrome, bowel infarction or obstruction, serositis in patients without cirrhosis. Ascitic fluid to serum albumin ratio <0.5 in cirrhosis (>90% accuracy). Total protein >2.5 mg/dL in cancer is only 56% accurate because of high protein content in 12–19% of these ascites cases as well as changes due to albumin infusion and diuretic therapies. Ascitic fluid to serum ratio for LD (>0.6) or protein (>0.5) is not more accurate (~56%) than total protein only for diagnosis of exudate. Ascitic fluid cholesterol is <55 mg/dL in cirrhosis (94% accuracy). Total WBC is usually <300/cu mm (one-half of cases) and PMN is usually <25% (two-thirds of cases). Findings cannot distinguish neoplasia from TB etiology. Cirrhosis findings similar with or without hepatocellular carcinoma. Cardiac ascites is associated with a blood–ascitic fluid albumin gradient >1.1 gm/dL but malignant ascitic fluid shows blood–ascitic fluid albumin gradient <1.1 gm/dL in 93% of cases. Infected ascitic fluid w· WBC >250/cu mm (sensitivity = 85%, specificity = 93%) and neutrophils >50% and are presumptive of bacterial peritonitis. w· pH <7.35 and arterial–ascitic fluid pH difference >0.10; both these findings are virtually diagnostic of bacterial peritonitis and absence of the above findings virtually excludes bacterial peritonitis. Ascitic fluid lactate >25 mg/dL and arterial–ascitic fluid difference >20 mg/dL are often present. Ascitic fluid LD is markedly increased. Ascitic fluid glucose is unreliable for diagnosis. Ascitic fluid phosphate, potassium, and GGT may also be increased. w· Gram stain is positive in 25% of cases. w· Ascitic fluid in blood culture bottles has 85% sensitivity. w· Acid-fast stains and culture establish the diagnosis of TB in only 25–50% of cases of TB. Total protein <1.0 gm/dL indicates high risk for spontaneous bacterial peritonitis. Secondary peritonitis shows polymicrobial infection, total protein ³1.0 gm/dL, ascitic fluid LD greater than serum upper limit of normal, and glucose <50 mg/dL compared to spontaneous bacterial peritonitis. Spontaneous bacterial peritonitis has prevalence of ~15%; due to E. coli ~50%, due to Klebsiella and other gram-negative or gram-positive bacteria, ~25% (especially streptococci). In continuous ambulatory peritoneal dialysis, monitor dialysate for (see Fig. 7-1 and Fig. 7-2): Fig. 7-1. Algorithm for differentiating secondary from spontaneous bacterial peritonitis (SBP).
- 116. Fig. 7-2. Algorithm for spontaneous bacterial peritonitis. w· Infection: Peritonitis is defined as WBC >100/cu mm, usually with >50% PMNs (normal value is <50 WBC/cu mm, usually mononuclear cells), or positive Gram stain or culture (most prevalent: coagulase-negative staphylococci, Staphylococcus aureus, Streptococcus spp.; multiple organisms, especially mixed aerobes and anaerobes, occur with bowel perforation). Successful therapy causes fall in WBC within first 2 days and return to <100/cu mm in 4–5 days; differential returns to predominance of monocytes in 4–7 days with increased eosinophils in 10% of cases. Patients check outflow bags for turbidity. Turbid dialysate can occasionally occur without peritonitis during first few months of placing catheter (due to catheter hypersensitivity) with WBC 100–8000/cu mm and 10–95% eosinophils, sometimes increased PMNs, and negative cultures. Occasional RBCs may be seen during menstruation or with ovulation at midcycle. Because of low WBC decision level, manual hemocytometer count rather than an automated instrument must be used. Metabolic change: Assay dialysate for creatinine and glucose; calculate ultrafiltrate volume by weighing dialysate fluid after 4-hr dwell time and subtracting it from preinfusion weight using specific gravity of 1.0. w Pancreatic disease: Ascitic fluid amylase greater than serum amylase is virtually specific for pancreatic disease, but both levels are normal in 10% of cases. Methemalbumin in serum or ascitic fluid and total protein >4.5 gm/dL indicate poor prognosis. Chylous ascites: Triglyceride is 2–8× serum level. Protein is 2–3 gm/dL. Due to lymphatic obstruction (e.g., lymphoma or carcinoma [60% of cases]), inflammation or obstruction of small intestine, trauma to chest or abdomen, filariasis; in pediatric patients, is often due to congenital lymphatic defects. w Malignant ascites: Increased fluid cholesterol (>45 mg/dL) and fibronectin (>10 mg/dL) have sensitivity of 90% and specificity of 82%. Positive cytology has sensitivity of 70% and specificity of 100%. Increased ascitic fluid CEA (>2.5 mg/dL) has sensitivity of 45% and specificity of 100%. w Criteria to diagnose penetrating abdominal wounds by peritoneal lavage >10,000 RBC/cu mm (>5000 RBC/cu mm for gunshot wounds). >500 WBC/cu mm or Bacteria, fecal, or vegetable matter on Gram stain or bile (Ictotest) or Detection of endotoxin by limulus amoebocyte lysate assay for ileocolic perforation or Amylase or ALP level has been used to detect small bowel or pancreatic injury. Increases in WBC, amylase, and ALP are often delayed >3 hrs. RBC and WBC counts of lavage fluid have most clinical utility. w Criteria to diagnose blunt abdominal trauma by peritoneal lavage with 10,000 mL of normal saline; falsely low RBC count if <600–800 mL of fluid is recovered. Grossly bloody fluid or >100,000 RBC/cu mm (newspaper print is unreadable through lavage tubing if RBC count is this high); negative test = <50,000 RBC/cu mm; equivocal results = 50,000–100,000; or >500 WBC/cu mm or Amylase >2.5× normal w Criteria to diagnose intestinal injury in blunt abdominal trauma by peritoneal lavage with 10,000 mL of normal saline, especially 3–18 hrs after injury If bloody ascites is not present, may signal solid organ injury >10,000 WBC/cu mm and WBC/cu mm ³(RBC/cu mm divided by 150) w To differentiate urine from ascitic or pleural fluid (in cases of possible GU tract fistula or accidental aspiration of bladder) Urine creatinine is >2× serum level. Uncontaminated ascitic or pleural fluid creatinine is usually same as serum level but always <2× serum level. Urea nitrogen also greater in urine. Increased serum inorganic phosphate in 25% of cases of ischemic bowel disease; >5.5 mg/dL indicates extensive bowel injury, acute renal failure, metabolic acidosis, and poorer prognosis. Peritoneal fluid bicarbonate value to differentiate site of penetrating wounds of GI tract: Wound Site Effect on Bicarbonate Value Stomach or duodenum proximal to pancreatic duct Decrease Duodenum just distal to pancreatic duct Increase Third part of duodenum, jejunum, or ileum Probably no effect Fluid Source Bicarbonate Values (mEq/L) (Reference Values) Peritoneal 24.0–29.0 Pancreatic 66.0–127.0 Duodenal 4.0–21.0 Jejunal 2.0–32.0 Ileal 2.3 Gastric — Plasma/venous blood 20.0–30.0 Ascites in Fetus or Neonate Due To
- 117. Nonimmune (occur in 1:3000 pregnancies) % of cases Cardiovascular abnormalities causing congestive heart failure (e.g., structural, arrhythmias) 40 Chromosomal (e.g., Turner's and Down syndromes are most common; trisomy 13, 15, 16, 18) 10–15 Hematologic disorders (any severe anemia) 10 Inherited, e.g., Alpha-thalassemia Hemoglobinopathies G-6-PD deficiency Other RBC enzyme defects Acquired, e.g., Fetal-maternal hemorrhage Twin-to-twin transfusion Congenital infection (parvovirus B19) Methemoglobinemia Congenital defects of chest and abdomen Structural, e.g., Diaphragmatic hernia Cystic adenomatoid malformation of lung Jejunal atresia Fetal lymphatic dysplasia Midgut volvulus Intestinal malrotation Peritonitis due to GI tract perforation Congenital infection (e.g., syphilis, TORCH [ toxoplasma, other agents, rubella, cytomegalovirus, herpes simplex] syndrome, hepatitis) Meconium peritonitis due to complications of cystic fibrosis Lymphatic duct obstruction Biliary atresia Bile ascites (rare) due to biliary tree perforation caused by congenital stenosis, choledochal cyst or stone. Intermittent acholic stools, dark urine, fluctuating hyperbilirubinemia. Bile-stained ascitic fluid with increased protein (2–4 gm/dL). IV administration of iodine 131 (131 I)–labeled rose bengal appearing in ascitic fluid makes the diagnosis early before bile staining occurs. Nonstructural, e.g., Congenital nephrotic syndrome Cirrhosis Cholestasis Hepatic necrosis GI tract obstruction Lower GU tract obstruction (e.g., usually due to posterior urethral valves, urethral atresia, ureterocele) is most common cause. Inherited skeletal dysplasias (enlarged liver causing extramedullary hematopoiesis) Fetal tumors, most often teratomas and neuroblastomas Vascular placental abnormalities Genetic metabolic disorders, e.g., Hurler's syndrome Gaucher's disease Niemann-Pick disease GM1 gangliosidosis type I I-cell disease Beta-glucuronidase deficiency Immune (maternal antibodies reacting to fetal antigens, e.g., Rh, C, E, Kell) CELIAC DISEASE (GLUTEN-SENSITIVE ENTEROPATHY, NONTROPICAL SPRUE, IDIOPATHIC STEATORRHEA) See Fig. 7-3.
- 118. Fig. 7-3. Algorithm for diagnosis of celiac sprue. w Steatorrhea demonstrated by positive Sudan stain on ³2 stool samples or quantitative determination of fat in 72-hr pooled stool sample. w Xylose tolerance test distinguishes malabsorption due to impaired transport across diseased mucosa from impaired pancreatic digestion in lumen. w Biopsy of small intestine shows characteristic although not specific mucosal lesions. Establishing the diagnosis is essential; patients should not be committed to gluten-free diet without first assessing intestinal mucosal histology. w Firm diagnosis requires definite clinical response to gluten-free diet, preferably with histologic documentation that mucosa has reverted to normal by repeat biopsy in 6–12 mos. If no response to rigid dietary control, GI lymphoma should be ruled out. w Gluten challenge is performed if diagnosis is uncertain and not documented by biopsy before gluten withdrawal, to determine if symptoms recur and mucosal changes occur. (Baseline biopsy followed by one-half slice bread, doubled every 3 days up to four slices daily for 4 wks or until symptoms recur, followed by repeat biopsy.) w Antigliadin antibodies (IgG is more sensitive but less specific than IgA) and antiendomysial antibodies (IgA is most specific; sensitivity = 80–100%) in serum of untreated patients. Is especially useful in patients in whom index of suspicion is very low or who have atypical features but consistent biopsy findings. Also present in patients with other small intestine mucosal diseases (e.g., Crohn's disease), 25% of patients with dermatitis herpetiformis, and rarely in those with autoimmune diseases. Decreased in celiac patients on gluten-free diet. Serial measurement to monitor compliance and therapy. Antireticulin antibodies are less sensitive (<50%) but more specific than antigliadin antibodies. Laboratory findings due to frequently associated diseases (e.g., especially lymphoma of intestine and elsewhere; also dermatitis herpetiformis, insulin-dependent diabetes, selective IgA deficiency, carcinoma of esophagus, small intestine, and breast; possibly IgA nephropathy, ulcerative colitis, thyroid disease, primary biliary cirrhosis, sclerosing cholangitis). In any such patients with unexplained diarrhea or malabsorption, celiac sprue should be ruled out. m Should always be considered in cases of iron-deficiency anemia without demonstrable bleeding, unexplained folate deficiency, or unexplained osteopenic bone disease. CHLORIDORRHEA, CONGENITAL (Rare autosomal recessive condition characterized by profound watery diarrhea beginning at birth due to ion transport defect in ileum and colon.) w Hypochloremic, hypokalemic acidosis with volume depletion w Copious acidic chloride-rich diarrhea Normal intestinal mucosal histology. Maternal hydramnios is almost always present. Similar rarer autosomal recessive condition of congenital sodium diarrhea with sodium-rich alkaline stool and systemic acidosis. COLITIS, COLLAGENOUS w Diagnosis is established by biopsy of colon in patients thought to have irritable bowel syndrome. Incidence ~3:1000 in such patients. ESR increased in some patients. Eosinophil count increased in some patients. COLITIS, PSEUDOMEMBRANOUS (Antibiotic-related diarrhea and colitis due to C. difficile) w Tissue culture assay is gold standard (>94% sensitivity, 99% specificity). Level of toxin is not related to clinical severity. w Diagnosis depends on detection of cytotoxin in stool. Demonstration of toxins (toxin A) or antigens by rapid immunoassays (EIA) show good sensitivity (64–87%) and specificity (99%). Rapid results make these tests useful for screening. Latex agglutination has variable and poor sensitivity and is not recommended as a single test. Glutamate dehydrogenase enzyme by latex agglutination or immunoassay lacks good specificity (enzyme found in other organisms). Stool assay for glutamate dehydrogenase enzyme combined with toxin A assay in one test may be more useful. For C. difficile–associated diarrhea both culture and cytotoxin assay should be performed. Counterimmunoelectrophoresis (CIE), gas-liquid chromatography (GLC), and Gram stain of stool have high false-negative and false-positive results. Stool culture is less efficient because some strains are nontoxigenic. >50% of healthy neonates, 2–5% of healthy adults, 25% of adults recently treated with antibiotics are carriers. Nontoxigenic strains may be found in 10–20% of hospitalized patients. Toxin testing alone does not detect 20–30% of C. difficile–associated diarrhea. PCR of stool for toxin A and/or B may be available. Fecal leukocytes in stool; large numbers in <50% of cases; bloody diarrhea in £10% of cases.
- 119. WBC >15,000/cu mm in <50% of cases. Hypoalbuminemia in £24% of cases. Laboratory findings due to dehydration and electrolyte imbalance in severe cases. COLITIS, ULCERATIVE, CHRONIC NONSPECIFIC Laboratory findings parallel severity of the disease Anemia due to blood loss (frequently Hb = 6 gm/dL). WBC usually normal unless complication occurs (e.g., abscess). ESR often normal or only slightly increased. With diarrhea and fever, Hb <7.5 gm/dL and ESR >30 mm/hr indicate severe disease. Hypoalbuminemia indicates severe disease of longer duration. Stools Positive for blood (gross and/or occult) Negative for usual enteric bacterial pathogens and parasites; high total bacterial count Changes in liver function Microscopic changes in needle biopsy of liver. Serum ALP often increased slightly. Other liver function tests usually normal. Changes in serum electrolytes due to diarrhea or to therapy with adrenal steroids or ACTH Laboratory changes due to complications or sequelae (e.g., malabsorption due to involvement of small intestine, perforation, abscess formation, hemorrhage, carcinoma, arthritis, sclerosing cholangitis) m Rectal biopsy COLON, CARCINOMA Blood in stool (occult or gross) Evidence of inflammation Increased WBC and ESR Anemia—usually hypochromic May be the only symptom of carcinoma of right side of colon (present in >50% of these patients) Stools sometimes negative for occult blood Laboratory evidence of liver metastases w Biopsy of colon lesion establishes the diagnosis Serum CEA m Villous tumor of rectum may cause secretory diarrhea with potassium loss and decreased serum potassium. Carcinoid tumors may cause increased 5-HIAA in urine. Laboratory findings due to underlying condition (e.g., hereditary polyposis, chronic nonspecific ulcerative colitis) Laboratory findings due to complications (e.g., hemorrhage, perforation, obstruction) DIARRHEA, ACUTE Osmotic (Malabsorptive) Diarrhea (Increased osmotically active solutes in bowel; diarrhea usually stops during fasting.) Due To Exogenous Laxatives (e.g., magnesium sulfate, milk of magnesia, sodium sulfate [Glauber's salt], sodium phosphate, polyethylene glycol/saline) Drugs (e.g., lactulose, colchicine, cholestyramine, neomycin, PAS) Foods (e.g., mannitol, sorbitol [in diet candy, chewing gum, soda]) Endogenous Congenital malabsorption Specific (e.g., lactase deficiency, fructose malabsorption) General (e.g., abeta- and hypobetalipoproteinemia, congenital lymphangiectasia, cystic fibrosis) Acquired malabsorption Specific (e.g., pancreatic disease, celiac sprue, parasitic infestation, rotavirus enteritis, metabolic disorders [thyrotoxicosis, adrenal insufficiency], jejunoileal bypass, bacterial overgrowth, short-bowel syndrome, inflammatory disease [mastocytosis, eosinophilic enteritis])
- 120. Secretory (Abnormal Electrolyte Transport) Diarrhea (Increased water and chloride secretion; normal water and sodium absorption may be inhibited.) Due To Exogenous Laxatives (e.g., aloe, anthraquinones, bisacodyl, castor oil, dioctyl sodium sulfosuccinate, phenolphthalein, senna) Drugs Diuretics (e.g., furosemide, thiazides), asthma drugs (theophylline), thyroid drugs Cholinergic drugs, e.g., Myasthenia gravis (cholinesterase inhibitors) Cardiac (quinidine) and antihypertensives (ACE inhibitors) Antidepressants (clozapine) Gout (colchicine) Toxins (e.g., arsenic, mushrooms, organophosphates, alcohol) Bacterial toxins (e.g., S. aureus, E. coli, Vibrio cholerae, Bacillus cereus, Campylobacter jejuni, Yersinia enterocolitica, Clostridium botulinum and perfringens) Endogenous Hormones Serotonin (carcinoid) Calcitonin (medullary carcinoma of thyroid) Villous adenoma Vipoma Gastric hypersecretion Z-E syndrome Systemic mastocytosis Basophilic leukemia Short-bowel syndrome Bile salts (e.g., disease or resection of terminal ileum) Fatty acids (e.g., disease of small intestine mucosa, pancreatic insufficiency) Congenital (e.g., congenital chloridorrhea, congenital sodium diarrhea) Watery stool Volume >1 L/day Blood and pus are absent. Stool osmolality close to plasma osmolality with no anion gap. Diarrhea usually continues during 24–48 hr fasting except for fatty acid malabsorption. Exudative Diarrhea (Active inflammation of bowel mucosa) Due To Inflammation Infectious (e.g., Shigella, Salmonella, Campylobacter, Yersinia, C. difficile, TB organisms, amebae) Idiopathic (e.g., ulcerative colitis, Crohn's disease) Injury (e.g., radiation) Ischemia (e.g., mesenteric thrombosis) Vasculitis Abscess (e.g., diverticulitis) Stool contains blood and pus. Some features of osmotic diarrhea may be present. 20–40% of cases of acute infectious diarrhea remain undiagnosed. Motility Disturbances Due To Decreased small intestinal motility (e.g., hypothyroidism, diabetes mellitus, amyloidosis, scleroderma, postvagotomy) Increased small intestinal motility (e.g., hyperthyroidism, carcinoid syndrome) Increased colonic motility (e.g., irritable bowel syndrome) DIARRHEA, CHRONIC Due To Infection (e.g., giardiasis, amebiasis, infection with Cryptosporidium, Isospora, Strongyloides, C. difficile)
- 121. Inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, collagenous colitis) Carbohydrate malabsorption (e.g., lactase or sucrase deficiency) Foods (e.g., ethanol, caffeine, sweeteners such as sorbitol, fructose) Drugs (e.g., antibiotics, antihypertensives, antiarrhythmics, antineoplastics, colchicine, cholestyramine; see previous Diarrhea, Acute) Laxative abuse factitious Endocrine (e.g., diabetes mellitus, adrenal insufficiency, hyper- or hypothyroidism) Hormone-producing tumors (e.g., gastrinoma, VIPoma, villous adenoma, medullary thyroid carcinoma, pheochromocytoma, ganglioneuroma, carcinoid tumor, mastocytosis, somatostatinoma, ectopic hormone production by lung or pancreatic carcinoma) Injury due to radiation, ischemia, etc. Infiltrations (e.g., scleroderma, amyloidosis, lymphoma) Colon carcinoma Previous surgery (e.g., gastrectomy, vagotomy, intestinal resection) Immune system disorders (e.g., systemic mastocytosis, eosinophilic gastroenteritis) Intraluminal maldigestion Bile duct obstruction, cirrhosis Bacterial overgrowth Pancreatic exocrine insufficiency Celiac sprue Whipple's disease Abetalipoproteinemia Dermatitis herpetiformis Intestinal lymphangiectasia Allergy Idiopathic DIVERTICULA OF JEJUNUM, MULTIPLE Laboratory findings due to malabsorption syndrome DIVERTICULITIS, ACUTE Increased WBC and ESR Hypochromic microcytic anemia (some patients) Occult blood in stool Cytologic examination of stool—negative for malignant cells Laboratory findings due to complications (e.g., hemorrhage, perforation, obstruction) DUMPING SYNDROME (Occurs in £ 70% of post–subtotal gastrectomy patients.) During symptoms may have Rapid prolonged alimentary hyperglycemia Decreased plasma volume Decreased serum potassium Increased blood and urine serotonin Hypoglycemic syndrome (occurs in <5% of post–subtotal gastrectomy patients) Prolonged alimentary hyperglycemia followed after 2 hrs by precipitous hypoglycemia Late hypoglycemia shown by 6-hr oral glucose tolerance test (OGTT) Stomal gastritis—anemia due to chronic bleeding Postgastrectomy malabsorption Postgastrectomy anemia (due to chronic blood loss, malabsorption, vitamin B 12 deficiency, etc.) Afferent-loop obstruction—marked increase in serum amylase to >1000 U Laboratory findings due to complications of gastric or duodenal ulcer e.g., hemorrhage, perforation, obstruction. Gastric analysis True achlorhydria after maximum stimulation rules out duodenal ulcer.
- 122. Normal secretion or hypersecretion does not prove the presence of an ulcer. DUODENAL ULCER, CHRONIC m Helicobacter pylori–associated gastritis is present in ~95% of all patients with duodenal ulcer except those with Z-E syndrome. Laboratory findings due to associated conditions Z-E syndrome MEN type I Chronic renal failure Kidney stones Alpha1-antitrypsin deficiency Systemic mastocytosis Chronic pancreatitis Mucoviscidosis RA Chronic pulmonary disease (e.g., pulmonary emphysema) Cirrhosis Certain drugs (e.g., ACTH) Crohn's disease Hyperparathyroidism Polycythemia vera Duodenal ulcer is absent in patients with ulcerative colitis (unless under steroid therapy), carcinoma of stomach, PA, pregnancy. Laboratory findings due to treatment Milk-alkali (Burnett's) syndrome—alkalosis, hypercalcemia, azotemia, renal calculi, or nephrocalcinosis Inadequate vagotomy—use insulin test meal. Gastric acidity shows late response >4.5 mEq total free acid in 30 mins or any early response. To obtain valid collection, tube must be correctly placed fluoroscopically. ENTERITIS, REGIONAL (CROHN'S DISEASE) No findings that are pathognomonic for this disease or distinguish it from ulcerative colitis. Increased WBC, ESR, CRP, other acute-phase reactants. Mild increase of WBC indicates activity, but marked increase suggests suppuration (e.g., abscess). ESR tends to be higher in disease of colon than of ileum. Anemia due to iron deficiency or vitamin B12 or folate deficiency or chronic disease Decreased serum albumin, increased gamma globulins Diarrhea may cause hyperchloremic metabolic acidosis, dehydration, decreased sodium, potassium, magnesium. Mild liver function test changes due to pericholangitis (especially increased serum ALP) Serum CEA may be increased. m Biopsy may show granulomas in ~50% of cases. Laboratory changes due to complications or sequelae (e.g., malabsorption, perforation and fistula formation, abscess formation, arthritis, sclerosing cholangitis) ENTEROCOLITIS, ACUTE MEMBRANOUS Laboratory findings due to antecedent condition Disease for which antibiotics are administered Myocardial infarction Surgical procedure Other Laboratory findings due to shock, dehydration w Culture of staphylococci from stool or rectal swab ENTEROCOLITIS, NECROTIZING, IN INFANCY (Syndrome of acute intestinal necrosis of unknown etiology especially associated with prematurity and exchange transfusions) No specific laboratory tests Bloody stools; no characteristic organisms Oliguria, neutropenia, anemia may be present. Persistent metabolic acidosis, severe hyponatremia, and DIC are a common triad in infants. In infants, significant organisms are often found by frequent repeated cultures of blood, urine, and stool. ENTEROPATHY, PROTEIN-LOSING Secondary (i.e., disease states in which clinically significant protein-losing enteropathy may occur as a manifestation) Giant hypertrophy of gastric rugae (Ménétrier's disease) Eosinophilic gastroenteritis
- 123. Gastric neoplasms Infections (e.g., Whipple's disease, bacterial overgrowth, enterocolitis, shigellosis, parasitic infestation, viral infection, C. difficile infection) Nontropical sprue Inflammatory and neoplastic diseases of small and large intestine, including ulcerative colitis, regional enteritis Constrictive pericarditis Immune diseases (e.g., SLE, milk allergy) Lymphatic obstruction (e.g., lymphoma, sarcoidosis, mesenteric TB) Primary (i.e., hypoproteinemia is the major clinical feature) Intestinal lymphangiectasia Nonspecific inflammatory or granulomatous disease of small intestine Serum total protein, albumin, and gamma globulin decreased Serum alpha and beta globulins normal Serum cholesterol usually normal Mild anemia Eosinophilia (occasionally) Serum calcium decreased Steatorrhea with abnormal tests of lipid absorption Increased permeability of GI tract to large molecular substances shown by IV 131 I-polyvinylpyrrolidone test (see section on protein malabsorption) Proteinuria absent ESOPHAGUS, CARCINOMA w Cytologic examination of esophageal washings is positive for malignant cells in 75% of patients. It is falsely positive in <2% of patients. w Diagnosis is confirmed by biopsy of tumor. ESOPHAGUS, INFECTIONS Due To Fungi Candida albicans (most common) Other Candida species Torulosis glabrata Aspergillus species Histoplasma capsulatum Blastomyces dermatitidis Viruses HSV (especially in AIDS patients) CMV (especially in AIDS patients) HIV-1 EBV VZV Bacteria Gram-positive, usual oral flora (e.g., Streptococcus viridans, Staphylococcus) Gram-negative cocci, rods, enteric bacilli Tubercle bacilli (rare; usually no evidence of active pulmonary disease) Actinomyces israelii Treponema pallidum Predisposing factors Immunosuppression (e.g., HIV infection) Drugs (e.g., corticosteroids, anticancer chemotherapy, radiation, broad-spectrum antibiotics) Debilitating illnesses or conditions (e.g., diabetes mellitus, chronic renal failure, burns, old age) Trauma (e.g., insertion of nasogastric tubes, tracheal intubation) w Diagnosis by cytologic brushings, biopsy, bacterial smears and cultures obtained via endoscope. ESOPHAGUS, SPONTANEOUS PERFORATION w Gastric contents in thoracocentesis fluid ESOPHAGUS INVOLVEMENT DUE TO PRIMARY SYSTEMIC DISEASES Scleroderma (esophageal involvement in >50% of patients with scleroderma) Esophageal varices (cirrhosis of liver) Malignant lymphoma
- 124. Bronchogenic carcinoma Infections Sarcoidosis Crohn's disease Behçet's disease Graft-versus-host disease Pemphigus vulgaris Bullous pemphigoid Benign mucous membrane pemphigoid Epidermolysis bullosa dystrophica GALLSTONE ILEUS Laboratory findings due to preceding chronic cholecystitis and cholelithiasis Laboratory findings due to acute obstruction of terminal ileum ( accounts for 1–2% of patients) GASTRIC ADENOMATOUS POLYP w Diagnosis is confirmed by biopsy of tumor. Gastric analysis—achlorhydria in 85% of patients Sometimes evidence of bleeding Polyps occur in 5% of patients with PA and 2% of patients with achlorhydria. GASTRIC CARCINOMA w Exfoliative cytology positive in 80% of patients; false-positive in <2%. w Biopsy of lesions confirms diagnosis. w Lymph node biopsy for metastases; needle biopsy of liver, bone marrow, etc. Tumor markers are not useful for early detection. Increased serum CEA (>5 ng/dL) in 40–50% of patients with metastases and 10–20% of patients with surgically resectable disease. May be useful for postoperative monitoring for recurrence or to estimate metastatic tumor burden. Increased serum alpha-fetoprotein (AFP) and CA 19-9 in 30% of patients, usually incurable. Gastric analysis Achlorhydria after histamine or betazole in 50% of patients Hypochlorhydria in 25% of patients Normal in 25% of patients Hyperchlorhydria rare Anemia due to chronic blood loss Occult blood in stool m Carcinoma of the stomach should always be searched for by periodic prophylactic screening in high-risk patients, especially those with PA, gastric atrophy, gastric polyps. GASTRIC LEIOMYOMA, LEIOMYOSARCOMA, MALIGNANT LYMPHOMA w Diagnosis is confirmed by biopsy of tumor. May show evidence of bleeding GASTRIC PEPTIC ULCER Laboratory findings due to underlying conditions Administration of ACTH and adrenal steroids Various drugs (e.g., NSAIDs) Acute burns (Curling's ulcer) Cerebrovascular accidents and trauma, and inflammation (Cushing's ulcer) Uremia Cirrhosis Laboratory findings due to complications Gastric retention—dehydration, hypokalemic alkalosis Perforation—increased WBC with shift to the left, dehydration, increased serum amylase, increased amylase in peritoneal fluid Hemorrhage
- 125. See Helicobacter pylori Curling's ulcer—hemorrhage 8–10 days and perforation 30 days after burn; causes death in 15% of fatal burn cases. Recurrent ulcer after partial gastrectomy (£3% of patients) may be due to inadequacy of operation, but acid secretory syndrome should be considered (e.g., gastrinoma, retained antrum syndrome) and serum gastrin should be assayed. GASTRITIS, BENIGN GIANT HYPERTROPHIC (MÉNÉTRIER'S DISEASE) m Serum protein and albumin decreased in 80% of cases due to loss of plasma proteins through gastric mucosa; gamma globulins may be decreased. Serum calcium may be low due to decreased serum albumin. Protein loss is nonselective in contrast to loss through glomerular membrane, in which loss of low-molecular-weight proteins is greater than loss of high-molecular-weight proteins. Hypochlorhydria by gastric analysis in 75% of cases. Gastric fluid taken during endoscopy shows increased protein concentration (normal level is 0.8–2.5 g/L) and protein electrophoresis resembles pattern of serum electrophoresis. Increased pH of gastric fluid (normal value is <2). Protein loss can also be determined by injecting 51 Cr-labeled albumin and measuring radioactivity in stool. Alpha 1-antitrypsin clearance (calculated by measuring trypsin in blood and stool) can also be used to measure protein loss because alpha 1-antitrypsin resists digestion by trypsin; this method can only be used if acid hyposecretion is present because the protein is destroyed by pH <3. w Diagnosis is confirmed by full-thickness gastric biopsy showing thickening of gastric mucosa due to hyperplasia of mucus-secreting glands (parietal and chief cells are usually diminished or absent); superficial biopsy may appear normal. Laboratory findings due to complications (e.g., iron-deficiency anemia due to chronic GI hemorrhage, edema due to hypoalbuminemia) Liver function tests are normal. Proteinuria is absent. GASTRITIS, CHRONIC Type A gastritis (autoimmune type; gastric antrum spared) Parietal cell antibodies and intrinsic factor antibodies help define those patients prone to PA. Achlorhydria Vitamin B12 deficient megaloblastosis Hypergastrinemia (due to hyperplasia of gastrin-producing cells) Gastric carcinoids Low serum pepsinogen I concentrations Laboratory findings due to other autoimmune diseases (e.g., Hashimoto's thyroiditis, Addison's disease, Graves' disease, myasthenia gravis, hypoparathyroidism, insulin-dependent diabetes mellitus) Type B gastritis (gastric antrum involved) H. pylori infection; is detectable in ~80% of patients with peptic ulcer and chronic gastritis. Diagnosis by biopsy, culture, direct Gram stain, urease test, serologic tests Hypogastrinemia (due to destruction of gastrin-producing cells in antrum) Chronic antral gastritis is consistently present in patients with benign gastric ulcer. w Diagnosis depends on biopsy of gastric mucosa. Anemia due to iron deficiency and malabsorption may occur. Gastric acid studies are of limited value. Severe hypochlorhydria or achlorhydria after maximal stimulation usually denotes mucosal atrophy. Due To H. pylori infection Other infections (other bacteria, viruses, parasites, fungi) Chemical effects (e.g., NSAIDs, bile reflux) Metaplastic atrophic disease (e.g., autoimmune) Eosinophilic gastroenteritis Crohn's disease Sarcoidosis Lymphocytic gastritis Ménétrier's disease GASTROENTERITIS, EOSINOPHILIC w Diagnosis requires histologic evidence of predominant eosinophilic infiltration of GI tract in absence of parasitic infection or extraintestinal disease.
- 126. Laboratory findings due to Diarrhea, malabsorption, protein-losing enteropathy with predominant disease of mucosal layer GI tract obstruction with predominant disease of muscular layer Eosinophilic ascites with predominant disease of serosal layer GASTROINTESTINAL DISEASES, GENETIC Atrophic gastritis (PA) MEN types I and II AD Gastric cancer Colon cancer Cancer family syndrome (cancer of colon, breast, endometrium) AD Familial polyposes (see Polyposis, Hereditary) Celiac disease Cystic fibrosis AR Shwachman syndrome AR Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) AD Hereditary pancreatitis AD Ehlers-Danlos syndrome type IV (bowel rupture) AD Tylosis (esophageal cancer; hyperkeratosis of palms and soles) AD Hereditary hollow visceral myopathy (intestinal pseudoobstruction) AD Familial Mediterranean fever (recurrent polyserositis) AR Hermansky-Pudlak syndrome (inflammatory bowel disease, platelet AR dysfunction, oculocutaneous albinism, pulmonary fibrosis) Lactase deficiency AR Sucrase-isomaltase deficiency AR Hartnup's disease AR Cystinuria AR Pancreatic lipase deficiency AR Congenital PA AR Imerslund-Graesback syndrome AR Congenital chloride diarrhea AR Hirschsprung's megacolon Acrodermatitis enteropathica AR AD = autosomal dominant; AR = autosomal recessive. GASTROINTESTINAL TRACT: CONDITIONS WITH NO USEFUL LABORATORY FINDINGS Chronic esophagitis Diverticula of esophagus and stomach Esophageal spasm Prolapse of gastric mucosa Foreign bodies in stomach HEMORRHAGE, GASTROINTESTINAL Due To Duodenal ulcer (25% of patients) Esophageal varices (18% of patients) Gastric ulcer (12% of patients) Gastritis (12% of patients) Esophagitis (6% of patients) Mallory-Weiss syndrome (5% of patients) Other (22% of patients) In addition to the main cause of bleeding, 50% of patients have an additional lesion that could cause hemorrhage (especially duodenal ulcer, esophageal varices, hiatus hernia). 40% of patients with previously known GI tract lesions bled from a different lesion. HERNIA, DIAPHRAGMATIC Microcytic anemia (due to blood loss) may be present. Stool may be positive for blood. HIRSCHSPRUNG'S DISEASE (AGANGLIONIC MEGACOLON) Rectal biopsy to include muscle layers shows absence of myenteric plexus ganglia in muscle layers. Only diagnostic if ganglia are present to rule out this diagnosis. Up to 15% of all infants with delayed passage of meconium have Hirschsprung's disease.
- 127. INFECTIONS OF GASTROINTESTINAL TRACT (See also Chapter 15, Infectious Diseases.) AIDS Gastrointestinal Involvement Mouth—Candida Esophagus—CMV, Candida, HSV Small intestine—CMV, Cryptosporidia, Giardia, Isospora belli, Microsporidia, M. avium-intracellulare Colon—Candida, amebae, Campylobacter, Chlamydia trachomatis, C. difficile, CMV, Histoplasma, M. avium-intracellulare, Salmonella, Shigella Rectum—HSV, C. trachomatis Liver and biliary tract—CMV hepatitis, ampullary stenosis, cryptosporidiosis, M. avium-intracellulare infection Agents of Infectious Gastroenteritis See Fig. 7-4. Fig. 7-4. Algorithm for etiology of infectious diarrhea. Bacteria cause the severest forms of infectious diarrhea; viruses (e.g., rotaviruses, Norwalk viruses) are most common causes. (PMNs = polymorphonuclear neutrophil leukocytes; EIEC = enteroinvasive; EHEC = enterohemorrhagic; ETEC = enterotoxigenic; EPEC = enteropathogenic; HVS = herpes simplex virus; CMV = cytomegalovirus.) (Adapted from Guerrant RL, Bobak DA. Bacterial and protozoal gastroenteritis. N Engl J Med 1991;325:327.) Agent Frequency (%) in Traveler's Diarrhea Enterotoxigenic E. coli 40–60 Shigella species 5–10 Salmonella species <5 Campylobacter species <5 Unknown agents 30–40 G. lamblia Rare E. histolytica Rare Enteropathogenic E. coli NA Enteroinvasive E. coli NA Enterohemorrhagic E. coli NA Rotavirus, groups A, B, C NA Norwalk viruses NA Enteric adenovirus Astrovirus Calicivirus Cryptosporidium species NA Balantidium coli I. belli Other bacteria to consider Y. enterocolitica V. cholerae, Vibrio parahaemolyticus Aeromonas hydrophila C. difficile, C. perfringens type A S. aureus B. cereus Helminths (see Chapter 15) NA = data on frequency not available. Parasites, Gastrointestinal See Chapter 15. INFLAMMATORY DISORDERS OF THE INTESTINE Idiopathic, e.g., ulcerative colitis, regional enteritis, colitis of indeterminate type (e.g., collagenous colitis) Infectious Bacteria (e.g., C. jejuni, C. difficile, Salmonella, Shigella sonnei, enteropathic E. coli, Yersinia, Aeromonas) Tubercle bacilli
- 128. Chlamydiae Viruses (e.g., rotavirus, CMV, HSV) Parasites (E. histolyticum, G. lamblia) Fungi (e.g., Cryptosporidium) Motility disorders (e.g., diverticulitis, solitary rectal ulcer syndrome) Circulatory disorders (e.g., ischemic colitis, associated with obstruction of colon) Iatrogenic Use of enemas, laxatives, drugs Radiation exposure After small intestine bypass and diversion of fecal stream Graft-versus-host disease Specific disease association Chronic granulomatous disease of childhood Immunodeficiency syndromes Hemolytic uremic syndrome Behçet's disease Miscellaneous Collagenous colitis Eosinophilic colitis and allergic proctitis Necrotizing enterocolitis Idiopathic ulcer of colon INTESTINAL OBSTRUCTION WBC is normal early. Later it tends to rise, with increase in PMNs; 15,000–25,000/cu mm suggests strangulation; >30,000/cu mm suggests mesenteric thrombosis. Hb and Hct concentrations are normal early but later increase, with dehydration. Urine specific gravity increases, with deficit of water and electrolytes unless preexisting renal disease is present. Urinalysis helps rule out renal colic, diabetic acidosis, etc. Gastric contents Positive guaiac test suggests strangulation; gross blood may be present if strangulated segment is high in jejunum. Rectal contents–gross rectal blood suggests carcinoma of colon or intussusception. Decreased serum sodium, potassium, chloride, and pH and increased CO 2 are helpful indications to follow the course of the patient and to guide therapy. Increased BUN suggests blood in intestine or renal damage. Serum amylase may be moderately increased in absence of pancreatitis. Increased serum LD, AST, CK, and phosphorus may indicate infarction of small intestine. In Neonate Due To Congenital mechanical Intrinsic (e.g., pyloric stenosis, meconium ileus, atresia, imperforate anus) Extrinsic (e.g., volvulus, malrotation, congenital bands, hernia) Acquired mechanical (e.g., intussusception, necrotizing enterocolitis, meconium plugs, adhesions, mesenteric thrombosis) Functional Hirschsprung's disease Paralytic ileus (e.g., sepsis, Pseudomonas enteritis, maternal drugs such as heroin, hypermagnesemia) Endocrine (e.g., hypothyroidism, adrenal insufficiency) Other (e.g., sepsis, CNS disease, meconium plug syndrome) Laboratory Findings in Neonate Gastric aspirate >15 mL or is bile stained. Vomitus is colorless when obstruction proximal to ampulla of Vater (e.g., pyloric atresia) but bile stained and alkaline with obstruction distal to ampulla. Bile-stained vomitus in a neonate is always abnormal and is to be considered a surgical problem until proved otherwise. Findings due to complications (e.g., perforation, infarction, enterocolitis, peritonitis, changes in fluid and electrolytes) Laboratory findings due to associated conditions Duodenal atresia is associated with Down syndrome (30% of cases) Intestinal malrotation (20% of cases) Congenital heart disease (17% of cases) Annular pancreas (20% of cases)
- 129. Renal anomalies (5% of cases) Tracheoesophageal anomalies (7% of cases) Polyhydramnios in 50% of cases of duodenal obstruction; 40% show hyperbilirubinemia Cystic fibrosis is associated with Meconium ileus Increased incidence of intestinal atresia LYMPHANGIECTASIA, INTESTINAL w Biopsy of small bowel or lymphangiography confirms the diagnosis. Decreased serum protein. IV infusion of 51 Cr-labeled albumin demonstrates excessive protein loss in stools. May manifest abnormal lymph nodes (inguinal, pelvic, retroperitoneal) and lymphedema between early infancy and childhood. MALABSORPTION See Fig. 7-5. Fig. 7-5. Algorithm for workup of malabsorption. (Adapted from Roberts IM. Workup of the patient with malabsorption. Postgrad Med 1987;8:32.) Due To Inadequate mixing of food with bile salts and lipase (e.g., pyloroplasty, subtotal or total gastrectomy, gastrojejunostomy) Inadequate lipolysis due to lack of lipase (e.g., cystic fibrosis of the pancreas, chronic pancreatitis, cancer of the pancreas or ampulla of Vater, pancreatic fistula, vagotomy) Inadequate emulsification of fat due to lack of bile salts (e.g., obstructive jaundice, severe liver disease, bacterial overgrowth of small intestine, disorders of terminal ileum) Primary absorptive defect in small bowel Inadequate absorptive surface due to extensive mucosal disease (e.g., regional enteritis, tumors, amyloid disease, scleroderma, irradiation) Biochemical dysfunction of mucosal cells (e.g., celiac sprue syndrome, severe starvation, intestinal infections or infestations, or administration of drugs such as neomycin sulfate, colchicine, or PAS) Obstruction of mesenteric lymphatics (e.g., by lymphoma, carcinoma, Whipple's disease, intestinal TB) Inadequate length of normal absorptive surface (e.g., surgical resection, fistula, shunt) Miscellaneous (e.g., "blind loops" of intestine, diverticula, Z-E syndrome, agammaglobulinemia, endocrine and metabolic disorders) Chronic infection (e.g., in common variable hypogammaglobulinemia, 50–55% of patients have chronic diarrhea and malabsorption due to specific pathogen such as G. lamblia or overgrowth of bacteria in small bowel) Factitious w Fat absorption indices (steatorrhea) Direct qualitative stool examination ³2 random stool samples are collected on diet of >80 gm of fat daily. Interpretation Gross—oil droplets, egg particles, buttery materials Microscopic examination after staining for fat (e.g., oil red O, Sudan) Sensitivity >94% in moderate/severe fat malabsorption (>10% of ingested fat excreted); ~75% in mild/moderate fat malabsorption (6–10% of ingested fat excreted); positive in ~14% of normal persons. 4+ fat in stool means excessive fat loss. Interference Neutral fat Mineral and castor oil ingestion Dietetic low-calorie mayonnaise ingestion
- 130. Rectal suppository use Quantitative determination of fecal fat is gold standard test to establish the diagnosis of fat malabsorption. Interpretation Normal is <7 gm/24 hrs when a 3-day pooled stool sample is collected on diet of 80–100 gm of fat/day. <5 gm/24 hrs (or <4% of measured fat intake) on diet of <50 gm of fat/day for a 3-day period. Determination parallels but is more sensitive than triolein 131 I test in chronic pancreatic disease. Increased In Chronic pancreatic disease (>9.5 gm/24 hrs) May also be increased in High fiber diet (>100 gm/day). When dietary fat is ingested in solid form (e.g., whole peanuts). Neonatal period. Weight–much heavier (>300 gm/24 hrs) than normal (normal weight is <200 gm/24 hrs or normal fecal solids of 25–30 gm/24 hrs). Serum trypsinogen <10 ng/mL in 75–85% of patients with severe chronic pancreatitis (those with steatorrhea) and 15–20% of those with mild to moderate disease; occasionally low in patients with cancer of pancreas; normal (10–75 ng/mL) with nonpancreatic causes of malabsorption. Bentiromide used to differentiate pancreatic exocrine insufficiency (abnormal result) from intestinal mucosal disease (normal result). w Secretin-cholecystokinin is the most sensitive and reliable test of chronic pancreatic disease. Indirect indices of fat absorption; these lack sensitivity and specificity for routine screening. Serum cholesterol may be decreased. PT may be prolonged due to malabsorption of vitamin K. Serum carotene is always abnormal in steatorrhea unless therapy is successful. Not recommended for screening; poor precision at lower end of reference range. May also be low in liver disease, high fever, hyperthyroidism, chronic illness, and decreased dietary intake (blood level falls within 1 wk but vitamin A level is unaffected by dietary change for 6 mos because of much larger body stores). May be increased in hyperlipidemia and hypothyroidism. Normal level is 70–290 µg/dL; 30–70 µg/dL indicates mild depletion; <30 indicates severe depletion. Carotene tolerance test: Measure serum carotene after daily oral loading of carotene for 3–7 days. Low values for serum carotene levels are usually associated with steatorrhea. Increase of serum carotene by >35 µg/dL indicates previously low dietary intake of carotene and/or fat. Decreased In Steatorrhea. Serum carotene increases >30 µg/dL. Patients with sprue in remission with normal fecal fat excretion may still show low carotene absorption. Mineral oil interferes with carotene absorption. On a fat-free diet only 10% is absorbed. Vitamin A tolerance test (for screening steatorrhea) Measure plasma vitamin A level 5 hrs after ingestion. Normal rise is 9× fasting level. Flat curve in liver disease Not useful after gastrectomy With vitamin A as ester of long-chain fatty acid, flat curve occurs in both pancreatic disease and intestinal mucosal abnormalities; when water-soluble forms of vitamin A are used, the curve becomes normal in patients with pancreatic disease but remains flat in those with intestinal mucosal abnormalities. Triolein 131 I and oleic acid 131 I absorption with measurement of blood, breath, or fecal radioactivity; sensitive and specific for screening but may not be routinely available. Triolein 131 I absorption test used to screen patients with steatorrhea. Normal: ³10% of administered radioactivity appears in the blood within 6 hrs; <5% appears in the feces; indicates that digestion of fat in the small bowel and absorption of fat in the small bowel are normal. Abnormal: perform an oleic acid 131 I absorption test. Triolein 14 C breath test 14 C-labeled triolein is administered and 14 CO2 is measured in collected breath. Said to have >85% sensitivity and specificity for fat malabsorption. Interferences False-positives Poor gastric emptying (e.g., gastric surgery, diabetes mellitus) CO2 retention (e.g., chronic lung disease) Impaired metabolism (e.g., severe liver disease) Dilution of 14 CO2 (e.g., hyperlipidemia, ascites, obesity) Apparently healthy persons False-negatives Increased CO2 production (e.g., hyperthyroidism, fever) Mild degree of fat malabsorption Oleic acid 131 I absorption test: normal values same as for the triolein absorption test. Interpretation An abnormal result indicates a defect in small bowel mucosal absorption function (e.g., sprue, Whipple's disease, regional enteritis, tuberculous enteritis, collagen
- 131. diseases involving the small bowel, extensive resection). Abnormal pancreatic function does not affect the test. Most common laboratory abnormalities are decreased serum carotene, albumin, and iron, increased ESR, increased stool weight (>300 gm/24 hrs) and stool fat (>7 gm/24 hrs), anemia. w Normal D-xylose test, low serum trypsinogen, pancreatic calcification on radiograph of abdomen establish diagnosis of chronic pancreatitis. If calcification is absent (as occurs in 70–80% of cases), abnormal contents of pancreatic secretion after secretin-cholecystokinin stimulation or abnormal bentiromide tests establishes diagnosis of chronic pancreatitis. Anemia is due to deficiency of iron, folic acid, vitamin B 12, or various combinations, depending on their decreased absorption. Carbohydrate absorption indices Oral GTT—limited value Flat curve or delayed peak occurs in celiac disease and nontropical sprue. Curve is normal in pancreatic insufficiency. D-Xylose tolerance test of carbohydrate absorption Measure total 5-hr urine excretion; may also measure serum levels at 2 hrs. Accuracy is 90% in distinguishing normal levels in pancreatic disease from decreased levels in intestinal mucosal disease and intestinal bacterial overgrowth, but opinions vary on usefulness. Also decreased in renal disease, myxedema, and the elderly although absorption is normal. Disaccharide malabsorption Due To Primary malabsorption (congenital or acquired) due to absence of specific disaccharidase in brush border of small intestine mucosa Isolated lactase deficiency (also called milk allergy, milk intolerance, congenital familial lactose intolerance, lactase deficiency) is most common of these defects; occurs in ~10% of whites and 60% of blacks; infantile type shows diarrhea, vomiting, failure to thrive, malabsorption, etc.; often appears first in adults; become asymptomatic when lactase is removed from diet. Sucrose-isomaltose malabsorption (inherited recessive defect) Oral sucrose tolerance curve is flat, but glucose plus fructose tolerance test is normal. Occasionally an associated malabsorption is noted with increased stool fat and abnormal D-xylose tolerance test although intestinal biopsy is normal. Hydrogen breath test after sucrose challenge. Intestinal biopsy with measurement of disaccharidase activities. Sucrose-free diet causes cessation of diarrhea. Glucose-galactose malabsorption (inherited autosomal recessive defect that affects kidney and intestine) Oral glucose or galactose tolerance curve is flat, but intravenous tolerance curves are normal. Glucosuria is common. Fructose tolerance test is normal. Secondary malabsorption Resection of >50% of disaccharidase activity Lactose is most marked, but there may also be sucrose. Oral disaccharide tolerance (especially lactose) is abnormal, but intestinal histology and enzyme activity are normal. Diffuse intestinal disease—especially celiac disease in which activity of all disaccharidases may be decreased, with later increase as intestine becomes normal on gluten-free diet; also cystic fibrosis of pancreas, severe malnutrition, ulcerative colitis, severe Giardia infestation, blind-loop syndrome, beta-lipoprotein deficiency, effect of drugs (e.g., colchicine, neomycin, birth control pills). Oral tolerance tests (especially lactose) are frequently abnormal, with later return to normal with gluten-free diet. Tolerance tests with monosaccharides may also be abnormal because of defect in absorption as well as digestion. Bacterial overgrowth—see Table 7-1 Table 7-1. Infectious Foodborne Diseases Culture of duodenal aspirate showing >105 colony-forming units of anaerobic organisms is considered diagnostic. [14 C]d-xylose breath test has good specificity. Hydrogen breath tests (glucose-H2, lactulose-H2)—not recommended due to limited sensitivity and specificity. Laboratory tests for lactase deficiency (Similar tests for other disaccharide deficiencies can be performed.) Oral lactose tolerance curve is flat (blood glucose rises <20–25 mg/dL in blood drawn 15, 30, 60, and 90 mins after 50–100 gm dose of lactose) but tolerance test is normal using constituent monosaccharides (25 gm each of glucose and galactose) indicating isolated lactase deficiency rather than general mucosal absorptive defect. Normal: Blood glucose increases >24 mg/dL above fasting level; may increase >20–25 mg/dL in diabetics despite impaired lactose absorption. Abnormal: glucose increases <20 mg/dL above fasting level. False abnormal test may be due to delayed gastric emptying or small bowel transit or delayed blood collection. Poor sensitivity–largely replaced by breath hydrogen lactose test. Stool examination
- 132. After ingestion of 50–100 gm of lactose, frothy diarrheal stools typically show low pH (4.5–6.0; normal is >7.0), high osmolality, positive test for reducing substances (e.g., Clinitest tablets; >0.5% is abnormal; 0.25–0.5% is suspicious; 0.25% is normal); found in children but rarely in adults. Chromatography detects specific carbohydrates. Fecal studies are of limited value. Hydrogen breath test measures (by gas chromatography) amount of H2 exhaled at 2 hrs after ingestion of 50 gm of lactose in fasting state. Normal is 0 to 0.11 mL/min; in lactase deficiency, 0.31 to 2.50 mL/min. Peak or cumulative 4-hr values also differentiates these patients. Based on production of H 2 by bacteria in colon from unabsorbed lactose. False-negative test due to absence of H 2-producing bacteria in colon or prior antibiotic therapy in ~20% of patients. Similar test can be used to detect disaccharidase deficiency and small intestine bacterial overgrowth. Endoscopic intestinal biopsy for histologic examination and enzyme activity assay is now considered obsolete. Protein absorption indices Normal fecal nitrogen is <2 gm/day. Marked increase is seen in sprue and severe pancreatic deficiency. Measure plasma glycine or urinary excretion of hydroxyproline after gelatin meal. Plasma glycine increases 5× in 2 hrs in normal persons. In those with cystic fibrosis of the pancreas, the increase is <2.5×. Serum albumin may be decreased. 131 I-Polyvinylpyrrolidone test Give 15–25 µCi of 131 I-Polyvinylpyrrolidone IV and collect all stools for 4–5 days. Interpretation Normal: <2% is excreted in feces when the mucosa of the GI tract is intact. In protein-losing enteropathy, >2% of administered radioactivity appears in stool. Electrolyte absorption indices Serum calcium, magnesium, potassium, and vitamin D may be decreased. 51 Cr albumin test (IV dose of 30–50 µCi) shows increased excretion in 4-day stool collection due to protein-losing enteropathy. Biopsy of small intestine mucosa is excellent for verification of sprue, celiac disease, and Whipple's disease. Culture for bacterial overgrowth should be considered in malabsorption associated with abnormal intestinal motility (e.g., scleroderma) or anatomic abnormalities (e.g., diverticula). Positive if >105 –106 organisms/mL from upper intestinal contents but may vary from one location to another; should be collected for anaerobic and aerobic culture. Perform with peroral intestinal biopsy. If breath tests using 14 C–bile acid or 14 C–D-xylose or hydrogen are available, they are more sensitive and specific for bacterial overgrowth. Breath test for bile acid malabsorption: Oral radiolabeled 14 C-glycocholate undergoes bacterial deconjugation in colon. 14 CO2 derived from glycine is absorbed in bowel, excreted by lungs, and measured in breath. This simulates secretion of bile acids into duodenum and 95% resorption in terminal ileum. Identifies bacterial overgrowth or impaired ileal absorption of bile acids. Interpretation Normal: ~5% enters the colon. Increased: Bacterial overgrowth in small intestine allows earlier bacterial deconjugation and therefore more 14 CO2 appears in breath. Disease or resection of terminal ileum allows more bile acids into colon, where they undergo bacterial conjugation. Schilling test: Performed before and after administration of antibiotics; is a useful adjunct to intestinal culture to detect bacterial overgrowth. (See Table 7-2.) Table 7-2. Interpretation of Schilling Test MALLORY-WEISS SYNDROME (Spontaneous cardioesophageal laceration after retching) Laboratory findings due to hemorrhage from cardioesophageal laceration MECKEL'S DIVERTICULUM Laboratory findings due only to complications Gastrointestinal hemorrhage Intestinal obstruction Perforation or intussusception (~20% of patients; the other 80% of patients are asymptomatic) m Should be suspected when GI tract bleeding and symptoms of appendicitis occur together. MEGACOLON, TOXIC
- 133. (Atonic dilatation of colon due to transmural inflammation) Due To Severe ulcerative colitis (most common cause) Crohn's disease Pseudomembranous colitis Ischemic colitis Bacterial colitis Amebiasis Laboratory findings due to sepsis (e.g., increased WBC and PMNs) Bloody diarrhea PERITONITIS, ACUTE See Fig. 7-1 and Fig. 7-2. Primary Laboratory findings due to nephrotic syndrome and postnecrotic cirrhosis and occasionally bacteremia in children and cirrhosis with ascites in adults. w Gram stain of direct smear and culture of peritoneal fluid usually shows streptococci in children. In adults is due to E. coli (40–60%) or Streptococcus pneumoniae (15%), other gram-negative bacilli, and enterococci; usually one organism. May be due to Mycobacterium tuberculosis. w Diagnostic peritoneal lavage fluid shows WBC count >200/cu mm in 99% of cases. Marked increase in WBC (£50,000/cu mm) and PMN (80–90%). Secondary Laboratory findings due to perforation of hollow viscus (e.g., appendicitis, perforated ulcer, volvulus). Usually more than one organism is found. w Occurs and recurs very frequently in continuous ambulatory peritoneal dialysis. Suggested by turbid dialysate (indicates >300 WBC/cu mm); Gram stain and culture may be negative and leukocytosis may be absent. Due to gram-positive bacteria in ~70%, enteric gram-negative bacilli and Pseudomonas aeruginosa in 20–30%, others in 10–20%, sterile in 10–20%. If more than one pathogen, rule out perforated viscus. PLUMMER-VINSON SYNDROME Hypochromic anemia associated with dysphagia and cardiospasm in women POLYPOSIS (GASTROINTESTINAL), HEREDITARY See Table 7-3. Table 7-3. Comparison of Some Inherited Gastrointestinal Polyps Laboratory findings due to intestinal polyps and due to associated lesions Familial polyposis of colon Occasional discrete polyps of colon and rectum Peutz-Jeghers syndrome Gardner's syndrome (see next section) Turcot's syndrome (CNS tumors) Oldfield's syndrome (extensive sebaceous cysts) Z-E syndrome Generalized juvenile polyposis Laboratory findings due to complications (e.g., bleeding, intussusception, obstruction, malignancy) PROCTITIS, ACUTE w Rectal Gram stain preparation shows >1 PMN/HPF (1000×). In homosexual men, specific cause can be found in 80% of cases completely studied. The most common causes are C. trachomatis (non–lymphogranuloma venereum strains) in >75% of cases, N. gonorrhoeae, lymphogranuloma venereum, HSV type II, T. pallidum. Histopathology of rectal biopsy in acute proctocolitis due to C. trachomatis is indistinguishable from Crohn's disease; culture and serologic tests for C. trachomatis and serologic tests for lymphogranuloma venereum strains should be performed in such cases. Primary or secondary syphilitic proctitis may be very severe and of variable appearance; serologic test for syphilis should be performed.
- 134. SPRUE, TROPICAL (Probably an infectious disease due to persistent toxicogenic coliform bacteria in small intestine, e.g., Klebsiella pneumoniae, Enterobacter cloacae, E. coli; responds to antibiotic therapy.) Initial bout of acute watery diarrhea followed by persistent, progressive course if untreated. Malabsorption, e.g., Steatorrhea in 50–90% of cases Deficiency of folate and vitamin B12 (not corrected by adding intrinsic factor) Abnormal xylose tolerance in most cases Oral GTT abnormal in ~50% of cases Histologic changes seen in jejunal biopsy. SYSTEMIC DISEASES, GASTROINTESTINAL MANIFESTATIONS AIDS Allergy Amyloidosis Bacterial infection (lymphogranuloma venereum) Cirrhosis (esophageal varices, hemorrhoids, peptic ulcer) Collagen diseases (e.g., scleroderma, polyarteritis nodosa, SLE) Cystic fibrosis of pancreas Embolic accidents in rheumatic heart disease, bacterial endocarditis Hemolytic crises (e.g., sickle cell disease) Henoch's purpura Hirschsprung's disease Ischemic vascular disease Lead poisoning Lymphoma and leukemia Metastatic carcinoma Osler-Weber-Rendu disease Parasitic infestation (schistosomiasis) Peptic ulcer associated with other diseases (in 8–22% of patients with hyperparathyroidism, 10% of patients with pituitary tumor, etc.) Porphyria Uremia Z-E syndrome (peptic ulcer) SYSTEMIC DISEASES, ORAL MANIFESTATIONS Hematologic diseases Acute leukemia—edema and hemorrhage Granulocytopenia—ulceration and inflammation Iron-deficiency anemia—atrophy PA—glossitis Polycythemia—erosions Infections Bacterial (e.g., diphtheria, scarlet fever, syphilis, Vincent's angina) Fungal (e.g., actinomycosis, histoplasmosis, mucormycosis, moniliasis) Viral (e.g., HSV infection, herpangina, measles, infectious mononucleosis) Systemic diseases (e.g., SLE, primary amyloidosis, Osler-Weber-Rendu disease) Vitamin deficiencies (e.g., pellagra, riboflavin deficiency, scurvy, folate deficiency) SYSTEMIC MANIFESTATIONS IN SOME GASTROINTESTINAL DISEASES Anemia (e.g., due to bleeding occult neoplasm) Arthritis, uveitis, etc., in ulcerative colitis Carcinoid syndrome Endocrine manifestations due to replacement by metastatic tumors of GI tract Vitamin deficiency (e.g., sprue, malabsorption) TUMORS OF SMALL INTESTINE See Table 7-4.
- 135. Table 7-4. Comparison of Two Major Types of Lymphoma w Biopsy of lesions confirms the diagnosis. Laboratory findings due to complications, e.g., hemorrhage, obstruction, intussusception, malabsorption Laboratory findings due to underlying condition, e.g., Peutz-Jeghers syndrome, carcinoid syndrome Laboratory findings due to conditions with increased risk of small bowel tumor GI Tract Condition Tumor Celiac sprue Non-Hodgkin's lymphoma, adenocarcinoma Crohn's disease Adenocarcinoma Familial adenomatous polyposis Adenocarcinoma, adenoma Postcolectomy ileostomy Adenocarcinoma Neurofibromatosis Adenocarcinoma, leiomyoma AIDS Non-Hodgkin's lymphoma Nodular lymphoid hyperplasia Non-Hodgkin's lymphoma Immunoproliferative small bowel disease Non-Hodgkin's lymphoma VASCULAR OCCLUSION, MESENTERIC Chronic (mesenteric arterial insufficiency) Laboratory findings due to malabsorption and starvation Acute Marked increase in WBC (³15,000–25,000/cu mm) with shift to the left. Infarction of intestine may cause increased serum LD, AST, CK, BUN, and phosphorus. Increased plasma lactate with metabolic acidosis has been suggested as indicator for surgery in patients with acute abdomen. Laboratory findings due to intestinal hemorrhage, obstruction, shock. VILLOUS ADENOMA OF RECTUM Stool contains large amount of mucus tinged with blood; frequent watery diarrhea. Serum potassium may be decreased due to secretory diarrhea. w Biopsy of lesion establishes the diagnosis. WHIPPLE'S DISEASE (INTESTINAL LIPODYSTROPHY) (Multiorgan disease due to Tropheryma whippleii) w Characteristic biopsy of proximal intestine (especially duodenum) and mesenteric lymph nodes establishes the diagnosis by light (using special stains) and characteristic electron microscopy showing bacilli. Has also been observed in other tissues (e.g., liver, lymph nodes, heart, CNS, eye, kidney, synovium, lung). Organism has not been cultured. w PCR to amplify bacterial 16S ribosomal RNA in infected tissues, mononuclear cells of peripheral blood, cells of pleural effusion. Anemia of chronic disease in 90% of cases; occasionally due to iron deficiency; rarely due to folate or B 12 deficiency. Hypogammaglobulinemia is usual. Many patients are anergic with impaired immune function. Laboratory findings due to involvement of various organs, e.g., malabsorption syndrome with steatorrhea in most patients, wasting syndrome, seronegative arthritis, sarcoid-like illness. 1 Wolfe MM, Soll AH. The physiology of gastric acid secretion. N Engl J Med 1988;319:1707. 2 Rosenfeld L. Gastric tubes, meals, acid and analysis: rise and decline. Clin Chem 1997;43:837. 3 Frucht H, et al. Secretin and calcium provocative tests in the Zollinger-Ellison syndrome. Ann Intern Med 1989;111:713. 4 Ahlquist DA. Accuracy of fecal occult blood screening for colorectal neoplasia. A perspective study using Hemoccult and HemoQuant tests. JAMA 1993;269:1262. 5 Ransohoff DH, Lang CA. Suggested technique for fecal occult blood testing and interpretation in colorectal cancer screening. Ann Intern Med 1997;126:808. 6 Ransohoff DH, Lang CA. Screening for colorectal cancer with the fecal occult blood test: a background paper. Ann Intern Med 1997;126:811. 7 Knight KK, et al. Occult blood screening for colorectal cancer. JAMA 1989;261:587. 8 Fleischer DE, et al. Detection and surveillance of colorectal cancer. JAMA 1989;261:580.
- 136. CHAPTER 8 HEPATOBILIARY DISEASES AND DISEASES OF THE PANCREAS Interpretation of Diagnostic Tests CHAPTER 8 HEPATOBILIARY DISEASES AND DISEASES OF THE PANCREAS Common Test Patterns Abscess of Liver, Pyogenic Biliary Atresia, Extrahepatic, Congenital Biliary Obstruction, Complete (Intrahepatic or Extrahepatic) Breat-Milk Jaundice Cholangitis, Acute Cholangitis, Primary Sclerosing Cholecystitis, Acute Cholecystitis, Chronic Choledocholithiasis Cholelithiasis Cholestasis Cholestasis, Benign Recurrent Intrahepatic Cholestasis, Neonatal Cirrhosis, Primary Biliary (Cholangiolitic Cirrhosis, Hanot's Hypertrophic Cirrhosis, Chronic Nonsuppurative Destructive Cholangitis, etc.) Cirrhosis of Liver Crigler-Najjar Syndrome (Hereditary Glucuronyl Transferase Deficiency) Dubin-Johnson Syndrome (Sprinz-Nelson Syndrome) Fatty Liver Fatty Liver of Pregnancy, Acute Gallbladder and Bile Duct Cancer Gilbert's Disease Heart Failure (Congestive), Liver Function Abnormalities Hemochromatosis Hemochromatosis, Neonatal Hepatic Encephalopathy Hepatic Failure, Acute Hepatitis, Acute Viral Hepatitis, Alcoholic Hepatitis, Autoimmune Chronic Active Hepatitis, Chronic Active Hepatitis A Hepatitis B Hepatitis C (Formerly Non-A, Non-B Hepatitis) Hepatitis D (Delta) Hepatitis E Hepatitis G Hepatitis, Neonatal Hepatocellular Carcinoma (Hepatoma) Hyperbilirubinemia, Neonatal Hyperbilirubinemia, Neonatal Nonphysiologic Hyperbilirubinemia, Neonatal Physiologic Hyperbilirubinemia; Neonatal, Transient Familial (Lucey-Driscoll Syndrome) Hyperbilirubinemia in Older Children Jaundice (Cholestatic and Hepatocellular), Comparison Metabolism, Inborn Errors, Causing Liver Disorder Pylephlebitis, Septic Rotor's Syndrome Space-Occupying Lesions Transplantation of Liver Trauma Wilson's Disease Amylase, Serum Lipase, Serum Cystic Fibrosis of Pancreas Macroamylasemia Pancreatic Carcinoma Pancreatitis, Acute Pancreatitis, Chronic Pseudocyst of Pancreas LIVER FUNCTION TESTS COMMON TEST PATTERNS See Table 8-1. Table 8-1. Increased Serum Enzyme Levels in Liver Diseases See Fig. 8-1, Fig. 8-2 and Fig. 8-3. Fig. 8-1. Algorithm illustrating workup for jaundice.
- 137. Fig. 8-2. Algorithm illustrating sequential abnormal liver function test interpretation. (Alb = albumin; Bil = bilirubin; CHF = congestive heart failure; Glob = globulin; I = increased; N = normal. Enzymes all in same U/L.) (Adapted from Henry JB. Clinical diagnosis and management by laboratory methods, 16th ed. Philadelphia: WB Saunders, 1979.) Fig. 8-3. Antibody markers in hepatitis A virus infection. (IgG = immunoglobulin G; IgM = immunoglobulin M.) (Reproduced with permission of Abbott Laboratories, Pasadena, CA.) Patterns of abnormalities rather than changes in single test results are particularly useful despite sensitivities of only 65% in some cases. Test results may be abnormal in many conditions that are not primarily hepatic (e.g., heart failure, sepsis, infections such as brucellosis, SBE), and individual test results may be positive in conditions other than liver disease. Results on individual tests are normal in a high proportion of patients with proven specific liver diseases, and normal values may not rule out liver disease. Serum bilirubin (direct/total ratio) <20% direct. Constitutional (e.g., Gilbert's disease, Crigler-Najjar syndrome). Hemolytic states. 20–40% direct. Favors hepatocellular disease rather than extrahepatic obstruction. Disorders of bilirubin metabolism (e.g., Dubin-Johnson, Rotor's syndromes). 40–60% direct: Occurs in either hepatocellular or extrahepatic type. >50% direct: Favors extrahepatic obstruction rather than hepatocellular disease. Serum total bilirubin Not a sensitive indicator of hepatic dysfunction; may not reflect degree of liver damage. Must be >2.5 mg/dL to produce clinical jaundice. >5 mg/dL seldom occurs in uncomplicated hemolysis unless hepatobiliary disease is also present. Is generally less markedly increased in hepatocellular jaundice (<10 mg/dL) than in neoplastic obstructions (£20 mg/dL) or intrahepatic cholestasis. In extrahepatic biliary obstruction, bilirubin may rise progressively to a plateau of 30–40 mg/dL (due in part to balance between renal excretion and diversion of bilirubin to other metabolites). Such a plateau tends not to occur in hepatocellular jaundice, and bilirubin may exceed 50 mg/dL (partly due to concomitant renal insufficiency and hemolysis). Concentrations are generally higher in obstruction due to carcinoma than that due to stones. In viral hepatitis, higher serum bilirubin suggests more liver damage and longer clinical course. In acute alcoholic hepatitis, >5 mg/dL suggests a poor prognosis. Increased serum bilirubin with normal ALP suggests constitutional hyperbilirubinemias or hemolytic states. Normal serum bilirubin, AST, and ALT with increased ALP (of liver origin) and LD suggests obstruction of one hepatic duct or metastatic or infiltrative disease of liver. Metastatic and granulomatous lesions of liver cause 1.5–3.0× increase of serum ALP and LD. Due to renal excretion, maximum bilirubin = 10–35 mg/dL; if renal disease is present, level may reach 75 mg/dL. Direct bilirubin >1.0 mg/dL in an infant always indicates disease. AST and ALT Most sensitive tests for acute hepatocellular injury (e.g., viral, drug related). >500 U/L suggests such a diagnosis. Seldom >500 U/L in obstructive jaundice, cirrhosis, viral hepatitis in AIDS, alcoholic liver disease. Most marked increase (100–2000 U/L) occurs in viral hepatitis, drug injury, carbon tetrachloride poisoning. >4000 indicates toxic injury, e.g., from acetaminophen. Patient is rarely asymptomatic with level >1000 U/L. AST >10× normal indicates acute hepatocellular injury but lesser increases are nonspecific and may occur with virtually any other form of liver injury. Usually <200 U/L in posthepatic jaundice and intrahepatic cholestasis. <200 U/L in 20% of patients with acute viral hepatitis. Usually <50 U/L in fatty liver. <100 U/L in alcoholic cirrhosis; ALT is normal in 50% and AST is normal in 25% of these cases. <150 U/L in alcoholic hepatitis (may be higher if patient has delirium tremens). <200 U/L in 65% of patients with cirrhosis. <200 U/L in 50% of patients with metastatic liver disease, lymphoma, and leukemia. Normal values may not rule out liver disease: ALT is normal in 50% of cases of alcoholic cirrhosis and AST is normal in 25% of cases. AST soaring to peak of 1000–9000 U/L and declining by 50% within 3 days and to <100 U/L within a week suggests shock liver with centrolobular necrosis (e.g., due to congestive heart failure, arrhythmia, sepsis, GI hemorrhage); serum bilirubin and ALP reflect underlying disease. Rapid rise of AST and ALT to very high levels (e.g., >600 U/L and often >2000 U/L) followed by a sharp fall in 12–72 hrs is said to be typical of acute biliary duct obstruction. Abrupt AST rise may also be seen in acute fulminant viral hepatitis (rarely >4000 U and declines more slowly; positive serologic tests) and acute chemical injury.
- 138. Degree of increase has low prognostic value. Serial determinations reflect clinical activity of liver disease. Mild increase of AST and ALT (usually <500 U/L) with ALP increased >3× normal indicates cholestatic jaundice, but more marked increase of AST and ALT (especially >1000 U/L) with ALP increased <3× normal indicates hepatocellular jaundice. Increased concentration has poor correlation with extent of liver cell necrosis and has little prognostic value. AST/ALT ratio >2 with ALT <300 U/L is suggestive of alcoholic hepatitis, and ratio >3 is highly suggestive, in cases of liver disease. Greater increase in AST than in ALT also occurs in cirrhosis and metastatic liver disease. In patients with cirrhosis or portal hypertension, AST/ALT ratio ³3 suggests primary biliary cirrhosis. Greater increase in AST than in ALT favors viral hepatitis, posthepatic jaundice, intrahepatic cholestasis. AST is increased in AMI and in muscle diseases, but ALT is normal. ALT is more specific for liver disease than AST. Serum ALP Is the best indicator of biliary obstruction but does not differentiate intrahepatic cholestasis from extrahepatic obstruction. Is increased out of proportion to other liver function tests. Increases before jaundice occurs. High values (>5× normal) favor obstruction and normal levels virtually exclude this diagnosis. Markedly increased in infants with congenital intrahepatic bile duct atresia but is much lower in extrahepatic atresia. Increase (3–10× normal) with only slightly increased transaminases may be seen in biliary obstruction and the converse in liver parenchymal disease (e.g., cirrhosis, hepatitis). Increased (2–10× normal) in early infiltrative (e.g., amyloid) and space-occupying diseases of the liver (e.g., tumor, granuloma, abscess). Increased >3× normal in £5% of acute hepatitis. <3× normal is nonspecific and may occur in all types of liver diseases (e.g., infiltrative liver diseases, cirrhosis, chronic hepatitis, viral hepatitis) and in diseases affecting the liver (e.g., congestive heart failure). GGT/ALP ratio >5 favors alcoholic liver disease. Isolated increase of GGT is a sensitive screening and monitoring test for alcoholism. Increased GGT due to alcohol or anticonvulsant drugs is not accompanied by increased ALP. Serum 5'-NT and LAP levels parallel the increase in ALP in obstructive type of hepatobiliary disease, but the 5'-NT is increased only in the latter and is normal in pregnancy and bone disease, whereas the LAP is increased in pregnancy but usually normal in bone disease. GGT is normal in bone disease and pregnancy. Therefore, these enzymes are useful in determining the source of increased serum ALP. Although serum 5'-NT usually parallels ALP in liver disease, it may not increase proportionately in individual patients. Serum Enzyme Biliary Obstruction PregnancyChildhood; Bone Disease ALP I I I 5'-NT I N N LAP I I N GGT I N N I = increased; N = normal. Test for antimitochondrial antibodies to rule out primary biliary cirrhosis in females (present in >90% of cases;) and radiologic studies to rule out primary sclerosing cholangitis. Bilirubin (“bile”) in urine implies increased serum direct bilirubin and excludes hemolysis as the cause. Often precedes clinical icterus. May occur without jaundice in anicteric or early hepatitis, early obstruction, or liver metastases. (Tablets detect 0.05–0.1 mg/dL; dipsticks are less sensitive; test is negative in normal persons.) Complete absence of urine urobilinogen strongly suggests complete bile duct obstruction; level is normal in incomplete obstruction. Decreased in some phases of hepatic jaundice. Increased in hemolytic jaundice and subsiding hepatitis. Increase may indicate hepatic damage even without clinical jaundice (e.g., some patients with cirrhosis, metastatic liver disease, congestive heart failure). Presence in viral hepatitis depends on phase of disease. (Normal is <1 mg or 1 Ehrlich unit per 2-hr specimen.) Serum cholesterol May be normal or slightly decreased in hepatitis. Markedly decreased in severe hepatitis or cirrhosis. Increased in posthepatitic jaundice or intrahepatic cholestasis. Markedly increased in primary biliary cirrhosis. PT May be prolonged due to lack of vitamin K absorption in obstruction or lack of synthesis in hepatocellular disease. Not useful when only slightly prolonged. Corrected within 24–48 hrs by parenteral administration of vitamin K (10 mg/day for 3 days) in obstructive but not in hepatocellular disease. Failure to correct suggests poor prognosis; extensive hepatic necrosis should be considered. Markedly prolonged PT is a good index of severe liver cell damage in hepatitis and cirrhosis and may herald onset of fulminant hepatic necrosis. Serum gamma globulin Tends to increase with most forms of chronic liver disease. Increases are not specific; found in other chronic inflammatory and neoplastic diseases. Moderate increases (e.g., >3 gm/dL) are suggestive of chronic active hepatitis; marked increases are suggestive of autoimmune chronic hepatitis. Polyclonal increases in IgG and IgM are found in most cases of cirrhosis. Increased IgM alone may suggest primary biliary cirrhosis. Increased IgA may occur in alcoholic cirrhosis. Immunoglobulins are usually normal in obstructive jaundice. Serum albumin is slow to reflect liver damage. Is usually normal in hepatitis and cholestasis. Increase toward normal by 2–3 gm/dL in treatment of cirrhosis implies improvement and more favorable prognosis than if no increase with therapy. Some patients do not present the usual pattern. Liver function test abnormalities may occur in systemic diseases, e.g., SLE, sarcoidosis, TB, SBE, brucellosis, sickle cell disease. A confusing pattern may occur in mixed forms of jaundice (e.g., sickle cell disease producing hemolysis and complicated by pigment stones causing duct obstruction). DISORDERS OF THE LIVER, GALLBLADDER, BILIARY TREE, AND PANCREAS
- 139. ABSCESS OF LIVER, PYOGENIC Due To Biliary tract infection, 33% Direct extension, 25% Trauma, 15% Bacteremia, 10% Pyelophlebitis, 6% Unknown, 10% w Gram stain and culture Gram-negative bacilli (e.g., Escherichia coli, Klebsiella spp.) Anaerobes (e.g., Bacteroides fragilis) Staphylococcus aureus or streptococci are found in children with bacteremia. w Abnormalities of liver function tests Decreased serum albumin in 50% of cases; increased serum globulin Increased serum ALP in 75% of cases Increased serum bilirubin in 20–25% of cases; >10 mg/dL usually indicates pyogenic rather than amebic origin and suggests poorer prognosis because of more tissue destruction See Space-Occupying Lesions Increase in WBC due to increase in granulocytes in 70% of cases Anemia in 60% of cases Ascites is unusual compared to other causes of space-occupying lesions. Laboratory findings due to complications (e.g., right pleural effusion in 20% of cases, subphrenic abscess, pneumonia, empyema, bronchopleural fistula) w Patients with amebic abscess of liver due to Entamoeba histolytica also show positive serologic tests for ameba. Stools may be negative for cysts and trophozoites. Needle aspiration of abscess may show E. histolytica in 50% of patients. Characteristic brown or anchovy-sauce color may be absent; secondary bacterial infection may be superimposed. See Echinococcus granulosus cyst. BILIARY ATRESIA, EXTRAHEPATIC, CONGENITAL m Direct serum bilirubin is increased in early days of life in some infants but not until second week in others. Level is often <12 mg/dL during first months, with subsequent rise later in life. m Laboratory findings as in Biliary Obstruction, Complete (see next section). w Liver biopsy to differentiate from neonatal hepatitis. Laboratory findings due to sequelae (e.g., biliary cirrhosis, portal hypertension, frequent infections, rickets, hepatic failure) 131I-rose bengal excretion test (see Neonatal Hepatitis) Most important to differentiate this condition from neonatal hepatitis, for which surgery may be harmful. >90% of cases of extrahepatic biliary obstruction in newborns are due to biliary atresia; occasional cases may be due to choledochal cyst (causes intermittent jaundice in infancy), bile plug syndrome, or bile ascites (associated with spontaneous perforation of the common bile duct). BILIARY OBSTRUCTION, COMPLETE (INTRAHEPATIC OR EXTRAHEPATIC) m Typical pattern of extrahepatic obstruction includes increased serum ALP (>2–3× normal), AST <300 U/L, increased direct serum bilirubin. In extrahepatic type, the increased ALP is related to the completeness of obstruction. Normal ALP is extremely rare in extrahepatic obstruction. Very high levels may also occur in cases of intrahepatic cholestasis. Serum LAP parallels ALP. AST is increased (£ 300 U) and ALT is increased £ 200 U); levels usually return to normal in 1 wk after relief of obstruction. In acute biliary duct obstruction (e.g., due to common bile duct stones or acute pancreatitis), AST and ALT are increased >300 U (and often >2000 U) and decline 58–76% in 72 hrs without treatment; simultaneous serum total bilirubin shows less marked elevation and decline, and ALP changes are inconsistent and unpredictable. Direct serum bilirubin is increased; indirect serum bilirubin is normal or slightly increased. Serum cholesterol is increased (acute, 300–400 mg/dL; chronic, £ 1000 mg/dL). Serum phospholipids are increased.
- 140. PT is prolonged, with response to parenteral vitamin K more frequent than in hepatic parenchymal cell disease. Urine bilirubin is increased; urine urobilinogen is decreased. Stool bilirubin and urobilinogen are decreased (clay-colored stools). Laboratory findings due to underlying causative disease are noted (e.g., stone, carcinoma of duct, metastatic carcinoma to periductal lymph nodes). Bile Duct Obstruction (One) m Characteristic pattern is serum bilirubin that remains normal in the presence of markedly increased serum ALP. BREAST-MILK JAUNDICE (Due to the presence in mother's milk of 5-b-pregnane-3-a-20-b-diol, which inhibits glucuronyl transferase activity) m Severe unconjugated hyperbilirubinemia. Develops in 1% of breast-fed infants by fourth to seventh day. Reaches peak of 15–25 mg/dL by second to third week, then gradually disappears in 3–10 wks in all cases. If nursing is interrupted, serum bilirubin falls rapidly by 2–6 mg/dL in 2–6 days and may rise again if breast-feeding is resumed; if interrupted for 6–9 days, serum bilirubin becomes normal. No other abnormalities are present. Kernicterus does not occur. CHOLANGITIS, ACUTE Marked increase in WBC (£ 30,000/cu mm) with increase in granulocytes m Blood culture positive in ~30% of cases; 25% of these are polymicrobial. m Laboratory findings of incomplete duct obstruction due to inflammation or of preceding complete duct obstruction (e.g., stone, tumor, scar). See Choledocholithiasis. m Laboratory findings of parenchymal cell necrosis and malfunction Increased serum AST, ALT, etc. Increased urine urobilinogen CHOLANGITIS, PRIMARY SCLEROSING (Chronic fibrosing inflammation of intra- and extrahepatic bile ducts predominantly in men younger than age 45 years; rare in pediatric patients; £ 75% of cases are associated with inflammatory bowel disease, especially ulcerative colitis; slow, relentless, progressive course of chronic cholestasis to death [usually from liver failure]. 25% of patients are asymptomatic at time of diagnosis.) w Diagnosis should not be made if there is previous bile duct surgery, gallstones, suppurative cholangitis, bile duct tumor, or damage due to floxuridine, AIDS, congenital duct anomalies. w Characteristic cholangiogram is required for diagnosis; distinguishes it from primary biliary cirrhosis. m Cholestatic biochemical profile for >6 mos Serum ALP may fluctuate but is always increased >1.5× upper limit of normal (usually ³3× upper limit of normal). Serum GGT is increased. Serum AST is mildly increased in >90%. ALT is greater than AST in three-fourths of cases. Serum bilirubin is increased in one-half of patients; occasionally is very high; may fluctuate markedly; gradually increases as disease progresses. Persistent value >1.5 mg/dL is poor prognostic sign that may indicate irreversible, medically untreatable disease. Increased gamma globulin in 30% of cases and increased IgM in 40–50% of cases ANCAs in ~65% of cases and ANAs in <35% are present at higher levels than in other liver diseases, but diagnostic significance is not yet known. In contrast to primary biliary cirrhosis, antimitochondrial antibody, smooth-muscle antibody and RF are negative in >90% of patients. HBsAg is negative. m Liver biopsy provides only confirmatory evidence in patients with compatible history, laboratory, and radiographic findings. Liver copper is usually increased but serum ceruloplasmin is also increased. Laboratory findings due to sequelae Cholangiocarcinoma in 10–15% of patients may cause increased serum CA 19-9. Portal hypertension, biliary cirrhosis, secondary bacterial cholangitis, steatorrhea and malabsorption, cholelithiasis, liver failure. Laboratory findings due to underlying disease, e.g., £ 7.5% of ulcerative colitis patients have this disease; many fewer patients with Crohn's disease. Associated with syndrome of retroperitoneal and mediastinal fibrosis. CHOLECYSTITIS, ACUTE Increased ESR, WBC (average 12,000/cu mm; if >15,000 suspect empyema or perforation), and other evidence of acute inflammatory process Serum AST is increased in 75% of patients. Increased serum bilirubin in 20% of patients (usually <4 mg/dL; if higher, suspect associated choledocholithiasis)
- 141. Increased serum ALP (some patients) even if serum bilirubin is normal Increased serum amylase and lipase in some patients Laboratory findings of associated biliary obstruction if such obstruction is present Laboratory findings of preexisting cholelithiasis (some patients) Laboratory findings of complications (e.g., empyema of gallbladder, perforation, cholangitis, liver abscess, pyelophlebitis, pancreatitis, gallstone ileus) CHOLECYSTITIS, CHRONIC May be mild laboratory findings of acute cholecystitis or no abnormal laboratory findings. May be laboratory findings of associated cholelithiasis. CHOLEDOCHOLITHIASIS During or soon after an attack of biliary colic Increased WBC Increased serum bilirubin in approximately one-third of patients Increased urine bilirubin in approximately one-third of patients Increased serum and urine amylase Increased serum ALP m Laboratory evidence of fluctuating or transient cholestasis. Persistent increase of WBC, AST, ALT suggests cholangitis. Laboratory findings due to secondary cholangitis, acute pancreatitis, obstructive jaundice, stricture formation, etc. In duodenal drainage, crystals of both calcium bilirubinate and cholesterol (some patients); 50% accurate (only useful for nonicteric patients) CHOLELITHIASIS Laboratory findings of underlying conditions causing hypercholesterolemia (e.g., diabetes mellitus, malabsorption) may be present. Laboratory findings of causative chronic hemolytic disease (e.g., hereditary spherocytosis) Laboratory findings due to complications (e.g., cholecystitis, choledocholithiasis, gallstone ileus) CHOLESTASIS See Table 8-2. m Increased serum ALP m Increased GGT, 5'-NT, and LAP parallel ALP and confirm the hepatic source of ALP. m Increased serum cholesterol and phospholipids but not triglycerides m Increased fasting serum bile acid (>1.5 µg/mL) with ratio of cholic acid to chenodeoxycholic acid >1 in primary biliary cirrhosis and many intrahepatic cholestatic conditions but <1 in most chronic hepatocellular conditions (e.g., Laënnec's cirrhosis, chronic active hepatitis). (Relatively little experience exists with this test.) Cholestasis may occur without hyperbilirubinemia. Table 8-2. Comparison of Various Types of Cholestatic Disease Due To Canalicular Drugs (e.g., estrogens, anabolic steroids)—most common cause (see Table 8-3)
- 142. Table 8-3. Comparison of Three Main Types of Liver Disease Due to Drugs Normal pregnancy Alcoholic hepatitis Infections, e.g., Acute viral hepatitis Gram-negative sepsis Toxic shock syndrome AIDS Parasitic, fungal infection Sickle cell crisis Postoperative state after long procedure and multiple transfusions Benign recurrent familial intrahepatic cholestasis (rare) Non-Hodgkin's lymphoma more often than Hodgkin's disease Amyloidosis Sarcoidosis Interlobular Bile Ducts Sclerosing pericholangitis (associated with inflammatory bowel disease) Primary biliary cirrhosis Postnecrotic cirrhosis (20% of cases) Congenital intrahepatic biliary atresia Interlobular and Larger Intrahepatic Bile Ducts Multifocal lesions (e.g., metastases, lymphomas, granulomas) Larger Intrahepatic Bile Ducts Sclerosing cholangitis Intraductal stones Intraductal papillomatosis Cholangiocarcinoma Caroli's disease (congenital biliary ectasia) Extrahepatic Ducts (Surgical or Extrahepatic Jaundice) Carcinoma (e.g., pancreas, ampulla, bile ducts, gallbladder) Stricture, stone, cyst, etc., of ducts Pancreatitis (acute, chronic), pseudocysts Increased risk of cholangiocarcinoma in progressive cholestatic diseases. CHOLESTASIS, BENIGN RECURRENT INTRAHEPATIC (Familial condition; attacks begin after age 8 yrs, last weeks to months, complete resolution between episodes, may recur after months or years; exacerbated by estrogens.) Increased serum ALP
- 143. Transaminase usually <100 U. Serum bilirubin may be normal or £ 10 mg/dL. Liver biopsy shows centrolobular cholestasis without inflammation. CHOLESTASIS, NEONATAL Due To Idiopathic neonatal hepatitis 50–60% Extrahepatic biliary atresia 20% Metabolic disease Alpha1-antitrypsin deficiency 15% Cystic fibrosis Tyrosinemia Galactosemia Niemann-Pick disease Defective bile acid synthesis Infection (e.g., CMV infection, syphilis, sepsis, GU tract infection) Toxic causes (e.g., drugs, parenteral nutrition) Other conditions Paucity of bile ducts (Alagille syndrome) Indian childhood cirrhosis Hypoperfusion/shock CIRRHOSIS, PRIMARY BILIARY (CHOLANGIOLITIC CIRRHOSIS, HANOT'S HYPERTROPHIC CIRRHOSIS, CHRONIC NONSUPPURATIVE DESTRUCTIVE CHOLANGITIS, ETC.) (Multisystem autoimmune disease; chronic nonsuppurative inflammation and destruction of small intrahepatic bile ducts producing chronic cholestasis and cirrhosis) w Diagnostic Criteria Laboratory findings of Cholestatic pattern (increased ALP) of long duration (may last for years) not due to known cause (e.g., drugs). Antimitochondrial autoantibodies present. Confirmed patency of bile ducts (e.g., with ultrasonography or computed tomographic [CT] scan). Compatible liver biopsy is highly desirable. w Serum ALP is markedly increased; is of liver origin. Reaches a plateau early in the course and then fluctuates within 20% thereafter; changes in serum level have no prognostic value. 5'-NT and GGT parallel ALP. This is one of the few conditions that elevates both serum ALP and GGT to striking levels. w Serum mitochondrial antibody titer is strongly positive (1:40–1:80) in ~95% of patients and is hallmark of disease (98% specificity); titer >1:160 is highly predictive of primary biliary cirrhosis (PBC) even in absence of other findings. Does not correlate with severity or rate of progression. Titers differ greatly in patients. Similar titers occur in 5% of patients with chronic hepatitis; low titers occur in 10% of patients with other liver disease; rarely found in normal persons. Titer usually decreases after liver transplantation but generally remains detectable. w Serum bilirubin is normal in early phase but increases in 60% of patients with progression of disease and is a reliable prognostic indicator; an elevated level is a poor prognostic sign. Direct serum bilirubin is increased in 80% of patients; levels >5 mg/dL in only 20% of patients; levels >10 mg/dL in only 6% of patients. Indirect bilirubin is normal or slightly increased. w Laboratory findings show relatively little evidence of parenchymal damage. AST and ALT may be normal or slightly increased (up to 1–5× normal), may fluctuate within a narrow range, and have no prognostic significance. Serum albumin, globulin, and PT normal early; abnormal values indicate advanced disease and poor prognosis; not corrected by therapy. w Marked increase in total cholesterol and phospholipids with normal triglycerides; serum is not lipemic; serum triglycerides become elevated in late stages. Associated with xanthomas and xanthelasmas. In early stages, LDL and VLDL are mildly elevated and HDL is markedly elevated (thus atherosclerosis is rare). In advanced stage, LDL is markedly elevated with decreased HDL and presence of lipoprotein X (nonspecific abnormal lipoprotein seen in other cholestatic liver disease). m Serum IgM is increased in ~75% of patients; levels may be very high (4–5× normal). Other serum immunoglobulins are also increased. Hypocomplementemia Polyclonal hypergammaglobulinemia w Biopsy of liver categorizes the four stages and helps assess prognosis, but needle biopsy is subject to sampling error because the lesions may be spotty; findings consistent with all four stages may be found in one specimen. m Serum ceruloplasmin is characteristically elevated (in contrast to Wilson's disease).
- 144. Liver copper may be increased 10–100× normal; correlates with serum bilirubin and advancing stages of disease. ESR is increased 1–5× normal in 80% of patients. Urine contains urobilinogen and bilirubin. Laboratory findings of steatorrhea, including the following: Serum 25-hydroxyvitamin D and vitamin A are usually low. PT is normal or restored to normal by parenteral vitamin K. Laboratory findings due to associated diseases >80% of patients have at least one other and >40% have at least two other circulating antibodies to autoimmune disease (e.g., RA, autoimmune thyroiditis [hypothyroidism in 20% of patients], Sjögren's syndrome, scleroderma) although not useful diagnostically. Laboratory findings due to sequelae and complications Portal hypertension, hypersplenism Treatment-resistant osteoporosis Hepatic encephalopathy, liver failure Renal tubular acidosis (due to copper deposition in kidney) is frequent but usually subclinical. Increased susceptibility to urinary tract infection is associated with advanced disease. Should be ruled out in an asymptomatic female with elevated serum ALP without obesity, diabetes mellitus, alcohol abuse, use of some drugs. CIRRHOSIS OF LIVER w Criteria for diagnosis liver biopsy or at least three of the following: Hyperglobulinemia, especially with hypoalbuminemia Low-protein (<2.5 g/dL) ascites Evidence of hypersplenism (usually thrombocytopenia, often with leukopenia and less often with Coombs'-negative hemolytic anemia) Evidence of portal hypertension (e.g., varices) Characteristic "corkscrew" hepatic arterioles on celiac arteriography Shunting of blood to bone marrow on radioisotope scan Abnormality of serum bilirubin, transaminases, or ALP is often not present and therefore not required for diagnosis. m Serum bilirubin is often increased; may be present for years. Fluctuations may reflect liver status due to insults to the liver (e.g., alcoholic debauches). Most bilirubin is of the indirect type unless cirrhosis is of the cholangiolitic type. Higher and more stable levels occur in postnecrotic cirrhosis; lower and more fluctuating levels occur in Laënnec's cirrhosis. Terminal icterus may be constant and severe. m Serum AST is increased (<300 U) in 65–75% of patients. Serum ALT is increased (<200 U) in 50% of patients. Transaminases vary widely and reflect activity or progression of the process (i.e., hepatic parenchymal cell necrosis). Serum ALP is increased in 40–50% of patients. m Serum total protein is usually normal or decreased. Serum albumin parallels functional status of parenchymal cells and may be useful for following progress of liver disease; but it may be normal in the presence of considerable liver cell damage. Decreasing serum albumin may reflect development of ascites or hemorrhage. Serum globulin level is usually increased; it reflects inflammation and parallels the severity of the inflammation. Increased serum globulin (usually gamma) may cause increased total protein, especially in chronic viral hepatitis and posthepatitic cirrhosis. Serum total cholesterol is normal or decreased. Progressive decrease in cholesterol, HDL, LDL with increasing severity. Decrease is more marked than in chronic active hepatitis. LDL may be useful for prognosis and selection of patients for transplantation. Decreased esters reflect more severe parenchymal cell damage. Urine bilirubin is increased; urobilinogen is normal or increased. BUN is often decreased (<10 mg/dL); increased with GI hemorrhage. Serum uric acid is often increased. Electrolytes and acid-base balance are often abnormal and reflect various combinations of circumstances at the time, such as malnutrition, dehydration, hemorrhage, metabolic acidosis, respiratory alkalosis. In cirrhosis with ascites, the kidney retains increased sodium and excessive water, causing dilutional hyponatremia. Blood ammonia is increased in liver coma and cirrhosis and with portacaval shunting of blood. Anemia reflects increased plasma volume and some increased destruction of RBCs. If more severe, rule out hemorrhage in GI tract, folic acid deficiency, excessive hemolysis, etc. WBC is usually normal with active cirrhosis; increased (<50,000/cu mm) with massive necrosis, hemorrhage, etc.; decreased with hypersplenism. m Laboratory findings due to complications or sequelae, often in combination Portal hypertension. Ascites. Esophageal varices. Portal vein thrombosis. Liver failure. Hepatocarcinoma. Abnormalities of coagulation mechanisms (see Chapter 11), e.g., Prolonged PT (does not respond to parenteral vitamin K as frequently as in patients with obstructive jaundice). Prolonged bleeding time in 40% of cases due to decreased platelets and/or fibrinogen (see Chapter 11). Hepatic encephalopathy. Increased arterial ammonia.
- 145. CSF glutamine >35 mg/dL (due to conversion from ammonia); correlates with depth of coma and more sensitive than arterial ammonia. Spontaneous bacterial peritonitis—in £ 10% of alcoholic cirrhosis cases. 70% have positive blood culture; usually single organism, especially E. coli, Pneumococcus, Klebsiella. Hepatorenal syndrome. Most commonly death is due to liver failure, bleeding, infections. Laboratory findings due to causative/associated diseases or conditions Frequency in USA • Chronic viral hepatitis (HBV with or without HDV, HCV) 10% • Alcoholism 60–70% • Wilson's disease Rare • Autoimmune chronic active hepatitis • Hemochromatosis 5% • Mucoviscidosis • Glycogen-storage diseases • Galactosemia • Alpha1-antitrypsin deficiency Rare • Porphyria • Fructose intolerance • Tyrosinosis • Infections (e.g., congenital syphilis, schistosomiasis) • Gaucher's disease • Ulcerative colitis • Osler-Weber-Rendu disease • Venous outflow obstruction (e.g., Budd-Chiari syndrome, venoocclusive disease, congestive heart failure) • Biliary disease (e.g., primary biliary cirrhosis, sclerosing cholangitis 5–10% • Cryptogenic 10–15% CRIGLER-NAJJAR SYNDROME (HEREDITARY GLUCURONYL TRANSFERASE DEFICIENCY) (Rare familial autosomal recessive disease due to marked congenital deficiency or absence of glucuronyl transferase, which conjugates bilirubin to bilirubin glucuronide in hepatic cells [counterpart is the homozygous Gunn rat]) See Table 8-4. Table 8-4. Differential Diagnosis of Hereditary Jaundice with Normal Liver Chemistries and No Signs or Symptoms of Liver Disease Type I Indirect serum bilirubin is increased; it appears on first or second day of life, rises in 1 wk to peak of 12–45 mg/dL, and persists for life. No direct bilirubin in serum or urine. Fecal urobilinogen is very low. Liver function tests are normal; sulfobromsulfophthalein (BSP) is normal. Liver biopsy is normal. No evidence of hemolysis is found. Untreated patients often die of kernicterus by age 18 mos. Nonjaundiced parents have diminished capacity to form glucuronide conjugates with menthol, salicylates, and tetrahydrocortisone. Type I should always be ruled out when persistent unconjugated bilirubin levels of 20 mg/dL are seen after 1 wk of age without obvious hemolysis and especially after breast-milk jaundice has been ruled out. This syndrome has been divided into two groups: Type I Type II Transmission Autosomal recessive Autosomal dominant Hyperbilirubinemia More severe (usually >20 mg/dL) Less severe and more variable (usually 20 mg/dL) Kernicterus Frequent Absent Bile Essentially colorless Normal color Bilirubin-glucuronide Totally absent Present
- 146. Bilirubin concentration Very low (<10 mg/dL) Only traces of conjugated bilirubin Nearly normal (50–100 mg/dL) Stool color Pale yellow Normal Parents Normal serum bilirubin in both parents Partial defect (~50%) in glucuronide conjugation in both parents One parent usually shows minimal to severe icterus Defect in glucuronide conjugation may be pressent in only one parent Type II Patients have partial deficiency of glucuronyl transferase (autosomal dominant with incomplete penetrance). Not related to type I syndrome; may be homozygous form of Gilbert's disease. Patient may not become jaundiced until adolescence. Neurologic complications are rare. Serum indirect bilirubin = 6–25 mg/dL. Increases with fasting or removal of lipid from diet. May decrease to <5 mg/dL with phenobarbital treatment. DUBIN-JOHNSON SYNDROME (SPRINZ-NELSON SYNDROME) (Autosomal recessive disease due to inability to transport bilirubin-glucuronide through hepatocytes into canaliculi, but conjugation of bilirubin-glucuronide is normal. Characterized by mild chronic, recurrent jaundice; hepatomegaly and right upper quadrant abdominal pain may be present. Usually is compensated except in periods of stress. Jaundice [innocuous and reversible] may be produced by estrogens, birth control pills, or last trimester of pregnancy. May resemble mild viral hepatitis.) See Table 8-4. m Serum bilirubin is increased (3–10 mg/dL; rarely £ 30 mg/dL); significant amount is direct. Urine contains bile and urobilinogen. w BSP excretion is impaired with late (1.5- to 2-hr) increase; virtually pathognomonic. m Other liver function tests are normal. w Urine total coproporphyrin is usually normal but ~80% is coproporphyrin I (normally 75% is coproporphyrin III); diagnostic of Dubin-Johnson syndrome. Not useful to detect individual heterozygotes. m Liver biopsy shows large amounts of yellow-brown or slate-black pigment in centrolobular hepatic cells (lysosomes) and small amounts in Kupffer's cells. FATTY LIVER Laboratory findings are due to underlying conditions (most commonly alcoholism; nonalcoholic fatty liver is commonly associated with non–insulin dependent diabetes mellitus [£ 75%], obesity [69–100%], hyperlipidemia [20–81%]; malnutrition, toxic chemical exposure) w Biopsy of liver establishes the diagnosis. Nonalcoholic fatty liver is distinguished by negligible history of alcohol consumption and negative random blood alcohol assays. Liver function tests Most commonly, serum AST and ALT are increased 2–3×; usually ALT >AST. Serum ALP is normal or slightly increased in <50% of patients. Increased serum ferritin (£ 5×) and transferrin saturation in ~60% of cases. Other liver function tests are usually normal. Serologic tests for viral hepatitis are negative. Cirrhosis occurs in £ 50% of alcoholic and £ 17% of nonalcoholic cases. Biochemically different form occurs in acute fatty liver of pregnancy, Reye's syndrome, tetracycline administration. Fatty liver may be the only postmortem finding in cases of sudden, unexpected death.1 FATTY LIVER OF PREGNANCY, ACUTE (Incidence of 1 per 13,328 deliveries; usually occurs after 35th week of pregnancy. Medical emergency because of high maternal and fetal mortality, which is markedly improved by termination of pregnancy.) Often associated with toxemia Increased AST and ALT to ~300 U (rarely >500 U) are used for early screening in suspicious cases; ratio is not helpful in differential diagnosis. Increased WBC in >80% of cases (often >15,000/cu mm) Evidence of DIC in >75% of patients Serum uric acid is increased disproportionately to BUN and creatinine, which may also be increased. Serum bilirubin may be normal early but will rise unless pregnancy terminates. Blood ammonia is usually increased. Blood glucose is often decreased, sometimes markedly. Neonatal liver function tests are usually normal, but hypoglycemia may occur. w Biopsy of liver confirms the diagnosis.
- 147. GALLBLADDER AND BILE DUCT CANCER Laboratory findings reflect varying location and extent of tumor infiltration that may cause partial intrahepatic duct obstruction or obstruction of hepatic or common bile duct, metastases in liver, or associated cholangitis; 50% of patients have jaundice at the time of hospitalization. Laboratory findings of duct obstruction are of progressively increasing severity in contrast to the intermittent or fluctuating changes due to duct obstruction caused by stones. A papillary intraluminal duct carcinoma may undergo periods of sloughing, producing the findings of intermittent duct obstruction. Anemia is present. w Cytologic examination of aspirated duodenal fluid may demonstrate malignant cells. m Silver-colored stool due to jaundice combined with GI bleeding may be seen in carcinoma of duct or ampulla of Vater. Laboratory findings of the preceding cholelithiasis are present (gallbladder cancer occurs in ~3% of patients with gallstones). GILBERT'S DISEASE (Chronic, benign, intermittent, familial [autosomal dominant with incomplete penetrance], nonhemolytic unconjugated hyperbilirubinemia with evanescent increases of indirect serum bilirubin, which is usually discovered on routine laboratory examinations; due to defective transport and conjugation of unconjugated bilirubin. Jaundice is usually accentuated by pregnancy, fever, exercise, and various drugs, including alcohol and birth control pills. Rarely identified before puberty. May be mildly symptomatic. 3–7% prevalence in total population.) See Table 8-4. w Presumptive diagnostic criteria Exclusion of other diseases. Unconjugated hyperbilirubinemia on several occasions. Liver chemistries and hematologic parameters are normal. w Indirect serum bilirubin is increased transiently and has been previously normal at least once in £ 33% of patients. It may rise to 18 mg/dL but usually is <4 mg/dL. Considerable daily and seasonal fluctuation. Fasting (<400 calories/day) for 72 hrs causes elevated indirect bilirubin to increase >100% in Gilbert's disease but not in healthy persons (increase <0.5 mg/dL) or those with liver disease or hemolytic anemia. Fasting bilirubin returns to baseline 12–24 hrs after resumption of normal diet. Combination of basal total bilirubin >1.2 mg/dL and fasting increase of unconjugated bilirubin >1 mg/dL has sensitivity of 84%, specificity of 78%, positive predictive value of 85%, negative predictive value of 76%. Provocative tests are rarely needed. Direct serum bilirubin is normal but may give elevated results by liquid diazo methods but not by dry methods or chromatography. Enzyme inducers (e.g., phenobarbital) normalize unconjugated bilirubin in 1–2 wks. Prednisone administration reduces bilirubin concentration. Liver function tests are usually normal. Fecal urobilinogen usually normal but may be decreased. Urine shows no increased bilirubin. Liver biopsy is normal. HEART FAILURE (CONGESTIVE), LIVER FUNCTION ABNORMALITIES Pattern of abnormal liver function tests is variable depending on severity of heart failure; the mildest cases show only slightly increased ALP and slightly decreased serum albumin; moderately severe cases also show slightly increased serum bilirubin and GGT; one-fourth to three-fourths of the most severe cases also show increased AST and ALT (£ 200 U/L) and LD (£ 400 U/L). All return to normal when heart failure responds to treatment. Serum ALP is usually the last to become normal, and this may occur weeks to months later. Serum bilirubin is frequently increased (indirect more than direct); usually 1–5 mg/dL. It usually represents combined right- and left-sided failure with hepatic engorgement and pulmonary infarcts. Serum bilirubin may suddenly rise rapidly if superimposed myocardial infarction occurs. AST and ALT are disproportionately increased compared with other liver function tests in left-sided heart failure. PT may be slightly increased, with increased sensitivity to anticoagulant drugs. Serum cholesterol and esters may be decreased. Urine urobilinogen is increased. Urine bilirubin is increased in the presence of jaundice. These findings may occur with marked liver congestion due to other conditions (e.g., Chiari's syndrome [occlusion of hepatic veins] and constrictive pericarditis). HEMOCHROMATOSIS2, 3 and 4 See Fig. 8-4. Fig. 8-4. Sequence of tests for hemochromatosis screening and treatment.
- 148. Due To Hereditary hemochromatosis is an autosomal recessive defect in the ability of the duodenum to regulate iron absorption; abnormal gene present in 10% of white Americans; frequency of homozygosity >3 in 1000. 1–3% of heterozygotes develop iron overload; may be due to coincidental condition with altered iron absorption or metabolism. Other primary causes of iron overload (may have one hemochromatosis allele) Neonatal hemochromatosis Juvenile hemochromatosis African iron overload Aceruloplasminemia Secondary Increased intake (e.g., excessive medicinal iron ingestion, long-term frequent transfusions, Bantu siderosis) Anemias with increased erythropoiesis (especially thalassemia major; also thalassemia minor, some other hemoglobinopathies, paroxysmal nocturnal hemoglobinuria, sideroblastic anemias, refractory anemias with hypercellular bone marrow, pyruvate kinase deficiency, pyridoxine-responsive anemia, X-linked iron-loading anemia, etc.) Chronic hemodialysis Porphyria cutanea tarda (minor) Alcoholic liver disease (minor; deposited in Kupffer's cells, not hepatocytes) After portal-systemic shunt Congenital atransferrinemia w Increased transferrin saturation (= serum iron ÷ total iron-binding capacity × 100); usually >70% and frequently approaches 100%; repeat fasting transferrin saturation >60% in men and >50% in women without other known causes probably represents hemochromatosis; 50–62% usually indicates heterozygous state but occasionally found in homozygous persons. Most heterozygotes have no detectable changes unless a secondary cause (e.g., thalassemia) is present. If value is increased, patient should be retested (fasting) twice at weekly intervals. Screening discovers hemochromatosis in 2–3 of 1000 persons; should be sought especially in patients with diabetes mellitus, congestive heart failure, idiopathic cardiomyopathy, arthritis, alcoholic cirrhosis, bronze skin, hypogonadism. w Increased serum ferritin (usually >1000 µg/L); increased in approximately two-thirds of patients with hemochromatosis. Is good index of total body iron but has limited value for screening because may be increased in acute inflammatory conditions and less sensitive than transferrin saturation in early cases. May not be increased in patients who have not yet accumulated excess amounts of iron (e.g., children, young adults, premenopausal women). >5000 µg/L indicates tissue damage (e.g., liver degeneration) with release of ferritin into circulation. >350 µg/L in fasting men and >250 µg/L in women is recommended for screening. Critical threshold associated with cirrhosis is unknown. Liver biopsy is probably not indicated if serum ferritin is normal. w Serum iron is increased (usually >200 µg/dL in women and >300 µg/dL in men and typically >1000 µg/dL) but should not be only screening test because of many other conditions in which it occurs. Confirm by measuring repeat fasting sample at least two more times. Serum iron levels may show marked diurnal variation, with lowest values in evening and highest between 7 a.m. and noon. w TIBC is decreased (~200 µg/dL; often approaches zero; generally higher in secondary than primary type). w Liver biopsy is needed to confirm or refute diagnosis, grade amount of iron, and assess tissue damage (presence of fibrosis/cirrhosis, other liver diseases). Is indicated when repeat fasting serum ferritin (>750 mg/L) and transferrin saturation are increased after 4–6 wks of abstinence from alcohol. Histologic examination confirms increased stainable iron (special stain) in perilobular hepatocytes and biliary epithelium in hereditary hemochromatosis with little in Kupffer's cells (in contrast to secondary iron overload) or bone marrow, with or without inactive cirrhosis. In later stages, liver biopsy alone does not distinguish hereditary hemochromatosis from secondary hemochromatosis. Liver iron is increased (normal 200–2000 µg/gm in men and 200–1600 µg/gm in women). >1000 µg/100 mg of dry liver is consistent with homozygous state but level may reach 5000. Some heterozygotes may reach 1000 µg/100 mg but do not progress beyond this level. Fibrosis or cirrhosis usually does not occur at levels <2000 µg/100 mg dry liver unless alcoholism is also present. For chemical analysis of iron, use acid-washed needle and place specimen in iron-free container. Liver iron and serum ferritin may also be increased in alcoholic cirrhosis but levels are not as abnormal (<2× normal) as in hemochromatosis. Liver iron must be related to patient age: hepatic iron index (micrograms/gram divided by 55.8 × age) in homozygotes is ³1.9; in heterozygotes usually £ 1.5. False negative may be due to phlebotomy treatment; false positive may be due to secondary hemosiderosis. Another calculation is liver iron (micromoles/gram dry weight) divided by patient age; value >2 in homozygotes; <2 in heterozygotes, healthy persons, patients with alcoholic liver disease. Other tests to assess iron stores (when liver biopsy is not possible) Chelating agent (0.5 gm IM deferoxamine mesylate) causes urinary excretion >5 mg/24 hrs in hereditary hemochromatosis but <2 mg/24 hrs in normal persons. Measures only chelatable iron rather than total iron stores so may underdiagnose hereditary hemochromatosis; not a useful diagnostic test. Weekly phlebotomy for 5–10 wks causes iron deficiency in alcoholic liver disease but >50 weekly phlebotomies are required in hereditary hemochromatosis. m Presence of excess iron in other tissue biopsy sites (e.g., synovia, GI tract) should arouse suspicion of hereditary hemochromatosis; iron stains should be done. Bone marrow biopsy stained for iron is not useful for diagnosis of hereditary hemochromatosis. Liver function tests depend on presence and degree of liver damage (e.g., cirrhosis). On average, women have serum ferritin concentrations 1000 µg/L less than men; men have twice the incidence of cirrhosis (25%) and diabetes (15%) compared with women. Laboratory findings due to involvement of various organs Insulin-dependent diabetes mellitus in 40–75% of cases; glucose intolerance Osteoarthritis and chondrocalcinosis (pseudogout) in 50% of cases Cardiomyopathy in 33% of cases (congestive heart failure) Hypogonadism/pituitary dysfunction in ~50% of cases Skin pigmentation Underlying diseases m Laboratory findings due to complications and sequelae Increased susceptibility to severe bacterial infection, especially Yersinia sepsis (also occurs in other iron overload conditions). Cirrhosis in 69% of cases. Does not resolve with phlebotomy. Increased risk of hepatocellular carcinoma. Associated alcoholism. Hepatocellular carcinoma develops in £ 30% of cases and has become the chief cause of death in hereditary hemochromatosis. Portal hypertension. m When diagnosis of hereditary hemochromatosis is established, other family members should be screened; one-fourth of siblings have the disease; 5% of patients' children are homozygous for hemochromatosis gene. Relatives with negative results should be rescreened every 5 yrs.
- 149. m Genotyping is not used for screening to discover sporadic cases but useful to identify patient's siblings at risk because HLA-identical sibs almost always are also homozygous for hemochromatosis gene and at high risk for developing clinical disease. May be useful to distinguish patients with primary hereditary hemochromatosis from cirrhotic patients with secondary iron overload and siderosis. DNA test for hereditary hemochromatosis gene is available, but diagnostic role is being evaluated. C282Y or H63D present in 69–97% of affected patients; would not identify £ 31% of clinically affected patients. May ultimately replace HLA typing. Adequate treatment with phlebotomy (1–3 U/wk) sufficient to maintain a mild anemia is determined by Hct (37–39%) before each phlebotomy. If >40%, an additional treatment may be scheduled. Serum iron and ferritin are used only when anemia become refractory to establish whether iron stores are exhausted. Maintenance phlebotomy (4–6 U/yr) can be monitored with serum ferritin to indicate normal amount of storage iron. Insulin requirement decreases in more than one-third of diabetics; liver function tests often improve; arthritis, impotence, and sterility usually do not improve. Removal of 450–500 mL of blood causes loss of 200–250 mg of iron. HEMOCHROMATOSIS, NEONATAL (Severe iron overload disorder with onset in utero. Death usually occurs soon after birth.) Oligohydramnios or less commonly polyhydramnios may indicate intrauterine growth retardation or fetal hydrops. m Fulminant liver failure including hyperbilirubinemia, decreased transaminases, glucose, and albumin. Increased AFP. Variable fibrinogen consumption, thrombocytopenia, anemia, acanthocytosis. w Marked hepatic and extrahepatic (e.g., heart, pancreas, adrenal; not spleen) siderosis with relative lack in RE cells. Liver iron analysis not useful because high in healthy newborn. HEPATIC ENCEPHALOPATHY (Neurologic and mental abnormalities in some patients with liver failure) m Blood ammonia is increased in 90% of patients but does not reflect the degree of coma. Normal level in comatose patient suggests another cause of coma. Not reliable for diagnosis but may be useful to follow individual patients. May be increased by tight tourniquet or vigorously clenched fist; thus arterial specimen may be preferable. Respiratory alkalosis due to hyperventilation is frequent. Hyponatremia and iatrogenic hypernatremia are frequent complications and are associated with a higher mortality rate. Hypokalemic metabolic alkalosis may occur due to diuretic excess. Serum amino acid profile is abnormal. All serum amino acids are markedly increased in coma due to acute liver failure. CSF is normal except for increased glutamine level. w Diagnosis is clinical; characteristic laboratory findings are supportive but not specific. HEPATIC FAILURE, ACUTE Due To Infection Viral hepatitis (e.g., hepatitis A, B, C, D, E; HSV 1, 2, 6; EBV, CMV). Acute liver failure related to HSV is usually associated with immunosuppressive therapy. Develops in ~1–3% of adults with acute icteric type B hepatitis with resultant death. Other causes rare (e.g., amebic abscesses, disseminated TB). Drugs (e.g., acetaminophen, methyltestosterone, isoniazid, halothane, idiosyncratic reaction) Toxins (e.g., phosphorus, death-cap mushroom [Amanita phalloides]) Acute fatty liver Pregnancy Reye's syndrome Drugs (e.g., tetracycline) Ischemic liver necrosis Shock Budd-Chiari syndrome (acute) Wilson's disease with intravascular hemolysis Congestive heart failure Extracorporeal circulation during open heart surgery Marked infiltration by tumor Acute leukemia Lymphoma Hodgkin's disease Non-Hodgkin's lymphoma Burkitt's lymphoma Malignant histiocytosis m Serum bilirubin progressively increases; may become very high.
- 150. Increased serum AST, ALT, may fall abruptly terminally; serum ALP and GGT may be increased. Serum cholesterol and esters are markedly decreased. Decreased albumin and total protein Electrolyte abnormalities, e.g., Hypokalemia (early) Metabolic alkalosis due to hypokalemia Respiratory alkalosis Lactic acidosis Hyponatremia, hypophosphatemia Hypoglycemia in ~5% of patients m Laboratory findings associated with Hepatic encephalopathy Hepato-renal syndrome Coagulopathy Decreased factors II, V, VII, IX, X cause prolonged PT and aPTT ( PT is never normal in acute hepatic failure ). Decreased antithrombin III. Platelet count <100,000 in two-thirds of patients. Hemorrhage, especially in GI tract Bacterial and fungal infections, especially streptococci and S. aureus Ascites As patient deteriorates, titers of HBsAg, and HBeAg may often fall and disappear. HEPATITIS, ACUTE VIRAL See Table 8-5 and Fig. 8-5. Table 8-5. Comparison of Different Types of Viral Hepatitis Fig. 8-5. Algorithm illustrating use of serologic tests for diagnosis of acute hepatitis. Different types of viral hepatitis cannot be distinguished by clinical features or routine chemistries; serologic tests are needed. Prodromal Period w Serologic markers appear in serum (Table 8-6).
- 151. Table 8-6. Serologic Markers of Viral Hepatitis Bilirubinuria occurs before serum bilirubin increases. Increase in urinary urobilinogen and total serum bilirubin just before clinical jaundice occurs. m Serum AST and ALT both rise during the preicteric phase and show very high peaks (>500 U) by the time jaundice appears. ESR is normal. Leukopenia (lymphopenia and neutropenia) is noted with onset of fever, followed by relative lymphocytosis and monocytosis; may find plasma cells and <10% atypical lymphocytes (in infectious mononucleosis level is >10%). Asymptomatic Hepatitis Biochemical evidence of acute hepatitis is scant and often absent. Acute Icteric Period (Tests show parenchymal cell damage.) Serum bilirubin is 50–75% direct in the early stage; later, indirect bilirubin is proportionately more. Serum AST and ALT fall rapidly in the several days after jaundice appears and become normal 2–5 wks later. In hepatitis associated with infectious mononucleosis, peak levels are usually <200 U and peak occurs 2–3 wks after onset, becoming normal by the fifth week. In toxic hepatitis, levels depend on severity; slight elevations may be associated with therapy with anticoagulants, anovulatory drugs, etc.; poisoning (e.g., carbon tetrachloride) may cause levels £ 300 U. In severe toxic hepatitis (especially carbon tetrachloride poisoning), serum enzymes may be 10–20× higher than in acute hepatitis and show a different pattern, i.e., increase in LD > AST > ALT. In acute hepatitis, ALT > AST > LD. Other liver function tests are often abnormal, depending on severity of the disease—bilirubinuria, abnormal serum protein electrophoresis, ALP, etc. Serum cholesterol/ester ratio is usually depressed early; total serum cholesterol is decreased only in severe disease. Serum phospholipids are increased in mild but decreased in severe hepatitis. Plasma vitamin A is decreased in severe hepatitis. Urine urobilinogen is increased in the early icteric period; at peak of the disease it disappears for days or weeks; urobilinogen simultaneously disappears from stool. ESR is increased; falls during convalescence. Serum iron is often increased. Urine: Cylindruria is common; albuminuria occurs occasionally; concentrating ability is sometimes decreased. Defervescent Period Diuresis occurs at onset of convalescence. Bilirubinuria disappears, whereas serum bilirubin is still increased. Urine urobilinogen increases. Serum bilirubin becomes normal after 3–6 wks. ESR falls. Anicteric Hepatitis Laboratory findings are the same as in the icteric type, but abnormalities are usually less marked and serum bilirubin shows slight or no increase. Acute Fulminant Hepatitis with Hepatic Failure Cholangiolitic Hepatitis Same as acute hepatitis, but evidence of obstruction is more prominent (e.g., increased serum ALP and direct serum bilirubin), and tests of parenchymal damage are less marked (e.g., AST increase may be 3–6× normal). Chronic Hepatitis See Table 8-7.
- 152. Table 8-7. Comparison of Types of Hepatitis D Virus (HDV) Infections Occurs in 5–10% of adults with acute HBV. HBV hepatitis is generally divided into three stages: Stage of acute hepatitis: Usually lasts 1–6 mos with mild or no symptoms. AST and ALT are increased >10×. Serum bilirubin is usually normal or only slightly increased. HBsAg gradually rises to high titers and persists; HBeAg also appears. Gradually merges with next stage. Stage of chronic hepatitis: Transaminases increased >50% for >6 mos duration; may last only 1 yr or for several decades with mild or severe symptoms; most cases resolve, but some develop cirrhosis and liver failure. AST and ALT fall to 2–10× normal range. HBsAg usually remains high, and HBeAg remains present. Chronic carrier stage: Patients are usually, but not always, healthy and asymptomatic. AST and ALT fall to normal or <2× normal. HBeAg disappears, and anti-HBe appears. HBsAg titer falls although may still be detectable; anti-HBs subsequently develops, marking the end of carrier stage. Anti-HBc is usually present in high titer (>1:512). Laboratory findings due to sequelae, e.g., GN or nephrotic syndrome due to deposition of HBeAg or HBcAg in glomeruli, which often progresses to chronic renal failure. HEPATITIS, ALCOHOLIC5 w Diagnosis is established by liver biopsy and history of alcohol intake. Liver biopsy should be performed for any alcoholic patient with enlarged liver as the only way to make definite diagnosis of alcoholic hepatitis. Many alcoholics have normal liver biopsies. m Increased serum GGT and MCV >100 together or separately are useful clues for occult alcoholism. Ratio of desialylated transferrin to total transferrin >0.013 has been reported to have 81% sensitivity and 98% specificity for ongoing alcohol consumption. Serum AST is increased (rarely >300 U/L), but ALT is normal or only slightly elevated. AST and ALT are more specific but less sensitive than GGT. Levels of AST and ALT do not correlate with severity of liver disease. AST/ALT ratio >1 associated with AST <300 U/L will identify 90% of patients with alcoholic liver disease; is particularly useful for differentiation from viral hepatitis, in which increase of AST and ALT are about the same. Cholestasis in £ 35% of patients. In acute alcoholic hepatitis, GGT level is usually higher than AST level. GGT is often abnormal in alcoholics even with normal liver histology. Is more useful as index of occult alcoholism or to indicate that elevated serum ALP is of bone or liver origin than to follow course of patient, for which AST and ALT are most useful. Serum ALP may be normal or moderately increased in 50% of patients and is not useful as a diagnostic test. Serum bilirubin may be mildly increased except with cholestasis; is not useful as a diagnostic test. However, if bilirubin continues to increase during a week of therapy in the hospital, a poor prognosis is indicated. Decreased serum albumin and increased polyclonal globulin with disproportionately increased IgA are frequent. Decreased albumin means long-standing or relatively severe disease. Increased PT that is not corrected by parenteral administration of 10 mg/day of vitamin K for 3 days is best indicator of poor prognosis. Discriminant function to assess severity of alcoholic hepatitis = 4.6 × (PT [secs] – control PT) + serum bilirubin. Discriminant function >32 is equated with severe disease. Increased WBC (>15,000) in up to one-third of patients with shift to left (WBC is decreased in viral hepatitis); normal WBC may indicate folic acid depletion. Anemia in >50% of patients may be macrocytic (folic acid or vitamin B12 deficiency), microcytic (iron or pyridoxine deficiency), mixed, or hemolytic. Metabolic alkalosis may occur due to K+ loss with pH normal or increased, but pH <7.2 often indicates that disease is becoming terminal. In terminal stage of chronic alcoholic liver disease (last week before death), there is often decrease of serum sodium and albumin and increase of PT and serum bilirubin; AST and LD decrease from previously elevated levels. Indocyanine green (50 mg/kg) is abnormal in 90% of patients. Compared to nonalcoholic patients, alcoholic patients as a group show an increase in a number of blood components (e.g., AST, phosphorus, ALP, GGT, MCV, MCH, Hb, WBC) and a decrease in others (e.g., total protein, BUN); however, these variations usually remain within the reference range. These changes may last for >6 wks after abstaining from alcohol. Laboratory findings due to sequelae or complications
- 153. Fatty liver Cirrhosis Portal hypertension Infections (e.g., GU tract, pneumonia, peritonitis) DIC Hepatorenal syndrome Encephalopathy HEPATITIS, AUTOIMMUNE CHRONIC ACTIVE w Criteria for diagnosis (all must be present for definite diagnosis)6 Probable Definite Increased serum AST or ALT concentrations X X Increased serum ALP <3× normal concentration X Increased serum total or gamma globulin or IgG >1.5× upper limit of normal X 1.0–1.5× upper limit of normal X Antibody titers to nucleus, smooth muscle or liver/kidney microsome type 1 >1:80 (adults) or >1:20 (children) X Lower titers or presence of other antibodies X Absence of markers for viral hepatitis (HAV, HBV, HCV, CMV, EBV) X X Absence of excess alcohol consumption <25 gm/day (women) or <35 gm/day (men) X <40 gm/day (women) or <50 gm/day (men) X Exposure to blood products No X Yes, but unrelated to disease X Exposure to hepatotoxic drugs No X Yes, but unrelated to disease X Compatible histologic findings and absence of biliary lesions, copper deposits or other changes suggestive of other causes of lobular hepatitis X X HEPATITIS, CHRONIC ACTIVE (Inflammatory liver disease present >6 mos.) Due To Viruses HBV (with or without HDV) HCV (with or without hepatitis G virus [HGV]) Metabolic disorders Wilson's disease Alpha1-antitrypsin deficiency Hemochromatosis Primary biliary cirrhosis Sclerosing cholangitis Drugs, e.g., Methyldopa Nitrofurantoin Isoniazid Oxyphenacetin Nonalcoholic fatty liver Alcoholic hepatitis Autoimmune causes Type I (lupoid) (anti–smooth muscle; antiactin) Type II (anti–kidney-liver-microsomal) Type III (anti–soluble liver antigen) HEPATITIS A Serum bilirubin usually 5–10× normal. Jaundice lasts a few days to 12 wks. Usually not infectious after onset of jaundice. Serum AST and ALT increased to hundreds for 1–3 wks. Relative lymphocytosis is frequent. Serologic Tests for Viral Hepatitis A (HAV)7
- 154. See Table 8-5, Table 8-6, Fig. 8-3, Fig. 8-5 and Fig. 8-6. Fig. 8-6. Hepatitis serologic profiles. A: Antibody response to hepatitis A. B: Hepatitis B core window identification. C, D: Hepatitis B chronic carrier profiles: no seroconversion (C); late seroconversion (D). (Reproduced with permission of Hepatitis Information Center, Abbott Laboratories, Abbott Park, IL.) w Anti-HAV IgM appears at the same time as symptoms in >99% of cases, peaks within first month, becomes nondetectable in 12 mos (usually 6 mos). Presence confirms diagnosis of recent acute infection. w Anti-HAV–total is predominantly IgG except immediately after acute HAV infection, when it is mostly IgM and IgA. Almost always positive at onset of acute hepatitis and is usually detectable for life; found in 45% of adult population; indicates previous exposure to HAV, recovery, and immunity to type A hepatitis. Negative anti-HAV–total effectively excludes acute HAV. Positive anti-HAV–total does not distinguish recent from past infection, for which anti-HAV IgM test is needed. Test for anti-HAV–total is relatively insensitive (minimum detection amount = 100 mU/mL) and may not detect protective antibody response after one dose of inactivated HAV vaccine (minimum protective antibody is <10 mU/mL). Serial testing is usually not indicated. Tests for anti-HAV–total and anti-HAV IgM are not influenced by normal doses of immune globulin. HAV antigen and HAV RNA are available only as research tools. HEPATITIS B See Table 8-5, Table 8-6, Fig. 8-5 and Fig. 8-6. Serologic Tests for Viral Hepatitis B (HBV) See Table 8-6, Table 8-8, Table 8-9, Table 8-10, Table 8-11 and Table 8-12. Table 8-8. Serologic Tests for Hepatitis B Virus Infections Table 8-9. Serologic Tests for Hepatitis B Virus Infection Follow-Up
- 155. Table 8-10. Serologic Tests for Prenatal Screening for Hepatitis B Virus Table 8-11. Serologic Tests for Candidate for Hepatitis B Virus Vaccination Table 8-12. Serologic Tests for Hepatitis B Virus Vaccination Follow–Up Use Differential diagnosis of hepatitis Screening of blood and organ donors Determination of immune status for possible vaccination Hepatitis B Surface Antigen (HBsAg) w Earliest indicator of HBV infection. Usually appears in 27–41 days (as early as 14 days). Appears 7–26 days before biochemical abnormalities. Peaks as ALT rises. Persists during the acute illness. Usually disappears 12–20 wks after onset of symptoms or laboratory abnormalities in 90% of cases. Is the most reliable serologic marker of HBV infection. Persistence >6 mos defines carrier state. May also be found in chronic infection. Hepatitis B vaccination does not cause a positive HBsAg. Titers are not of clinical value. Present sensitive assays detect <1.0 ng/mL of circulating antigen, which is the level needed to find 10–15% of reactive blood donors who carry antigen but express only low levels. Is never detected in some patients, and diagnosis is based on presence of HBc IgM. HBsAg and Blood Transfusions Transfusion of blood containing HBsAg causes hepatitis or appearance of HBsAg in blood in >70% of recipients; needle stick with such blood causes hepatitis in 45% of cases. Transfusion of blood not containing HBsAg causes anicteric hepatitis in 16% of recipients and icteric hepatitis in 2%. Screening out of blood donors with HBsAg reduces posttransfusion hepatitis by 25–40%. When HBsAg carriers are discovered (e.g., in screening program), 60–80% show some evidence of hepatic damage. Persons with a positive test for HBsAg should never be permitted to donate blood or plasma. HBsAg is found in Chronic persistent hepatitis 50% Chronic active hepatitis 25% Cirrhosis 3% Patients undergoing multiple transfusions 3.8% Drug addicts 4.2% Blood donor population <0.1% Prevalence in United States 0.25% Antibody to HBsAg (Anti-HBsAg) w Presence of antibody (titer ³10 mU/mL); (without detectable HBsAg) indicates recovery from HBV infection, absence of infectivity, and immunity from future HBV infection; patient does not need gamma globulin administration if exposed to infection; this blood can be transfused. May also occur after transfusion by passive transfer. Found in 80% of patients after clinical cure. Appearance may take several weeks or months after HBsAg has disappeared and after ALT has returned to normal, causing a “serologic gap” during which time (usually 2- to 6-wk “window”) only IgM–anti-HBsAg can identify patients who are recovering but may still be infectious.
- 156. Presence can be used to show efficiency of immunization program. Appears in ~90% of healthy adults after three-dose deltoid muscle immunization; 30–50% of these lose antibodies in 7 yrs and require boosters. Revaccination of nonresponders produces adequate antibody in <50% after three additional doses. A few persons acquire HBV infection after developing high titers of anti-HBsAg due to a mutant HBV virus. In fulminant hepatitis—antibody is produced early and may coexist with low antigen titer. In chronic carriers—no IgM antibody is present but antigen titers are very high. Hepatitis Be Antigen (HBeAg) w Indicates highly infectious state. Appears within 1 wk after HBsAg; in acute cases disappears before disappearance of HBsAg; is found only when HBsAg is found. Occurs early in disease before biochemical changes and disappears after serum ALT peak. Usually lasts 3–6 wks. Is a marker of active HBV replication in liver; with few exceptions, is present only in persons with circulating HBV DNA and is used as alternative to HBV DNA assay. Is useful to determine resolution of infection. Persistence >20 wks suggests progression to chronic carrier state and possible chronic hepatitis. Presence in HBsAg-positive mothers indicates 90% chance that infant will acquire HBV infection. Absence of HBeAg is not indicator of benign nonprogressive disease. May be HBeAg negative and HBV DNA positive in patients infected with an HBV mutant who do not synthesize HBeAg. Antibody to HBe (Anti-HBe) w Appears after HBeAg disappears and remains detectable for years. Indicates decreasing infectivity, suggests good prognosis for resolution of acute infection. Association with anti-HBc in absence of HBsAg and anti-HBs confirms recent acute infection (2–16 wks). Antibody to Hepatitis B Core Antigen–Total (Anti-HBc–Total) w Occurs early in acute infection, 4–10 wks after appearance of HBsAg, at same time as clinical illness; persists for years or for lifetime. Anti-HBc–total and HBsAg are always present and anti-HBsAg is absent in chronic HBV infection. w Anti-HBc IgM is the earliest specific antibody; usually occurs 2 wks after HBsAg. Is found in high titer for a short time during the acute disease stage that covers the serologic window and then declines to low levels during recovery (see Fig. 8-6); may be detectable £ 6 mos. May be the only serologic marker present after HBsAg and HBeAg have subsided but before these antibodies have appeared (serologic gap or window). Because this is the only test unique to recent infection, it can differentiate acute from chronic HBV. It is the only serologic test that can differentiate recent and remote infection with one specimen. However, because some patients with chronic hepatitis B infection become positive for anti-HBc IgM during flares, it is not an absolutely reliable marker of acute illness. Before anti-HBc IgM disappears, anti-HBc IgG appears and lasts indefinitely. Anti-HBc detects virtually all persons who have been previously infected with HBV and can therefore serve as surrogate test for other infectious agents (e.g., HCV). Exclusion of anti-HBc–positive donors reduces the incidence of posttransfusion hepatitis and possibly of other virus infections (e.g., AIDS) due to the frequency of dual infection. Present without other serologic markers and with normal AST in ~2% of routine blood donors; 70% of cases are due to recovery from subclinical HBV (and individual may be infectious) and the rest are considered false-positives. False-positive anti-HBc can be confirmed by immune response pattern to hepatitis B vaccination. Anti-HBc is not protective (unlike anti-HBsAg) and therefore cannot be used to distinguish acute from chronic infection. w HBV DNA (by PCR) is the most sensitive and specific assay for early evaluation of HBV and may be detected when all other markers are negative (e.g., in immunocompromised patients). May become negative before HBeAg becomes negative. Measures HBV replication even when HBeAg is not detectable. Marked decrease in patients who respond to therapy; those with concentrations <200 ng/L are more likely to respond to therapy. Other Laboratory Findings m Very high serum ALT and bilirubin are not reliable indicators of patient's clinical course, but prolonged PT, especially >20 secs, indicates the likely development of acute hepatic insufficiency; therefore the PT should be performed when patient is first seen. Acute fulminant hepatitis may be indicated by triad of prolonged PT, increased PMNs, and nonpalpable liver with likely development of coma. Acute viral hepatitis B completely resolves in 90% of patients within 12 wks with disappearance of HBsAg and development of anti-HBs. Relapse, usually within 1 yr, has been recognized in 20% of patients by some elevation of ALT and changes in liver biopsy. Chronic hepatitis (disease for >6 mos and ALT >50% above normal): 70% of these patients have benign chronic persistent hepatitis and 30% have chronic active hepatitis that can progress to cirrhosis and liver failure. Effective treatment of chronic HBV hepatitis causes ALT, HBeAg, and HBV DNA to become normal. Chronic carriers have also been defined as those who are either HBsAg positive on two occasions >6 mos apart or have one specimen that is HBsAg positive and anti-HBc IgM negative but anti–HBc-positive. 10% of adults and 90% of children £ 4 yrs old become chronic carriers; 25% of these develop cirrhosis and high risk of hepatoma. HBV carriers should be screened periodically with serum AFP and ultrasonography or CT scan of liver for hepatoma. Laboratory indicators for favorable response to interferon: Pretreatment serum ALT >100 U/L (high ALT may indicate better host immune response to HBV) HBV DNA <200 ng/L (pg/mL) Absence of HIV Also duration <4 yrs and acquisition of infection after 6 yrs of age Laboratory effects of interferon treatment: Serum ALT may increase to >1000 U/L. 10% of patients show sustained disappearance of HBV DNA and clearance of HBeAg. If serum ALT is persistently increased despite lack of HBeAg, presence of an HBeAg-negative mutant that may have emerged during treatment is suggested. 5–10% of patients with seroconversion due to therapy will have reactivation in next 10 yrs; this is usually transitory. Laboratory contraindications to interferon therapy for chronic hepatitis B: Liver decompensation Serum albumin <3.0 gm/L Serum bilirubin >3.0 mg/dL PT increased >3× Portal hypertension (e.g., ascites, bleeding esophageal varices, encephalopathy) Hypersplenism WBC <2000/cu mm Platelet count <70,000 Autoimmune disease (e.g., RA, polyarteritis nodosa)
- 157. Major system impairment Other (e.g., pregnancy, current IV drug abuse, psychiatric) HEPATITIS C (FORMERLY NON-A, NON-B HEPATITIS)8, 9 See Fig. 8-7, Table 8-5 and Table 8-6. Fig. 8-7. Comparison of serum ALT and anti–hepatitis C virus findings in acute hepatitis C. Chronic infection is indicated by broken lines. (CTS/M = counts/minute; RIA = radioimmunoassay; ULN = upper limit of normal.) Can remain infectious for years. ~85% of acute cases become chronic with viremia. Of chronic carriers with or without abnormal ALT values, 15% experience resolution. 70% develop chronic hepatitis (average time = 10 yrs). 10–20% develop cirrhosis despite normal liver function tests (average time = 20 yrs). ~50% die of consequences of HCV infection. Fulminant hepatitis is rare. Hepatocellular carcinoma may occur in ~20% of cirrhosis patients (average time = 30 yrs) and 1–5% of those with HCV infections. 50–75% of all liver cancers are HCV associated. ~40% of liver transplantations in United States are performed to treat chronic hepatitis C with cirrhosis. Routine screening for HCV should be performed and HCV should be ruled out in hepatitis in persons who Ever injected illegal drugs. Received clotting factor concentrates produced before 1987 (70–90% of severe hemophiliacs are infected with HCV). Ever were on long-term hemodialysis. Ever received blood from donor who later tested positive for HCV (2–7% of blood donors in United States are asymptomatic carriers). Ever received blood or components or organ transplant before July 1992. Have persistently abnormal serum ALT. Causes £ 25% of sporadic cases of acute viral hepatitis in adults, 90% of cases of posttransfusion hepatitis. Source of infection: injected drug use = 42%; occupational exposure = ~5%; transfusion = <1%; dialysis = 0.6%; household contact = 3%; heterosexual transmission = 6% (cumulative risk may be 18%); unidentified = 42%. Perinatal infection at time of birth in 5% of infants of HCV-infected mothers. Biochemical and histologic evidence of abnormality occurs in 7% of sporadic cases, £ 60% of posttransfusion cases, and £ 80% of immunosuppressed patients. Occult HBV infection is present in approximately one-third of patients with chronic HCV liver disease by HBV DNA analysis of liver biopsy. 10 m May be associated with mixed cryoglobulinemia with vasculitis (see Chapter 11), thyroiditis, Sjögren's syndrome, membranoproliferative GN, and porphyria cutanea tarda, which should be ruled out in cases of hepatitis C, and HCV infection should be ruled out in patients with those disorders. Patients with alcoholic liver disease have more rapidly progressive disease with higher ALT values and more severe histologic changes. Increased Serum Transaminases mLevels characteristically show unpredictable waxing and waning pattern, returning to almost normal levels (formerly called acute “relapsing” hepatitis); pattern is highly suggestive but only occurs in 25% of cases. May be extreme (>10× normal). Patients with monophasic ALT response usually recover completely with no biopsy evidence of residual disease. ALT is usually <800 U. ALT cannot be relied on to determine whether to perform liver biopsy in chronic hepatitis C; biopsy is needed to define severity. ALT is primary marker to monitor therapy. In chronic HCV, AST/ALT ratio >1 has specificity and positive predictive value of 100% for cirrhosis although sensitivity is 52%. Ratio does not correlate with serum ALP, bilirubin, albumin, or PT. Anicteric patients with ALT >300 U/L are at high risk for progressing to chronic hepatitis. Liver Biopsy Use Diagnose chronic active hepatitis
- 158. Assess disease progression and indication for antiviral therapy No consistent correlation between serum ALT and severity of liver pathology; significant liver damage can occur with normal ALT. Exclude coexisting or alternative (e.g., alcohol-related) diseases w Antibody to Hepatitis C Virus (anti-HCV) (by EIA) Use Screening of populations with low and high prevalence, including blood donors Initial evaluation of patients with liver disease, including those with increased serum ALT Positive results should be verified by a supplemental assay (i.e., recombinant immunoblot assay [RIBA]) showing reactivity with ³2 viral antigens; indeterminate in £ 10% of cases. Interpretation Indicates past or present infection but does not differentiate between acute, chronic, and resolved infection. Sensitivity ³97%; only ~80% in chronic carriers. Low positive predictive value in low-prevalence population. Seroconversion: average time after exposure = 2–3 wks with EIA-3. Detected in 80% of patients within 15 wks, in >90% within 5 mos, in >97% by 6 mos after exposure or 2–3 mos after increase in ALT. Therefore serial assay of anti-HCV and ALT for up to 1 yr after suspected acute hepatitis may be needed for diagnosis. Negative EIA rules out HCV infection in low-risk group. Present in 70–85% of cases of chronic posttransfusion NANB hepatitis but is relatively infrequent in acute cases. Present in 70% of IV drug abusers, 20% of hemodialysis patients, and only 8% of homosexual men positive for HIV. Prevalence in normal blood donors is 0.5–2.0%. In routine blood donor screening, estimates are that 40–70% of initial reactors prove not to be true positives. Surrogate markers fail to detect one-third to one-half of blood units positive for anti-HCV. Found in 7–10% of transfusion recipients. Only one-third of anti-HCV donors had increased ALT and 54% were positive for anti-HBc. In one study, anti-HCV was positive in 75% of patients with hepatocellular carcinoma, 56% of patients with cirrhosis, and 7% of controls. Present in various quality assurance and calibration sera; overall rate = 43% with much higher rates in some proficiency samples. Because resolves slowly, is considered chronic only with evidence of activity >12 mos. Interferences False-positive Autoimmune diseases (£ 80% of cases of autoimmune chronic active hepatitis). EIA and RIBA are also found in polyarteritis nodosa (~10%) and SLE (~2%). RF. Hypergammaglobulinemia. Paraproteinemia. Passive antibody transfer. Anti-idiotypes. Anti–superoxide dismutase (a human enzyme used in the cloning process). Repeated freezing and thawing or prolonged storage of blood specimens. False-negative Early acute infection Immunosuppression Immunoincompetence Repeated freezing and thawing or prolonged storage of blood specimens RIBA Positive EIA should be evaluated with RIBA-2; negative RIBA indicates false-positive EIA. Positive RIBA indicates past or previous exposure. Confirms positive EIA in >50% of cases; in high-risk population RIBA confirms diagnosis in >88% of cases. Increasingly replaced by HCV RNA. HCV RNA Assay (By reverse transcriptase PCR [RT-PCR]) Qualitative tests Use Diagnose acute HCV infection before seroconversion; can detect virus as early as 1–2 wks after exposure. Detection may be intermittent; one negative RT-PCR is not conclusive. Monitor patients on antiviral therapy Evaluate indeterminate RIBA results
- 159. False-positive and false-negative results may occur. Quantitative Tests (RT-PCR and branched DNA; not presently approved by U.S. Food and Drug Administration.) Quantitative tests from different manufacturers do not yield identical results. Determines concentration of HCV RNA. Large spontaneous fluctuations in RNA level; therefore should measure two times or more to evaluate changes due to therapy. RT-PCR yields positive results for 75–85% of persons positive for anti-HCV and >95% of persons with acute or chronic HCV hepatitis. Use May be used to assess likelihood of response to antiviral therapy. Patients with pretreatment level <2 million copies/mL (by PCR or quantitative branched DNA) are most likely to respond to interferon therapy. Positive test after 12 wks of interferon therapy predicts failed response; negative test has ~30% predictive value for sustained response. Less sensitive than qualitative test RT-PCR. Earliest marker for diagnosis of fulminant hepatitis C. Negative test in patient with fulminant hepatitis rules out HCV infection. Confirm persistent HCV infection after liver transplantation when anti-HCV is positive and serum ALT is normal. Diagnose chronic hepatitis patients with Negative anti-HCV False-positive serologic tests due to autoantibodies Not used to exclude diagnosis of HCV infection. Not used to determine treatment end point. HCV Genotyping Presently a research tool with no clinical utility. At least six genotypes and >90 subtypes. A correlation may exist between genotype and disease. Mixed infections often occur. HCV Genotype Occurrence (%) 1a 37Higher rate of chronic hepatitis; poorer response to interferon therapy and higher likelihood of relapse 1b 30More severe liver disease; higher risk of hepatocellular carcinoma Other genotypes have various geographic distributions. Antiviral therapy is recommended for patients with greatest risk of progression to cirrhosis Positive anti-HCV with Persistently increased ALT Detectable HCV RNA Liver biopsy showing at least moderate inflammation and necrosis or fibrosis Indicators of response to antiviral therapy ~50% show normal serum ALT. 33% lose detectable HCV RNA in serum; loss associated with remission. Presence after sustained response to interferon indicates late relapse. 50% relapse after therapy ends. Decreased interferon response occurs in <15% of patients; indicated by Higher serum HCV RNA titers HCV genotype 1 Laboratory contraindications to interferon therapy Persistently increased serum ALT Cytopenias Hyperthyroidism Renal transplantation Evidence of autoimmune disease No tests are routinely available for other HCV viruses. HEPATITIS D (DELTA) See Table 8-5, Table 8-6 and Table 8-7. Hepatitis D is due to a transmissible virus that depends on HBV for expression and replication. It may be found for 7–14 days in the serum during acute infection. Delta agent can be an important cause of acute or chronic hepatitis. The course depends on the presence of HBV infection. HDV hepatitis is often severe with relatively high mortality in acute disease and frequent development of cirrhosis in chronic disease. Chronic HDV infection is more severe and has higher mortality than other types of viral hepatitis. Prevalence in United States is 1–10% of HBsAg carriers, principally in high-risk groups of IV drug abusers and multiply transfused patients but uncommon in other groups at risk for HBV infection (e.g., health care workers, male homosexuals). Serologic Tests for HDV
- 160. See Table 8-5, Table 8-6, Table 8-7 and Table 8-13. Table 8-13. Serologic Diagnosis of Hepatitis B Virus (HBV) and Hepatitis D Virus (HDV) Serum HDAg and HDV-RNA appear during incubation period after HBsAg and before rise in AST, which often shows a biphasic elevation. HBsAg and HDAg are transient; HDAg resolves with clearance of HBsAg. Anti-HDV appears soon after clinical symptoms but titer is often low and short-lived. Anti-HDV–total test is commercially available; HDAg and anti-HDV-IgM testing is available only in research laboratories. Coinfection means simultaneous acute HBV and acute HDV infection; usually causes acute limited illness with additive liver damage due to each virus, followed by recovery. Usually is self-limited; <5% of cases become chronic. ~3% have fulminant course. Superinfection means acute HDV infection in a chronic HBV carrier. Mortality = 2–20%; >80% develop chronic hepatitis. Serum anti-HDV appears and rises to high sustained titers indicating continuing replication of HDV; intrahepatic HDAg is present. HDV-RNA persists in low titers. w Diagnosis of HDV hepatitis is made by presence of anti-HDV in patient with HBsAg-positive hepatitis. Anti-HDV assay should not be performed unless diagnosis of HBV is confirmed. w Acute coinfection is distinguished from superinfection by presence of serum HBsAg and anti-HBc-IgM, which indicate acute HBV. w Chronic HDV infection occurs in £ 80% of acute cases; shows presence of HBsAg and high titer of anti-HDV (RIA titer >1:100 suggests chronic HDV hepatitis) and absence of anti-HBc-IgM in serum. Confirm by liver biopsy showing HDAg by immunofluorescence or immunoperoxidase. w Serum anti-HDV-IgM documents acute HDV infection; low levels remain in persistent infection. Western blot can demonstrate serum HDV-Ag when RIA is negative. Persistence correlates with development of chronic HDV hepatitis and viral antigen in liver biopsy. DNA probe for HDV-RNA in serum to monitor HDV replication. Serum anti-HDV may be sought in patients with HBsAg-positive chronic or acute hepatitis in high-risk group or with severe disease or with biphasic acute hepatitis or acute onset in chronic hepatitis. HEPATITIS E See Table 8-5 and Table 8-6. Recent travel to certain areas (e.g., Mexico, India, Africa, Burma, Russia) w Serologic markers for hepatitis A, B, and C and other causes of acute hepatitis (e.g., EMB, CMV) are absent. w Antibody to hepatitis E can be detected by fluorescent antibody blocking assay and by Western blot; not commercially available. HEPATITIS G11,12 and 13 (Due to single-stranded RNA virus of Flaviviridae family. HGV RNA found in ~1–2% of American blood donors; higher in multiply transfused persons, those with hepatitis B or C, drug addicts. Benign course; more studies needed to determine if causes acute or chronic hepatitis.) Infection tends to persist for many years. Serum ALT is persistently normal; increase is due to concomitant HCV infection. Serologic assays under development. Detected by RT-PCR. Of hemodialysis patients £ 5% are HGV positive. ~25% have anti-HCV and ~15% are PCR positive for HCV. ~5% are HBsAg positive. >50% had anti-HBs or anti-HBc (representing resolved HBV infection). HEPATITIS, NEONATAL Infectious Causes Adenovirus Rubella Coxsackievirus B Syphilis CMV Toxoplasmosis HAV and HBV Varicella HSV Unknown agent
- 161. Listeria Metabolic Causes Alpha1-antitrypsin deficiency—causes 20–35% of cases of neonatal liver disease. Cystic fibrosis rarely presents as prolonged neonatal jaundice. Dubin-Johnson syndrome Fructosemia Galactosemia Gaucher's disease Glycogen storage disease type IV Histiocytosis X Hypothyroidism Hypopituitarism Leprechaunism Niemann-Pick disease Tyrosinemia Zellweger syndrome Jaundice in infants receiving parenteral alimentation—many are premature and have various complications (e.g., RDS, septicemia, acidosis, congenital heart disease). Increased AST, ALT, ALP Serum proteins normal Increased serum bile acids Increased serum ammonia Abnormal plasma amino acid patterns (increased threonine, serine, methionine) Associated with Hemolytic Disease of Newborn Occurred in 10% of cases (“inspissated bile” syndrome) before modern prevention of Rh disease. Cord blood direct bilirubin ³2 mg/dL indicates that syndrome will develop. Jaundice may persist for 3–4 wks. Most cases have required exchange transfusion. Clinical and Laboratory Findings Jaundice at birth, or days or weeks later. Both direct and indirect bilirubin levels are increased in variable proportions. Mild hemolytic anemia is usual. Increased AST, ALT, etc.; may be marked and usually greater than in biliary atresia, but increases are not useful for differentiating the two conditions. Laboratory findings as in acute viral hepatitis . Liver biopsy to differentiate from biliary atresia and to avoid unnecessary surgery is useful in ~65% of patients but it may be misleading. 131I-rose bengal excretion test indicates complete biliary obstruction if <10% of the radioactivity is excreted in stools during 48–72 hrs and incomplete obstruction if >10%. Complete obstruction is found in all infants with biliary atresia and in ~20% with neonatal hepatitis and severe cholestasis. Administration of phenobarbital and cholestyramine increases the 131 I-rose bengal excretion in neonatal hepatitis but not in extrahepatic atresia. Some authors have suggested a repeat test in 3–4 wks before exploratory surgery if rose bengal test indicates complete obstruction. Laboratory tests for various causal agents. Laboratory findings of chronic liver disease, which develops in 30–50% of these infants. Whenever mother has hepatitis during pregnancy or is HBsAg positive, test cord blood and baby's blood every 6 mos. If baby develops HBsAg or anti-HBs, measure liver chemistries at periodic intervals. Infants who acquire hepatitis in utero or at time of birth may develop clinical acute hepatitis with abnormal liver chemistries, benign course, or development of HBsAb. Infants who are asymptomatic but develop HBsAg often become chronic carriers with biochemical and liver biopsy evidence of chronic hepatitis and increased likelihood of hepatoma. (See Serologic Tests for HBV. HEPATOCELLULAR CARCINOMA (HEPATOMA) w Serum AFP present in 50% of white and 75–90% of nonwhite patients; may be present for up to 18 mos before symptoms; is sensitive indicator of recurrence in treated patients but a normal postoperative level does not ensure absence of metastases. Levels >500 ng/dL in adults strongly suggest primary carcinoma of liver. w Serum GGT hepatoma-specific band (HSBs I', II, II') by electrophoresis activity >5.5 U/L has sensitivity of 85%, specificity of 97%, accuracy of 92%. Does not correlate with AFP or tumor size.14 Laboratory findings associated with underlying disease (>60% occur with preexisting cirrhosis). Hemochromatosis (£ 20% of patients die of hepatoma). HBV, HCV. More frequent in postnecrotic than in alcoholic cirrhosis.
- 162. Cirrhosis associated with alpha1-antitrypsin deficiency and other inborn errors of metabolism, e.g., tyrosinemia. Clonorchis sinensis infection is associated with cholangiosarcoma. Relative absence of hepatoma associated with cirrhosis of Wilson's disease. Sudden progressive worsening of laboratory findings of underlying disease (e.g., increased serum ALP, LD, AST, bilirubin). w Hemoperitoneum—ascites in ~50% of patients but tumor cells found irregularly. Laboratory findings due to obstruction of hepatic veins (Budd-Chiari syndrome), portal veins, or inferior vena cava may occur. Occasional marked hypoglycemia unresponsive to epinephrine injection; occasional hypercalcemia. ESR and WBC sometimes increased. Anemia is common; polycythemia occurs occasionally. Serologic markers of HBV frequently present. CEA in bile is increased in patients with cholangiocarcinoma and intrahepatic stones but not in patients with benign stricture, choledochal cysts, sclerosing cholangitis. Increases with progression of disease and declines with tumor resection. Does not correlate with serum bilirubin or ALP. Serum CEA is usually normal. HYPERBILIRUBINEMIA, NEONATAL Due To Unconjugated Increased destruction of RBCs Isoimmunization (e.g., incompatibility of Rh, ABO, other blood groups) Biochemical defects of RBCs (e.g., G-6-PD deficiency, pyruvate deficiency, hexokinase deficiency, congenital erythropoietic porphyria, alpha and gamma thalassemias) Structural defects of RBCs (e.g., hereditary spherocytosis, hereditary elliptocytosis, infantile pyknocytosis) Infection Viral (e.g., rubella) Bacterial (e.g., syphilis) Protozoal (e.g., toxoplasmosis) Extravascular blood (e.g., subdural hematoma, ecchymoses, hemangiomas) Erythrocytosis (e.g., maternal-to-fetal or twin-to-twin transfusion, delayed clamping of umbilical cord) Increased enterohepatic circulation Any cause of delayed bowel motility Pyloric stenosis—unconjugated hyperbilirubinemia >12 mg/dL develops in 10–25% of infants, usually during second or third week, at which time vomiting begins; jaundice is due to decreased hepatic glucuronyl transferase activity of unknown mechanism. Duodenal and jejunal obstruction may also be associated with exaggerated unconjugated hyperbilirubinemia; level becomes normal 2–3 days after surgical relief. In Hirschsprung's disease, unconjugated hyperbilirubinemia is usually more mild. Meconium ileus, meconium plug syndrome. Hypoperistalsis (e.g., induced by drugs, fasting) Endocrine and metabolic Neonatal hypothyroidism—associated with prolonged and exaggerated unconjugated hyperbilirubinemia in 10% of cases and is promptly alleviated by thyroid hormone therapy. Always rule out congenital hypothyroidism in cases of unexplained persistent or excessive unconjugated hyperbilirubinemia; may be the only manifestation of hypothyroidism. Infants of diabetic mothers—associated with higher incidence of prolonged and exaggerated unconjugated hyperbilirubinemia of unknown mechanism; not related to severity or duration of diabetes. Drugs and hormones (e.g., breast-milk jaundice, Lucey-Driscoll syndrome, novobiocin). Galactosemia. Tyrosinosis. Hypermethionemia. Heart failure. Hereditary glucuronyl-transferase deficiency. Gilbert's syndrome. Interference of albumin binding of bilirubin Drugs (e.g., aspirin, sulfonamides) Severe acidosis Hematin Free fatty acids (e.g., periods of stress, inadequate caloric intake) Prematurity (serum albumin may be 1–2 gm/dL less than in full-term infants) Neonatal physiologic hyperbilirubinemia
- 163. Conjugated Premature infants with these conditions have more severe hyperbilirubinemia than full-term infants. Biliary obstruction—usually due to extrahepatic biliary atresia but may be due to choledochal cyst, obstructive inspissated bile plugs, or bile ascites Neonatal hepatitis Sepsis, especially E. coli pyelonephritis (moderate azotemia, acidosis, increased serum bilirubin, slight hemolysis, normal or slightly increased AST) Hereditary diseases (e.g., galactosemia, alpha 1-antitrypsin deficiency, cystic fibrosis, hereditary fructose intolerance, tyrosinemia, infantile Gaucher's disease, familial intrahepatic cholestasis [Byler's disease]) In the course of hemolytic disease of the newborn—due to liver damage of unknown cause. Differential Diagnosis Unconjugated hyperbilirubinemia is serum level >1.5 mg/dL. Conjugated hyperbilirubinemia is direct-reacting serum level >1.5 mg/dL when this fraction is >10% of total serum bilirubin (because in newborn with marked elevation of unconjugated bilirubin level, £ 10% of the unconjugated bilirubin will act as direct reacting in the van den Bergh reaction). Mixed hyperbilirubinemia shows conjugated bilirubin as 20–70% of total and usually represents disorder of hepatic cell excretion or bile transport. Visible icterus before 36 hrs of age indicates hemolytic disorder. Diagnostic studies should be performed whenever serum bilirubin is >12 mg/dL. After hemolytic disease and hepatitis, the most frequent cause of hyperbilirubinemia is enterohepatic circulation of bilirubin. Visible icterus persisting after seventh day is usually due to impaired hepatic excretion, most commonly due to breast-milk feeding or congenital hypothyroidism. Increase in direct bilirubin usually indicates infection or inflammation of liver, but can also be seen in galactosemia and tyrosinosis. HYPERBILIRUBINEMIA, NEONATAL NONPHYSIOLOGIC See Fig. 8-8. Fig. 8-8. Algorithm for workup of neonatal jaundice and anemia. Cause should be sought for underlying pathologic jaundice if: Total serum bilirubin is >7 mg/dL during first 24 hrs or increases by >5 mg/dL/day or visible jaundice. Peak total serum bilirubin is >12.5 mg/dL in white or black full-term infants or >15 mg/dL in Hispanic or premature infants. Direct serum bilirubin is >1.5 mg/dL. Clinical jaundice lasts longer than 7 days in full-term or 14 days in premature infants or occurs before age 36 hrs or with dark urine (containing bile). Initial tests in unconjugated hyperbilirubinemia: Serial determinations of total and direct bilirubin CBC including RBC morphology, platelet count, normoblast and reticulocyte counts Blood type, mother and infant Direct Coombs' test Maternal blood for antibodies and hemolysins Blood cultures Urine microscopy and culture Serologic tests for infection Serum thyroxine (T4) and thyroid-stimulating hormone (TSH) Urine for non–glucose reducing substances HYPERBILIRUBINEMIA, NEONATAL PHYSIOLOGIC (Transient unconjugated hyperbilirubinemia [“physiologic jaundice”] that occurs in almost all newborns) In normal full-term neonate, average maximum serum bilirubin is 6 mg/dL (up to 12 mg/dL is in physiologic range), which occurs during the second to fourth days and then rapidly falls to ~2.0 mg/dL by fifth day (phase I physiologic jaundice). Declines slowly to <1.0 mg/dL during fifth to tenth days, but may take 1 mo to fall to <2 mg/dL (phase II physiologic jaundice). Phase I due to deficiency of hepatic bilirubin glucuronyl transferase activity and sixfold increase in bilirubin load presented to liver. In Asian and American Indian newborns, the average maximum serum levels are approximately double (10–14 mg/dL) the levels in non-Asians, and kernicterus is more frequent. Serum bilirubin >5 mg/dL during first 24 hrs of life is indication for further workup because of risk of kernicterus. In older children (and adults) icterus is apparent clinically when serum bilirubin is >2 mg/dL, but in newborns clinical icterus is not apparent until serum bilirubin is >5–7 mg/dL; therefore only half of full-term newborns show clinical jaundice during first 3 days of life.
- 164. In premature infants—average maximum serum bilirubin is 10–12 mg/dL and occurs during the fifth to seventh days. Serum bilirubin may not fall to normal until 30th day. Further workup is indicated in all premature infants with clinical jaundice because of risk of kernicterus in some low-birth-weight infants with serum levels of 10–12 mg/dL. In postmature infants and half of small-for-date infants—serum bilirubin is <2.5 mg/dL and physiologic jaundice is not seen. When mothers have received phenobarbital or used heroin, physiologic jaundice is also less severe. When a pregnant woman has unconjugated hyperbilirubinemia, similar levels occur in cord blood, but when the mother has conjugated hyperbilirubinemia (e.g., hepatitis), similar levels are not present in cord blood. HYPERBILIRUBINEMIA; NEONATAL, TRANSIENT FAMILIAL (LUCEY-DRISCOLL SYNDROME) Syndrome is due to progestational steroid in mother's serum only during last trimester of pregnancy, which inhibits glucuronyl transferase activity; disappears ~2 wks postpartum. Newborn infants have severe nonhemolytic unconjugated hyperbilirubinemia, usually up to 20 mg/dL during first 48 hrs, and a high risk of kernicterus. HYPERBILIRUBINEMIA IN OLDER CHILDREN Due To All cases of conjugated hyperbilirubinemia also show some increase of unconjugated serum bilirubin. Unconjugated Gilbert's disease Administration of drugs (e.g., novobiocin) Occasionally other conditions (e.g., thyrotoxicosis, after portacaval shunt in cirrhosis) Conjugated Dubin-Johnson syndrome Rotor's syndrome Acute viral hepatitis causes most cases in children. Cholestasis due to chemicals and drugs or associated with other diseases (e.g., Hodgkin's disease, sickle cell disease) JAUNDICE (CHOLESTATIC AND HEPATOCELLULAR), COMPARISON Hepatocellular Cholestasis Infiltration Disease example Acute viral hepatitis Common duct stone Metastatic tumor Serum bilirubin (mg/dL) 4–8 6–20* Usually <4, often normal AST, ALT (U/mL) Markedly increased, often 500–1000 May be slightly increased, <200 May be slightly increased, <100 Serum ALP 1–2× normal 3–5× normal† 2–4× normal PT Increased in severe disease Increased in chronic cases Normal Response to parenteral vitamin K No Yes *Serum bilirubin >10 mg/dL is rarely seen with common duct stone and usually indicates carcinoma. † Increased serum ALP <3× normal in 15% of patients with extrahepatic biliary obstruction, especially if obstruction is incomplete or due to benign conditions. Occasionally AST and LD are markedly increased in biliary obstruction or liver cancer. METABOLISM, INBORN ERRORS, CAUSING LIVER DISORDER Inborn Errors of Carbohydrate Metabolism Glycogen storage diseases Galactosemia Fructose intolerance Inborn Errors of Protein Metabolism Tyrosinemia Urea cycle enzyme defects Inborn Errors of Lipid Metabolism Gaucher's disease Gangliosidosis Cholesterol ester storage disease Niemann-Pick disease Lipodystrophy Wolman's disease Others Mucopolysaccharidoses Wilson's disease Hepatic porphyria Alpha1-antitrypsin deficiency Byler's disease
- 165. Cystic fibrosis PYLEPHLEBITIS, SEPTIC Increased WBCs and PMNs in >90% of patients; usually >20,000/cu mm Anemia of varying severity Moderate increase in serum bilirubin in ~33% of patients Other liver function tests positive in ~25% of patients Needle biopsy of liver not helpful; contraindicated Blood culture sometimes positive Laboratory findings due to preceding disease (e.g., acute appendicitis, diverticulitis, ulcerative colitis) Laboratory findings due to complications (e.g., portal vein occlusion) ROTOR'S SYNDROME (Autosomal recessive, familial, asymptomatic, benign defective uptake and storage of conjugated bilirubin and possibly in transfer of bilirubin from liver to bile or in intrahepatic binding; usually detected in adolescents or adults. Jaundice may be produced or accentuated by pregnancy, birth control pills, alcohol, infection, surgery.) See Table 8-4. m Mild chronic fluctuating nonhemolytic conjugated hyperbilirubinemia (usually <10 mg/dL). BSP excretion is impaired. Other liver function test are normal. Liver biopsy is normal; no pigment is present. m Urine coproporphyrins are markedly increased especially coproporphyrin I (increased more than III). SPACE-OCCUPYING LESIONS Due To Neoplasms (e.g., primary hepatocellular carcinoma, metastasis) Cysts Echinococcus £ 40% of patients with autosomal dominant polycystic renal disease Abscesses (amebic, pyogenic) Granulomas Sarcoidosis Infections (e.g., TB, cat-scratch bacillus, Q fever, Lyme disease, secondary syphilis) Drugs (e.g., gold, quinidine, diltiazem, hydralazine, methimazole, tocainide) m Increased serum ALP is the most useful index of partial obstruction of the biliary tree in which serum bilirubin is usually normal and urine bilirubin is increased. Increased in 80% of patients with metastatic carcinoma. Increased in 50% of patients with TB. Increased in 40% of patients with sarcoidosis. Increased frequently in patients with amyloidosis. Increase in serum LAP parallels that in ALP but is not affected by bone disease. Whenever the ALP is increased, a simultaneous increase of 5'-NT establishes biliary disease as the cause of the elevated ALP. AST is increased in 50% of patients (£ 300 U). ALT is increased less frequently (£ 150 U). m Detection of metastases by panel of blood tests (ALP, LD, transaminase, bilirubin) has sensitivity of 85%. ALP or GGT alone has sensitivity of 25–33% and specificity of £ 75%. Serum LD is often increased in cancer even without liver metastases. Radioactive scanning of the liver has 65% sensitivity. w Blind needle biopsy of the liver is positive in 65–75% of patients. m Laboratory findings due to primary disease (e.g., increased serum CEA in colon carcinoma, carcinoid syndrome, pyogenic liver abscess) TRANSPLANTATION OF LIVER Indications
- 166. Liver Failure Due To Arterial thrombosis Autoimmune liver disease Biliary atresia (infants) Budd-Chiari syndrome Cirrhosis Alcoholic Postnecrotic Primary biliary Secondary biliary Hepatitis Inborn errors of metabolism Alpha1-antitrypsin deficiency Protein C deficiency Crigler-Najjar syndrome type I Cystic fibrosis Erythropoietic protoporphyria Glycogen storage diseases type I and IV Hemophilias A and B Homozygous type II hyperlipoproteinemia Hyperoxaluria type I Niemann-Pick disease Tyrosinemia Urea cycle enzyme deficiencies Wilson's disease Laboratory indications, e.g., Portal hypertension with intractable ascites Hypersplenism and/or bleeding esophageal varices Poor synthesis function (e.g., decreased albumin, fibrinogen, prolonged PT) Progressive hyperbilirubinemia Liver trauma Polycystic liver disease Rejection of liver transplant (causes 20% of retransplants) Reye's syndrome Sclerosing cholangitis Unresectable liver neoplasms confined to liver Venoocclusive disease Contraindications Extrahepatic neoplasms Positive serology for HBsAg, HBcAb, HIV Sepsis other than of hepatobiliary system Stage 4 hepatic coma Unrelated failure of other organ systems Postoperative Complications Early Reported Incidence Primary nonfunction due to graft ischemia 5–10% Portal vein thrombosis Hepatic artery thrombosis 5–10% Hyperacute rejection Early acute rejection Immunosuppressant therapy toxicity Hepatorenal syndrome £ 9.8% Hepatopulmonary syndrome £ 13.2% Infection/sepsis Later Acute and chronic rejection Side effects of immunosuppressant therapy Biliary stenosis Recurrence of disease (especially hepatitis B, hepatitis C, EBV-associated lymphoproliferative disorders) Vanishing bile duct syndrome Rejection Most episodes occur within first 3 mos; patients are usually asymptomatic. Electrolytes must be monitored rapidly to treat cardiac arrest due to sudden release of large amounts of potassium from perfused liver and to monitor IV fluid replacement. Ionized calcium is lost due to chelation by citrate in transfused blood; left ventricular dysfunction may occur when serum level is <1.2 mEq/L. Serum sodium is monitored to avoid postoperative neurologic complications due to rapid increase during transplant and postoperative periods (e.g., central pontine
- 167. myelinolysis). Normalization of serum HCO3 – and anion gap signifies early function of liver transplant and of kidneys. m Serum GGT is the most sensitive marker for rejection; rises early during rejection before serum ALP and bilirubin. Is more specific than other markers because other complications (e.g., CMV infection) cause relatively low levels compared with AST and ALT. m Serum ALP lags behind serum GGT and bilirubin indicators of rejection. In uncomplicated cases, serum ALP and GGT remain within reference range. m AST and ALT rise after reperfusion of the allograft; increase to >4–5× upper limit of reference range even in uncomplicated cases. Persistent or late increases may be due to rejection or to other causes such as viral infections (e.g., CMV, HSV, adenovirus), occlusion of hepatic artery, liver abscess. m Serum total and direct bilirubin are monitored with enzymes and are useful to help differentiate between biliary obstruction (suggesting rejection) and hepato-cellular disease. Increase may be early sign of rejection but less useful than enzymes. Monitoring of serum cyclosporine is important because it is metabolized in the liver and proportion of cyclosporine and its metabolites may be altered when postoperative liver function is not maintained. PT and aPTT monitor synthesis of coagulation factors; specific factor measurements are not needed. Cultures from appropriate sites are performed for evidence of infection. w Liver biopsy is gold standard for diagnosis. Distinguish causes of rejection that have no specific biochemical pattern (e.g., acute rejection, chronic rejection, opportunistic viral infection, recurrence of HBV infection, CMV, changes in hepatic blood perfusion, unrecognized disease in donor liver). Differentiate from cholangitis, hepatitis, ischemic injury, which may mimic rejection. Substantial number of false-positives occur. Laboratory findings due to immunosuppression therapy Nephrotoxicity Liver toxicity (e.g., serum cyclosporine concentration >1200 ng/dL) Infection (e.g., bacterial, fungal, HBV, CMV, HSV, EBV) Cancer (e.g., non-Hodgkin's lymphoma, Kaposi's sarcoma, carcinomas of cervix, perineum, lip) Complications of hypertension In rare cases, genetic defects (e.g., factor XI deficiency) can be transmitted to the recipient and cause postoperative complications. TRAUMA Serum LD is frequently increased (>1400 U) 8–12 hrs after major injury. Shock due to any injury may also increase LD. Other serum enzymes and liver function tests are not generally helpful. Findings of abdominal paracentesis Bloody fluid (in ~75% of patients) confirming traumatic hemoperitoneum and indicating exploratory laparotomy. Nonbloody fluid (especially if injury occurred >24 hrs earlier). Microscopic—some red and white blood cells. Determine amylase, protein, pH, presence of bile. WILSON'S DISEASE15 (Autosomal recessive defect impairs copper excretion by liver, causing copper accumulation in liver.) Heterozygous gene for Wilson's disease occurs in 1 of 200 in the general population; 10% of these have decreased serum ceruloplasmin; liver copper is not increased (<250 µg/gm of dry liver). Serum copper and ceruloplasmin and urine copper levels are inadequate to detect heterozygous state. Homozygous gene (clinical Wilson's disease) occurs in 1 of 200,000 in the general population. Screening with DNA probes may become useful to detect homozygous infants. Serum Ceruloplasmin Decreased (<20 mg/dl) In Wilson's disease. (It is normal in 2–5% of patients with overt Wilson's disease.) May not be decreased in Wilson's disease with acute or fulminant liver involvement (ceruloplasmin is an acute-phase reactant). Healthy infants (therefore cannot use test for Wilson's disease in first year of life) 10–20% of persons heterozygous for Wilson's disease Renal protein loss (e.g., nephrosis) Malabsorption (e.g., sprue) Malnutrition Inherited ceruloplasmin deficiency (rare) w Serum ceruloplasmin (<20 mg/dL) with increased hepatic copper (>250 µg/gm) occurs only in Wilson's disease or normal infants aged <6 mos. Increased In Pregnancy
- 168. Use of estrogen or birth control pills Thyrotoxicosis Cirrhosis Cancer Acute inflammatory reactions (e.g., infection, RA) (May cause green color of plasma.) Total serum copper is decreased and generally parallels serum ceruloplasmin. Not a good indicator because changes during course of disease. w Free (nonceruloplasmin) copper in serum is increased and causes excess copper deposition in tissues and excretion in urine. Calculated from difference between total serum copper and ceruloplasmin-bound copper. Free copper (µg/dL) = total serum copper (µg/dL) – ceruloplasmin (mg/dL) × 3. Is virtually 100% sensitive and specific. Urinary copper is increased (>100 µg/24 hrs; normal <50 µg/24 hrs); may be normal in presymptomatic patients and increased in other types of cirrhosis. w Liver biopsy shows high copper concentration (>250 µg/gm of dry liver; normal = 20–45) and should be used to confirm the diagnosis. (Special copper-free needle should be used.) Copper concentrations may vary between nodules; thus extensive sampling may be necessary to confirm diagnosis. May also be elevated in cholestatic syndromes (e.g., primary biliary cirrhosis, primary sclerosing cholangitis, extrahepatic biliary cirrhosis, Indian childhood cirrhosis), which are easily differentiated from Wilson's disease by increased serum ceruloplasmin. m Histochemical staining of paraffin-embedded liver specimens for copper and copper-associated protein is diagnostic in appropriate clinical context but may be negative in Wilson's disease and present in other hepatic disorders. Liver biopsy may show no abnormalities, moderate to marked fatty changes with or without fibrosis, or active or inactive cirrhosis. m Findings of liver function tests may not be abnormal, depending on the type and severity of disease. In patients presenting with acute fulminant hepatitis, Wilson's disease is suggested if a disproportionately low serum ALP and relatively mild increase in AST and ALT are seen. Should also be ruled out in any patient <30 yrs with hepatitis (with negative serology for viral hepatitis), Coombs'-negative hemolysis, or neurologic symptoms to allow early diagnosis and treatment of Wilson's disease. w Radiocopper loading test: 64 Cu is administered IV or by mouth and serum concentration is plotted against time. Serum 64 Cu disappears within 4–6 hrs and then reappears in persons without Wilson's disease; secondary reappearance is absent in Wilson's disease because incorporation of 64 Cu into ceruloplasmin is decreased. Useful test in patients with normal ceruloplasmin levels or increased hepatic copper due to other forms of liver disease, or heterozygous carriers of Wilson's disease gene, or when liver biopsy is contraindicated. Aminoaciduria (especially cystine and threonine), glucosuria, hyperphosphaturia, hypercalciuria, uricosuria, and decreased serum uric acid and phosphorus may occur due to renal proximal tubular dysfunction; distal renal tubular acidosis is less common. Coombs'-negative nonspherocytic hemolytic anemia may occur. Other tests that have been used in diagnosis of heterozygotes may not be available locally: D-penicillamine administration induces increased urinary copper excretion. Excretion of radioactive copper. Conversion of ionic radioactive copper to radioactive ceruloplasmin. Copper content of cultured fibroblasts. DNA markers have been used for detection of homozygous and heterozygous patients. Laboratory findings due to complications Cirrhosis and sequelae (e.g., ascites, esophageal varices, liver failure). Hypersplenism (e.g., anemia, leukopenia, thrombocytopenia). Acute liver failure characterized by very high serum bilirubin (often >30 mg/dL) and decreased ALP; ALP/bilirubin ratio <2.0 is said to distinguish this from other causes of liver failure. Laboratory findings due to effects of therapeutic agents Long-term treatment with copper-depleting agents may sometimes cause a mild sideroblastic anemia and leukopenia due to copper deficiency. Penicillamine toxicity (e.g., nephrotic syndrome, thrombocytopenia, etc.). All transplant recipients have complete reversal of underlying defects in copper metabolism. TESTS FOR PANCREATIC DISEASE AMYLASE, SERUM See Fig. 8-9. Fig. 8-9. Algorithm for increased serum amylase and lipase. (ULN = upper limit of normal.)
- 169. (Composed of pancreatic and salivary types of isoamylases; distinguished by various methodologies; nonpancreatic etiologies are almost always salivary; both types may be increased in renal insufficiency.) Increased In Acute pancreatitis. Urine levels reflect serum changes by a time lag of 6–10 hrs. Acute exacerbation of chronic pancreatitis Drug-induced acute pancreatitis (e.g., aminosalicylic acid, azathioprine, corticosteroids, dexamethasone, ethacrynic acid, ethanol, furosemide, thiazides, mercaptopurine, phenformin, triamcinolone) Obstruction of pancreatic duct by Stone or carcinoma Drug-induced spasm of Oddi's sphincter (e.g., opiates, codeine, methyl choline, cholinergics, chlorothiazide) to levels 2–15× normal Partial obstruction plus drug stimulation (see discussion of cholecystokinin-secretin test) Biliary tract disease Common bile duct obstruction Acute cholecystitis Complications of pancreatitis (pseudocyst, ascites, abscess) Pancreatic trauma (abdominal injury; after ERCP) Altered GI tract permeability Ischemic bowel disease or frank perforation Esophageal rupture Perforated or penetrating peptic ulcer Postoperative upper abdominal surgery, especially partial gastrectomy (up to 2× normal in one-third of patients) Acute alcohol ingestion or poisoning Salivary gland disease (mumps, suppurative inflammation, duct obstruction due to calculus, radiation) Malignant tumors (especially pancreas, lung, ovary, esophagus; also breast, colon); usually >25× ULN, which is rarely seen in pancreatitis Advanced renal insufficiency. Often increased even without pancreatitis. Macroamylasemia Others, e.g., chronic liver disease (e.g., cirrhosis; £ 2× normal), burns, pregnancy (including ruptured tubal pregnancy), ovarian cyst, diabetic ketoacidosis, recent thoracic surgery, myoglobinuria, presence of myeloma proteins, some cases of intracranial bleeding (unknown mechanism), splenic rupture, dissecting aneurysm It has been suggested that a level >1000 U/L is usually due to surgically correctable lesions (most frequently stones in biliary tree), the pancreas being negative or showing only edema; but 200–500 U is usually associated with pancreatic lesions that are not surgically correctable (e.g., hemorrhagic pancreatitis, necrosis or pancreas). Increased serum amylase with low urine amylase may be seen in renal insufficiency and macroamylasemia. Serum amylase £ 4× normal in renal disease only when creatinine clearance is <50 mL/min due to pancreatic or salivary isoamylase but rarely >4× normal in absence of acute pancreatitis. Decreased In Extensive marked destruction of pancreas (e.g., acute fulminant pancreatitis, advanced chronic pancreatitis, advanced cystic fibrosis). Decreased levels are clinically significant only in occasional cases of fulminant pancreatitis. Severe liver damage (e.g., hepatitis, poisoning, toxemia of pregnancy, severe thyrotoxicosis, severe burns) Methodologic interference by drugs (e.g., citrate and oxalate decrease activity by binding calcium ions) Amylase–creatinine clearance ratio = (urine amylase concentration ÷ serum amylase concentration) × (serum creatinine concentration ÷ urine creatinine concentration) × 100 Normal: 1–5% Macroamylasemia: <1%; very useful for this diagnosis. Acute pancreatitis: >5%; use is presently discouraged for this diagnosis. May Be Normal In Patients with relapsing chronic pancreatitis Patients with hypertriglyceridemia (technical interference with test) Frequently normal in patients with acute alcoholic pancreatitis. LIPASE, SERUM16 (Method should always include colipase in reagent.) See Fig. 8-9.
- 170. Increased In Acute pancreatitis Perforated or penetrating peptic ulcer, especially with involvement of pancreas Obstruction of pancreatic duct by Stone Drug-induced spasm of Oddi's sphincter (e.g., codeine, morphine, meperidine, methacholine, cholinergics), to levels 2–15× normal Partial obstruction plus drug stimulation Chronic pancreatitis Acute cholecystitis Small bowel obstruction Intestinal infarction Acute and chronic renal failure (increased 2–3× in 80% of patients and 5× in 5% of patients) Organ transplant (kidney, liver, heart), especially with complications (e.g., organ rejection, CMV infection, cyclosporin toxicity) Alcoholism Diabetic ketoacidosis After ERCP Some cases of intracranial bleeding (unknown mechanism) Macro forms in lymphoma, cirrhosis Drugs Induced acute pancreatitis (see preceding section on serum amylase) Cholestatic effect (e.g., indomethacin) Methodologic interference (e.g., pancreozymin [contains lipase], deoxycholate, glycocholate, taurocholate [prevent inactivation of enzyme], bilirubin [turbidimetric methods]) Chronic liver disease (e.g., cirrhosis) (usually £ 2× normal) Decreased In Methodologic interference (e.g., presence of hemoglobin, calcium ions) Usually Normal In Mumps Values are lower in neonates. Macroamylasemia DISEASES OF THE PANCREAS CYSTIC FIBROSIS OF PANCREAS17 (Autosomal recessive disorder with abnormal ion transport due to failure of chloride regulation; incidence of 1 in 1500 to 1 in 2000 in whites with a carrier frequency of 1 in 20; 1 in 17,000 in American blacks; marked heterogeneity among patients.) Quantitative Pilocarpine Iontophoresis Sweat Test (Properly Performed) w Striking increase in sweat sodium (>60 mEq/L) and chloride (>60 mEq/L) and, to a lesser extent, potassium is present in virtually all homozygous patients; value is 3–5× higher than in healthy persons or in those with other diseases. Is consistently present throughout life from time of birth, and degree of abnormality is not related to severity of disease or organ involvement. Sensitivity = 98%, specificity = 83%, positive predictive value = 93%. Sweat chloride is somewhat more reliable than sodium for diagnostic purposes. In children, chloride >60mEq/L is considered positive for cystic fibrosis. 40–60 mEq/L is considered borderline and requires further investigation. <40 mEq/L is considered normal. £ 80 mEq/L may be normal for adults. On occasion 1–2% of cystic fibrosis patients have normal, borderline, or variable values. Rare patients with borderline values have only mild disease. Sweat potassium is not diagnostically valuable because of overlap with normal controls. Increased sweat sodium and chloride are not useful for detection of heterozygotes (who have normal values) or for genetic counseling. w Sweat chloride ³80 mEq/L on repeated occasions with characteristic clinical manifestations or family history confirm diagnosis of cystic fibrosis. A broad range of sweat values is seen in patients with this disease and in normal persons but overlap is minimal. Sweat values (mEq/L) Chloride Sodium Potassium
- 171. Mean Range Mean Range Mean Range Cystic fibrosis 115 79–148 111 75–145 23 14–30 Normal 28 8–43 28 16–46 10 6–17 Note that one instrument (Wescor; Logan, Utah) measures sweat conductivity, not sweat chloride, which is not equivalent. Sweat conductivity measurement is considered a screening test; patients with values ³50 mEq/L should have quantitative sweat chloride test. Interferences Sweat testing is fraught with problems and technical and laboratory errors are very frequent; should be performed in duplicate and repeated at least once on separate days on samples >100 mg of sweat. Values may be increased to cystic fibrosis range in healthy persons when sweat rate is rapid (e.g., exercise, high temperature), but pilocarpine test does not increase sweating rate. Mineralocorticoids decrease sodium concentration in sweat by ~50% in normal subjects and 10–20% in cystic fibrosis patients, whose final sodium concentration remains abnormally high. Increased In Endocrine disorders Untreated adrenal insufficiency (Addison's disease) Hypothyroidism Vasopressin-resistant diabetes insipidus Familial hypoparathyroidism Pseudohypoaldosteronism Metabolic disorders Malnutrition Glycogen storage disease type I (von Gierke's disease) Mucopolysaccharidosis IH and IS Fucosidosis Genitourinary disorders Klinefelter's syndrome Nephrosis Allergic/immunologic disorders Hypogammaglobulinemia Prolonged infusion with prostaglandin E 1 Atopic dermatitis Neuropsychologic disorders Anorexia nervosa Autonomic dysfunction Others Ectodermal dysplasia G-6-PD deficiency Serum chloride, sodium, potassium, calcium, and phosphorus are normal unless complications occur (e.g., chronic pulmonary disease with accumulation of CO 2; massive salt loss due to sweating causing hyponatremia). Urine electrolytes are normal. Submaxillary saliva has slightly increased chloride and sodium but not potassium; considerable overlap with results for normal persons prevents diagnostic use. Submaxillary saliva is more turbid, with increased calcium, total protein, and amylase. These changes are not generally found in parotid saliva. Serum protein electrophoresis shows increasing IgG and IgA with progressive pulmonary disease; IgM and IgD are not appreciably increased. Serum albumin is often decreased (because of hemodilution due to cor pulmonale; may be found before cardiac involvement is clinically apparent). m Laboratory changes secondary to complications that should also suggest diagnosis of cystic fibrosis Salt-loss syndromes Hypochloremic metabolic alkalosis and hypokalemia due to excessive loss of electrolytes in sweat and stool Acute salt depletion Respiratory abnormalities Chronic lung disease (especially upper lobes) with laboratory changes of decreased pO 2, accumulation of CO2, metabolic alkalosis, severe recurrent infection, secondary cor pulmonale, etc. Nasal polyps, pansinusitis; normal sinus radiographs are strong evidence against cystic fibrosis. BAL usually shows increased PMNs (>50% in cystic fibrosis; ~3% in normal persons) with high absolute neutrophil count; is strong evidence of cystic fibrosis even in absence of pathogens. Bacteriology: Special culture techniques should be used in these patients. Before 1 yr of age, S. aureus is found in 25% and Pseudomonas in 20% of respiratory tract cultures; in adults Pseudomonas grows in 80% and S. aureus in 20%. Haemophilus influenzae is found in 3.4% of cultures. Pseudomonas aeruginosa is found increasingly often after treatment of staphylococcal infection, and special identification and susceptibility tests should be performed on P. aeruginosa. Pseudomonas cepacia is becoming more important in older children. Increasing serum antibodies against P. aeruginosa can document probable infection when cultures are negative. Gastrointestinal abnormalities Chronic/recurrent pancreatitis. Pancreatic enzyme activity is lost in 80% of patients, decreased in 10%, and normal in 10% of patients. Protein-calorie malnutrition, hypoproteinemia, fat-soluble vitamin deficiency (see Malabsorption). Stool and duodenal fluid show lack of trypsin digestion of radiographic film gelatin; useful screening test up to age 4; decreased chymotrypsin production (see bentiromide test). Impaired glucose intolerance in ~40% of patients, with glycosuria and hyperglycemia
- 172. in 8%, precedes diabetes mellitus. Cirrhosis (in >25% of patients at autopsy), especially before age 30 years; hypersplenism; cholelithiasis. Meconium ileus during early infancy; causes 20–30% of cases of neonatal intestinal obstruction; present at birth in 8% of these children. Almost all of them will develop the clinical picture of cystic fibrosis. GU tract abnormalities Aspermia in 98% due to obstructive changes in vas deferens and epididymis, confirmed by testicular biopsy. w Neonatal screening using dried filter paper blood test that measures immunoreactive trypsin has been used. Normal in £ 10% of cystic fibrosis infants. Increased false-negative rate in meconium ileus. w DNA genotyping (using blood; can use buccal scrapings) to confirm diagnosis based on two mutations is highly specific but not very sensitive. Supports diagnosis of cystic fibrosis, but failure to detect gene mutations does not exclude cystic fibrosis because of large number of alleles. Substantial number of cystic fibrosis patients have unidentified gene mutation. Helpful when sweat test is borderline or negative. Can also be used for prenatal diagnosis and carrier screening. Identical genotypes can be associated with different degrees of disease severity. w Nasal electrical potential-difference measurements may be more reliable than sweat tests but are much more complex to perform. MACROAMYLASEMIA w Serum amylase persistently increased (often 1–4× normal) without apparent cause. Serum lipase is normal. Normal pancreatic to salivary amylase ratio. Urine amylase normal or low. m Amylase–creatinine clearance ratio <1% with normal renal function is very useful for this diagnosis; should make the clinician suspect this diagnosis. w Macroamylase is identified in serum by special gel filtration or ultracentrifugation technique. May be found in ~1% of randomly selected patients and 2.5% of persons with increased serum amylase. Same findings may also occur in patients with normal-molecular-weight hyperamylasemia in which excess amylase is principally salivary gland isoamylase types 2 and 3. When associated with pancreatic disease, serum lipase may be elevated. PANCREATIC CARCINOMA18 Body or Tail Laboratory tests are often normal. m Serum markers for tumor CA 19-9, CEA, etc. (see Chapter 16) In carcinoma of pancreas, CA 19-9 has sensitivity of 70%, specificity of 87%, positive predictive value of 59%, negative predictive value of 92%. No difference in sensitivity between local disease and metastatic disease. Often normal in early stages, therefore not useful for screening. Increased value may help differentiate benign disease from cancer. Declines to normal in 3–6 mos if cancer is completely removed, so may be useful for prognosis and follow-up. Detects tumor recurrence 2–20 wks before clinical evidence appears. Not specific for pancreas because high levels may also occur in other GI cancers, especially those affecting colon and bile duct. Testosterone/dihydrotestosterone ratio is <5 (normal = ~10) in >70% of men with pancreatic cancer (due to increased conversion by tumor). Less sensitive but more specific than CA 19-9; present in higher proportion of stage I tumors. w The most useful diagnostic test is ultrasonography or CAT scanning followed by ERCP (at which time fluid is also obtained for cytologic and pancreatic function studies). This combination correctly diagnoses or rules out cancer of pancreas in ³90% of cases. ERCP with brush cytology has sensitivity £ 25% and specificity £ 100%. CEA level in bile (obtained by percutaneous transhepatic drainage) was reported increased in 76% of a small group of cases. Serum amylase and lipase may be slightly increased in early stages (<10% of cases); with later destruction of pancreas, they are normal or decreased. They may increase after secretin-pancreozymin stimulation before destruction is extensive; therefore, the increase is less marked with a diabetic glucose tolerance curve. Serum amylase response is less reliable. m Glucose tolerance curve is of the diabetic type with overt diabetes in 20% of patients with pancreatic cancer. Flat blood sugar curve with IV tolbutamide tolerance test indicates destruction of islet cell tissue. Unstable, insulin-sensitive diabetes that develops in an older man should arouse suspicion of carcinoma of the pancreas. w Secretin-cholecystokinin stimulation evidences duct obstruction when duodenal intubation shows decreased volume of duodenal contents (<10 mL/10-min collection period) with usually normal bicarbonate and enzyme levels in duodenal contents. Acinar destruction (as in pancreatitis) shows normal volume (20–30 mL/10-min collection period), but bicarbonate and enzyme levels may be decreased. Abnormal volume, bicarbonate, or both is found in 60–80% of patients with pancreatitis or cancer. In carcinoma, the test result depends on the relative extent and combination of acinar destruction and of duct obstruction. Cytologic examination of duodenal contents shows malignant cells in 40% of patients. Malignant cells may be found in up to 80% of patients with periampullary cancer. Serum LAP is increased (>300 U) in 60% of patients with carcinoma of pancreas due to liver metastases or biliary tract obstruction. It may also be increased in chronic liver disease. w Triolein 131 I test demonstrates pancreatic duct obstruction with absence of lipase in the intestine causing flat blood curves and increased stool excretion. Radioisotope scanning of pancreas may be done (selenium 75) for lesions >2 cm. w Needle biopsy has reported sensitivity of 57–96%; false-positives are rare. Head The abnormal pancreatic function tests and increased tumor markers that occur with carcinoma of the body of the pancreas may be evident. w Laboratory findings due to complete obstruction of common bile duct Serum bilirubin increased (12–25 mg/dL), mostly direct (increase persistent and nonfluctuating). Serum ALP increased. Urine and stool urobilinogen absent. Increased PT; normal after IV vitamin K administration.
- 173. Increased serum cholesterol (usually >300 mg/dL) with esters not decreased. Other liver function tests are usually normal. PANCREATITIS, ACUTE19 w Serum lipase increases within 3–6 hrs with peak at 24 hrs and usually returns to normal over a period of 8–14 days. Is superior to amylase; increases to a greater extent and may remain elevated for up to 14 days after amylase returns to normal. In patients with signs of acute pancreatitis, pancreatitis is highly likely (clinical specificity = 85%) when lipase ³5× ULN, if values change significantly with time, and if amylase and lipase changes are concordant. ( Lipase should always be determined whenever amylase is determined.) New methodology improves clinical utility. Urinary lipase is not clinically useful. It has been suggested that a lipase/amylase ratio >3 (and especially >5) indicates alcoholic rather than nonalcoholic pancreatitis. Acute pancreatitis or organ rejection is highly likely if lipase is ³5× ULN, but unlikely if <3× ULN. (See Fig. 8-9) w Serum amylase increase begins in 3–6 hrs, rises rapidly within 8 hrs in 75% of patients, reaches maximum in 20–30 hrs, and may persist for 48–72 hrs. >95% sensitivity during first 12–24 hrs. The increase may be £ 40× normal, but the height of the increase and rate of fall do not correlate with the severity of the disease, prognosis, or rate of resolution; however, an increase of >7–10 days suggests an associated cancer of pancreas or pseudocyst, pancreatic ascites, or nonpancreatic cause. Similar high values may occur in obstruction of pancreatic duct; they tend to fall after several days. >10% of patients with acute pancreatitis (especially when seen more than 2 days after onset of symptoms) may have normal values, even when dying of acute pancreatitis . May also be normal in patients with relapsing chronic pancreatitis and patients with hypertriglyceridemia (technical interference with test). Frequently normal in acute alcoholic pancreatitis. Acute abdomen due to GI infarction or perforation rather than acute pancreatitis is suggested by only moderate increase in serum amylase and lipase (<3× ULN), evidence of bacteremia. 10–40% of patients with acute alcoholic intoxication have elevated serum amylase (about half of amylases are salivary type); patients often present with abdominal pain, but increased serum amylase is usually <3× ULN. Levels >25× ULN indicate metastatic tumor rather than pancreatitis. w Serum pancreatic isoamylase can distinguish elevations due to salivary amylase, which may account for 25% of all elevated values. (In healthy persons, 40% of total serum amylase is pancreatic type and 60% is salivary type.) Only slight increase in serum amylase and lipase values suggests a different diagnosis than acute pancreatitis. Many drugs increase both amylase and lipase in serum. Serum calcium is decreased in severe cases 1–9 days after onset (due to binding to soaps in fat necrosis). The decrease usually occurs after amylase and lipase levels have become normal. Tetany may occur. (Rule out hyperparathyroidism if serum calcium is high or fails to fall in hyperamylasemia of acute pancreatitis.) Increased urinary amylase tends to reflect serum changes by a time lag of 6–10 hrs, but sometimes increased urine levels are higher and of longer duration than serum levels. The 24-hr level may be normal even when some of the 1-hr specimens show increased values. Measurement of amylase levels in hourly samples of urine may be useful. Ratio of amylase clearance to creatinine clearance is increased (>5%) and its use avoids the problem of timed urine specimens; also increased in any condition that decreases tubular reabsorption of amylase (e.g., severe burns, diabetic ketoacidosis, chronic renal insufficiency, multiple myeloma, acute duodenal perforation). Considered not specific; its use now discouraged by some but still recommended by others. Serum bilirubin may be increased when pancreatitis is of biliary tract origin but is usually normal in alcoholic pancreatitis. Serum ALP, ALT, and AST may increase and parallel serum bilirubin rather than amylase, lipase, or calcium levels. Marked amylase increase (e.g., >2000 U/L) also favors biliary tract origin. Fluctuation >50% in 24 hrs of serum bilirubin, ALP, ALT, and AST suggests intermittent biliary obstruction. m Serum trypsin (by RIA) is increased. High sensitivity makes a normal value useful for excluding acute pancreatitis. But low specificity (increased in large proportion of patients with hepatobiliary, bowel, and other diseases and renal insufficiency; increased in 13% of patients with chronic pancreatitis and 50% with pancreatic carcinoma) and RIA technology limit utility. WBC is slightly to moderately increased (10,000–20,000/cu mm). Hemoconcentration occurs (increased Hct). Hct may be decreased in severe hemorrhagic pancreatitis. Glycosuria appears in 25% of patients. Methemalbumin may be increased in serum and ascitic fluid in hemorrhagic (severe) but not edematous (mild) pancreatitis; may distinguish these two conditions but not useful in diagnosis of acute pancreatitis. Hypokalemia, metabolic alkalosis, or lactic acidosis may occur. Laboratory findings due to predisposing conditions (may be multiple) Alcohol abuse accounts for ~36% of cases. Biliary tract disease accounts for 17% of cases. Idiopathic origin accounts for >36% of cases. Infections (especially viral such as mumps, coxsackievirus and CMV infections, AIDS). Trauma and postoperative condition account for >8% of cases. Drug effects (e.g., steroids, thiazides, azathioprine, estrogens, sulfonamides; valproic acid in children) account for >5% of cases. Hypertriglyceridemia (hyperlipidemia types V, I, IV) accounts for 7% of cases. Hypercalcemia from any cause. Tumors (pancreas, ampulla). Anatomic abnormalities of ampullary region causing obstruction (e.g., annular pancreas, Crohn's disease, duodenal diverticulum). Hereditary. Renal failure; renal transplantation. Miscellaneous (e.g., collagen vascular disease, pregnancy, ischemia, scorpion bites, parasites obstructing pancreatic duct [ Ascaris, fluke], Reye's syndrome, fulminant hepatitis, severe hypotension, cholesterol embolization). Laboratory findings due to complications Pseudocysts of pancreas. Pancreatic abscess. Polyserositis (peritoneal, pleural, pericardial, synovial surfaces). Ascites may develop, cloudy or bloody or “prune juice” fluid, 0.5–2.0 L in volume, containing increased amylase with a level higher than that of serum amylase. No bile is evident (unlike in perforated ulcer). Gram stain shows no bacteria (unlike in infarct of intestine). Protein >3 gm/dL and marked increase in amylase. ARDS (with pleural effusion, alveolar exudate, or both) may occur in ~40% of patients; arterial hypoxemia is present. DIC. Hypovolemic shock. Others. Prognostic laboratory findings On admission WBC >16,000/cu mm Blood glucose >200 mg/dL
- 174. Serum LD >350 U/L Serum AST >250 U/L Age >55 yrs Within 48 hrs Serum calcium <8.0 mg/dL Decrease in Hct >10 points Increase in BUN >5 mg/dL Arterial pO2 <60 mm Hg Metabolic acidosis with base deficit >4 mEq/L Mortality 1% if three signs are positive 15% if three or four signs are positive 40% if five or six signs are positive 100% if seven or more signs are positive Degree of amylase elevation has no prognostic significance. PANCREATITIS, CHRONIC See also Malabsorption. w Cholecystokinin-secretin test measures the effect of IV administration of cholecystokinin and secretin on volume, bicarbonate concentration, and amylase output of duodenal contents and increase in serum lipase and amylase. This is the most sensitive and reliable test (gold standard) for chronic pancreatitis, especially in the early stages. Is technically difficult and is often not performed accurately; gastric contamination must be avoided. Some abnormality occurs in >85% of patients with chronic pancreatitis. Amylase output is the most frequent abnormality. When all three are abnormal, there is a greater frequency of abnormality in the tests listed below. Normal duodenal contents Volume: 95–235 mL/hr Bicarbonate concentration: 74–121 mEq/L Amylase output: 87,000–267,000 mg Serum amylase and lipase increase after administration of cholecystokinin and secretin in ~20% of patients with chronic pancreatitis. They are more often abnormal when duodenal contents are normal. Normally serum lipase and amylase do not rise above normal limits. Fasting serum amylase and lipase are increased in 10% of patients with chronic pancreatitis. Serum pancreolauryl test Fluorescein dilaurate taken with breakfast is acted on by a pancreas-specific cholesterol ester hydrolase, releasing fluorescein, which is absorbed from gut and measured in serum; preceded by administration of secretin and followed by administration of metoclopramide. Reported sensitivity = 82%, specificity 91%. 20 Diabetic OGTT results in 65% of patients with chronic pancreatitis and frank diabetes in >10% of patients with chronic relapsing pancreatitis. When GTT is normal in the presence of steatorrhea, the cause should be sought elsewhere than in the pancreas. w Laboratory findings due to malabsorption (occurs when >90% of exocrine function is lost) and steatorrhea. Bentiromide test is usually abnormal with moderate to severe pancreatic insufficiency. Schilling test may show mild malabsorption of Vitamin B12. Xylose tolerance test and small bowel biopsy are not usually done but are normal. Chemical analysis of fecal fat demonstrates steatorrhea. It is more sensitive than tests using triolein 131 I. Triolein 131 I testing is abnormal in one-third of patients with chronic pancreatitis. Starch tolerance test is abnormal in 25% of patients with chronic pancreatitis. Laboratory findings due to causes of chronic pancreatitis and pancreatic exocrine insufficiency Alcoholism in 60–70% Idiopathic in 30–40% Obstruction of pancreatic duct (e.g., trauma, pseudocyst, pancreas divisum, cancer or obstruction of duct or ampulla) Other causes occasionally (e.g., cystic fibrosis, primary hyperparathyroidism, heredity, protein caloric malnutrition, miscellaneous [Z-E syndrome, Shwachman syndrome, alpha1-antitrypsin deficiency, trypsinogen deficiency, enterokinase deficiency, hemochromatosis, parenteral hyperalimentation]) w Radioactive selenium scanning of pancreas yields variable findings in different clinics. CT, ultrasonography, ERCP are most accurate for diagnosing and staging chronic pancreatitis. PSEUDOCYST OF PANCREAS Serum direct bilirubin is increased (>2 mg/dL) in 10% of patients. Serum ALP is increased in 10% of patients. Fasting blood sugar is increased in <10% of patients. Duodenal contents after secretin-pancreozymin stimulation usually show decreased bicarbonate content (<70 mEq/L) but normal volume and normal content of amylase, lipase, and trypsin. w Findings of pancreatic cyst aspiration21 Best when panel of tests is used. High fluid viscosity and CEA indicate mucinous differentiation and exclude pseudocyst, serous cystadenoma, other nonmucinous cysts or cystic tumors. Increased CA 72-4, CA 15-3, and tissue polypeptide antigen are markers of malignancy; if all are low, pseudocyst or serous cystadenoma is most likely. CA 125 is increased in serous cystadenoma. Pancreatic enzymes, leukocyte esterase, and NB/70K are increased in pseudocysts. Cytologic examination.
- 175. Laboratory findings of preceding acute pancreatitis (this is mild and unrecognized in one-third of patients). Persistent increase of serum amylase and lipase after an episode of acute pancreatitis may indicate formation of a pseudocyst. Laboratory findings due to conditions preceding acute pancreatitis (e.g., alcoholism, trauma, duodenal ulcer, cholelithiasis). Laboratory findings due to complications Infection Perforation Hemorrhage by erosion of blood vessel or into a viscus 1Sheth SG, Gordon FD, Chopra S. Nonalcoholic Steatohepatitis. Ann Intern Med 1997;126:137. 2 Mendlein J, et al. Iron overload, public health and genetics. Ann Intern Med 1998;129:921. 3 Edwards CQ, Kushner JP. Screen for hemochromatosis. N Engl J Med 1993;328:1616. 4Press RD, et al. Hepatic iron overload. Am J Clin Pathol 1998;109:577. 5 Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med 1997;126:137. 6Czaja AJ. The variant forms of autoimmune hepatitis. Ann Intern Med 1996;125:588. 7 Lemon SM. Type A viral hepatitis: epidemiology, diagnosis, and prevention. Clin Chem 1997; 43:1494. 8 MMWR Recommendations for prevention and control of hepatitis C virus infection and HCV-related chronic disease. US Department of Health and Human Services, Centers for Disease Control and Prevention; 1998 Oct 16; 47/no RR-19. 9 Fairfax MR, Merline JR, Podzorski RP. Am Soc Clin Pathol. Check Sample Microbiology No. 97-1. 10 Cacciola I, et al. Occult hepatitis B virus infections in patients with chronic hepatitis C liver disease. N Engl J Med 1999;341:22. 11 Masuko K, et al. Infection with hepatitis GB virus C in patients on maintenance hemodialysis. N Engl J Med 1996;334:1485. 12 Alter HJ. The cloning and clinical implications of HGV and HGBV-C. N Engl J Med 1996;334:1536. 13De Lamballerie X, Charrel RN, Dussol B. Hepatitis GB virus C in patients on hemodialysis. N Engl J Med 1996;334:1549. 14 Yao DF, et al. Diagnosis of hepatocellular carcinoma by quantitative detection of hepatoma-specific bands of serum g-glutamyltransferase. Am J Clin Pathol 1998;110:743. 15Stremmel W, et al. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med 1991;115:720. 16 Tietz NW, Shuey DF. Lipase in serum—the elusive enzyme: an overview. Clin Chem 1993;39:746. 17 Stern RC. The diagnosis of cystic fibrosis. N Engl J Med 1997;336:487. 18 Warshaw AL, Fernandez-del Castillo C. Pancreatic cancer. N Engl J Med 1992;326:455. 19 Ranson JHC. Etiological and prognostic factors in human acute pancreatitis: a review. Am J Gastroenterol 1982;77:633. 20Dominguez-Munoz JE, Malfertheiner P. Optimized serum pancreolauryl test for differentiating patients with and without chronic pancreatitis. Clin Chem 1998;44:869. 21 Centeno BA. Fine needle aspiration biopsy of the pancreas. Clin Lab Med 1998;18:401.
- 176. CHAPTER 9 CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS Interpretation of Diagnostic Tests CHAPTER 9 CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS Cerebrospinal Fluid (CSF), Abnormal CSF, Normal CSF, Normal Values Dexamethasone Suppression Test (DST) Abscess, Brain Abscess, Epidural of Spinal Cord/Extradural, Intracranial Acquired Immunodeficiency Syndrome (AIDS), Neurologic Manifestations Arteritis, Cranial Arachnoiditis, Chronic Adhesive Bassen-Kornzweig Syndrome Cerebellar Ataxia, Progressive, with Skin Telangiectasias (Louis-Bar's Syndrome) Cerebrovascular Accident (Nontraumatic) Cobalamin Deficiency Causing Neuropsychiatric Disorders Coma and Stupor Dementia, Senile (Alzheimer-Pick Disease; Cerebral Atrophy) Empyema, Subdural, Acute Encephalopathy, Hypertensive Glomus Jugulare Tumor Guillain-Barré Syndrome Leukemic Involvement of CNS Leukodystrophy, Metachromatic Lindau-von Hippel Disease (Hemangioblastomas of Retina and Cerebellum) Meningitis, Aseptic Meningitis, Bacterial Meningitis, Chemical Meningitis, Chronic Meningitis, Mollaret's Meningitis, Tuberculous Meningitis/Encephalomyelitis, Acute Viral Meningoencephalitis, Primary Amebic Multiple Sclerosis (MS) Myelitis Neuritis/Neuropathy, Multiple Neuritis of One Nerve or Plexus Prion Diseases Pseudotumor Cerebri Refsum's Disease Retardation, Mental Reye's Syndrome Seizures that may be Accompanied by Laboratory Abnormalities Spinal Cord, Infarction Spinal Cord Tumor Spondylosis, Cervical Thrombophlebitis, Cavernous Sinus Trauma, Head Tuberculoma of Brain Tumor of Brain Von Recklinghausen's Disease (Multiple Neurofibromas) LABORATORY TESTS FOR DISORDERS OF THE NERVOUS SYSTEM CEREBROSPINAL FLUID (CSF), ABNORMAL See Table 9-1. Table 9-1. Cerebrospinal Fluid (CSF) Findings in Various Conditions Gross Appearance Viscous CSF may occur with metastatic mucinous adenocarcinoma (e.g., colon), large numbers of cryptococci, severe meningeal infection, or, rarely, injury to annulus fibrosus with release of nucleus pulposus fluid. Turbidity may be due to increased WBCs (>200/cu mm) or RBCs (>400/cu mm), or presence of bacteria (>10 5 /mL) or other microorganisms (fungi, amebae), contrast media, or epidural fat aspirated during lumbar puncture. Clots or pellicles indicate protein >150 mg/dL. CSF with RBC >6000/cu mm appears grossly bloody; with RBC = 500–6000/cu mm appears cloudy, xanthochromic, or pink-tinged (in bright light in clear glass tubes containing >1 mL of CSF). Xanthochromia caused by bilirubin, may be due to Bleeding within 2–36 hrs. Minimum period for bilirubin detection is 12 hrs. Traumatic lumbar puncture >2 hrs earlier. Hemorrhage into CSF (e.g., subarachnoid or intracerebral hemorrhage). Is present in all patients for £ 2 wks and 70% of patients at 3 wks. Serum bilirubin >6 mg/dL. Protein >100 mg/dL usually causes CSF to look faintly yellow. WBCs CSF WBCs may be corrected for presence of blood (e.g., traumatic tap, subarachnoid hemorrhage) by subtracting 1 WBC for each 700 RBCs/cu mm counted in CSF if the CBC is normal. If significant anemia or leukocytosis is present:
- 177. (RBC and WBC are cells/cu mm) In normal CSF, minimal blood contamination may cause £ 2 PMN/25 RBCs, or £ 10 PMN/25–100 RBCs. CSF WBC count (>3000/cu mm) with predominantly PMNs strongly suggests bacterial cause and is >2000/cu mm in 38% of cases. When WBC <1000/cu mm in bacterial meningitis, one-third of cases have >50% lymphocytes or mononuclear cells. However, WBCs are usually PMNs in early stages of all types of meningitis; mononuclear cells only appear in a second specimen 18–24 hrs later. Low WBC counts do not rule out acute bacterial meningitis. Neutrophilic leukocytes are found in: Bacterial infections (e.g., Nocardia, Actinomyces, Arachnia, Brucella) Fungal infections (Blastomyces, Coccidioides, Candida, Aspergillus, Zygomycetes, Cladosporium, Allescheria) Chemical meningitis Other conditions (e.g., SLE) Lymphocytic cells are found in: Bacterial infections (e.g., Treponema pallidum, Leptospira, Actinomyces israelii, Arachnia propionica, 90% of Brucella cases, Borrelia burgdorferi [Lyme disease], Mycobacterium tuberculosis) Fungal infections (e.g., Cryptococcus neoformans, Candida spp., Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitides, Sporotrichum schenckii, Allescheria boydii, Cladosporium trichoides) Parasitic diseases (e.g., toxoplasmosis, cysticercosis) Viral infections (e.g., mumps, lymphocytic choriomeningitis, infection with human T-cell leukemia virus [HTLV] type III or echovirus) Parameningeal disorders (e.g., brain abscess) Noninfectious disorders (e.g., neoplasms, sarcoidosis, multiple sclerosis, granulomatous arteritis) Eosinophils may be found in: Lymphoma Helminth infection (e.g., angiostrongyliasis, cysticercosis) Rarely other infections (e.g., TB, syphilis, Rocky Mountain spotted fever, coccidioidomycosis) Microbiology/Serology Smears for Gram and acid-fast stains must be routinely centrifuged on all CSF specimens because other findings may be normal in meningitis. Occasionally animal inoculations may be required. Gram stain of CSF sediment is negative in 20% of cases of bacterial meningitis because at least 10 5 bacteria/mL of CSF must be present to demonstrate 1–2 bacteria/100× microscopic field. Gram stain is positive in 90% of cases due to pneumococci, 85% of cases due to Haemophilus influenzae, 75% of cases due to meningococci, and 50% of cases due to Listeria monocytogenes, but only 30–50% of cases due to gram-negative enteric bacilli. If antibiotics have been given before CSF obtained, Gram stain may be negative. Stains are positive in <60% of cases of treated bacterial meningitis, <5% of cases of TB meningitis, 20–70% of cases of fungal meningitis and <2% of cases of brain abscess. Sensitivity of Gram stain is increased by using fluorescent techniques with acridine orange. Positive CSF culture has sensitivity of 92%, specificity of 95%, false-negative rate of 8%, and false-positive rate of 5%. Limulus amebocyte lysate is a rapid specific indicator of endotoxin produced by gram-negative bacteria ( Neisseria meningitidis, H. influenzae type b, Escherichia coli, Pseudomonas). Is not affected by prior antibiotic therapy; is more rapid and sensitive than CIE. Often is not routinely available. Serologic methods are often preferred (e.g., positive in 85% of coccidioidal cases compared with culture, which is positive in 37% of cases) especially in syphilis, brucellosis, Lyme disease. Blood and CSF serology are positive in CNS syphilis; positive in 7–10% of active cases of infectious mononucleosis. PCR to detect HSV and human enteroviruses in meningitis and encephalitis. Antigen detection (latex agglutination) for H. influenzae type b, C. neoformans, N. meningitidis, Streptococcus pneumoniae, Streptococcus agalactiae has replaced CIE. Use Abnormal CSF chemistries or cell count with negative Gram stain and culture (e.g., prior antibiotic therapy). Not indicated for screening or if chemistry is normal and CSF cell count is <50/cu mm unless patient is immunocompromised. Not indicated if Gram stain is positive. Interpretation Negative results are not conclusive; positive results should be confirmed by culture, especially to determine antibiotic susceptibility. Test for H. influenzae type b antigen in CSF has reported sensitivity of 74%, specificity of 100%, positive predictive value of 100%, negative predictive value of 99%. Antigen detection is less sensitive in urine and serum than in CSF specimens. Specific antigens have also been detected in urine and other body fluids in nonmeningeal infections (e.g., pneumococcal pneumonia, H. influenzae epiglottitis, legionnaire's disease). Interferences False-positive results for group B streptococci may occur due to colonization of perineum. Misleading positive results with H. influenzae type b may occur in both urine and CSF due to recent immunization with H. influenzae type b vaccine. CSF Chemistries CSF glucose Decreased by utilization by bacteria (pyogens or tubercle bacilli), WBCs, or occasionally cancer cells in CSF. Lags behind blood glucose by ~1 hr. May rapidly become normal after onset of antibiotic therapy. Is decreased in only ~50% of cases of bacterial meningitis. <45 mg/dL is almost always abnormal; <40 mg/dL is always abnormal. Normally is ~50–65% of blood glucose, which should always be drawn simultaneously. In acute bacterial meningitis, CSF/serum ratio of glucose is usually <0.5; a ratio <0.4 has 80% sensitivity and 96% specificity for distinguishing acute bacterial meningitis from acute viral meningitis; a ratio <0.25 is found in <1% of acute viral meningitis cases and in 44% of acute bacterial meningitis cases, even when CSF glucose is normal. A ratio of <8.0 is significant in infants.
- 178. May also be decreased in acute infection due to syphilis, Lyme disease, 10–20% of cases of lymphocytic choriomeningitis, and encephalitis due to mumps or HSV but generally rare in viral infections or parameningeal processes. May also be decreased in rheumatoid meningitis, lupus myelopathy, and other causes of chronic meningitis such as bacterial infection (e.g., Brucella, M. tuberculosis), syphilis, fungal infection ( Cryptococcus, Coccidioides), parasitic infection (e.g., cysticercosis), granulomatous meningitis (e.g., sarcoid), chemical meningitis, carcinomatous meningitis, hypoglycemia, and subarachnoid hemorrhage. CSF protein, glucose, and WBC levels may not return to normal in ~50% of patients with clinically cured bacterial meningitis and therefore are not recommended as a test of cure. CSF protein Total protein may be corrected for presence of blood (e.g., due to traumatic tap or intracerebral hemorrhage) by subtracting 1 mg/dL of protein for each 1000 RBCs/cu mm if serum protein and CBC are normal and CSF protein and cell count are determined on same tube of CSF. Serum protein levels must be normal to interpret any CSF protein values and should therefore always be measured concurrently. May not be increased in early stages of many types of meningitis. Normal in 10% of patients with bacterial meningitis (20% of cases of meningococcal meningitis). Usually >150 mg/dL in bacterial meningitis. Increase occurs especially with S. pneumoniae. >100 mg/dL distinguishes bacterial from aseptic meningitis (82% sensitivity and 98% specificity). >172 mg/dL occurs in 1% of acute viral meningitis cases and 50% of acute bacterial meningitis cases but may be normal in 10% of acute bacterial meningitis cases). >200 mg/dL distinguishes bacterial from aseptic meningitis (86% sensitivity and 100% specificity). >500 mg/dL is infrequent and occurs chiefly in bacterial meningitis, bloody CSF, or cord tumor with spinal block and occasionally in polyneuritis and brain tumor. >1000 mg/dL suggests subarachnoid block; with complete spinal block, the lower the level of the cord tumor, the higher the protein concentration. Rarely >200 mg/dL in viral meningitis. When antibiotic treatment of bacterial meningitis is started before CSF is obtained, protein may be only slightly elevated. May show mild to moderate elevation in myxedema (25% of cases), uremia, connective tissue disorders, or Cushing's syndrome. Decreased CSF protein (3–20 mg/dL) may occur in hyperthyroidism, one-third of patients with benign intracranial hypertension, after removal of large volumes of CSF (e.g., during pneumoencephalography), in children 6–24 mos of age. CSF and serum ACE are increased in 50–70% of cases of neurosarcoidosis. CSF lactate has been reported useful to differentiate bacterial from viral meningitis; is independent of serum concentrations. Due to sequelae of increased WBC. If <3 mmol/L (normal range), viral meningitis is most likely. If >4.2 mmol/L, bacterial (including TB) or fungal meningitis is most likely. If 3–6 mmol/L with negative Gram stain and prior antibiotic therapy, partially treated bacterial meningitis is most likely. In bacterial meningitis, level is still high after 1–2 days of antibiotic therapy. In cases with mild symptoms and negative Gram stain with few PMNs, CSF lactate may differentiate mild bacterial from very early viral meningitis. May also be increased in non-Hodgkin's lymphoma with meningeal involvement, severe cerebral malaria, head injury, and anoxia. CSF chloride reflects only blood chloride level, but in tuberculous meningitis a decrease of 25% may exceed the serum chloride decrease because of dehydration and electrolyte loss. It is not useful in diagnosis of tuberculous meningitis. CSF glutamine >35 mg/dL is associated with hepatic encephalopathy (due to conversion from ammonia). CSF Enzymes Normal CSF is not permeable to serum enzymes. Changes in AST are irregular and generally of limited diagnostic value. If determinations of AST, LD, and CK in CSF are all performed, at least one shows marked increase in 80% of patients with cortical stroke (usually due to emboli), but this is not noted in patients with lacunar stroke (usually due to small-vessel hypertensive disease). Generally are not useful in diagnosis of CNS diseases. Transaminase (AST) Increased In Large infarcts of brain during first 10 days. In severe cases, serum AST may also be increased; occurs in ~40% of patients. ~40% of CNS tumors (various benign, malignant, and metastatic), depending on location, growth rate, etc.; chiefly useful as indicator of organic neurologic disease. Some other conditions (e.g., head injury, subarachnoid hemorrhage) Lactate Dehydrogenase Increased In Cerebrovascular accidents—increase occurs frequently, reaches maximum level in 1–3 days, and is apparently not related to xanthochromia, RBC, WBC, protein, sugar, or chloride levels. Subarachnoid and subdural hemorrhage cause increase of all LD isoenzymes especially LD-3, LD-4, and LD-5 (not due only to hemolysis). CNS tumors—LD-5 >9% and decreased LD-1/LD-5 ratio <2.5 in absence of infection or hemorrhage suggests tumor in meninges. LD-5 >10% suggests higher grade malignancy. Increase in LD-3, LD-4, and occasionally LD-5 may occur in leukemic and lymphomatous infiltration. Meningitis—is sensitive indicator of meningitis (in specimen with no blood); normal or mild increase in viral meningitis; more marked increase in bacterial meningitis. Bacterial meningitis shows increase of LD-4 and LD-5; viral meningitis shows increase of LD-1 and LD-2; TB meningitis shows increase of LD-1, LD-2, LD-3 (especially LD-3); HIV alone does not alter LD isoenzyme pattern; isoenzyme changes may appear only in later stage and are of low sensitivity. Creatine Kinase (CK Total) Not Useful Because Does not consistently increase in various CNS diseases. No relationship to CSF protein, WBC, or RBC values No pattern of relationship to LD and AST in CSF No correlation of serum CK and CSF CK In global anoxic or ischemic brain insults due to respiratory or cardiac arrest, CK-BB level 24–72 hrs after injury can be used to estimate overall extent of brain damage; good correlation with neurologic prognosis after resuscitation. Less correlation with outcome in head trauma and stroke. Not recommended for estimating
- 179. stroke size. CSF CK-BB levels association with neurologic injury Higher levels indicate poorer prognosis. <5 U/L: Only mild injury; most patients awaken, some minimal deficit. >10 U/L: Substantial brain injury; guarded prognosis. 5–20 U/L: Mild to moderate; often moderate to severe impairment; guarded prognosis. 21–50 U/L: Severe impairment; poor prognosis; few patients awaken; most die in hospital. >50 U/L: Patients rarely regain minimal reflexes or responsiveness; poor prognosis; usually die in hospital. CSF CK-MM is normally absent and, if present, indicates blood contamination due to traumatic tap or subarachnoid hemorrhage. Mitochondrial CK is found with high CK-BB levels; not used to estimate prognosis or brain damage. Tumor Markers Increased CSF CEA has been reported to be helpful in diagnosis of suspected metastatic carcinoma (from breast, lung, bowel) with negative cytology. Beta-glucuronidase has been reported to be increased in 75% of patients with metastatic leptomeningeal adenocarcinoma and 60% of patients with acute myeloblastic leukemia involving CNS. Normal = <49 mU/L, indeterminate = 49–70 mU/L, suspicious = >70 mU/L. Lysozyme (muramidase) is increased in various CNS tumors, especially myeloid and monocytic leukemias, but is also increased when neutrophils are increased (e.g., bacterial meningitis). Gamma-aminobutyric acid is decreased in CSF in Huntington's disease. Colloidal gold test is no longer used; replaced by electrophoresis/immunofixation of CSF. IgG in CSF is increased 14–35% in two-thirds of patients with neurosyphilis. IgG oligoclonal bands are seen in neurosyphilis and multiple sclerosis. In eclampsia, CSF shows gross or microscopic blood and increased protein (up to 200 mg/dL) in most cases. Glucose is normal. Uric acid is increased (to 3× normal level) in all cases, reflecting the marked increase in serum level. (In normal pregnancy, CSF values have same reference range as in nonpregnant women.) CSF, NORMAL Found In Korsakoff's syndrome Wernicke's encephalopathy Alzheimer's disease Jakob-Creutzfeldt disease Tuberous sclerosis (protein rarely increased) Idiopathic epilepsy (If protein is increased, rule out neoplasms; if cell count is increased, rule out neoplasm or inflammation.) Narcolepsy, cataplexy, etc. Parkinson's disease Hereditary cerebellar degenerations Huntington's disease Migraine Ménière's syndrome Psychiatric conditions (e.g., neurocirculatory asthenia, hysteria, depression, anxiety, schizophrenia) (Rule out psychiatric condition as a manifestation of primary disease, e.g., drugs, porphyria, primary endocrine diseases.) Transient cerebral ischemia Amyotrophic lateral sclerosis Muscular dystrophy Progressive muscular atrophy Syringomyelia Vitamin B12 deficiency with subacute combined degeneration of spinal cord Pellagra Beriberi Subacute myelo-opticoneuropathy Minimal brain dysfunction of childhood Cerebral palsies Febrile convulsions of childhood See Chapter 12 for metabolic and hereditary diseases that affect the nervous system (e.g., gangliosidosis, mucopolysaccharidoses, glycogen storage disease).
- 180. CSF, NORMAL VALUES Measurement of these components should always be performed on simultaneously drawn blood samples. Appearance Clear, colorless: no clot Total cell count Adults, children 0–6/cu mm (all mononuclear cells) Infants <19/cu mm Neonates <30/cu mm Glucose 45–80 mg/dL (20 mg/dL less than blood level) Ventricular fluid 5–10 mg/dL higher than lumbar fluid Total protein Cisternal: 15–25 mg/dL Ventricular: 5–15 mg/dL Lumbar: 15–45 mg/dL 3 mos–60 yrs 15–100 mg/dL neonates 15–60 mg/dL >60 yrs Albumin 10–35 mg/dL Protein electrophoresis Transthyretin (prealbumin) 2–7% Albumin 56–76% Alpha1 globulin 2–7% Alpha2 globulin 4–12% Beta globulin 8–18% Gamma globulin 3–12% IgG <4.0 mg/dL <10% of total CSF protein Albumin index (ratio) <9.0 IgG synthesis rate 0.0–8.0 mg/day IgG index (ratio) 0.28–0.66 CSF IgG/albumin ratio 0.09–0.25 Oligoclonal bands Negative Myelin basic protein 0.0–4.0 ng/mL Chloride 120–130 mEq/L (20 mEq/L above serum values) Sodium 142–150 mEq/L Potassium 2.2–3.3 mEq/L Carbon dioxide 25 mEq/L pH 7.35–7.40 Transaminase (AST) 7–49 U LD ~10% of serum level LD-1 38–58% (LD-1 > LD-2) LD-2 26–36% LD-3 12–24% LD-4 1–7% LD-5 0–5% CK 0–5 U/L Bilirubin 0 Urea nitrogen 5–25 mg/dL Amino acids 30% of blood level Xanthochromia 0 Total volume (adults) ~140 mL Generation rate 0.35 mL/min = 500 mL/day DEXAMETHASONE SUPPRESSION TEST (DST) Blood is drawn at 11 p.m., 8 a.m., 12 noon, 4 p.m., and 11 p.m. for plasma cortisol. 1 mg of dexamethasone is given immediately after the first sample is taken. An abnormal test result is failure of suppression of plasma cortisol to £5 µg/dL in any sample after the first. Plasma dexamethasone should also be measured to avoid false values due to aberrant clearance of dexamethasone. Use A positive DST result “rules in” the diagnosis of melancholia (endogenous depression), but a negative DST result does not rule it out, because results may be positive in only 40–50% of such patients. In the presence of a positive DST result, appropriate drug treatment (e.g., tricyclic antidepressants) that results in normalization of DST with clinical recovery is a good prognostic sign, whereas failure of DST to normalize suggests a poor prognosis and the need for continued antidepressant therapy. Despite clinical improvement, treatment should be continued until DST results become negative (usually within 10 days). With relapse, DST may become abnormal when symptoms are still mild, before fully developed syndrome is present. The need to continue treatment is indicated if a positive DST result that became negative with therapy reverts to positive after drug treatment is discontinued or the drug dosage is lowered. Interference Certain drugs or substances that cause nonsuppression, especially phenytoin, barbiturates, meprobamate, carbamazepine, and alcohol (chronic high doses or withdrawal within 3 wks) can interfere with DST. Enhanced suppression may be caused by benzodiazepines (high doses), corticosteroids (spironolactone, cortisone, artificial glucocorticoids such as prednisone [topical and nasal forms]), and dextroamphetamine. Other drugs that are said to interfere include estrogens (not birth control pills), reserpine, narcotics, and indomethacin. Medical conditions including weight loss to 20% below ideal body weight, pregnancy or abortion within 1 mo, endocrine diseases, systemic infections, serious liver
- 181. disease, cancer, and other severe physical illnesses may also cause false-positive test results. Lithium maintenance therapy does not interfere with DST. With a 50% prevalence of melancholia in the population studied and fulfillment of certain medical criteria, DST was found to have a sensitivity of 67%, a specificity of 96%, and a confidence level of 94% in determining diagnosis. When only the 4 p.m. blood sample was used, the sensitivity was ~50%. However, there are still no clear indications for routine use of DST in clinical psychiatry, and many of the routine methods are not accurate at the decision level. Response of TSH to administration of thyrotropin-releasing hormone (TRH) has also been suggested as useful in the diagnosis of unipolar depression and prediction of relapse. These patients have a maximum rise in serum TSH level of <7 µU/mL (normal = 17±9 µU/mL). Use of this test with DST is said to add confidence to diagnosis of major unipolar depression; abnormal response to either test before treatment suggests that patient is particularly liable to have early relapse, unless there is laboratory proof as well as clinical evidence of recovery after treatment. DISEASES OF THE NERVOUS SYSTEM See Table 9-1. ABSCESS, BRAIN m CSF shows WBC ~25–300/cu mm and increased neutrophils, lymphocytes, and RBCs. Protein may be increased (75–300 mg/dL). Glucose is normal. Bacterial cultures are negative. Findings depend on stage and duration of abscess. w · With rupture, acute purulent meningitis with many organisms m Positive blood cultures in ~10% of patients. m Laboratory findings due to associated primary disease 10% of cases are due to penetrating skull trauma. 50% of cases are due to contiguous spread from sinuses, mastoids, middle ear. 20% of cases are cryptogenic. 20% of cases are due to hematogenous spread. Dental infections Primary septic lung disease (e.g., lung abscess, bronchiectasis, empyema) Cyanotic congenital heart disease (e.g., septal defects) Other causes Due To Usually mixed anaerobic (e.g., streptococci or Bacteroides) and aerobic (e.g., streptococci, staphylococci, or S. pneumoniae) organisms and gram-negative species (e.g., Proteus, Klebsiella, Pseudomonas) Staphylococcus predominates when due to penetrating trauma. Toxoplasma and Nocardia infections may be due to underlying AIDS. 20% of cultures are sterile. May be caused by almost any organism, including fungi and Nocardia. ABSCESS, EPIDURAL OF SPINAL CORD/EXTRADURAL, INTRACRANIAL CSF protein is increased (usually 100–400 mg/dL), and relatively few WBCs are present (lymphocytes and neutrophils). Most common organism is S. aureus, followed by Streptococcus and gram-negative bacilli. Laboratory findings due to preceding condition (e.g., adjacent osteomyelitis; bacteremia due to dental, respiratory, or skin infections) ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS), NEUROLOGIC MANIFESTATIONS See Acquired Immunodeficiency Syndrome, Chapter 15. Dementia (also called subacute encephalitis) is most common neurologic syndrome in AIDS; occurs in >50% of cases; may be initial or later manifestation. CSF abnormalities in 85% Increased protein (50–100 mg/dL) in 60% of patients Mild mononuclear pleocytosis (5–50 cells/cu mm) in 20% of patients w HIV antibodies Aseptic meningitis–may occur early or late, or be chronic recurrent. CSF may show 20–300 cells/cu mm Increased protein (may be 50–100 mg/dL) w HIV culture is usually positive. w Increased CSF/serum antibody ratio, indicating local antibody production Myelopathy–gradual onset; usually associated with dementia. Polymyositis is most common type
- 182. Peripheral neuropathies, some of which may resemble Guillain-Barré syndrome CSF may show Increased protein (50–100 mg/dL) Pleocytosis of 10–50 cells/cu mm Opportunistic infections of CNS Viral (e.g., CMV, HSV-I and HSV-II, papovavirus) Nonviral (e.g., Cryptococcus, Toxoplasma, Aspergillus fumigatus, Candida albicans, Coccidioides immitis, Mycobacterium avium-intracellulare, and M. tuberculosis, Nocardia asteroides, Listeria) Neoplasms (e.g., Kaposi's sarcoma, non-Hodgkin's lymphoma) Vascular (e.g., infarction, hemorrhage, vasculitis) Associated diseases (e.g., neurosyphilis) ARACHNOIDITIS, CHRONIC ADHESIVE (Due to spinal anesthesia, syphilis, etc.) CSF protein may be normal or increased. ARTERITIS, CRANIAL w ESR is markedly increased. BASSEN-KORNZWEIG SYNDROME m Abnormal RBCs (acanthocytes) are present in the peripheral blood smear. m There may be Marked deficiency of serum beta-lipoprotein and cholesterol Marked impairment of GI fat absorption Low serum carotene levels Abnormal pattern of RBC phospholipids CEREBELLAR ATAXIA, PROGRESSIVE, WITH SKIN TELANGIECTASIAS (LOUIS-BAR'S SYNDROME) (Autosomal recessive multisystem disease with cerebellar ataxia and oculocutaneous telangiectasia) See also Table 11-22. Some patients have Glucose intolerance. Abnormal liver function tests. Decreased or absent serum IgA and IgE causing recurrent pulmonary infections; IgM is present. Increased serum AFP. See also Table 11-7. CEREBROVASCULAR ACCIDENT (NONTRAUMATIC) Due To Hemorrhage Ruptured berry aneurysm (45% of patients) Hypertension (15% of patients) Angiomatous malformations (8% of patients) Miscellaneous causes (e.g., brain tumor, blood dyscrasia)—infrequent Undetermined cause (remainder of patients) Occlusion (e.g., thrombosis, embolism, etc.) in 80% of patients Especially if blood pressure is normal, always rule out ruptured berry aneurysm, hemorrhage into tumor, and angioma. Berry Aneurysm In early subarachnoid hemorrhage (<8 hrs after onset of symptoms), the test for occult blood may be positive before xanthochromia develops. After bloody spinal fluid occurs, WBC/RBC ratio may be higher in CSF than in peripheral blood. Bloody CSF clears by tenth day in 40% of patients. CSF is persistently abnormal after 21 days in 15% of patients. ~5% of cerebrovascular episodes due to hemorrhage are wholly within the parenchyma and CSF findings are normal. Embolism, Cerebral Laboratory findings due to underlying causative disease Bacterial endocarditis Nonbacterial thrombotic vegetations on heart valves Chronic rheumatic mitral stenosis with atrial thrombi Mural thrombus due to underlying myocardial infarction Myxoma of left atrium Fat embolism in fracture of long bones Air embolism in neck, chest, or cardiac surgery
- 183. CSF Usually findings are the same as in cerebral thrombosis. Hemorrhagic infarction develops in one-third of patients, usually producing slight xanthochromia several days later; some of these patients may have grossly bloody CSF (10,000 RBCs/cu mm). Septic embolism (e.g., bacterial endocarditis) may cause increased WBC (£ 200/cu mm with variable lymphocytes and PMNs), increased RBC (£ 1000/cu mm), slight xanthochromia, increased protein, normal glucose, and negative culture. Hemorrhage, Cerebral Increased WBC (15,000–20,000/cu mm); higher than in cerebral infarct (e.g., embolism, thrombosis) Increased ESR Urine Transient glycosuria Laboratory findings of concomitant renal disease Laboratory findings due to other causes of intracerebral hemorrhage (e.g., leukemia, aplastic anemia, purpuras, hemophilias, anticoagulant therapy, SLE, polyarteritis nodosa) CSF See Table 9-1 and Table 9-2. Table 9-2. Differentiation between Bloody Cerebrospinal Fluid (CSF) Due to Subarachnoid Hemorrhage and Traumatic Lumbar Puncture Laboratory findings due to other diseases that occur with increased frequency in association with berry aneurysm (e.g., coarctation of the aorta, polycystic kidneys, hypertension) Thrombosis, Cerebral Laboratory findings due to some diseases that may be causative Hematologic disorders (e.g., polycythemia, sickle cell disease, thrombotic thrombopenia, macroglobulinemia) Arterial disorders (e.g., polyarteritis nodosa, Takayasu's syndrome, dissecting aneurysm of aorta, syphilis, meningitis) Hypotension (e.g., myocardial infarction, shock) CSF Protein may be normal or increased to £ 100 mg/dL. Cell count may be normal or ³ 10 WBC/cu mm during first 48 hrs and rarely ³ 2000 WBC/cu mm transiently on third day. COBALAMIN DEFICIENCY CAUSING NEUROPSYCHIATRIC DISORDERS See pernicious anemia. More than 25% of patients may present with neuropsychiatric findings (e.g., paresthesias, sensory loss, ataxia and abnormal gait, mental or psychiatric disturbances) with some normal hematologic findings (e.g., Hct, MCV, WBC, platelet count, serum bilirubin, serum LD) and some abnormal findings (e.g., hypersegmentation of PMNs, macroovalocytes, mild megaloblastic bone marrow). w Serum cobalamin and Schilling test results may occasionally be only borderline decreased or even normal. w Increased serum methylmalonic acid and total homocysteine, which return to normal after cyanocobalamin therapy, confirm diagnosis. COMA AND STUPOR Due To Poisons, drugs, or toxins Sedatives (especially alcohol, barbiturates) Enzyme inhibitors (especially salicylates, heavy metals, organic phosphates, cyanide) Other (e.g., paraldehyde, methyl alcohol, ethylene glycol) Cerebral disorders Brain contusion, hemorrhage, infarction, seizure, or aneurysm Brain mass (e.g., tumor, hematoma, abscess) Subdural or epidural hematoma Venous sinus occlusion Hydrocephalus
- 184. Hypoxia Decreased blood O2 content and tension (e.g., lung disease, high altitude) Decreased blood O2 content with normal tension (e.g., anemia, carbon monoxide poisoning, methemoglobinemia) Infection (e.g., meningitis, encephalitis) Vascular abnormalities (e.g., subarachnoid hemorrhage, hypertensive encephalopathy, shock, AMI, aortic stenosis, Adams-Stokes syndrome, tachycardias) Metabolic abnormalities Acid-base imbalance (acidosis, alkalosis) Electrolyte imbalance (increased or decreased sodium, potassium, calcium, magnesium) Porphyrias Aminoacidurias Uremia Hepatic encephalopathy Other disorders (e.g., leukodystrophies, lipid storage diseases, Bassen-Kornzweig syndrome) Nutritional deficiencies (e.g., vitamin B12, thiamine, niacin, pyridoxine) Endocrine Pancreas (diabetic coma, hypoglycemia) Thyroid (myxedema, thyrotoxicosis) Adrenal gland (Addison's disease, Cushing's syndrome, pheochromocytoma) Pituitary gland (panhypopituitarism) Parathyroid (hypofunction or hyperfunction) Psychogenic conditions that may mimic coma Depression, catatonia Malingering Hysteria, conversion disorder DEMENTIA, SENILE (ALZHEIMER-PICK DISEASE; CEREBRAL ATROPHY)1 No abnormal laboratory findings are characteristic, but laboratory tests are useful to rule out other diseases that may resemble these syndromes but are amenable to therapy. Recommended tests in all patients with new onset of dementia should include: CBC, urinalysis, electrolyte and blood chemistry panel, screening metabolic panel, serum vitamin B12 and folate measurements, thyroid function tests (chemistry panel screens for some other endocrine disorders), serologic test for syphilis. In 200 patients >60 yrs with dementia, the causes were: Alzheimer's type 74.5% Due to drugs 9.5% Alcohol related 4.0% Hypothyroidism 3.0% Multiple infarcts 1.5% Hyperparathyroidism 1.0% Hyponatremia 1.0% Hypoglycemia 0.5% Unknown cause 3.5% Referred for dementia but diagnosis not confirmed 7.5% Other newly recognized conditions were low serum iron, folate, or cobalamin (8%), urinary tract infection (2.5%). BUN was also useful for diagnosis. EMPYEMA, SUBDURAL, ACUTE CSF Cell count is increased to a few hundred, with predominance of PMNs. Protein is increased. Glucose is normal. Bacterial smears and cultures are negative. WBC is usually increased (£ 25,000/cu mm). Laboratory findings due to preceding diseases Ear, nose, and throat infections, especially acute sinusitis or otitis media Intracranial surgery Streptococci are the most common organisms when preceding condition is sinusitis. S. aureus or gram-negative organisms are the most common organisms after trauma or surgery. ENCEPHALOPATHY, HYPERTENSIVE Laboratory findings due to changes in other organ systems and to other conditions Cardiac Renal Endocrine Toxemia of pregnancy Laboratory findings due to progressive changes that may occur (e.g., focal intracerebral hemorrhage) CSF frequently shows increased pressure and protein £100 mg/dL.
- 185. GLOMUS JUGULARE TUMOR CSF protein may be increased. GUILLAIN-BARRÉ SYNDROME w CSF shows albumino-cytologic dissociation with normal cell count and increased protein (average 50–100 mg/dL). Protein increase parallels increasing clinical severity; increase may be prolonged. CSF may be normal at first. Laboratory findings due to preceding disease may be present (e.g., acute infections of respiratory or GI tract [e.g., EBV, Campylobacter, VZV, M. pneumoniae, CMV, hepatitis, other viral, and rickettsial infections], Refsum's disease, immune disorders, endocrine disturbances, exposure to toxins, neoplasms). LEUKEMIC INVOLVEMENT OF CNS Intracranial hemorrhage is principal cause of death in leukemia (may be intracerebral, subarachnoid, subdural) More frequent when WBC is >100,000/cu mm and with rapid increase in WBC, especially in blastic crises Platelet count frequently decreased. Evidence of bleeding elsewhere CSF findings of intracranial hemorrhage w Meningeal infiltration of leukemic cells CNS is involved in 5% of patients with ALL at diagnosis and is the major site of relapse. Meninges are involved in <30% of patients with malignant lymphoma; most prevalent in diffuse large cell (“histiocytic”), lymphoblastic, and immunoblastic leukemia; occurs in one-third to one-half of patients with Burkitt's lymphoma and 15–20% of patients with non-Hodgkin's lymphoma. Hodgkin's disease seldom involves CNS. Involvement by CLL, well-differentiated lymphocytic lymphoma, and plasmacytoid lymphomas is very rare. CSF may show Increased pressure and protein. Glucose decreased to <50% of blood level. w · Increased cells that are often not recognized as blast cells because of poor preservation and that may be identified by cytochemical, immunoenzymatic, immunofluorescent, and flow cytometry techniques. w · Malignant cells are found in 60–80% of patients with meningeal involvement. Complicating meningeal infection (e.g., various bacteria, opportunistic fungi) LEUKODYSTROPHY, METACHROMATIC (Rare lipidosis due to deficiency of arylsulfatase A; infantile and adult forms) m Urine sediment may contain metachromatic lipids (from breakdown of myelin products). CSF protein may be normal or increased £ 200 mg/dL. w Biopsy of dental or sural nerve stained with cresyl violet showing accumulation of metachromatic sulfatide is diagnostic. Also increased in brain, kidney, liver. w Conjunctival biopsy shows metachromatic inclusions within Schwann cells. See Metabolic and Hereditary Diseases, Chapter 12, for other conditions that affect the CNS. LINDAU-VON HIPPEL DISEASE (HEMANGIOBLASTOMAS OF RETINA AND CEREBELLUM) Laboratory findings due to associated conditions (e.g., polycythemia, pheochromocytomas, renal cell carcinoma, cysts of kidney and epididymis, benign cysts and nonfunctional neuroendocrine tumors of pancreas). MENINGITIS, ASEPTIC CSF Protein is normal or slightly increased. Increased cell count shows predominantly PMNs at first, mononuclear cells seen later. Glucose is normal. Bacterial cultures are negative. If glucose levels are decreased, rule out TB, cryptococcosis, leukemia, lymphoma, metastatic carcinoma, sarcoidosis, drug induction. Due To Infections Viral (especially poliomyelitis; infection with coxsackievirus, echovirus, HIV, EBV; lymphocytic choriomeningitis; and many others). Culture positive in ~40% of cases, especially with enteroviruses. Bacterial (e.g., incompletely treated or very early bacterial meningitis, bacterial endocarditis, parameningeal infections such as brain abscess, epidural abscess, paranasal sinusitis). Spirochetal (e.g., leptospirosis, syphilis, Lyme disease). Tuberculous (CSF glucose levels may not be decreased until later stages). Fungal (e.g., Candida, Coccidioides, Cryptococcus). Protozoan (e.g., Toxoplasma gondii).
- 186. Amebic (e.g., Naegleria). Mycoplasmal. Rickettsial (e.g., Rocky Mountain spotted fever). Helminthic. Chemical meningitis Drug-induced meningitis (e.g., ibuprofen, trimethoprim, immune globulin, sulfadiazine, azathioprine, antineoplastic drugs)—onset usually within 24 hrs of drug ingestion Systemic disorders Vasculitis, collagen vascular disease Sarcoid Behçet's syndrome Vogt-Koyanagi syndrome Harada syndrome Mollaret's meningitis Neoplasm (e.g., leukemia, metastatic carcinoma) SLE MENINGITIS, BACTERIAL See Table 9-3. Table 9-3. Etiology of Bacterial Meningitis by Age w Bacteria can be identified in CSF in only 90% of patients. Culture is more reliable than Gram stain, although results of the stain offer a more immediate guide to therapy. Gram stain is positive in ~70% of patients; sensitivity is increased by cytocentrifugation of specimen. When Gram stain is positive, CSF is more likely to show decreased glucose, increased protein, and increased RBCs. 75% of cases are due to N. meningitidis, S. pneumoniae, H. influenzae. In Listeria meningitis, the Gram stain is usually negative and the cellular response is usually monocytic, which may cause this meningitis to be mistakenly diagnosed as due to virus, syphilis, TB, Lyme disease, etc. Gram stain of scrapings from petechial skin lesions demonstrate pathogen in ~70% of patients with meningococcemia; Gram stain of buffy coat of peripheral blood and, less often, peripheral blood smear may reveal this organism. w Detection of bacterial antigen (rapid latex agglutination assay has largely replaced CIE) in CSF for S. pneumoniae, group B Streptococcus (S. agalactiae), H. influenzae, some strains of N. meningitidis. Not affected by previous antimicrobial therapy that might inhibit growth in culture. H. influenzae infection is now rare due to routine immunization of children. Not likely to be useful if CSF chemistry and cell count are normal unless patient is immunocompromised. False-positive for H. influenza may occur due to recent immunization; should not be performed if patient recently vaccinated. False-positive for group B Streptococcus antigen in urine is common due to its colonization of perineum. w Blood culture is usually positive if patient has not received antibiotics. Laboratory findings due to presence of infection (e.g., increased number of band forms, toxic granulations, Döhle's bodies, vacuolization of PMNs). Laboratory findings due to preceding diseases Pneumonia, otitis media, sinusitis, skull fracture before pneumococcal meningitis Neisseria epidemics before this meningitis Bacterial endocarditis, septicemia, etc. S. pneumoniae in alcoholism, myeloma, sickle cell anemia, splenectomy, immunocompromised state Cryptococcus and M. tuberculosis in steroid therapy and immunocompromised state Gram-negative bacilli in immunocompromised state H. influenzae in splenectomy Lyme disease Laboratory findings due to complications (e.g., Waterhouse-Friderichsen syndrome, subdural effusion) w Most frequent and important differential diagnosis is between acute bacterial meningitis and acute viral meningitis. The most useful test results that favor the diagnosis of acute bacterial meningitis rather than acute viral meningitis are 2 ,3 : CSF positive by bacterial stain, culture, or antigen detection. Decreased CSF glucose. Decreased CSF/serum ratio of glucose (<0.25 in <1% of acute viral meningitis cases and 44% of acute bacterial meningitis cases), even if CSF glucose is normal. Increased CSF protein >1.72 gm/L (1% of acute viral meningitis and 50% of acute bacterial meningitis cases). CSF WBC >2000/cu mm in 38% of acute bacterial meningitis cases and PMN >1180/cu mm, but low counts do not rule out acute bacterial meningitis. Peripheral WBC is useful only if WBC (>27,200/cu mm) and total PMN (>21,000/cu mm) counts are very high, which occurs in relatively few patients; leukopenia is common in infants and elderly patients. Combination of findings can exclude acute viral meningitis and rule in acute bacterial meningitis, but none of them can establish the diagnosis of acute viral
- 187. meningitis, and absence of these findings cannot exclude acute bacterial meningitis. MENINGITIS, CHEMICAL (Due to injection of anesthetic, antibiotic, radiopaque dye, etc., or to rupture into CSF of contents of epidermoid tumor or craniopharyngioma) CSF Pleocytosis is mild to moderate, largely lymphocytic. Protein shows variable increase. Glucose is usually normal. MENINGITIS, CHRONIC (Symptoms for >4 wks) CSF WBC of 100–400 WBC/cu mm, preponderance of lymphocytes. Glucose often decreased. Protein is usually moderately or markedly increased. Due To Various infections TB is most common cause. Bacteria (e.g., Brucella). Spirochetes (e.g., leptospirosis, syphilis, Lyme disease). Fungus (e.g., Candida, Coccidioides, Cryptococcus). Protozoa (e.g., T. gondii). Ameba (e.g., Naegleria). Mycoplasma. Rickettsia. Helminths. Systemic disorders Vasculitis, collagen vascular disease Sarcoid Neoplasm (e.g., leukemia, lymphoma, metastatic carcinoma) Mollaret's meningitis MENINGITIS, MOLLARET'S w Numerous recurrent episodes (2–7 days each) of aseptic meningitis occur over several years with symptom-free intervals in which mild leukopenia and eosinophilia are seen. Other organ systems are not involved. The patient frequently has a history of previous severe trauma with fractures and concussions. CSF w · During first 12–24 hrs may contain up to several thousand cells/cu mm, predominantly PMNs and 66% of a large type of mononuclear cell. The mononuclear cells (sometimes called “endothelial” cells) are of unknown origin and significance and are characterized by vague nuclear and cytoplasmic outline with rapid lysis, even while being counted in the hemocytometer chamber; they may be seen only as “ghosts” and are usually not detectable after the first day of illness. After the first 24 hrs, the PMNs disappear and are replaced by lymphocytes, which, in turn, rapidly disappear when the attack subsides. Protein may be increased £ 100 mg/dL. Glucose is normal or may be slightly decreased. MENINGITIS, TUBERCULOUS See Chapter 15. MENINGITIS/ENCEPHALOMYELITIS, ACUTE VIRAL For infectious, postvaccinal, postexanthematous, and postinfectious, encephalomyelitis/ meningitis see Chapter 15. In the United States, HSV and rabies are most common endemic causes of encephalitis; outside of North America, Japanese B encephalitis is most common epidemic infection. Postinfectious encephalomyelitis patients have an invariable, irreversible demyelinating syndrome; it is most commonly associated with varicella and URI (especially influenza) in the United States but measles is the most common cause worldwide. Vaccination has reduced the incidence of acute and postinfectious encephalitis due to measles, mumps, rubella, and yellow fever. Vaccination has greatly decreased incidence of poliomyelitis, but a few cases of vaccine-associated infections occur. Coxsackievirus and echovirus usually cause benign aseptic meningitis. CSF shows increased protein and lymphocytes. Laboratory findings due to preceding condition (e.g., measles) are noted. w PCR of CSF or fresh brain tissue for panel detection of HSV, VZV, enteroviruses, eastern equine encephalitis virus, St. Louis encephalitis virus, CMV, EBV, California serogroup viruses, and rabies (in saliva) makes 72-hr diagnosis possible on one sample and should replace culture, mouse inoculation, immunoassay, serology, and brain biopsy. w Paired serum samples during acute and convalescent periods may show seroconversion or fourfold increase in specific antibody titers.
- 188. w ELISA to detect IgM in CSF is sensitive and specific for Japanese B encephalitis; IgM is usually present at hospitalization and almost always present by third day of illness. w HSV can be cultured from CSF in 50–75% of patients with meningitis and <5% with encephalitis. w Detection of HSV antigen in CSF is reported to be 80% sensitive and 90% specific if performed within 3 days of onset of illness. Brain biopsy is most sensitive and specific for HSV and its mimics. w Brain biopsy is currently reserved for patients who do not respond to acyclovir therapy and have unknown abnormality on CT scan or magnetic resonance image (MRI). w Brain biopsy is also required for diagnosis of progressive multifocal leukoencephalopathy. MENINGOENCEPHALITIS, PRIMARY AMEBIC (Due to free-living amebas—Naegleria) Increased WBC, predominantly neutrophils CSF findings Fluid may be cloudy, purulent, or sanguinopurulent. Protein is increased. Glucose is usually decreased; may be normal. Increased WBCs are chiefly PMNs. RBCs are frequently present also. Motile amebas are seen in hemocytometer chamber or on wet mount using phase or diminished light. w · Amebas are seen on Wright's, Giemsa, hematoxylin-eosin stains. Gram stain and cultures are negative for bacteria and fungi. w · Culture of tissue or CSF on agar or cell culture demonstrates organisms. w · Electron microscopy allows precise classification of amebas. w · Indirect immunofluorescent antibody (IFA) and immunoperoxidase assays are reliable methods to identify amebas in tissue sections. MULTIPLE SCLEROSIS (MS) w Diagnosis should not be made on the basis of CSF findings unless there are multiple clinical lesions over time and in anatomic location. No changes of diagnostic value yielded by peripheral blood studies or routine CSF tests. CSF WBC is slightly elevated in ~25% of patients but usually < 20 mononuclear cells/cu mm; >25 cells/cu mm in <1% of cases. >50 cells/cu mm should cast doubt on diagnosis. Albumin, glucose, and pressure are normal. CSF changes are found in >90% of MS patients. CSF total protein May be mildly increased in ~25% of patients; not very useful test by itself. Decreased values and values >100 mg/dL should cast doubt on diagnosis. CSF gamma globulin is increased in 60–75% of patients regardless of whether the total CSF protein is increased. Gamma globulin ³ 12% of CSF total protein is abnormal if no corresponding increase in serum gamma globulin is seen; but may also be increased in other CNS disorders (e.g., syphilis, subacute panencephalitis, meningeal carcinomatosis) and may also be increased when serum electrophoresis is abnormal due to non-CNS diseases (e.g., RA, sarcoidosis, cirrhosis, myxedema, multiple myeloma). CSF IgG concentration w · Increased (reference range <4.0 mg/dL) in ~70% of cases, often when total protein is normal. w · Increase in production of IgG is expressed as ratio of CSF to serum albumin to rule out increased IgG due to disruption of blood–brain barrier (see Table 9-4). Table 9-4. Formulas for Central Nervous System Immunoglobulin G (IgG) Synthesis CSF IgG does not correlate with duration, activity, or course of MS. May also be increased in patients with other inflammatory demyelinating diseases (e.g., neurosyphilis, acute Guillain-Barré syndrome), in 5–15% of patients with miscellaneous neurologic diseases, and in a few normal persons; recent myelography is said to invalidate the test. w CSF IgG/albumin ratio indicates in situ production of IgG. Abnormal in 90% of MS patients and 18% of non–MS neurologic patients. w CSF IgG synthesis rate is increased in 90% of MS patients and 4% of non—MS patients. w IgG index indicates IgG synthesis in CNS. Occurs in 90% of MS patients; may also occur in other neurologic diseases (e.g., meningitis). CSF IgM and IgA may also be increased but are not useful for diagnosis. Albumin index Increase Indicates CSF contaminated with blood (e.g., traumatic tap) or increased permeability of blood–brain barrier (e.g., aged persons, obstruction of CSF circulation,
- 189. diabetes mellitus, SLE of CNS, Guillain-Barré syndrome, polyneuropathy, cervical spondylosis). Use To prevent misinterpretation of falsely increased CSF IgG concentrations w Oligoclonal proteins (due to abnormal gamma globulins) by high-voltage electrophoresis or isoelectric focusing of concentrated CSF shows discrete bands. Should always be performed on paired CSF and serum samples. Found in 85–95% of patients with definite MS and 30–40% with possible MS (specificity = 79%); it is the most sensitive marker of MS. Positive results also occur in £10% of patients with noninflammatory neurologic disease (e.g., meningeal carcinomatosis, cerebral infarction) and £40% of patients with inflammatory CNS disorders (e.g., neurosyphilis, viral encephalitis, progressive rubella encephalitis, subacute sclerosing panencephalitis, bacterial meningitis, toxoplasmosis, cryptococcal meningitis, inflammatory neuropathies, trypanosomiasis). Oligoclonal bands in serum may occur in leukemias, lymphomas, some infections and inflammatory diseases, immune disorders. Not known to correlate with severity, duration, or course of MS. Persists during remission. During steroid treatment, prevalence of oligoclonal bands and other gamma globulin abnormalities may be reduced by 30–50%. 90% of MS patients have oligoclonal bands in CSF, at least two of which are not present in simultaneously examined serum. A few patients with definite multiple sclerosis may have normal CSF immunoglobulins and lack oligoclonal bands. w Myelin basic protein Indicates recent myelin destruction; it is increased in 70–90% of MS patients during an acute exacerbation and usually returns to normal within 2 wks. Useful for following course of MS but not for screening. May be helpful very early in course of MS before oligoclonal bands have appeared or in ~10% of patients who do not develop these bands. It is frequently increased in other causes of demyelination and tissue destruction (e.g., meningoencephalitis, leukodystrophies, metabolic encephalopathies, SLE of CNS, brain tumor, head trauma, amyotrophic lateral sclerosis, cranial irradiation and intrathecal chemotherapy, 45% of patients with recent stroke) and other disorders (e.g., diabetes mellitus, chronic renal failure, vasculitis, carcinoma of vasculitis, immune complex diseases, pancreas). Falsely increased by contamination with blood. Increased association with certain histocompatibility antigens (e.g., whites with B7 and Dw2 antigen). MYELITIS CSF may be normal or may show increased protein and cells (20–1000/cu mm—lymphocytes and mononuclear cells). Laboratory findings due to causative condition (e.g., poliomyelitis, herpes zoster, TB, syphilis, parasitosis, abscess, multiple sclerosis, postvaccinal myelitis) NEURITIS/NEUROPATHY, MULTIPLE Laboratory findings due to causative disease Infections, e.g., EBV (mononucleosis associated: CSF shows increased protein and up to several hundred mononuclear cells). Diphtheria: CSF protein is 50–200 mg/dL. Lyme disease. HIV-1. Hepatitis. Leprosy. Postvaccinal effect Metabolic conditions (e.g., pellagra, beriberi, combined systemic disease, pregnancy, porphyria)—CSF usually normal. In ~70% of patients with diabetic neuropathy, CSF protein is increased to >200 mg/dL. Uremia—CSF protein is 50–200 mg/dL; occurs in a few cases of chronic uremia. Collagen disease Polyarteritis nodosa—CSF usually normal; nerve involvement in 10% of patients SLE Neoplasm (leukemia, multiple myeloma, carcinoma)—CSF protein often increased; may be associated with an occult primary neoplastic lesion outside CNS. Amyloidosis Sarcoidosis Toxic conditions due to drugs and chemicals (especially lead, arsenic, etc.) Alcoholism—CSF usually normal Bassen-Kornzweig syndrome Refsum's disease Chédiak-Higashi syndrome Guillain-Barré syndrome Cranial Nerve, Multiple Laboratory findings due to causative conditions Trauma Aneurysms Tumors (e.g., meningioma, neurofibroma, carcinoma, cholesteatoma, chordoma) Infections (e.g., herpes zoster)
- 190. Benign polyneuritis associated with cervical lymph node tuberculosis or sarcoidosis NEURITIS OF ONE NERVE OR PLEXUS Laboratory findings due to causative disease Infections (e.g., diphtheria, herpes zoster, leprosy) Sarcoidosis Tumor (leukemia, lymphoma, carcinomas)—may find tumor cells in CSF. Serum sickness Bell's palsy Idiopathic Facial Palsy, Peripheral Acute Laboratory findings due to causative disease Idiopathic (Bell's palsy)—occasional slight increase in cells in CSF Infection Viral (e.g., VZV, HSV, HIV, EBV infection, poliomyelitis, mumps, rubella) Bacterial (e.g., Lyme disease, syphilis, leprosy, diphtheria, cat-scratch disease, M. pneumoniae infection) Parasitic (e.g., malaria) Meningitis Encephalitis Local inflammation (otitis media, mastoiditis, osteomyelitis, petrositis) Trauma Tumor (acoustic neuromas, tumors invading the temporal bone) Granulomatous (e.g., sarcoidosis) and connective tissue diseases Diabetes mellitus Hypothyroidism Uremia Drug reaction Postvaccinal effect Paget's disease of bone Melkersson-Rosenthal syndrome Lyme disease and Guillain-Barré syndrome may produce bilateral palsy. Hemianopsia, Bitemporal Laboratory findings due to causative disease Usually pituitary adenoma Also metastatic tumor, sarcoidosis, Hand-Schuller-Christian disease, meningioma of sella, and aneurysm of circle of Willis Ophthalmoplegia Laboratory findings due to causative disease Diabetes mellitus Myasthenia gravis Hyperthyroid exophthalmos Trigeminal Neuralgia (Tic Douloureux) Laboratory findings due to causative disease Usually idiopathic. May also stem from multiple sclerosis or herpes zoster. Retrobulbar Neuropathy CSF is normal or may show increased protein and £ 200/cu mm lymphocytes. m Multiple sclerosis ultimately develops in 75% of these patients. PRION DISEASES (Due to proteinaceous infectious particles that do not use nucleic acids to mediate transmission) Causes Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, kuru, Gerstmann-Sträussler-Scheinker disease, fatal familial insomnia Scrapie (sheep) Mad cow disease (bovine spongiform degeneration) w Diagnosis based on biopsy showing pathologic changes and demonstration of prions or a known prion gene mutation. PSEUDOTUMOR CEREBRI (Benign intracranial hypertension with neurologic complex of headache and papilledema without mass lesion or ventricular obstruction) CSF normal except for increased pressure Laboratory findings due to associated conditions (only obesity has been reported consistently) (e.g., Addison's disease, infection, metabolic conditions [acute hypocalcemia and other electrolyte disturbances, empty sella syndrome, pregnancy], drugs [psychotherapeutic drugs, sex hormones and oral contraceptives,
- 191. corticosteroid administration, usually after reduction of dosage or change to different preparation], immune diseases [SLE, polyarteritis nodosa, serum sickness], other conditions [sarcoidosis, Guillain-Barré syndrome, head trauma, various anemias]) REFSUM'S DISEASE (Rare hereditary recessive lipidosis of the nervous system with retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, nerve deafness, and ichthyosis) CSF shows albuminocytologic dissociation (normal cell count with protein usually increased to 100–700 mg/dL). RETARDATION, MENTAL Laboratory findings due to underlying causative condition (see appropriate separate sections) Prenatal Infections (e.g., syphilis, rubella, toxoplasmosis, CMV infection) Metabolic abnormalities (e.g., diabetes mellitus, eclampsia, placental dysfunction) Chromosomal disorders (e.g., Down syndrome, trisomy 18, cri du chat syndrome, Klinefelter's syndrome) Metabolic abnormalities Amino acid metabolism (e.g., phenylketonuria, maple syrup urine disease, hemocystinuria, cystathioninuria, hyperglycemia, argininosuccinicaciduria, citrullinemia, histidinemia, hyperprolinemia, oasthouse urine disease, Hartnup's disease, Joseph's syndrome, familial iminoglycinuria) Lipid metabolism (e.g., Batten disease, Tay-Sachs disease, Niemann-Pick disease, abetalipoproteinemia, Refsum's disease, metachromatic leukodystrophy) Carbohydrate metabolism (e.g., galactosemia, mucopolysaccharidoses) Purine metabolism (e.g., Lesch-Nyhan syndrome, hereditary orotic aciduria) Mineral metabolism (e.g., idiopathic hypercalcemia, pseudohypoparathyroidism and pseudopseudohypoparathyroidism) Other syndromes (e.g., tuberous sclerosis, Louis-Bar's syndrome) Perinatal Kernicterus Prematurity Anoxia Trauma Postnatal Poisoning (e.g., lead, arsenic, carbon monoxide) Infections (e.g., meningitis, encephalitis) Metabolic abnormalities (e.g., hypoglycemia) Postvaccinal encephalitis Cerebrovascular accidents Trauma REYE'S SYNDROME (Acute noninflammatory encephalopathy with fatty changes in liver and kidney and rarely in heart and pancreas. Occurs typically in child recovering from influenza, varicella, or nonspecific viral illness and is associated with use of aspirin.) w Diagnostic Criteria CSF shows <8 WBC/cu mm. Serum AST, ALT, or ammonia ³ 3× ULN Fatty liver seen histologically. See Hepatic Failure, Acute. SEIZURES THAT MAY BE ACCOMPANIED BY LABORATORY ABNORMALITIES Associated Conditions Neoplasms Circulatory disorders (e.g., thrombosis, hemorrhage, embolism, hypertensive encephalopathy, vascular malformations) Hematologic disorders (e.g., sickle cell anemia, leukemia) Metabolic abnormalities Carbohydrate metabolism (e.g., hypoglycemia, glycogen storage disease) Amino acid metabolism (e.g., phenylketonuria, maple syrup urine disease) Lipid metabolism (e.g., leukodystrophies, lipidoses) Electrolyte balance (e.g., decreased sodium, calcium, and magnesium, increased sodium)
- 192. Other disorders (e.g., porphyria) Allergic disorders (e.g., drug reaction, postvaccinal) Infections Meningitis, encephalitis Postinfectious encephalitis (e.g., measles, mumps) Fetal exposure (e.g., rubella, measles, mumps) Degenerative brain diseases SPINAL CORD, INFARCTION CSF changes same as in cerebral hemorrhage or infarction. Laboratory findings due to causative condition Polyarteritis nodosa Dissecting aneurysm of aorta Arteriosclerosis of aorta with thrombus formation Iatrogenic causes (e.g., aortic arteriography, clamping of aorta during cardiac surgery) SPINAL CORD TUMOR w CSF protein is increased. It may be very high and associated with xanthochromia when a block of the subarachnoid space is present. With complete block, for cord tumors located at lower levels, protein concentration is higher. See Table 9-2. SPONDYLOSIS, CERVICAL CSF shows increased protein in some cases. THROMBOPHLEBITIS, CAVERNOUS SINUS CSF is usually normal unless associated subdural empyema or meningitis is present, or it may show increased protein and WBC with normal glucose, or it may be hemorrhagic. Mucormycosis may cause this clinical appearance in diabetic patients. Laboratory findings due to preceding infections, complications (e.g., meningitis, brain abscess), or other causes of venous thromboses (e.g., sickle cell disease, polycythemia, dehydration). TRAUMA, HEAD Laboratory findings due to single or various combinations of brain injuries Contusion, laceration, subdural hemorrhage, extradural hemorrhage, subarachnoid hemorrhage Laboratory findings due to complications (e.g., pneumonia, meningitis) In possible skull fractures, w · CSF transferrin shows a double band but only a single transferrin band is seen in other fluids (serum, nasal secretions, saliva, tears, lymph). w · If enough (100 µL) fluid can be obtained to perform immunofixation, IgM is 5× higher, prealbumin is 12× higher, and transferrin is 2× higher in CSF than in serum. The suggestion has been made that nasal secretions may be differentiated from CSF by absence of glucose (measured using test tapes or tablets) in nasal secretions, but this is not reliable because nasal secretions may normally contain glucose. Hemorrhage, Acute Epidural CSF is usually under increased pressure; it is clear unless associated cerebral contusion, laceration, or subarachnoid hemorrhage is present. Hematoma, Subdural CSF findings are variable–clear, bloody, or xanthochromic, depending on recent or old associated injuries (e.g., contusion, laceration). Chronic subdural hematoma fluid is usually xanthochromic; protein content is 300–2000 mg/dL. Anemia is often present in infants. TUBERCULOMA OF BRAIN CSF shows increased protein with small number of cells. The tuberculoma may be transformed into TB meningitis with increased protein and cells (50–300/cu mm), and decreased glucose. Laboratory findings due to TB elsewhere. TUMOR OF BRAIN CSF CSF is clear but is occasionally xanthochromic or bloody if there is hemorrhage into the tumor. WBC may be increased £ 150 cells/cu mm in 75% of patients; normal in others.
- 193. Protein is usually increased. Protein is particularly increased with meningioma of the olfactory groove and with acoustic neuroma. w · Tumor cells may be demonstrable in 20–40% of patients with all types of solid tumors, but failure to find malignant cells does not exclude meningeal neoplasm. Glucose may be decreased if cells are present. Brain stem gliomas, which are characteristically found in childhood, are usually associated with normal CSF. Usually normal in diencephalic syndrome of infants due to glioma of hypothalamus. Laboratory findings due to underlying causative disease (e.g., primary brain tumors, metastatic tumors, leukemias and lymphomas, infections [tuberculoma, schistosomiasis, cryptococcosis, hydatid cyst], pituitary adenomas [CSF protein and pressure usually normal]) Laboratory findings due to associated genetic conditions (e.g., tuberous sclerosis, neurofibromatosis, Turcot's syndrome) VON RECKLINGHAUSEN'S DISEASE (MULTIPLE NEUROFIBROMAS) CSF findings of brain tumor if acoustic neuroma occurs. 1 Larson EB, et al. Diagnostic tests in the evaluation of dementia. A prospective study of 200 elderly outpatients. Arch Intern Med 1986;146:1917. 2 Spands A, Harrell FE, Durack DT. Differential diagnosis of acute meningitis. an analysis of the predictive value of initial observations. JAMA 1989;262:2700. 3 Bailey EM, Domenico P, Cunha, BA. Bacterial or viral meningitis. Postgrad Med 1990;88:217.
- 194. CHAPTER 10 MUSCULOSKELETAL AND JOINT DISEASES Interpretation of Diagnostic Tests CHAPTER 10 MUSCULOSKELETAL AND JOINT DISEASES Creatine and Creatinine Creatine Tolerance Test Enzymes (Serum) in Diseases of Muscle Myoglobinemia and Myoglobinuria Adynamia Episodica Hereditaria (Gamstorp's Disease) Dystrophy, Muscular Dystrophy, Myotonic Eosinophilia-Myalgia Syndrome Hyperthermia, Malignant Muscle, Metabolic Diseases Myasthenia Gravis (MG) Myopathy Associated with Alcoholism Myopathy: Myotubular, Mitochondrial, and Nemaline (Rod) Paralysis, Familial Periodic Polymyositis Alkaline Phosphatase (ALP), Bone-Specific, Serum Calcium, Serum Hydroxyproline, Urine Osteocalcin Pyridinium Cross-Links and Deoxypyridinoline, Urine Telopeptide, N-Terminal and C-Terminal Telopeptide, Urine Embolism, Fat Hypophosphatemia, Primary (Familial Vitamin D–Resistant Rickets) Osteoectasia, Familial Osteomyelitis Osteopenia Osteopetrosis (Albers-Schönberg Disease; Marble Bone Disease) Paget's Disease of Bone (Osteitis Deformans) Rickets Rickets, Vitamin D Dependent Sarcoma, Osteogenic Tumor of Bone, Metastatic Tumor of Bone, Osteolytic Arthritis, Associated with Hemochromatosis Arthritis, Associated with Ulcerative Colitis/Regional Enteritis Arthritis, Associated with Whipple's Disease Arthritis, Infective Arthritis, Juvenile Rheumatoid Arthritis, Rheumatoid (RA) Chondrocalcinosis (“Pseudogout”) Felty's Syndrome Gout Monoarthritis, Acute Ochronosis Osteoarthritis Polyarthritis and Fever Polymyalgia Rheumatica Arthritis Associated with Psoriasis Reiter's Syndrome Sjögren's Syndrome Spondylitis, Ankylosing Rheumatoid (Marie-Strümpell Disease) LABORATORY TESTS FOR SKELETAL MUSCLE DISEASES CREATINE AND CREATININE Increased blood creatinine, decreased creatinine excretion, increased creatine excretion Occurs In Progressive muscular dystrophy Decreased muscle mass in Neurogenic atrophy Polymyositis Addison's disease Hyperthyroidism Male eunuchoidism CREATINE TOLERANCE TEST (Ingestion of 1–3 gm creatine) Normal: Creatine is not increased in blood or urine. Decreased muscle mass: Blood and urine creatine increases in Neurogenic atrophy Addison's disease Male eunuchoidism Polymyositis Hyperthyroidism Other disorders ENZYMES (SERUM) IN DISEASES OF MUSCLE1 See Table 10-1.
- 195. Table 10-1. Increased Serum Enzyme Levels in Muscle Diseases Creatine kinase (CK) is the test of choice. It is more specific and sensitive than AST and LD and more discriminating than aldolase, but AST is more significantly associated with inflammatory myopathy and more useful in these cases. (See Chap. 3) Increased In Polymyositis Muscular dystrophy Myotonic dystrophy Some metabolic disorders Malignant hyperthermia Prolonged exercise; peak 24 hrs after extreme exercise (e.g., marathon); smaller increases in well-conditioned atheletes Normal In Scleroderma Acrosclerosis Discoid LE Muscle atrophy of neurologic origin (e.g., old poliomyelitis, polyneuritis) Hyperthyroid myopathy Decreased In RA (approximately two-thirds of patients) Skeletal Muscle Disorders That May Cause Increased Serum CK-MB Drugs (e.g., alcohol, cocaine, halothane [malignant hyperthermia], ipecac) Dermatomyositis/polymyositis Muscular dystrophy (Duchenne's, Becker's) Exercise myopathy; slight-to-significant increases in 14–100% of persons after extreme exercise (e.g., marathons); smaller increases in well-conditioned athletes Familial hypokalemic periodic paralysis Endocrine (e.g., hypoparathyroid, acromegaly; hypothyroidism rarely increases CK-MB £6% of total) Rhabdomyolysis Infections Viral (e.g., HIV, EBV, influenza virus, picornaviruses, coxsackievirus, echovirus, adenoviruses) Bacterial (e.g., Staphylococcus, Streptococcus, Clostridium, Borrelia) Fungal Parasitic (e.g., trichinosis, toxoplasmosis, schistosomiasis, cysticercosis) Skeletal muscle trauma (severe) MYOGLOBINEMIA AND MYOGLOBINURIA DISEASES OF SKELETAL MUSCLES ADYNAMIA EPISODICA HEREDITARIA (GAMSTORP'S DISEASE) w Transient increase in serum potassium occurs during the attack; attack is induced by administration of potassium. Urine potassium excretion is unchanged before or during the attack. DYSTROPHY, MUSCULAR (Genetic primary myopathies) See Table 10-2 and Fig. 10-1.
- 196. Table 10-2. Laboratory Findings in the Differential Diagnosis of Some Muscle Diseases Figure 10-1. Algorithm for serum enzymatic diagnosis of chronic muscle disease. Serum enzymes are not useful diagnostically in patients receiving immunosuppressive therapy in which the cause of muscle weakness is uncertain and muscle biopsy is required. (From Hood D, Van Lente F, Estes M. Serum enzyme alterations in chronic muscle disease: (a biopsy-based diagnostic assessment. Am J Clin Pathol 1991;95:402.) w Serum enzymes (CK is most useful) are increased, especially in Young patients. Highest levels (£50× normal) are found at onset of disease in infancy or childhood, with gradual return to normal. The more rapidly progressive dystrophies (such as the Duchenne type). They may be slightly or inconsistently increased in the limb-girdle and facioscapulohumeral types. The active early phase. Increased levels are not constant and are affected by patient's age and duration of disease. Enzymes may be increased before disease is clinically evident. Elevated serum enzyme levels are not affected by steroid therapy. Preclinical diagnosis of Duchenne's and Becker's dystrophies in families with history of disease or for screening. Serum CK is always increased in affected children (5–100× ULN of adults) to peak by 2 yrs of age; then begins to fall as disease becomes manifest. Persistent normal CK virtually rules out this diagnosis. Begin testing at 2–3 mos of age. (Note: Normal children have very high CK levels during first few days, which fall to 3× ULN by fourth day and fall to 2–3× adult level during first month of life; levels remain higher than adult levels during first 2 yrs.) Neonatal screening that is positive with whole blood should be confirmed with serum. CK is >3× ULN for age in all boys with Duchenne's dystrophy and >2× ULN in those with Becker's dystrophy. Sex-linked dystrophy is virtually the only cause of high values in normal neonates. High values persist in patients with dystrophy but not in those with false-positive results. Neonatal screening of girls has been discontinued. Prenatal screening at 18–20 wks of gestation by placental aspiration of fetal blood has been abandoned due to false-negative and false-positive results. Clinical diagnosis. CK is increased in almost all patients with Duchenne's dystrophy (average 30× ULN) and Becker's dystrophy (average 10× ULN). Diagnosis is in doubt if CK is normal. Highest levels occur in young patients and decrease with age so that level is ~50% less at 7 yrs of age; levels usually consistently exceed 5× ULN but in terminal cases may decline further. Except for polymyositis, CK is normal or <5× ULN in other myopathies and neurogenic atrophy. CK-MB of up to 10% of total is sometimes seen in Becker's and limb-girdle dystrophies. In Duchenne's dystrophy CK-MB is increased (10–15% of total) in 60–90% of patients; CK-BB may be slightly increased; CK-MM is chief fraction. CK-MB may be slightly increased (usually <4%) in carriers with increased total CK. Serum aldolase is increased in ~20% of patients. Serum LD is increased in ~10% of patients. AST is increased in ~15% of patients. Identify female carriers. CK is increased in carriers with two affected sons or one affected son and one affected male relative in ~70% of cases of Duchenne's dystrophy and 50% of cases of Becker's dystrophy. Highest levels and greatest frequency occur in younger carriers; may only be present during childhood and not in later life. Levels may be up to 10× ULN but usually <3× ULN; average = 1.5× ULN. Values overlap with those of normal females; therefore, special precautions are needed: draw blood after normal activity in afternoon or evening but not after vigorous or prolonged exercise or IM injections or during pregnancy; recheck three times at weekly intervals; values are higher in blacks than in whites. w Dystrophin protein determined by Western blot on punch biopsy of muscle is absent in Duchenne's dystrophy and decreased or abnormally formed in Becker's dystrophy. w Immunofluorescence performed on open biopsy specimen of muscle is used to confirm Western blot results in males or to diagnose females with suspected dystrophinopathy. w Recombinant DNA technology (Southern blot and PCR) allows Prenatal diagnosis by chorionic villous sampling at 12th week of gestation Diagnosis of carriers Diagnosis and differential diagnosis (e.g., differentiation from limb-girdle dystrophy) Muscle biopsy specimen shows muscle atrophy but no cellular infiltration. Urine creatine is increased; urine creatinine is decreased. These changes are less marked in limb-girdle and facioscapulohumeral dystrophies than in Duchenne's dystrophy. ESR is usually normal.
- 197. Thyroid function tests are normal. Laboratory findings due to myocardial damage in most female carriers older than age 16 yrs. Limb-Girdle Dystrophy (Heterogeneous group of disorders in both sexes; autosomal recessive disorder that begins in second decade and progresses to disability by 30 yrs of age and death by 50 yrs of age) Serum CK is increased in 70% of patients to average of 10× ULN. Not useful to detect carriers. Not useful to distinguish it from other autosomal recessive forms of dystrophy, myopathy, or neurologic disorders (e.g., hereditary proximal spinal muscular atrophy). Facioscapulohumeral Dystrophy (Begins in late adolescence; normal life span) Serum CK is increased in 75% of patients to average 3× ULN. Frequently normal by 50 yrs of age. DYSTROPHY, MYOTONIC (Autosomal dominant disorder that presents in adolescence) Serum CK is increased in 50% of patients to average of 3× ULN. Increased creatine in urine may occur irregularly. Findings due to atrophy of testicle and androgenic deficiency are noted. Urine 17-KS are decreased. Thyroid function may be decreased. EOSINOPHILIA-MYALGIA SYNDROME (Associated with ingestion of L-tryptophan; patient may also have arthralgias, fatigue, fever, edema, and skin, lung, and neurologic changes.) w Diagnostic Criteria Eosinophil count >1000/cu mm. Muscle biopsy specimen shows inflammation. No evidence of trichinosis on biopsy or serologic tests. Absence of infection, neoplasm, or primary connective tissue disease that could cause myalgia. Generalized myalgia sufficiently severe to impair daily activity. Moderate increase of serum aldolase and LD but serum CK shows minimal or no increase. Mild to moderate increase of AST, ALT, GGT. ESR is normal or increased. CRP, serum globulin, serum protein electrophoresis, IgE are normal. HYPERTHERMIA, MALIGNANT2 (Rare autosomal dominant syndrome triggered by various inhalational and local anesthetic agents, muscle relaxants [e.g., succinylcholine, tubocurarine], and various types of stress causing hyperthermia, muscle rigidity, and 70% fatality) Due To Excess heat production Exertional Heat stroke Malignant hyperthermia of anesthesia Neuroleptic malignant syndrome (in ~0.2% of patients who receive various phenothiazines, butyrophenones, or thioxanthenes; most often haloperidol) Lethal catatonia Thyrotoxicosis Pheochromocytoma Drugs (e.g., salicylate intoxication, cocaine, amphetamines) Delirium tremens Status epilepticus Generalized tetanus Decreased heat dissipation Heat stroke Dehydration Anticholinergic agents Autonomic dysfunction Extensive occlusive dressings Neuroleptic malignant syndrome Disorders of hypothalamic function Encephalitis Cerebrovascular accidents Trauma
- 198. Neuroleptic malignant syndrome Granulomatous lesions (e.g., sarcoidosis, infections) w Combined metabolic and respiratory acidosis is the most consistent abnormality and is diagnostic in the presence of muscle rigidity or rising temperature. pH is often <7.2, base excess is >–10, hypoxia is present, and arterial pCO2 is 70–120 mm Hg. Immediate arterial blood gas analysis should be performed. w Increased serum potassium (>7 mEq/L) and calcium initially with below-normal values later. w Serum CK, LD, and AST are markedly increased with peak in 24–48 hrs after surgery; CK is often 20,000–100,000 U/L. w Myoglobinemia and myoglobinuria due to rhabdomyolysis may be present early. Oliguria with acute renal shutdown may occur later. Coagulopathy, including DIC, may occur later but is infrequent. Resting serum CK may be elevated in relatives. However, the sensitivity and specificity of serum CK are too low to warrant its use for diagnosis or screening and should not be used to diagnose susceptibility to malignant hyperthermia. w Diagnosis confirmed by in vitro exposure of biopsied skeletal muscle to incremental doses of caffeine and halothane. Test is done at very few laboratories. MUSCLE, METABOLIC DISEASES Endocrine Hypothyroidism (rarely associated with myotonia) Increased serum CK in 60–80% of patients to average 4–8× ULN; becomes normal 4–6 wks after treatment. CK-MB is rarely increased £6% of total. Decreased urine creatine Increased creatine tolerance Other serum enzyme levels are normal. Hyperthyroidism Normal serum enzyme levels Increased urine creatine Decreased creatine tolerance Normal muscle biopsy findings Causes some cases of hypokalemic periodic paralysis. Acromegaly Serum CK may be increased to average of 2× ULN. Cushing's syndrome and adrenal corticosteroid therapy Increased serum enzymes—uncommon and may be due to the primary disease. Muscle biopsy—degenerative and regenerative changes in scattered muscle fibers; no inflammatory cell infiltration Increased urine creatine Other endocrinopathies (e.g., hypoadrenalism, hyperparathyroidism) Inherited metabolic myopathies (see Chapter 12) Glycogen storage diseases (types II, III, V, VII) Disordered lipid metabolism (muscle carnitine deficiency) MYASTHENIA GRAVIS (MG) See Table 10-2. w Acetylcholine receptor (AChR)–binding antibodies Present in >85% of patients with generalized MG Present in >70% of patients with ocular MG Present in >80% of patients in remission w AChR-blocking antibodies Present in >50% of patients with generalized MG Present in 30% of patients with ocular MG Present in 19% of patients in remission Present in only 1% of MG patients without AChR-binding antibodies Not detected by AChR-modulating antibody assay More often associated with more severe forms of disease w AChR-modulating antibodies Highest activity (>90%) in MG patients with thymoma Present in >70% of patients with ocular MG Does not distinguish between AChR-binding and AChR-blocking antibodies Useful when AChR-binding antibodies are not detected (e.g., in patients with recent, mild, or ocular MG) w Striational antibodies to skeletal muscle cross striations are found in 30% of adult MG patients. ~90% of myasthenia gravis patients with thymoma; absence argues against thymoma. £25% of patients with thymoma without MG. May be useful to predict risk of MG in patients with thymoma and to predict recurrence of thymoma. ~5% of patients with Lambert-Eaton myasthenic syndrome. Less frequent within 1 yr of onset of MG. Less frequent in patients receiving immunosuppressive drug therapy. Rare in MG patients <20 yrs old; increased frequency with each decade of disease after onset. Absent in congenital MG. 25% of patients treated with D-penicillamine. Graft-versus-host disease in marrow transplant recipients. Can be used for monitoring autoimmune complications of marrow transplantation. Autoimmune liver diseases: >90% of seropositive patients, have more than one type of autoantibody. Other immunologic abnormalities are frequent.
- 199. Anti-DNA antibodies in 40% of cases. ANA, anti–parietal cell, anti–smooth muscle, antimitochondrial, antithyroid antibodies, RF, etc., may be found. Thymic tumor develops in up to 15–20% of generalized MG patients; 70% of patients have thymic hyperplasia with germinal centers in medulla. CBC, ESR, thyroid function tests, serum enzymes, and electrolyte levels are normal. May be associated with thyrotoxicosis, RA, PA, SLE. High frequency of associated diabetes mellitus is seen, especially in older patients; therefore GTT should be performed with or without cortisone. Always rule out cancer of lung. MYOPATHY ASSOCIATED WITH ALCOHOLISM Acute Increased serum CK, AST, and other enzymes. Serum CK increased in 80% of patients; rises in 1–2 days; reaches peak in 4–5 days; lasts ~2 wks. CK in CSF is normal, even when serum level is elevated. Gross myoglobinuria. Acute renal failure (some patients). Chronic—may show some or all of the following changes. Increased serum CK in 60% of patients to average of 2× ULN Increased AST and other enzymes due to liver as well as muscle changes Increased urine creatine Diminished ability to increase blood lactic acid with ischemic exercise Abnormalities on muscle biopsy (support the diagnosis) Myoglobinuria MYOPATHY: MYOTUBULAR, MITOCHONDRIAL, AND NEMALINE (ROD) Routine laboratory studies including serum enzymes are normal. w Muscle biopsy with histochemical staining establishes the diagnosis. PARALYSIS, FAMILIAL PERIODIC See Table 10-3. Table 10-3. Types of Periodic Paralysis w Serum potassium is decreased during the attack. Urine potassium excretion decreases at the same time. Serum enzymes are normal. POLYMYOSITIS (Nongenetic primary inflammatory myopathy; may be idiopathic or due to infection or may be associated with skin disease [dermatomyositis] or collagen or malignant disease; 10–20% of patients older than 50 yrs of age have a neoplasm.) m Serum enzymes Serum CK is the most useful. Increased in 70% of patients. Levels may vary greatly (£50× normal). Degree of increase is highest in children and usually reflects the activity of the disease but can be normal in active disease; decrease usually occurs 3–4 wks before improvement in muscle strength and increase occurs 5–6 wks before clinical relapse; the level frequently becomes normal with steroid therapy (in ~3 mos) or in chronic myositis. Serum aldolase is increased in 75% of patients. Serum LD is increased in 25% of patients. Serum AST is increased in ~25% of the patients. Serum alpha-hydroxybutyric dehydrogenase may be increased, paralleling the increased LD. w Muscle biopsy findings are definitive; also for dermatomyositis and inclusion-body myositis. They also help to exclude other types of myositis. Total eosinophil count is frequently increased. WBC may be increased in fulminant disease. Mild anemia may occur. ESR is moderately to markedly increased; may be normal; not clinically useful.
- 200. Thyroid function tests are normal. Urine shows a moderate increase in creatine and a decrease in creatinine. Myoglobinuria occurs occasionally in severe cases. Increased ANA titers are found in 20% of patients. RF tests may be positive in 50% of patients. Serum gamma globulins may be increased. Associated carcinoma is present in £20% of patients and in £5% of patients older than 40 yrs (especially those with cancer of lung or breast). The polymyositis may antedate the neoplasm by up to 2 yrs. Other types of inflammatory myositis w • Inclusion-body myositis shows characteristic biopsy finding of basophilic rimmed vacuoles with intranuclear filaments on electron microscopy. Serum CK is normal or only slightly increased. LABORATORY TESTS FOR BONE DISEASES ALKALINE PHOSPHATASE (ALP), BONE-SPECIFIC, SERUM Use Marker for bone formation Increased In Paget's disease; may be more sensitive than total ALP, especially when activity is low. Primary hyperparathyroidism Osteomalacia Osteoporosis Pregnancy CALCIUM, SERUM See Chapter 3 and Chapter 13. HYDROXYPROLINE, URINE Use Marker of collagen (including bone) turnover Limited diagnostic value; largely replaced by following tests. Increased In Increased collagen catabolism (e.g., especially Paget's disease; hyperparathyroidism, acromegaly, psoriasis, burns) Certain inborn errors of metabolism (e.g., hydroxyprolinemia, familial aminoglycinuria) OSTEOCALCIN Use Marker of bone turnover rather than just of resorption or formation Assess patients at risk for osteoporosis Classify patients with established osteoporosis Determine efficacy of therapy in osteoporosis or bone metastases Increased In Increased bone formation (e.g., Paget's disease, primary hyperparathyroidism, healing fractures, osteogenic sarcoma, hyperthyroidism, effective therapy for osteoporosis) Decreased In Hypoparathyroidism Cushing's syndrome PYRIDINIUM CROSS-LINKS AND DEOXYPYRIDINOLINE, URINE (Stabilizing factors to type I bone collagen within organic matrix of mineralized bone; released into circulation; now measured by immunoassay.) Use Increase is marker of increased osteoclastic activity and bone demineralization.
- 201. TELOPEPTIDE, N-TERMINAL AND C-TERMINAL TELOPEPTIDE, URINE (Antibodies to intermolecular cross-links of type I bone collagen are recently developed markers of bone resorption.) Use Serial changes decide course of therapy and monitor response to therapy. Failure to change >30% after 4–8 wks of therapy may suggest need to change therapy. More specific to bone than pyridinoline, hydroxyproline, or calcium Not for diagnosis of osteoporosis Increased In (Indicates Bone Resorption) Paget's disease Osteoporosis Primary hyperparathyroidism Metastatic bone cancer DISEASES OF SKELETAL SYSTEM EMBOLISM, FAT (Occurs after trauma [e.g., fractures, insertion of femoral head prosthesis]) Unexplained decrease in Hb in 30–60% of patients Decreased platelet count in 80% of patients with rebound in 5–7 days mFree fat in urine in 50% of patients and in stained blood smear mFat globules in sputum (some patients) and BAL washings mFat globulinemia in 42–67% of patients and in 17–33% of controls Decreased arterial pO2 with normal or decreased pCO2 Arterial blood gas values are always abnormal in clinically significant fat embolism syndrome; are the most useful and important laboratory data. Patients show decreased lung compliance, abnormal ventilation-perfusion ratios, and increased shunt effect. Increased serum lipase in 30–50% of patients; 3–4 days after injury; increased free fatty acids; not of diagnostic value Increased serum triglycerides Normal CSF Hypocalcemia is a common nonspecific finding (due to binding to free fatty acids). w Laboratory findings alone are inadequate for diagnosis, prognosis, or management. HYPOPHOSPHATEMIA, PRIMARY (FAMILIAL VITAMIN D—RESISTANT RICKETS) (Hereditary metabolic defect in phosphate transport in renal tubules and possibly intestine) m Serum phosphorus is markedly decreased. Serum calcium is relatively normal. Serum ALP is moderately increased. Stool calcium is increased, and urine calcium is decreased. w Administration of vitamin D does not cause serum phosphorus to increase (in contrast to ordinary rickets), but urine and serum calcium may be increased with sufficiently large dose. Serum phosphorus usually remains low; increase of >4 mg/dL may indicate renal injury due to vitamin D toxicity. Treatment is monitored by choosing dose of vitamin D that does not increase serum calcium by >11 mg/dL or urine calcium by >200 mg/day. Renal aminoaciduria is absent, in contrast to ordinary rickets. OSTEOECTASIA, FAMILIAL (Uncommon inherited disorder of membranous bone characterized by painful swelling of the periosteal soft tissue and spontaneous fractures) Serum ALP is increased. Serum acid phosphatase and aminopeptidase are also increased. OSTEOMYELITIS
- 202. w Organism is identified by culture of bone biopsy material in 50–70% of patients; blood culture is positive in ~50% of patients; results of sinus drainage cultures in chronic osteomyelitis do not correlate with causative organism unless Staphylococcus aureus is cultured from sinus. m Microbiology S. aureus causes almost all infections of hip and two-thirds of infections of skull, vertebrae, and long bones. Other bacteria may be present simultaneously and contribute to infection. S. aureus causes 90% of cases of hematogenous osteomyelitis, which occurs principally in children, but only 50% of blood cultures are positive. Group B streptococci, S. aureus, and Escherichia coli are chief organisms in neonates. Haemophilus influenzae type b, S. aureus, group A Streptococcus, and Salmonella are chief organisms in older children. S. aureus, coagulase-negative staphylococci, gram-negative bacilli (especially Pseudomonas aeruginosa, Serratia marcescens, E. coli) are most frequent organisms. Staphylococcus epidermidis is the most common organism involved in total hip arthroplasty infection. Gram-negative bacteria cause most infections of mandible, pelvis, and small bones. Salmonella is more commonly found in patients with sickle cell and some other hemoglobinopathies. Diabetic patients with foot ulcers and surgical infections that extend to bone usually have polymicrobial infection, often including anaerobic infection. Most infections due to Candida, Aspergillus, and other fungi occur in diabetic and immunocompromised patients. Candida infection also occurs in patients with central and hyperalimentation lines. Patients are often on steroid and antibiotic therapy. Mucor occurs in patients with poorly controlled diabetes. IV drug abusers frequently have osteomyelitis of sternoclavicular joints due most commonly to P. aeruginosa and S. aureus. Puncture wounds of calcaneus usually involve pseudomonal organisms. Cranial involvement in neonates after scalp fetal monitoring during labor is mainly associated with group B Streptococci, E. coli, and staphylococci. Histoplasmosis is described in AIDS patients. HSV infection and vaccinia have been described in immunocompromised patients. Coccidioides immitisinfection may occur in endemic areas. WBC may be increased, especially in acute cases. ESR is increased in <50% of patients but may be an important clue in occult cases (e.g., intervertebral disk space infection). Laboratory findings due to underlying conditions (e.g., postoperative status, radiotherapy, foreign body, tissue gangrene, contiguous infection) m Vertebral osteomyelitis May be due to unusual organisms (e.g., Mycobacterium tuberculosis, fungi, Brucella). Increased WBC in <50% of patients. Increased ESR in >80% of patients. Blood culture may be positive. Aspiration of involved site with stains, cultures, and histologic examination. Gram-positive cocci, especially S. aureus, are most common. Gram-negative enteric bacilli, especially E. coli and Salmonella, cause ~30% of cases, especially in sickle cell disease. P. aeruginosa infection is associated with IV drug abuse. Brucella infection occurs in certain parts of the world. Laboratory findings due to predisposing factors (e.g., diabetes, IV drug abuse, GU tract infection) or complications (e.g., epidural or subdural abscess, aortic involvement) OSTEOPENIA (Generic term for decreased mineralized bone on radiographic study, but radiographic study cannot distinguish osteomalacia from osteoporosis in most patients unless pseudofractures are seen.) All serum chemistry values may be normal in any form of osteopenia. All chemistry values are commonly normal in osteomalacia, especially that coexisting with osteoporosis, which occurs in 20% of patients. Serum vitamin D level that is below normal (e.g., 15 ng/mL of 25-hydroxy–vitamin D) suggests osteomalacia w Diagnosis is established by bone biopsy, which may be combined with tetracycline labeling. During therapeutic trial of calcium and vitamin D, serum and urine calcium should be monitored monthly to avoid toxicity. Urine calcium is maintained at <300 mg/gm of creatinine and serum calcium at <10.2 mg/dL by reducing dose of vitamin D. OSTEOPETROSIS (ALBERS-SCHÖNBERG DISEASE; MARBLE BONE DISEASE) Normal serum calcium, phosphorus, and ALP Serum acid phosphatase increased (some patients) Myelophthisic anemia (some patients) Laboratory findings due to complications (e.g., osteomyelitis) PAGET'S DISEASE OF BONE (OSTEITIS DEFORMANS) w Marked increase in serum ALP (in 90% of cases) is directly related to severity and extent of disease; sudden additional increase with development of osteogenic sarcoma occurs in ~1% of patients. May be normal in patients with monostotic disease (~15% of symptomatic patients). Bone-specific serum ALP is more sensitive marker of bone formation. Serum calcium increased during immobilization (e.g., due to intercurrent illness or fracture). Normal or slightly increased serum phosphorus Frequently increased urine calcium; renal calculi common. Increase in urinary pyridinium cross-link pyridinoline is better indicator of bone resorption than the increase in urinary hydroxyproline, which may be marked. Osteocalcin is often normal.
- 203. Biochemical response to calcitonin therapy Initial decrease of serum ALP and urinary hydroxyproline followed by return to former values despite continued therapy—occurs in ~20% of cases. Serum ALP and urinary hydroxyproline decrease 30–50% in 3–6 mos and maintain those values for duration of therapy—occurs in >50% of cases. Serum ALP and urinary hydroxyproline become normal only in previously untreated patients with only small increase in bone turnover—occurrence is unusual. w Radionuclide scan shows areas of heavy uptake in affected bones. RICKETS Due To Low serum calcium-phosphorus product Vitamin D deficiency Hypophosphatemia Vitamin D–resistant rickets Fanconi's syndrome Excess intake of phosphate-binding antacids Hypophosphatemic nonrachitic bone disease Tumor-induced osteomalacia Renal tubular acidosis Normal or high serum calcium-phosphorus product Renal osteomalacia Hypophosphatasia m Serum ALP is increased. This is the earliest and most reliable biochemical abnormality; it parallels the severity of the rickets. It may remain elevated until bone healing is complete. Serum calcium is usually normal or slightly decreased. Serum phosphorus is usually decreased. In some persons, serum calcium and phosphorus may be normal. Generalized renal aminoaciduria is present; it disappears when adequate vitamin D is given. Serum calcium and phosphorus rapidly become normal after institution of vitamin D therapy. w Serum 25-hydroxy–vitamin D is low (usually <5 ng/mL; normal = 10–20 ng/mL). Vitamin D–deficient state is suggested by Low serum phosphorus Severe liver disease Malabsorption Anticonvulsant therapy RICKETS, VITAMIN D DEPENDENT w Blood level of 1,25-dihydroxyvitamin D is very low in type I (autosomal recessive deficiency of 1-a-hydroxylase enzyme in kidney) and increased in type II (group of genetic disorders causing increased end-organ resistance to 1,25-dihydroxyvitamin D). Serum calcium is frequently decreased, sometimes causing tetany. Serum phosphorus is decreased but not as markedly or as consistently as in hypophosphatemic rickets. Increased serum ALP, parathormone, and urinary cyclic adenosine monophosphate. Urine calcium is decreased. Generalized renal aminoaciduria is present. w Findings return to normal after adequate vitamin D is given (may require very large doses). SARCOMA, OSTEOGENIC Marked increase in serum ALP (£40× normal); reflects new bone formation and parallels clinical course (e.g., metastasis, response to therapy); is said to occur in only 50% of patients. Laboratory findings due to metastases—80% of patients have lung metastases at time of diagnosis. Laboratory findings due to preexisting diseases (e.g., Paget's disease). w Histologic examination of lesion establishes diagnosis. TUMOR OF BONE, METASTATIC w Biopsy confirms the diagnosis Osteolytic metastases (especially from primary tumor of bronchus, breast, kidney, or thyroid) Urine calcium is often increased; marked increase may reflect increased rate of tumor growth. Serum calcium and phosphorus may be normal or increased. Serum ALP is usually normal or slightly to moderately increased.
- 204. Serum acid phosphatase is often slightly increased, especially in prostatic metastases. Osteoblastic metastases (especially from primary tumor in prostate) Serum calcium is normal; it is rarely increased. Urine calcium is low. Serum ALP is usually increased. Serum acid phosphatase is increased in prostatic carcinoma. Serum phosphorus is variable. m Increased concentration of markers of bone turnover (pyridinoline and deoxypyridinoline, and associated N-telopeptides, serum bone ALP), which may predict metastases in breast, prostate, lung cancers. TUMOR OF BONE, OSTEOLYTIC (E.g., Ewing's sarcoma) Usually normal serum calcium, phosphorus, and ALP. w Biopsy establishes the diagnosis. NORMAL VALUES—SYNOVIAL FLUID Volume 1.0–3.5 mL pH Parallels serum Appearance Clear, pale yellow, or straw-colored; viscous, does not clot Fibrin clot 0 Mucin clot Good WBC (per cu mm) <200 (even in presence of leukocytosis in blood) Neutrophils <25% Crystals Free 0 Intracellular 0 Fasting uric acid, bilirubin Approximately the same as in serum Total protein ~25–30% of serum protein Mean = 1.8 gm/dL Abnormal if >2.5 gm/dL; inflammation is moderately severe if >4.5 gm/dL Glucose <10 mg/dL lower than serum level of simultaneously drawn blood Culture No growth LABORATORY TESTS FOR JOINT DISEASES Acute-phase reactants, e.g., ESR, CRP Anti–Borrelia burgdorferi antibodies Anticardiolipin antigens Anticytoplasmic antigens ANA (see Table 17-1) Complement (C3, C4, CH50) Cryoglobulins Immune complexes (C1q binding, Raji cell assay) RF Synovial fluid examination (see Table 10-4 and Table 10-5) Table 10-4. Synovial Fluid Findings in Various Diseases of Joints
- 205. Table 10-5. Synovial Fluid Findings in Acute Inflammatory Arthritis of Various Etiologies a DISEASES OF JOINTS ARTHRITIS, ASSOCIATED WITH HEMOCHROMATOSIS w Laboratory findings of hemochromatosis Negative RF No subcutaneous nodules w Biopsy of synovia: iron deposits in synovial lining but not in cartilage; little iron in deep macrophages. Hemarthrosis—iron diffusely distributed in macrophages (e.g., in hemophilia, trauma, and pigmented villonodular synovitis). Osteoarthritis—small amount of iron that is limited to deep macrophages. RA—iron in both deep macrophages and lining cells. Frequently associated with chondrocalcinosis. ARTHRITIS, ASSOCIATED WITH ULCERATIVE COLITIS/REGIONAL ENTERITIS RA, ankylosing spondylitis (in £20% of patients with Crohn's disease), or acute synovitis (monoarticular or polyarticular—absent RF) may be present. Joint fluid is sterile on the basis of both bacteriologic and microscopical findings. It is similar to fluid of RA and Whipple's disease (in cell count, differential count, specific gravity, viscosity, protein, glucose, poor mucin clot formation). Joint fluid examination is principally useful in evaluating monarticular involvement to rule out suppurative arthritis. Synovial biopsy findings are similar to RA biopsy findings. Abnormal laboratory results (e.g., increased ESR, WBC, platelets) are related to activity of bowel disease. Absent RF and ANAs. ARTHRITIS, ASSOCIATED WITH WHIPPLE'S DISEASE Findings of a nonspecific synovitis ARTHRITIS, INFECTIVE w Joint fluid (see Table 10-4) Bacterial In purulent arthritis, organism is recovered from joint in 90% of patients and from blood in 50% of patients. Most often due to S. aureus (60%) and Streptococcus species. Gram stain is positive in ~50% of patients; it is particularly useful for establishing diagnosis promptly and in cases in which cultures are negative. Culture may be negative because of prior administration of antibiotics. In tuberculous arthritis Gram stain and bacterial cultures are negative, but acid-fast stain, culture for tubercle bacilli, guinea pig inoculation, and biopsy of synovia confirm the diagnosis. In children, most common organisms are H. influenzae type b, S. aureus, various streptococci, and gram-negative bacilli. In young adults, >50% of cases are due to Neisseria gonorrhoeae; rest are due to S. aureus, streptococci, or gram-negative bacilli. Viral (e.g., mumps, rubella, HBV infection, parvovirus B19 infection) Fungal (e.g., Sporothrix schenckii, C. immitis, candida, Blastomyces dermatitidis) w • If five biopsies are cultured, bacterial growth in two or less or only in broth media indicates contamination, but growth in all five in solid and broth media suggests infection. Laboratory findings due to preexisting infections (e.g., SBE, meningococcic meningitis, pneumococcal pneumonia, typhoid, gonorrhea, Lyme disease, TB, rat-bite fever, syphilis) Infection of prosthetic joints Early onset (within first 3 mos) Delayed onset (within first 2 yrs—two-thirds of patients) Due to organisms introduced during surgery or to those of nosocomial infection, which multiply slowly (50% of cases occur >1 yr later). Most common are skin flora (e.g., S. epidermidis, other coagulase-negative staphylococci, Corynebacterium sp.) Late onset (after 2 yrs—one-third of cases) Due to hematogenous seeding from infected focus (e.g., GU tract, dental) Increased WBC and ESR support diagnosis of infection rather than aseptic loosening of prosthesis. ARTHRITIS, JUVENILE RHEUMATOID
- 206. See Table 10-8. Table 10-8. Erythrocyte Sedimentation Rate (ESR) in Differential Diagnosis of Juvenile Rheumatoid Arthritis Latex fixation and other serologic tests for RF are negative, but RF and circulating immune complexes can be demonstrated by various special techniques. Reported incidence of ANAs is 4–88% depending on clinical type and laboratory technique. ARTHRITIS, RHEUMATOID (RA) See Table 10-6 and Table 10-7. Table 10-6. Comparison of Rheumatoid Arthritis and Osteoarthritis Table 10-7. Serologic Tests in Various Rheumatoid Diseases w American Rheumatism Association has 11 criteria for diagnosis of RA; seven are required for diagnosis of classic RA, five for definite RA, and three for probable RA. Four laboratory findings included in these criteria are positive serum test for RF (by any method; positive in <5% of normal control subjects), poor mucin clotting of synovial fluid, characteristic histologic changes in synovium, and characteristic histologic changes in rheumatoid nodules. w Serologic tests for RF (autoantibodies to immunoglobulins) using nephelometry, latex, bentonite, or sheep or human RBCs Use slide test only for screening; confirm positive result with tube dilution (nephelometry). Significant titer is ³1:80. In RA, titers are often 1:640 to 1:5120 and sometimes £1:320,000. Titers in conditions other than RA are usually <1:80. Gives useful objective evidence of RA, but a negative result does not rule out RA. Negative in one-third of patients with definite RA. Positive result in <50% during first 6 mos of disease. Various methods show sensitivity of 50–75% and specificity of 75–90%. Positive in 80% of “typical” cases; high titers in patients with splenomegaly, vasculitis, subcutaneous nodules, or neuropathy. Titer may decrease during remission but rarely becomes negative. Progressive increases in titer during the first 2 yrs indicate a more severe course. Positive in 5–10% of healthy population; progressive increase with age in £25–30% of persons older than 70 yrs. Positive in 5% of rheumatoid variants (arthritis associated with ulcerative colitis, regional enteritis, Reiter's syndrome, juvenile RA, rheumatoid spondylitis, tophaceous gout, pseudogout). Positive in 5% of cases of scleroderma, mixed connective tissue disease, polymyositis, polymyalgia rheumatica. Positive in 10–15% of patients with SLE. Positive in 90% of patients with primary Sjögren's syndrome or cryoglobulinemic purpura. Positive in 10–40% of patients with Waldenström's macroglobulinemia, chronic infections (e.g., syphilis, leprosy, brucellosis, TB, SBE), viral infections (e.g., hepatitis, EBV infection, influenza, vaccinations [positive in £10% of cases of parvovirus B19–associated arthritis]), parasitic diseases (e.g., malaria, schistosomiasis, trypanosomiasis, filariasis), chronic liver disease, infectious hepatitis, chronic pulmonary interstitial fibrosis, etc. Positive in £20% of cases of psoriatic arthritis. Positive in 25% of cases of sarcoid arthritis. Negative in osteoarthritis, ankylosing spondylitis, rheumatic fever, suppurative arthritis. ANA present in up to 28% of patients (see Table 10-7). Serum complement is usually normal except in patients with vasculitis; depressed level is usually associated with very high levels of RF and immune complexes, and Table 16-1). Immune complexes—monoclonal RF and C1q-binding assays are positive more frequently than other assays in RA but correlate poorly with disease activity. Positive
- 207. test for mixed cryoglobulins indicates presence of immune complexes and is associated with increased incidence of extra-articular manifestations, especially vasculitis. Not clinically useful. Increased ESR, CRP, and other acute-phase reactants. ESR is often used as guide to activity and to therapy but is normal in 5% of patients. Very high ESR (>100 mm/hr) is distinctly unusual in early cases. WBC is usually normal; a slight increase may be seen early in active disease. Mild thrombocytosis occurs frequently as an acute-phase reactant. Serum protein electrophoresis shows increase in globulins, especially in gamma and alpha 2-globulins, and decreased albumin. Moderate normocytic hypochromic anemia of chronic disease with decreased serum iron, normal TIBC, and normal iron stores (serum ferritin and bone marrow iron); not responsive to iron, folic acid, vitamin B 12 administration or splenectomy. If Hct is <26%, search for other cause of anemia (e.g., GI tract bleeding). Anemia diminishes as patient goes into remission or responds to therapy. Serum CK is decreased below normal in >60% of patients; not associated with decreased serum aldolase and myosin, which indicates that decrease is not due to general impairment of muscle function. Serum calcium, phosphorus, ALP, uric acid, and ASOT are normal. Synovial biopsy is especially useful in monoarticular form to rule out TB, gout, etc. Synovial fluid glucose may be greatly decreased (<10 mg/dL); mucin clotting is fair to poor. (See Table 10-4.) Laboratory findings due to extra-articular involvement (usually occurs late in severe disease) (e.g., pleural or pericardial effusion, interstitial pulmonary fibrosis) Laboratory findings due to therapeutic drugs (e.g., salicylates, NSAIDs, gold, penicillamine). See Amyloidosis. CHONDROCALCINOSIS (“PSEUDOGOUT”) w Joint fluid contains crystals identified as calcium pyrophosphate dihydrate, inside and outside of WBCs and macrophages; differentiated from urate crystals under polarized light, which distinguishes from gout. See Table 10-4, Table 10-5 and Table 10-9. Crystals may also be identified by other means (e.g., chemical, x-ray diffraction). Table 10-9. Birefringent Materials in Synovial Fluid Blood and urine findings are normal. Laboratory findings due to associated conditions (e.g., hyperparathyroidism, hypothyroidism, acromegaly, hemochromatosis, gout, hypomagnesemia, degenerative arthritis) FELTY'S SYNDROME (Occurs in 5–10% of patients with far-advanced RA associated with splenomegaly and leukopenia and rheumatoid nodules) w Serologic tests for RF are positive in high titers. ANAs are usually present. Titers of immune complexes are high and complement levels are lower than those in patients with RA. Leukopenia (<2500/cu mm) and granulocytopenia are present. Anemia and thrombocytopenia due to hypersplenism may occur and respond to splenectomy. GOUT Due To Primary (i.e., inborn) (30% of patients) Idiopathic Increased purine biosynthesis Lesch-Nyhan syndrome Secondary (70% of patients) Overproduction (10% of secondary cases) Neoplastic and hemolytic conditions (e.g., leukemia, polycythemia vera, secondary polycythemia, malignant lymphomas). Blood dyscrasias are found in ~10% of patients with clinical gout. Psoriasis. Increased breakdown of adenosine triphosphate Glycogen storage diseases (types I, III, V, VII) Alcohol ingestion
- 208. Myocardial infarction Decreased renal function (90% of secondary cases) Decreased renal clearance. Chronic renal disease Chronic lead intoxication Increased organic acids (e.g., lactate, beta-hydroxybutyrate in diabetic ketoacidosis, acute ethanol intoxication, toxemia of pregnancy, starvation) Drugs (e.g., diuretics, aspirin, cyclosporin) (£20% of cases). May cause £50% of all new cases of gouty arthritis; this occurs later in life and in women is more common than primary gout. Also associated with hypertension (in one-third of patients with gout), familial hypercholesterolemia, obesity, acute intermittent porphyria, sarcoidosis, parathyroid dysfunction, myxedema. (See Table 10-9.) w Presence of crystals of monosodium urate from tophi or joint fluid viewed microscopically under polarized light—strongly negative birefringent needle-shaped crystals both inside and outside PMNs or macrophages establishes the diagnosis and differentiates it from pseudogout. Found in 90% of patients during an acute attack. Found in synovial fluid in 75% of patients between attacks. m Increased serum uric acid Does not establish the diagnosis of gout. Is normal in 30% of acute attacks. Several determinations may be required to establish increased values; beware of serum levels reduced to normal range as a result of recent aspirin use. Changes in therapy may cause wide fluctuations in serum uric acid levels. The incidence of gout occurring at various uric acid levels in men was found to be as follows: 1.1% at <6 mg/dL, 7.3% at 6–6.9 mg/dL, 14.2% at 7–7.9 mg/dL, 18.7% at 8–8.9 mg/dL, 83% at ³9 mg/dL. Many gout patients have levels <8 mg/dL and more than one-third never have an elevated level. Because the mean interval between first and second gout attacks is 11.4 yrs and only 25% have a second attack within 12 yrs, therapy for this group may not be cost effective. Serum uric acid is increased in ~25% of asymptomatic relatives. Approximately 10% of adult males have increased serum uric acid. Only 1–3% of patients with hyperuricemia have gout. Secondary hyperuricemia usually produces much higher serum uric acid than primary type. If serum uric acid is >10 mg/dL, underlying malignancy should be considered after renal failure has been ruled out. m Uric acid stones occur 3–10 times more frequently in gouty patients than in the general population even though 75% of gouty patients have normal 24-hr excretion of uric acid. When serum uric acid is <9 mg/dL or urine level is <700 mg/24 hrs, risk of renal calculi is <21%; when serum uric acid is >13 mg/dL or urine level is >1100 mg/24 hrs, risk is >50%. With primary gout, 10–25% of patients develop uric acid stones; in 40% of them, the stones appear >5 yrs before an episode of gout. 24-hr urine uric acid excretion If >600 mg/24 hrs, measurement should be repeated after 5-day purine-free diet. If <600 mg/24 hrs or urine uric acid/creatinine ratio is <0.6 and patient has no history of kidney or GU tract disease, treatment of hyperuricemia is with probenecid. If >600 mg/24 hrs or urine uric acid/creatinine ratio is >0.8 or the patient has a history of GU tract or kidney disease, allopurinol is drug of choice. Uric acid/creatinine ratios of 0.6–0.8 are indeterminate; ratios of 0.2–0.6 are considered normal or indicate underexcretion. 700–1000 mg/24 hrs is considered borderline. >1000 mg/24 hrs is abnormal and is indication for treatment in patients with asymptomatic hyperuricemia. Uric acid crystals and amorphous urates are normal findings in urinary sediment. Low-grade proteinuria occurs in 20–80% of persons with gout for many years before further evidence of renal disease appears. w Histologic examination of gouty nodule is characteristic. Moderate leukocytosis and increased ESR occur during acute attacks; normal at other times. RF is detectable in low titers in 10% of patients with gout or pseudogout; but RA rarely coexists with these conditions. Serum triglycerides are frequently increased, resulting in a high frequency of type IIb and type IV lipoprotein patterns; HDL-cholesterol level is frequently decreased. See Table 10-4, Table 10-5, Table 10-7. See sections on renal diseases and serum uric acid. MONOARTHRITIS, ACUTE Due To Infection Bacteria (N. gonorrhoeae) Spirochetes (e.g., Lyme disease, syphilis) Mycobacteria (TB, atypical mycobacteria) Viruses (e.g., HIV, HBV, HSV) Fungi (e.g., blastomycosis, Candida spp.) Crystals (e.g., monosodium urates, calcium pyrophosphate dihydrate, apatite, calcium oxalate, liquid lipid microspherules) Prosthetic joint (infection, aseptic loosening) Trauma Hemarthrosis (e.g., coagulopathy, trauma) Neoplasm (e.g., osteoid osteoma, pigmented villonodular synovitis, metastasis) Systemic diseases (e.g., RA, Reiter's syndrome, psoriasis, inflammatory bowel disease, sarcoidosis, serum sickness, hyperlipidemias, bacterial endocarditis, AIDS) OCHRONOSIS
- 209. (Lumbosacral spondylitis associated with scleral pigmentation and darkening of urine on alkalinization) See Alkaptonuria. OSTEOARTHRITIS See Table 10-6. Laboratory tests are normal and not helpful. ESR may be slightly increased (possibly because of soft-tissue changes secondary to mechanical alterations in joints). POLYARTHRITIS AND FEVER Type Useful Laboratory Tests Infectious Bacterial Septic arthritis Blood and synovial fluid culture Bacterial endocarditis Blood culture Lyme disease Serology Fungal and mycobacterial Culture; biopsy Viral Serology Postinfectious/reactive Rheumatic fever Reiter's syndrome Inflammatory bowel disease RA; Still's disease Systemic rheumatic disorders SLE Systemic vasculitis Crystal induced Gout Pseudogout Others Sarcoidosis Neoplasms Familial Mediterranean fever Mucocutaneous disorders, e.g., Henoch-Schönlein purpura Kawasaki's syndrome Erythema nodosum Erythema multiforme POLYMYALGIA RHEUMATICA m ESR is markedly increased; this is a criterion for diagnosis. Mild hypochromic or normochromic anemia is commonly found. WBC may be increased in some patients. Abnormalities of serum proteins are frequent, although no consistent or diagnostic pattern is found. Most frequently the albumin is decreased with an increase in alpha1 and alpha2 globulins and fibrinogen. Cryoglobulins are sometimes present. RF is present in serum in 7.5% of patients. Serum enzymes (e.g., AST, ALP) may be increased in one-third of patients. m Muscle biopsy specimen is usually normal or may show mild nonspecific changes. m Temporal artery biopsy findings are often positive because one-third of patients with giant cell arteritis present with polymyalgia rheumatica, which ultimately develops in 50–90% of these patients (see discussion of temporal arteritis). ARTHRITIS ASSOCIATED WITH PSORIASIS Arthritis occurs in ~2% of patients with psoriasis. No correlation is seen between skin activity and joint manifestations; either one may precede the other. Increased serum uric acid is due to increased turnover of skin cells in psoriasis. If serologic tests for RF are negative, should not be classified as RA. w No characteristic laboratory findings. REITER'S SYNDROME (Triad of arthritis, urethritis, and conjunctivitis has additional features: dermatitis, buccal ulcerations, circinate balanitis, and keratosis blennorrhagica. Triad is initially present in only one-third of patients.)
- 210. Increased acute-phase reactants Increased ESR parallels the clinical course. Increased CRP. WBC is increased (10,000–20,000/cu mm), as is the granulocyte count. Serum globulins are increased in long-standing disease. Nonbacterial cystitis, prostatitis, or seminal vesiculitis and subclinical infection of ileum and colon may be found. Significance of culturing various organisms or of serologic evidence of preceding infections is not determined. HLA-B27 is found in up to 90% of white patients; not diagnostically useful. SJöGREN'S SYNDROME3, 4 (Primary systemic autoimmune disease associated with decreased salivary and lacrimal gland secretion or may be secondary to RA, SLE, scleroderma, or vasculitis in one-half to two-thirds of patients. 90% of patients are female.) w Diagnostic Criteria A. Primary Sjögren's syndrome 1. Symptoms and objective signs of dry eyes and 2. Symptoms and objective signs of dry mouth, including biopsy of minor salivary gland and 3. Laboratory evidence of systemic autoimmune disease a. Increased RF titer ³1:320 (RF is present in £90% of primary and secondary Sjögren's syndrome) b. Increased ANA titer ³1:320 or c. Presence of anti-SS-A (Ro) or anti-SS-B (La) antibodies B. Secondary Sjögren's syndrome: above criteria plus sufficient features for diagnosis of SLE—found in 4–5% of patients with Sjögren's syndrome; Sjögren's syndrome is found in 50–98% of patients with SLE. RF—found in 30–55% of patients with Sjögren's syndrome; Sjögren's syndrome is found in 20–100% of patients with RA. Primary biliary cirrhosis—found in 3% of patients with Sjögren's syndrome; Sjögren's syndrome is found in 50–100% of patients with primary biliary cirrhosis. Polymyositis, generalized scleroderma. C. Not due to sarcoidosis; HIV, HTLV, HBV, HCV infection; or preexisting lymphoma; fibromyalgia; or other causes of keratitis sicca or enlarged salivary glands. w ANAs in speckled or homogeneous pattern are present in 65% of patients, more frequently in those with primary type. Anti-SS-A (Ro) is present in £88% of patients with primary type and <10% of those with secondary Sjögren's syndrome. Anti-SS-B (La) is present in £73% of patients with primary Sjögren's syndrome and <5% of those with secondary Sjögren's syndrome. Anti–salivary duct antibody is rare (<30%) in primary Sjögren's syndrome and frequent (76–83%) in secondary Sjögren's syndrome. Patients with primary Sjögren's syndrome also have higher levels of tissue antibodies (e.g., thyroglobulin [in 35%], gastric parietal, smooth muscle). Anti-dsDNA is not found. Mild normochromic, normocytic anemia occurs in 50% of patients. Leukopenia occurs in up to one-third of patients. ESR is usually increased. Serum protein electrophoresis shows increased gamma globulins (usually polyclonal), largely due to IgG. Laboratory findings due to concomitant diseases Immune complex GN may occur, but chronic tubulointerstitial nephritis is more characteristic. SPONDYLITIS, ANKYLOSING RHEUMATOID (MARIE-STRÜMPELL DISEASE) w No diagnostic laboratory test exists for this disorder. ESR is increased in £80% of patients. Mild to moderate hypochromic anemia develops in £30% of patients. Serologic tests for RF are positive in <15% of patients with arthritis of only the vertebral region. CSF protein is moderately increased in £50% of patients. Secondary amyloidosis develops in 6% of patients. Laboratory findings due to carditis and aortitis with aortic insufficiency, which occur in 1–4% of patients. Laboratory findings of frequently associated diseases (e.g., chronic ulcerative colitis, regional ileitis, psoriasis) are noted. Histocompatibility antigen HLA-B27 is found in 95% of these white patients and in lesser numbers with variants of this condition. ~20% of carriers of HLA-B27 have ankylosing spondylitis, but it is not helpful in establishing the diagnosis. 1 Rosalki SB. Serum enzymes in diseases of skeletal muscle. Clin Lab Med 1989;9:767. 2Simon HB. Hyperthermia. N Engl J Med 1993;329:483. 3 Collins RD Jr, Ball GV. Sjögren's syndrome: distinguishing primary from secondary. J Musculoskeletal Med 1984;1(5):42. 4 Fox RI. Sjögren's syndrome. Controversies and progress. Clin Lab Med 1997;17:431.
- 211. CHAPTER 11 HEMATOLOGIC DISEASES Interpretation of Diagnostic Tests CHAPTER 11 HEMATOLOGIC DISEASES Blood Smear—Red Blood Cells (RBCs) Blood Volume Bone Marrow Aspiration Bone Marrow Biopsy Coombs' (Antiglobulin) Test Erythropoietin, Plasma Ferritin, Serum Flow Cytometry Gene Rearrangement (bcr) Assay Gene Rearrangement Assay for Immunoglobulin Heavy (IgH) and Light (IgL-kappa) Chains and Gene Rearrangement Assay for Beta and Gamma T-Cell Receptor Genetic Hematologic Diseases, Molecular Diagnosis Haptoglobins, Serum Hemoglobin, Fetal (HbF) Hemoglobin, Serum Iron, Radioactive (59Fe), RBC Uptake Iron, Serum Iron (Hemosiderin), Stainable, in Bone Marrow Iron-Binding Capacity, Total (TIBC), Serum Kleihauer-Betke Test Leukocyte Alkaline Phosphatase (LAP) Staining Reaction Mean Corpuscular Hemoglobin (MCH) Mean Corpuscular Hemoglobin Concentration (MCHC) Mean Corpuscular Volume (MCV) Neutrophil Function Tests Nitroblue Tetrazolium Reduction in Neutrophils Osmotic Fragility Protoporphyrin, Free Erythrocyte (FEP) RBC Indices RBC Survival (51 Cr) Red Cell Distribution Width (RDW) Reticulocyte Count Reticulocyte Hemoglobin Reticulocyte Hemoglobin Content Transferrin, Serum Transferrin Receptor, Serum Transferrin Saturation, Serum Vitamin B12-Binding Capacity, Unsaturated White Blood Cell (WBC) Differential Count Acquired Immune Deficiency Syndrome (AIDS) Agammaglobulinemia, X-Linked (Bruton's Disease) Agranulocytosis Alder-Reilly Anomaly Alpha Heavy-Chain Disease Alpha1-Antitrypsin Deficiency Anemia, Acute Blood Loss Anemia, Aplastic Anemia, Fanconi's Anemia, Hemolytic, Acquired Anemia, Hemolytic, Microangiopathic Anemia, Hemolytic, Hereditary Nonspherocytic Anemia, Iron-Deficiency Anemia, Macrocytic, of Liver Disease Anemia, Macrocytic, of Sprue, Celiac Disease, Steatorrhea Anemia, Megaloblastic Anemia, Megaloblastic, of Pregnancy and Puerperium Anemia, Megaloblastic, Refractory to Folic Acid or Vitamin B12 Anemia, Myelophthisic Anemia of Chronic Diseases Anemia, Pathogenesis Classification Anemia, Pyridoxine-Responsive Anemia, Sideroblastic Anemia in Parasitic Infestations Anemia in Pregnancy Anemias (Hemolytic), Classification Aplasia, Congenital Pure Red Cell (Diamond-Blackfan Anemia) Ataxia-Telangiectasia Atransferrinemia Bisalbuminemia Chédiak-Higashi Syndrome Chemicals, Hematologic Effects Cryofibrinogenemia Cryoglobulinemia Elliptocytosis, Hereditary Erythrocyte Pyruvate Kinase Deficiency Erythrocytosis, Classification Glucose 6-Phosphate Dehydrogenase (G-6-PD) Deficiency in RBC Graft-Versus-Host Disease Granulomatous Disease, Chronic Heavy-Chain Diseases Hemoglobin C (HbC) Disease Hemoglobin D (HbD) Disease Hemoglobin E (HbE) Disease Hemoglobin F (HbF), Hereditary Persistence Hemoglobinopathies, Laboratory Screening Hemoglobins, Unstable Hemoglobins with Altered Oxygen Affinity Hemoglobinuria, Paroxysmal Cold Hemoglobinuria, Paroxysmal Nocturnal (Marchiafava-Micheli Syndrome) Hemolysis Hemolytic Disease of the Newborn (Erythroblastosis Fetalis) Indications for Exchange Transfusion Hemorrhage, Neonatal Histiocytosis X (Langerhans Cell Granulomatosis) Hodgkin's Disease and Other Malignant Lymphomas Hypereosinophilic Syndrome Hyperimmunoglobulinemia E Syndrome Hyperimmunoglobulinemia M Syndrome Hypoalbuminemia, Hypoanabolic Hypogammaglobulinemia, Common Variable (or “Acquired”) Immunodeficiency, Cellular, with Normal Immunoglobulins (Nezelof's Syndrome) Immunodeficiency, Classification Immunodeficiency, Screening Tests Immunoglobulin A (IgA) Deficiency, Selective Irradiation, Hematologic Effects Jordans Anomaly Leukemia, Acute Leukemia, Hairy Cell (Leukemic Reticuloendotheliosis) Leukemia, Lymphoblastic, Acute (ALL) Leukemia, Lymphocytic, Chronic (CLL) Leukemia, Myelogenous, Chronic Leukemia, Plasma Cell Leukemia, Prolymphocytic Leukemia, Risk Factors Leukemias, Nonlymphocytic, Acute Leukemias and Lymphomas, Diagnostic Methods Leukemia/Lymphoma Syndrome, Adult Human T Cell Lymphadenopathy, Angioimmunoblastic Lymphocytosis (Infectious), Acute Lymphoma, Cutaneous T-Cell Lymphoproliferative (Autoimmune) Syndrome Macroglobulinemia (Primary; Waldenström's) Marrow Transplantation, Complications May-Hegglin Anomaly Metaplasia, Agnogenic Myeloid (Idiopathic Myelofibrosis) Methemoglobinemia Monoclonal Gammopathies, Classification Monoclonal Gammopathy, Idiopathic (“Benign,” “Asymptomatic”) (Plasma Cell Dyscrasia of Unknown Significance; Monoclonal Gammopathy of Unknown Significance) Myelodysplastic (Preleukemic) Syndromes Myeloma, Multiple Myeloma, Multiple, Smoldering Myeloma, Nonsecretory Myeloma, Osteosclerotic Neutropenia, Periodic (Cyclic) Neutrophilia, Hereditary Giant Neutrophils, Hereditary Hypersegmentation
- 212. Orotic Aciduria, Hereditary Pancytopenia Pelger-Huët Anomaly Plasmacytoma, Solitary Polycythemia, Factitious Polycythemia, Relative (Stress Erythrocytosis) Polycythemia, Secondary Polycythemia Vera Pyropoikilocytosis, Hereditary Rhnull Disease Severe Combined Immunodeficiency Disorders (SCID) Sickle Cell Disease Spherocytosis, Hereditary Spleen, Decreased Function (Hyposplenism) Spleen, Increased Function (Hypersplenism) Stomatocytosis, Hereditary Sulfhemoglobinemia Thalassemias Thick Blood Syndrome, Neonatal Thymic Hypoplasia (DiGeorge Syndrome) Tumor of Bone Marrow Tumor of Thymus Wiskott-Aldrich Syndrome Anticoagulants, Circulating Antithrombin III Bleeding Time (BT) Clot Retraction Coagulation (Clotting) Time (Lee-White Clotting Time) Fibrinogen Degradation Products Heparin, Plasma Partial Thromboplastin Time, Activated (aPTT) Plasminogen Platelet Aggregation Studies Platelet Count Platelet Function Defects, Acquired Platelet Volume, Mean Protein C, Plasma Protein S, Plasma Prothrombin Consumption Prothrombin Time (PT) Ristocetin Cofactor Activity Thrombin Time Tourniquet Test Afibrinogenemia, Congenital Bernard-Soulier Syndrome Coagulation Disorders, Neonatal Coagulopathy due to Liver Disease Disseminated Intravascular Coagulation (DIC) Dysfibrinogenemia, Congenital Factor V Deficiency (Parahemophilia) Factor VII Deficiency Factor VII Deficiency, Congenital Factor VIII (Antihemophilic Globulin) Deficiency (Hemophilia) Factor IX (Plasma Thromboplastin Component) Deficiency (Christmas Disease; Hemophilia B) Factor X (Stuart-Prower) Deficiency Factor XI (Plasma Thromboplastin Antecedent) Deficiency Factor XII (Hageman Factor) Deficiency Factor XIII (Fibrin-Stabilizing Factor) Deficiency Glanzmann's Thrombasthenia HELLP Syndrome Hemorrhagic Disease of the Newborn Hemorrhagic Disorders, Classification Hypercoagulable State Hypofibrinogenemia, Congenital Purpura, Allergic Purpura, Idiopathic Thrombocytopenic (ITP; Werlhof's Disease), Immune Purpura, Nonthrombocytopenic Purpura, Thrombocytopenic Purpura, Thrombotic Thrombocytopenic (TTP); Hemolytic Uremic Syndrome Storage Pool Disease, Hereditary Thrombocytosis, Primary (Essential Thrombocythemia) Thrombocytosis, Reactive Transfusion of Blood von Willebrand's Disease HEMATOLOGIC LABORATORY TESTS BLOOD SMEAR—RED BLOOD CELLS (RBCs) See Fig. 11-1. Fig. 11-1. Sequence of laboratory tests for hemolytic anemia with normal Hb electrophoresis. (G-6-PD = glucose-6-phosphate dehydrogenase.) The smear may also confirm the RBC indices or indicate leukemia or other conditions. RBC Inclusions Basophilic or polychromatophilic macrocytes £ 15 in healthy persons. Increased erythropoiesis in hemorrhage or hemolysis. Called reticulocytes if supravital stain. Due to polyribosomes producing Hb. Increased MCV. Microcytes with stippling Thalassemia. Lead or heavy metal poisoning Cabot's rings Occasional in severe hemolytic anemias and PA Howell-Jolly bodies (dark purple spherical bodies) Megaloblastic anemia; thalassemia; hyposplenism; postsplenectomy state Pappenheimer bodies (siderotic granules) (purple coccoid granules at periphery) Anemias with defect of incorporating iron into Hb (e.g., sideroblastic anemia, thalassemia, lead poisoning, pyridoxine-unresponsive and pyridoxine-responsive anemias) Iron overload Heinz bodies* (precipitates of denatured Hb) Congenital G-6-PD deficiency Drug-induced hemolytic anemias (e.g., dapsone, phenacetin) Unstable Hb disorders after splenectomy Plasmodium trophozoites Malaria Reticulocytes* Reticulocytes
- 213. Abnormally Shaped RBCs Round Macrocytes Increased erythropoiesis (reticulocytosis) Round macrocytes Liver disease; alcoholism; postsplenectomy; hypothyroidism; increased MCV Oval (macro-ovalocytes) Megaloblastic anemia; cancer chemotherapy; myelodysplastic syndromes; increased MCV Microcytes Hypochromic anemias; decreased MCV Spherocytes Hereditary spherocytosis; immunohemolytic anemia; recent blood transfusion; usually decreased MCV, increased MCHC Stomatocytes Hereditary stomatocytosis Rh null disease Acute alcoholism (transient) Certain drugs (e.g., phenothiazines) Neoplastic, cardiovascular, hepatobiliary diseases Artifactual Target cells HbC disease or trait; HbD; HbE; HbS; thalassemia; iron-deficiency anemia; liver disease; postsplenectomy state; artifactual; decreased osmotic fragility Elongated Elliptocytes Hereditary (>25% in smear) Microcytic anemia (<25% in smear) Ovalocytes Megaloblastic anemia Teardrop (dacryocyte) Spent polycythemia Myelofibrosis Thalassemia (especially homozygous beta type) Sickle cells Sickle cell disorders (not in S trait) HbC crystalloids HbC trait or disease Spiculated Acanthocytes Abetalipoproteinemia (many are present) Postsplenectomy state (few are present) Fulminating liver disease (variable number) Burr cells (echinocytes; crenated RBCs) Usually artifactual; stomach cancer; GI bleeding; uremia; pyruvate kinase deficiency; hypophosphatemia; hypomagnesemia Schistocytes (helmet, triangle) Microangiopathic hemolytic anemia (e.g., DIC, thrombotic thrombocytopenic purpura [TTP]); prosthetic heart valves or severe valvular heart disease; severe burns; snakebite “Bite” cells Hemolysis, e.g., due to certain drugs with or without G-6-PD deficiency, unstable Hb RBC fragmentation (seen on peripheral blood smear >10/1000 RBCs] and on histogram of RBC size with automated cell counters) Cytotoxic chemotherapy for neoplasia; autoimmune hemolytic anemia; severe iron deficiency; megaloblastic anemia; acute leukemia; myelodysplasia; inherited structural abnormality of RBC membrane protein spectrin * Not seen with Wright's stain; requires supravital stain, e.g., cresyl violet. BLOOD VOLUME Blood volume determination is usually done using albumin tagged with iodine 125 ( 125 I) or 131 I; red cell mass may be measured by labeling RBCs with 51 Cr. Interferences In the presence of active hemorrhage, the isotope is lost via the bleeding site and a false value is produced. Use Differential diagnosis of polycythemia Radioisotopes should not be administered to children or pregnant women. BONE MARROW ASPIRATION Use When the Following Diagnoses Are Suspected Aplastic anemia, agranulocytosis Leukemia lymphomas Megaloblastic anemias Lipid storage diseases Metastatic cancer Multiple myeloma Waldenström's macroglobulinemia Idiopathic thrombocytopenic purpura (ITP) Hypersplenism Iron-deficiency anemia Indicated for diagnosis and for posttreatment follow-up of acute leukemia and cytopenia. BONE MARROW BIOPSY Use When the Following Diagnoses Are Suspected Disorders in which bone marrow aspiration is indicated (see previous section) Granulomatous diseases Amyloidosis
- 214. TTP Myelofibrosis—occurs in Agnogenic myeloid metaplasia Other myelodysplasias Hairy cell leukemia Metastatic carcinoma Miliary TB Granulomatous diseases Paget's disease Parathyroid disease After radiation therapy (e.g., for lymphoma) Benzene exposure Biopsy and aspirate are both required for staging carcinoma or lymphoma. COOMBS' (ANTIGLOBULIN) TEST Positive Direct Coombs ‘(Antiglobulin) Test Fig. 11-2. Fig. 11-2. Algorithm for workup of hemolytic anemia. (G-6-PD = glucose-6-phosphate dehydrogenase.) Use Detects immunoglobulin antibodies and/or complement on patient's RBC membrane (e.g., autoimmune hemolysis, hemolytic disease of newborn, drug-induced hemolysis, transfusion reactions) Interferences False-positive may occur in multiple myeloma and Waldenström's macroglobulinemia. Positive In Erythroblastosis fetalis Most cases of autoimmune hemolytic anemia, including £15% of certain systemic diseases, especially acute and chronic leukemias, malignant lymphomas, collagen diseases. Strength of reaction may be of prognostic value in patients with lymphoproliferative disorders. Delayed hemolytic transfusion reaction Drug induced, e.g., Alpha methyldopa (occurs in £30% of patients on continued therapy but <1% show hemolysis); rarely in first 6 mos of treatment. If not found within 12 mos, is unlikely to occur. Is dose related, with lowest incidence in patients receiving £1 gm daily. Reversal may take weeks to months after the drug is discontinued. L-dopa Others, e.g., acetophenetidin, ethosuximide, cephalosporins (most common with cephalothin; less frequent with cefazolin and cephapirin; reported in 3–50% of patients), mefenamic acid, penicillin (with daily IV dose of 20 million U/day for several weeks), procainamide, quinidine, quinine. Healthy blood donors (1 in 4000 to 1 in 8000 persons) May be weakly positive in renal disease, epithelial malignancies, RA, inflammatory bowel diseases. Weakly positive reactions are not usually clinically significant. Negative In Hemolytic anemias due to intrinsic defect in RBC (e.g., G-6-PD deficiency, hemoglobinopathies) 2–9% of patients with hemolytic anemia (due to smaller amount of IgG bound to RBC but similar response to splenectomy or steroid therapy or to IgM, IgA, or IgD rather than IgG). This is a diagnosis of exclusion. Positive Indirect Coombs' Test (Using patient's serum, which contains antibody) Use Cross matching for blood transfusion Detect and identify antibodies Specific antibody—usually isoimmunization from previous transfusion
- 215. “Nonspecific” autoantibody in acquired hemolytic anemia RBC phenotyping In genetic and forensic medicine To identify syngeneic twins for bone marrow transplantation Interferences Beware of false-positive and false-negative results due to poor-quality test serum, failure to use fresh blood (must have complement), etc. ERYTHROPOIETIN, PLASMA (Normal = 3.7–16.0 U/L by RIA) Use Differential diagnosis of polycythemia vera Indicator of need for erythropoietin therapy in patients with renal failure Interferences Decreased by high plasma viscosity, use of estrogens, beta-adrenergic blockers, agents that increase renal blood flow (e.g., enalapril, an inhibitor of angiotensin-converting enzyme) Circadian rhythm in hospitalized adults, with lowest values at 0800–1200 and 40% higher values in late evening. Increased Appropriately* In Extremely high: usually transfusion-dependent anemia with Hct = 10–25% and Hb = 3–7 gm/dL; e.g., aplastic anemia, severe hemolytic anemia, hematologic cancers Very high: patients have mild to moderate anemia with Hct = 25–40% or Hb = 7–12 gm/dL High: patients are more anemic, e.g., hemolytic anemia, myelodysplasia, exposure to chemotherapeutic or immunosuppressive drugs, AIDS Increased Inappropriately* In Some renal disorders Renal cysts Postrenal transplant Malignant neoplasms Renal adenocarcinoma (1–5% of cases) Juxtaglomerular cell tumor Nephroblastoma (Wilms' tumor) Hepatocellular carcinoma, or hemangiosarcoma Testicular carcinoma Malignant pheochromocytoma Breast carcinoma Nonmalignant neoplasms Meningioma Hemangioblastoma of brain (20% of cases), liver, or adrenal gland Leiomyoma of uterus Decreased Inappropriately* In Renal failure Autonomic neuropathy AIDS before zidovudine therapy Weeks 3 and 4 after bone marrow transplant Polycythemia vera Decreased Appropriately* In *Erythropoietin is normally inversely related to RBC volume, Hb, or Hct. Renal failure, RA, multiple myeloma, cancer FERRITIN, SERUM See Table 11-1, Table 11-9 and Table 11-10.
- 216. Table 11-1. Comparison of Iron-Deficiency Anemia Alone and Combined with Thalasemia Minor or Anemia of Chronic Disease Table 11-9. Laboratory Tests in Differential Diagnosis of Microcytic (MCV <80 fL) and Hypochromic (MCHC <30 gm/dL) Anemias Table 11-10. Comparison of Sample Values in Iron-Deficiency States Use Diagnosis of iron deficiency or excess; correlates with total body iron stores. Chief iron-storage protein in the body. Predict and monitor iron deficiency Determine response to iron therapy or compliance with treatment Differentiate iron deficiency from chronic disease as cause of anemia Monitor iron status in patients with chronic renal disease with or without dialysis Detect iron overload states and monitor rate of iron accumulation and response to iron-depletion therapy Population studies of iron levels and response to iron supplement Decreased In Iron deficiency. Is most sensitive and specific test for iron deficiency if MCV is not increased (e.g., pregnancy, infancy, polycythemia) or no vitamin C deficiency is present. Decreases before anemia and other changes occur. No other condition causes a low level. Returns to normal range within few days after onset of oral iron therapy; failure to produce serum ferritin level >50 ng/mL suggests noncompliance or continued iron loss. <18 ng/mL is associated with absent stainable iron in marrow. <12 ng/mL always indicates iron deficiency and no longer corresponds to severity of deficiency because iron stores are essentially exhausted. >80 ng/mL essentially excludes iron deficiency. Increased In Ferritin is an acute-phase reactant and thus is increased in many patients with various acute and chronic liver diseases, alcoholism (declines during abstinence), malignancies (e.g., leukemia, Hodgkin's disease), infection and inflammation (e.g., arthritis), hyperthyroidism, Gaucher's disease, AMI, etc. Serum ferritin may not be decreased when iron deficiency coexists with these conditions; in such cases, bone marrow stain for iron may be the only way to detect the iron deficiency. Iron overload (e.g., hemosiderosis, idiopathic hemochromatosis). Can be used to monitor therapeutic removal of excess storage iron. Transferrin saturation is more sensitive to detect early iron overload in hemochromatosis; serum ferritin is used to confirm diagnosis and as indication to proceed with liver biopsy. Ratio of serum ferritin (in ng/mL) to ALT (in U/L) >10 in iron-overloaded thalassemic patients but averages £2 in patients with viral hepatitis; ratio decreases with successful iron chelation therapy. Anemias other than iron deficiency (e.g., megaloblastic, hemolytic, sideroblastic, thalassemia major and minor, spherocytosis, porphyria cutanea tarda) Renal cell carcinoma due to hemorrhage within tumor End-stage renal disease; values ³1000 µg/L are not uncommon. Values <200 µg/L are specific for iron deficiency in these patients. Increases with age; is higher in men than in women, in women who use oral contraceptives, in persons who eat red meat compared with vegetarians.
- 217. FLOW CYTOMETRY Use Diagnosis of leukemias, myelodysplasia, and lymphomas by immunophenotyping Diagnosis of DNA content and DNA synthetic activity of tumors Enumeration of lymphocyte subsets (e.g., CD4+ T cells as surrogate marker for disease progression in AIDS) Stem cell (counting) transplantation Measurement of cell-bound antibody and sorting of subpopulations that differ in amount of bound antibody Use of anti-HbF monoclonal antibodies to detect HbF (can detect <0.05% fetal RBCs) More accurate than Kleihauer-Betke stain for quantitation of fetal-maternal hemorrhage Detect increased number of RBCs containing decreased HbF (“F” cells) in patients with hemoglobinopathies, some patients with myelodysplasia Reticulocyte counting HLA-B27 determination Mitogen stimulation evaluation Neutrophil function studies (e.g., phagocytosis, oxidative burst) GENE REARRANGEMENT (bcr) ASSAY wPCR has replaced Southern blot hybridization as preferred (more sensitive and specific) method to demonstrate reciprocal translocation of DNA from chromosome 9 (including the abl locus) to 22 (breakpoint cluster [ bcrs]), giving rise to shorter chromosome 22 (Ph1 ). bcr gene rearrangement is molecular equivalent of Ph1 translocation. Can be done on peripheral blood as well as marrow and is more sensitive than routine cytogenetic analysis. Use To diagnose Ph1 -negative cases (5% of CML patients) or to confirm Ph1 -positive CML To diagnose CML patients who present in blast crisis or are in blast transformation To rule out CML in myeloproliferative disorders with similar morphologic features To monitor CML patients treated with marrow transplant, chemotherapy, or interferon To detect minimal-residual disease To confirm complete remission To provide early detection of relapse To purge bcr-positive cells from autologous bone marrow before infusion Positive bcr gene rearrangement in acute leukemia indicates poor prognosis, especially in ALLs. Finding of same gene rearrangement in lymphocytes in a distant site biopsy is proof of metastasis. To diagnose many genetic disorders (e.g., HbS, HbC, beta thalassemias). Interferences False-negative PCR in Ph1 -positive patients may occur due to therapy with interferon alpha or, less commonly, with hydroxyurea. Contamination of PCR material. Interpretation Found in 95% of patients with CML, 5–10% of patients with ALL, and 1–2% of patients with acute myelogenous leukemia (AML). This rearrangement of bcr is typical of Ph1 -positive chronic myelogenous leukemia patients and is found in ~30% of Ph 1 -positive AML patients. GENE REARRANGEMENT ASSAY FOR IMMUNOGLOBULIN HEAVY (IGH) AND LIGHT (IGL-KAPPA) CHAINS AND GENE REARRANGEMENT ASSAY FOR BETA AND GAMMA T-CELL RECEPTOR Use Allows classification of almost all cases of ALL as T, B, or pre-B types. Used to confirm pathologic-immunologic diagnoses of T-cell and B-cell lymphomas that are difficult to classify. Interpretation Virtually all cases of non-T, non-B leukemias are recognized as pre-B types. £90% of cases of non-Hodgkin's lymphoma are derived from B cells. Their immunophenotypic abnormalities can be used to distinguish them from benign reactions in lymph nodes. GENETIC HEMATOLOGIC DISEASES, MOLECULAR DIAGNOSIS
- 218. RBC disorders Hereditary spherocytosis Hereditary pyropoikilocytosis Hereditary nonspherocytic hemolytic anemia—pyruvate kinase deficiency Hemolytic anemia—G-6-PD deficiency Porphyrias Hemoglobinopathies Sickle cell anemia HbC, HbSC, HbE, HbD diseases Beta- and alpha-thalassemias Hereditary persistence of HbF Hemoglobinopathies with unstable hemoglobins Neutrophil disorders Chronic granulomatous disease Myeloperoxidase deficiency Glutathione reductase and synthetase deficiencies Coagulation disorders Hemophilia A and B von Willebrand's disease Inherited resistance to activated protein C HAPTOGLOBINS, SERUM Use Indicator of chronic hemolysis (e.g., hereditary spherocytosis, pyruvate kinase deficiency). Such patients should not have splenectomy when serum haptoglobin is >40 mg/dL if infection and inflammation have been ruled out. After splenectomy, increased haptoglobin level indicates success of surgery for these conditions, e.g., haptoglobin reappears at 24 hrs and becomes normal in 4–6 days in hereditary spherocytosis patients treated with splenectomy. Diagnosis of transfusion reaction by comparison of concentrations in pretransfusion and posttransfusion samples. Posttransfusion reaction serum haptoglobin level decreases in 6–8 hrs; at 24 hrs it is <40 mg/dL or <40% of pretransfusion level. In paternity studies, may aid by determination of haptoglobin phenotypes. Increased In Conditions associated with increased ESR and alpha2 globulin (haptoglobin is also an acute-phase reactant) (e.g., infection, inflammation, trauma, necrosis of tissue, scurvy, amyloidosis, nephrotic syndrome, disseminated neoplasms such as Hodgkin's disease, lymphosarcoma, collagen diseases such as rheumatic fever, RA, and dermatomyositis). Thus these conditions may mask presence of concomitant hemolysis. One-third of patients with obstructive biliary disease Therapy with steroids or androgens Aplastic anemia (normal to very high) Diabetes mellitus Decreased or Absent In Hemoglobinemia (related to the duration and severity of hemolysis) due to Intravascular hemolysis (e.g., hereditary spherocytosis with marked hemolysis, pyruvate kinase deficiency, autoimmune hemolytic anemia, some transfusion reactions) Extravascular hemolysis (e.g., large retroperitoneal hemorrhage) Intramedullary hemolysis (e.g., thalassemia, megaloblastic anemias, sideroblastic anemias) Genetically absent in 1% of general population Parenchymatous liver disease (especially cirrhosis) Protein loss via kidney, GI tract, skin Infancy HEMOGLOBIN, FETAL (HbF) (Alkali denaturation method; confirmed by examination of Hb bands on electrophoresis) Normal >50% at birth; gradual decrease to ~5% by age 5 mos <2% older than age 2 years Use Diagnosis of various hemoglobinopathies
- 219. Increased In Various hemoglobinopathies (see Table 11-26 and Table 11-27). ~50% of patients with beta-thalassemia minor have high levels of HbF; even higher levels are found in virtually all patients with beta-thalassemia major. In sickle cell disease, HbF >30% protects the cell from sickling; therefore, even infants with homozygous HbS have few problems before age 3 mos. Table 11-26. Representative Laboratory Values of Some Common Hemoglobinopathies Table 11-27. Classification of Beta-Thalassemia Syndromes Hereditary persistence of HbF Nonhereditary refractory normoblastic anemia (one-third of patients) PA (50% of untreated patients); increases after treatment and then gradually decreases during next 6 mos; some patients still have slight elevation thereafter. Minimal elevation occurs in ~5% of patients with other types of megaloblastic anemia. Some patients with leukemia, especially juvenile myeloid leukemia with HbF of 30–60%, absence of Ph 1 , rapid fatal course, more pronounced thrombocytopenia, and lower total WBC count Multiple myeloma Molar pregnancy Patients with an extra D chromosome (trisomy 13-15, D1 trisomy) or an extra G chromosome (trisomy 21, Down syndrome, mongolism) Acquired aplastic anemia (due to drugs, toxic chemicals, or infections, or idiopathic); returns to normal only after complete remission and therefore is reliable indicator of complete recovery. Better prognosis in patients with higher initial level. Some chronic viral infections (e.g., CMV, EBV) Decreased In A rare case of multiple chromosome abnormalities (probably C/D translocation) HEMOGLOBIN, SERUM (Normal level = <10 mg/dL; visible level = ~20 mg/dL; <30 mg/dL is not accurate technically; >150 mg/dL causes hemoglobinuria; >200 mg/dL gives clear cherry red color to serum) Use Increase indicates intravascular hemolysis. Slight Increase In Sickle cell thalassemia HbC disease Moderate Increase In Sickle cell–HbC disease Sickle cell anemia Thalassemia major
- 220. Acquired (autoimmune) hemolytic anemia Marked Increase In Any rapid intravascular hemolysis Iron, Radioactive (59 Fe), RBC Uptake 59 Fe is injected IV, and blood samples are drawn in 3, 7, and 14 days for measurement of radioactivity. Use Study of kinetics of iron metabolism Decreased In Pure red cell aplasia—the rate of uptake of 59 Fe is markedly decreased. IRON, SERUM Use Differential diagnosis of anemias Diagnosis of hemochromatosis and hemosiderosis Should always be measured with TIBC for evaluation of iron deficiency. Diagnosis of acute iron toxicity Interferences Falsely increased by hemolysis, iron contamination of glassware Falsely decreased in lipemic specimens Iron dextran administration causes increase for several weeks (may be >1000 µg/dL) Increased In Idiopathic hemochromatosis Hemosiderosis of excessive iron intake (e.g., repeated blood transfusions, iron therapy, use of iron-containing vitamins) (may be >300 µg/dL) Decreased formation of RBCs (e.g., thalassemia, pyridoxine-deficiency anemia, PA in relapse) Increased destruction of RBCs (e.g., hemolytic anemias) Acute liver damage (degree of increase parallels the amount of hepatic necrosis) (may be >1000 µg/dL); some cases of chronic liver disease Use of progesterone birth control pills (may be >200 µg/dL) and pregnancy Premenstrual elevation 10–30% Acute iron toxicity; ratio of serum iron/TIBC not useful for this diagnosis. Decreased In Iron-deficiency anemia Normochromic (normocytic or microcytic) anemias of infection and chronic diseases (e.g., neoplasms, active collagen diseases) Nephrosis (due to loss of iron-binding protein in urine) PA at onset of remission Menstruation (decreased 10–30%) Diurnal variation—normal values in midmorning, low values in midafternoon, very low values (~10 µg/dL) near midnight. Diurnal variation disappears at levels <45 µg/dL. IRON (HEMOSIDERIN), STAINABLE, IN BONE MARROW (Present in RE cells and developing normoblasts [sideroblasts]) Use Is the gold standard for diagnosis of iron deficiency; its presence almost invariably rules out iron-deficiency anemia. Marrow iron disappears before the peripheral blood changes. Only individuals with decreased marrow iron are likely to benefit from iron therapy. Diagnosis of iron overload. Interferences May be normal or increased by injections of iron dextran (which is used very slowly) despite other evidence of iron-deficiency anemia.
- 221. Increased In Idiopathic hemochromatosis Hemochromatosis secondary to Increased intake (e.g., Bantu siderosis, excessive medicine ingestion). Anemias with increased erythropoiesis (especially thalassemia major; also thalassemia minor, some other hemoglobinopathies, paroxysmal nocturnal hemoglobinuria, ‘sideroachrestic' anemias, refractory anemias with hypercellular bone marrow, etc.). In hemolytic anemias, decrease or absence may signify acute hemolytic crisis. Liver injury (e.g., after portal shunt surgery). Atransferrinemia. Megaloblastic anemias in relapse Uremia (some patients) Chronic infection (some patients) Chronic pancreatic insufficiency Decreased In Iron deficiency (e.g., inadequate dietary intake, chronic bleeding, malignancy, acute blood loss). Rapidly disappears after hemorrhage. Polycythemia vera (usually absent in polycythemia vera but usually normal or increased in secondary polycythemia) PA in early phase of therapy Collagen diseases (especially RA, SLE) Infiltration of marrow (e.g., malignant lymphomas, metastatic carcinoma, myelofibrosis, miliary granulomas) Uremia Chronic infection (e.g., pulmonary TB, bronchiectasis, chronic pyelonephritis) Miscellaneous conditions (e.g., old age, diabetes mellitus) Myeloproliferative diseases–iron stores may be absent without other evidence of iron deficiency. Serum iron and TIBC may be normal in iron-deficiency anemia, especially if Hb is <9 gm/dL. IRON-BINDING CAPACITY, TOTAL (TIBC), SERUM (TIBC [µmol/L] = transferrin [mg/L] × 0.025) Unsaturated iron-binding capacity = TIBC – serum iron (µg/dL). Use Differential diagnosis of anemias Should always be performed whenever serum iron is measured to calculate percent saturation. Increased In Iron deficiency Acute and chronic blood loss Acute liver damage Late pregnancy Use of progesterone birth control pills Decreased In Hemochromatosis Cirrhosis of the liver Thalassemia Anemias of infection and chronic diseases (e.g., uremia, RA, some neoplasms) Nephrosis Hyperthyroidism KLEIHAUER-BETKE TEST (Acid-eluted stained smear of maternal blood shows pale maternal RBCs but pink fetal RBCs. Detects HbF. Quantitates amount [in mL] of fetal blood in maternal circulation. Normal <1%. Now measured more accurately by flow cytometry with anti-HbF antibodies.)
- 222. Use In Rh-negative women with Rh-positive fetuses to determine need for and dose of RhIg, especially in presence of blunt abdominal trauma, invasive procedures (e.g., chorionic villus biopsy), placenta previa, abruptio placenta. (See Hemolytic Disease of the Newborn.) Interferences False-positive in hemoglobinopathies (SS, SA, hereditary persistence of HbF) HbF increases in pregnancy in £25% of women. LEUKOCYTE ALKALINE PHOSPHATASE (LAP) STAINING REACTION (In untreated diseases) Use Differentiation of chronic myelogenous leukemia from leukemoid reaction Usually Increased In Leukemoid reaction Polycythemia vera Essential thrombocythemia (may be normal) Lymphoma (including Hodgkin's lymphoma, reticulum cell sarcoma) Acute and chronic lymphatic leukemia Multiple myeloma Myeloid metaplasia Aplastic anemia Agranulocytosis Bacterial infections Cirrhosis Obstructive jaundice Pregnancy and immediate postpartum period Administration of Enovid (mestranol and norethynodrel) Trisomy 21 Klinefelter's syndrome (XXY) Usually Decreased In Chronic myelogenous leukemia Paroxysmal nocturnal hemoglobinuria Hereditary hypophosphatasia Nephrotic syndrome Progressive muscular dystrophy Refractory anemia (siderotic) Sickle cell anemia Usually Normal In Secondary polycythemia Hemolytic anemia Infectious mononucleosis Viral hepatitis Lymphosarcoma Variable In PA
- 223. ITP Iron-deficiency anemia AML and idiopathic myelofibrosis Acute undifferentiated leukemia MEAN CORPUSCULAR HEMOGLOBIN (MCH) (Hb divided by RBC count) Use Limited value in differential diagnosis of anemias Instrument calibration Interferences (Increased In) Marked leukocytosis (>50,000/cu mm) Cold agglutinins In vivo hemolysis Monoclonal proteins in blood High heparin concentration Lipemia Decreased In Microcytic and normocytic anemias Increased In Macrocytic anemias Infants and newborns MEAN CORPUSCULAR HEMOGLOBIN CONCENTRATION (MCHC) (Hb divided by Hct) Use For laboratory quality control, chiefly because changes occur very late in the course of iron deficiency when anemia is severe. Instrument calibration Interferences (With automated cell counters) Decreased Marked leukocytosis (>50,000/cu mm) Increased Hemolysis (e.g., sickle cell anemia, hereditary spherocytosis, some cases of autoimmune hemolytic anemia) with shrinkage of RBCs, making them hyperdense Conditions with cold agglutinins or severe lipemia of serum Rouleaux or RBC agglutinates High heparin concentration Decreased In (<30.1 gm/dL) Hypochromic anemias. Normal value does not rule out any of these anemias. Low MCHC may not occur in iron-deficiency anemia when measured with automated instruments. Increased In Only in hereditary spherocytosis; should be suspected whenever MCHC is >36 gm/dL. Infants and newborns Not increased in PA.
- 224. MEAN CORPUSCULAR VOLUME (MCV) (Hct divided by RBC count with manual methods; measured directly by automated instruments) See Fig. 11-3, Table 11-2 and Table 11-3. Fig. 11-3. Sequence of laboratory tests in workup of anemia. This algorithm is meant only to illustrate the use of indices for preliminary classification of anemias; many of the subsequent steps in the diagnostic workup are not included. Note also that some conditions may appear in more than one category. (DIC = disseminated intravascular coagulation; G-6-PD = glucose-6-phosphate dehydrogenase.) (Adapted from Wintrobe M, et al. Clinical hematology. Philadelphia: Lea & Febiger, 1974.) Table 11-2. Red Blood Cell Indicesa Table 11-3. Classification of Red Blood Cell (RBC) Disorders by Mean Corpuscular Volume (MCV) and Red Cell Distribution Width (RDW) Use Classification and differential diagnosis of anemias Useful screening test for occult alcoholism Interferences Marked leukocytosis (>50,000/cu mm) (increased values) In vitro hemolysis or fragmentation of RBCs (decreased values) Warm autoantibodies Cold agglutinins (increased values) Methanol poisoning (increased values) Marked hyperglycemia (>600 mg/dL) (increased values) Marked reticulocytosis (>50%) due to any cause (increased values) Presence of microcytic and macrocytic cells in same sample may result in a normal MCV. Increased In Macrocytic anemias (MCV >95 fL and often >110 fL; MCHC >30 gm/dL) Megaloblastic anemia PA (vitamin B12 or folate deficiency) Sprue (e.g., steatorrhea, celiac disease, intestinal resection or fistula)
- 225. Macrocytic anemia of pregnancy Megaloblastic anemia of infancy Fish tapeworm infestation Carcinoma of stomach, after total gastrectomy Drugs, e.g., Oral contraceptives Anticonvulsants (e.g., phenytoin, primidone, phenobarbital) Antitumor agents (e.g., methotrexate, hydroxyurea, cyclophosphamide) Antimicrobials (e.g., sulfamethoxazole, sulfasalazine, trimethoprim, zidovudine, pyrimethamine) Orotic aciduria Di Guglielmo's disease Nonmegaloblastic macrocytic anemias; are usually normocytic (MCV usually <110 fL). Alcoholism Liver disease Anemia of hypothyroidism Accelerated erythropoiesis (some hemolytic anemias, posthemorrhage) Myelodysplastic syndromes (aplastic anemia, acquired sideroblastic anemia) Myelophthisic anemia Postsplenectomy Infants and newborns Normal In Normocytic anemias (MCV = 80–94 fL; MCHC >30 gm/dL) After acute hemorrhage Some hemolytic anemias Some hemoglobinopathies Anemias due to inadequate blood formation Myelophthisic Hypoplastic Aplastic Endocrinopathies (hypopituitarism, hypothyroidism, hypoadrenalism, hypogonadism) Anemia of chronic disease (chronic infections, neoplasms, uremia) Decreased In Microcytic anemias (MCV <80 fL; MCHC <30 gm/dL) Usually hypochromic Iron-deficiency anemia, e.g., Inadequate intake Poor absorption Excessive iron requirements Chronic blood loss Pyridoxine-responsive anemia Thalassemia (major or combined with hemoglobinopathy) Sideroblastic anemia (hereditary) Lead poisoning Anemia of chronic diseases (less than one-third of patients) Usually normocytic Anemia of chronic diseases Hemoglobinopathies Low MCV due to (in decreasing order of frequency) iron deficiency, alpha-thalassemia, heterozygous beta-thalassemias, chronic disease, abnormal HbC and HbE. NEUTROPHIL FUNCTION TESTS Morphology Light, phase, and electron microscopy (e.g., Chédiak-Higashi syndrome) Adherence To glass or spreading Aggregometer Flow cytometry–anti-CD18 and anti-sialyl-Lewis X positive Locomotion Random Chemotaxis Serum deficiencies (e.g., complement, immunoglobulins) Cell defects (e.g., hyperimmunoglobulinemia E, Chédiak-Higashi syndrome, Kartagener's syndrome, drugs, diabetes mellitus, uremia, etc.) Phagocytosis Uptake of latex beads, microorganisms Assay hexose monophosphate shunt Secretion Assay lysosome enzymes, lactoferrin B12-binding protein Bactericidal activity Nitroblue tetrazolium test (see following section) Killing of bacteria (e.g., Staphylococcus aureus)
- 226. Oxygen radical production (e.g., chronic granulomatous disease, G-6-PD deficiency) NITROBLUE TETRAZOLIUM REDUCTION IN NEUTROPHILS (Usual normal values reported are <10%, but considerable variation exists, and each laboratory should establish its own normal range.) Use Diagnosis of poor neutrophilic function (failure of nitroblue tetrazolium reduction), particularly in chronic granulomatous disease. Prenatal diagnosis is possible with fetal blood from placental vessels. Differentiating untreated bacterial infection from other conditions; rarely used. Increased In Bacterial infections, including miliary TB and tuberculous meningitis Nocardia and other systemic fungal infections Various parasitic infections (e.g., malaria) Chédiak-Higashi syndrome Idiopathic myelofibrosis Normal infants up to age 2 mos Pregnant women Patients taking birth control pills Some patients with lymphoma suppressed by chemotherapy Decreased or Normal (In absence of bacterial infection) Healthy persons Postpartum state Postoperative state (after 7–10 days) Cancer Tissue transplantation Other conditions with fever or leukocytosis not due to bacterial infection (e.g., RA) Decreased or Normal (In presence of bacterial infection) Antibiotic therapy–effectiveness of treatment indicated by reduction of previous elevation, sometimes in <6 hrs Localized infection Administration of corticosteroids and immunosuppressive drugs (contrary findings with corticosteroids have also been reported) Miscellaneous conditions, probably involving metabolic defects of neutrophil function Chronic granulomatous disease Neutrophilic deficiency of G-6-PD or myeloperoxidase SLE Sickle cell disease Chronic myelogenous leukemia Lipochrome histiocytosis Congenital and acquired agammaglobulinemia Other Increased (From previously determined normal level) Has been used to monitor development of infection in chronically ill patients; may increase before other clinical parameters change. Development of wound sepsis in burn patients Development of infection in uremic patients on chronic hemodialysis OSMOTIC FRAGILITY Use Diagnosis of hereditary spherocytic anemia Increased In
- 227. Hereditary spherocytic anemia (can be ruled out if a normal fragility is seen after 24-hr sterile incubation) Hereditary nonspherocytic hemolytic anemia Acquired hemolytic anemia (usually normal in paroxysmal nocturnal hemoglobinuria) Hemolytic disease of newborn due to ABO incompatibility Some cases of secondary hemolytic anemia (usually normal) After thermal injury Symptomatic hemolytic anemia in some cases of Malignant lymphoma Leukemia Carcinoma Pregnancy Cirrhosis Infection (e.g., TB, malaria, syphilis) Decreased In Early infancy Iron-deficiency anemia Thalassemia Sickle cell anemia Homozygous HbC disease Nutritional megaloblastic anemia Postsplenectomy Liver disease Jaundice PROTOPORPHYRIN, FREE ERYTHROCYTE (FEP) (Normal <100 µg/dL packed RBCs) Use Screening for lead poisoning and for iron deficiency Increased In Iron deficiency (even before anemia; thus is an early sensitive sign, useful for screening). Range 100–1000 µg/dL; average ~200 µg/dL. Chronic lead poisoning Most sideroblastic anemias (e.g., acquired idiopathic) Anemia of chronic diseases Normal or Decreased In Primary disorders of globin synthesis, e.g., Thalassemia minor (therefore useful to differentiate from iron deficiency) Pyridoxine-responsive anemia One form of sideroblastic anemia due to block proximal to protoporphyrin synthesis RBC INDICES See Table 11-2 and Fig. 11-3. Use Classification and differential diagnosis of anemias RBC SURVIVAL (51 CR) Use Confirm decreased RBC survival in various disorders affecting RBCs Increased In
- 228. Thalassemia minor In pure red cell anemia, one-half of the plasma radioactivity may not disappear for 7–8 hrs. In the healthy person, one-half of the radioactivity of plasma disappears in 1–2 hrs. Decreased In Idiopathic acquired hemolytic anemia Paroxysmal nocturnal hemoglobinuria Association with chronic lymphatic leukemia Association with uremia Congenital nonspherocytic hemolytic anemia Hereditary spherocytosis Elliptocytosis with hemolysis HbC disease Sickle cell–HbC disease Sickle cell anemia PA Megaloblastic anemia of pregnancy Normal In Sickle cell trait HbC trait Elliptocytosis without hemolysis or anemia RED CELL DISTRIBUTION WIDTH (RDW) (Normal = 11.5–14.5. No subnormal values have been reported.) Is coefficient of variation of the RBC size as determined by some newer automated blood cell counting instruments. Is quantitative measure of anisocytosis. Use Classification of anemias based on MCV and RDW is most useful to distinguish iron-deficiency anemia from that of chronic disease or heterozygous thalassemia and to improve detection of early iron or folate deficiency. RDW is more sensitive in microcytic than in macrocytic RBC conditions. Not helpful for patients without anemia. Hb distribution width and cell Hb distribution width are two other indices of RBC heterogeneity that can be obtained from newer hematology analyzers; may be useful for further segregation of thalassemic traits. Classification of RBC Disorders by MCV and RDW See Table 11-3. RETICULOCYTE COUNT Use Diagnosis of ineffective erythropoiesis or decreased RBC formation. Increase indicates effective RBC production. Index of therapeutic response to iron, folate, or vitamin B 12 therapy and to blood loss. Monitor treatment response after bone marrow suppression and transplantation. Monitor response to erythropoietin therapy. Increased In After blood loss or increased RBC destruction: normal increase is 3–6×. After iron therapy for iron-deficiency anemia. After specific therapy for megaloblastic anemias. Possibly other hematologic conditions (e.g., polycythemia, metastatic carcinoma in bone marrow, Di Guglielmo's disease).
- 229. Decreased In Ineffective erythropoiesis or decreased RBC formation Severe autoimmune type of hemolytic disease Aregenerative crises Megaloblastic disorders Alcoholism Myxedema Reticulocyte index corrects count for degree of anemia: Reticulocyte index = reticulocyte count × (patient's Hct)/45 × 1/1.85 (45 is assumed normal Hct; 1.85 is number of days required for reticulocyte to mature into an RBC) Reticulocyte index <2% indicates hypoproliferative component to anemia. Reticulocyte index >2–3% indicates increased RBC production. RETICULOCYTE HEMOGLOBIN1 (Absolute reticulocyte count multiplied by reticulocyte Hb content; in gm/L) RBC Hb = total Hb minus reticulocyte Hb Use Ratio of RBC Hb to reticulocyte Hb is a rough estimate of RBC survival and severity of hemolysis. Interpretation Normal = 55–98 SS disease = 5.7–13.9 SS disease (with three normal genes) = 6.1–26.3 SS disease (with two normal genes) = 9.7–19.7 SC disease (no alpha genes) = 19–54 RETICULOCYTE HEMOGLOBIN CONTENT2 (Performed using automated hematology analyzer) Use These are preliminary reports that require further study May be useful for diagnosis of iron deficiency and iron-deficiency anemia Early indicator (within 2 wks) of response to iron therapy in cases of iron-deficiency anemia Decreased In Iron deficiency Alpha- and beta-thalassemia Interpretation Normal = 55–98 TRANSFERRIN, SERUM See Table 11-10. Use Differential diagnosis of anemias Increased In Iron-deficiency anemia Pregnancy, estrogen therapy, hyperestrogenism Decreased In Hypochromic microcytic anemia of chronic disease Acute inflammation
- 230. Protein deficiency or loss, e.g., Thermal burns Chronic infections Chronic diseases (e.g., various liver and kidney diseases, neoplasms) Nephrosis Malnutrition Genetic deficiency TRANSFERRIN RECEPTOR, SERUM (Transmembrane proteins present on surface of most cells; reference range = 0.57–2.8 µg/L; varies with assay system; higher in blacks.) Use Differential diagnosis of microcytic anemias; increased in iron-deficiency anemias but not increased in anemia of chronic disease Diagnosis of iron deficiency in patients with chronic disease ( Table 11-10) Distinguish iron-deficiency erythropoiesis (iron-deficiency anemia) from physiologic depletion of iron stores (e.g., in pregnancy, childhood, adolescence) >20% increase over baseline within 2 wks of starting or increasing erythropoietin therapy predicts response to that dosage and indicates that Hb response is likely to follow. Evaluation of anemias when ferritin values may be increased to normal range due to acute-phase reaction if other causes of increased erythropoiesis are ruled out Increased In Disorders with hyperplastic erythropoiesis (e.g., iron-deficiency anemias, hemolytic anemias) Disorders with ineffective erythropoiesis (e.g., myelodysplastic syndromes, megaloblastic anemias) Persons living at high altitude Erythropoietin therapy Decreased In Disorders with reduced erythropoiesis (e.g., aplastic anemia, after bone marrow ablation for stem cell transplantation) Iron overload disorders TRANSFERRIN SATURATION, SERUM (Serum iron divided by TIBC; normal ³16%) Use Differential diagnosis of anemias Screening for hereditary hemochromatosis Increased In Hemochromatosis Hemosiderosis Thalassemia Use of progesterone birth control pills (£75%) Ingestion of iron (£100%) Iron dextran administration causes increase for several weeks (may be >100%). Decreased In Iron-deficiency anemia (usually <10% in established deficiency) Anemias of infection and chronic diseases (e.g., uremia, RA, some neoplasms) VITAMIN B12-BINDING CAPACITY, UNSATURATED (Normal range = 870–1800 ng/L) Use Minor criterion in diagnosis of polycythemia vera
- 231. Increased In Myeloproliferative diseases (especially polycythemia vera and CML) Pregnancy Use of oral contraceptive drugs Decreased In Hepatitis and cirrhosis WHITE BLOOD CELL (WBC) DIFFERENTIAL COUNT Use Diagnosis of myeloproliferative disorders, myelodysplasias, various other hematologic disorders Support diagnosis of various infections and inflammation Is often ordered inappropriately and has almost no value as a screening test. The neutrophil and band counts may be useful in acute appendicitis and neonatal sepsis with moderate sensitivity and specificity. Interferences Associated with automated WBC counters (artifact is corrected when manual WBC counts are performed) Leukocyte fragility due to immunosuppressive and antineoplastic drugs Lymphocyte fragility in lymphocytic leukemia Excessive clumping of leukocytes in monoclonal gammopathies (e.g., multiple myeloma), cryofibrinogenemia (e.g., SLE), in presence of cold agglutinins Causes of Neutropenia/Leukopenia See Fig. 11-4. Fig. 11-4. Algorithm for causes of neutropenia. (Absolute neutrophil count [total WBC × % segmented neutrophils and bands] <1800/cu mm; <1000 in blacks.) Decreased/ineffective production Infections, especially Bacterial (e.g., overwhelming bacterial infection, septicemia, miliary TB, typhoid, paratyphoid, brucellosis, tularemia) Viral (e.g., infectious mononucleosis, hepatitis, influenza, measles, rubella, psittacosis) Rickettsial (e.g., scrub typhus, sandfly fever) Other (e.g., malaria, kala-azar) Drugs and chemicals, especially Sulfonamides Antibiotics Analgesics Marrow depressants Arsenicals Antithyroid drugs Many others Ionizing radiation Hematopoietic diseases Folic acid and vitamin B12 deficiency Aleukemic leukemia Aplastic anemia Myelophthisis Decreased survival Felty's syndrome SLE Autoimmune and isoimmune neutropenias Splenic sequestration Drugs Abnormal distribution Hypersplenism
- 232. Miscellaneous Severe renal injury Neonatal and Infantile Causes (Neutrophil count <5000/cu mm during first few days or <1000/cu mm by end of first week of life) Maternal causes Associated with maternal neutropenia (e.g., SLE) Maternal drug ingestion and often associated with thrombocytopenia (e.g., sulfa drugs, thiazides, propylthiouracil, phenothiazines, trimethadione, amidopyrine) Associated with maternal isoimmunization to fetal leukocytes Inborn errors of metabolism (e.g., chronic tyrosinosis, maple syrup urine disease, ketotic hyperglycinemia, methylmalonic acidemia, isovaleric acidemia, propionic acidemia) Immune defects (e.g., X-linked agammaglobulinemia, dysgammaglobulinemia) Associated with phenotypic abnormalities (e.g., cartilage hair dysplasia, dyskeratosis congenita, Shwachman-Diamond syndrome [chronic hypoplastic neutropenia associated with pancreatic insufficiency]) Infantile genetic agranulocytosis Disorders of uncommitted stem cell proliferation Cyclic neutropenia Reticular dysgenesis (granulocytes and lymphocytes do not develop normally, absent thymus, low immunoglobulin concentrations, platelets and RBCs are unaffected) Disorders of myeloid stem cell proliferation Kostmann's agranulocytosis (moderate to severe neutropenia that may be associated with dysgammaglobulinemia, frequent chromosomal abnormalities, normal granulocytic maturation up to promyelocyte or myelocyte stage) Benign chronic granulocytopenia of childhood In children Adult type PA Defective secretion or type of gastric intrinsic factor (normal gastric mucosa and acid secretion, no antibodies to intrinsic factor or parietal cells, no associated endocrine deficiency) Imerslund-Graesbeck syndrome Pregnancy–progressive decrease in granulocyte count during pregnancy. Serum B12 is normal in megaloblastic anemia of pregnancy. Causes of Neutrophilia (Absolute neutrophil count >8000/cu mm) See Table 11-4 and Table 11-5. Table 11-4. Some Common Causes of Leukemoid Reaction Table 11-5. Comparison of Leukemia and Leukemoid Reaction Acute infections Localized (e.g., pneumonia, meningitis, tonsillitis, abscess) Generalized (e.g., acute rheumatic fever, septicemia, cholera) Inflammation (e.g., vasculitis) Intoxications Metabolic (uremia, acidosis, eclampsia, acute gout) Poisoning by chemicals, drugs, venoms, etc. (e.g., mercury, epinephrine, black widow spider)
- 233. Parenteral (foreign protein and vaccines) Acute hemorrhage Acute hemolysis of red blood cells Myeloproliferative diseases Tissue necrosis, e.g., AMI Necrosis of tumors Burns Gangrene Bacterial necrosis Physiologic conditions (e.g., exercise, emotional stress, menstruation, obstetric labor) Steroid administration (e.g., prednisone 40 mg orally) causes increased neutrophil leukocytes of 1700–7500 (peak in 4–6 hrs and return to normal in 24 hrs); no definite shift to left. Lymphocytes decrease 70% and monocytes decrease 90%. May be accompanied by shift to left of granulocytes, toxic granulation, Döhle's bodies, and cytoplasmic vacuolization. Causes of Lymphocytosis (>4000/cu mm in adults, >7200/cu mm in adolescents, >9000/cu mm in young children and infants) See Fig 11-5. Fig. 11-5. Algorithm for causes of lymphocytosis. Infections Pertussis Infectious lymphocytosis Infectious mononucleosis Infectious hepatitis CMV infection Mumps Rubella Varicella Toxoplasmosis Chronic TB Undulant fever Convalescence from acute infection Thyrotoxicosis (relative) Addison's disease Neutropenia with relative lymphocytosis Lymphatic leukemia Crohn's disease Ulcerative colitis Serum sickness Drug hypersensitivity Vasculitis Causes of Lymphocytopenia (<1500 in adults, <3000 in children) Increased destruction Chemotherapy or radiation treatment Corticosteroids (Cushing's syndrome, stress)
- 234. Increased loss via GI tract Intestinal lymphectasia Thoracic duct drainage Obstruction to intestinal lymphatic drainage (e.g., tumor, Whipple's disease, intestinal lymphangiectasia) Congestive heart failure Decreased production Aplastic anemia Malignancy, especially Hodgkin's disease Inherited immunoglobulin disorders (e.g., Wiskott-Aldrich syndrome, combined immunodeficiency, ataxia-telangiectasia) Infection (e.g., AIDS) Others (e.g., SLE, renal failure, miliary TB, myasthenia gravis, aplastic anemia) CD4 Lymphocytes (By flow cytometry; calculated as total WBC × % lymphocytes × % lymphocytes stained with CD4) Use Diagnosis of immune dysfunction, especially AIDS, in which severely depressed count is the single best predictor of imminent opportunistic infection and an increase is associated with therapeutic effect of drugs. May also be expressed as CD4/CD8 lymphocyte ratio but CD8 count is more labile and may diminish the value of the CD4 counts. Decreased In Acute minor viral infections. Should recheck in 3 mos. Also diurnal variation; peak evening values may be 2× morning values. Imprecision in total WBC and differential may cause 25% variability in CD4 values. Causes of Atypical Lymphocytes Lymphatic leukemia Viral infections Infectious lymphocytosis Infectious mononucleosis Infectious hepatitis Viral pneumonia and other exanthems of childhood Mumps Varicella CMV infection Pertussis Brucellosis Syphilis (in some phases) Toxoplasmosis Drug reactions and serum sickness Healthy persons may show up to 12% atypical lymphocytes. “Heterophile negative” infectious mononucleosis syndrome is most often seen in Early stage of infectious mononucleosis Toxoplasmosis CMV infection Infectious hepatitis Basophilic Leukocytes Use May be first sign of blast crisis or accelerated phase of CML Persistent basophilia may indicate unsuspected myeloproliferative disease. Diagnosis of basophilic leukemia Increased In (>50/cu mm or >1%) Chronic myelogenous leukemia Basophilic leukemia Polycythemia Myeloid metaplasia Hodgkin's disease
- 235. Postsplenectomy Chronic hemolytic anemia (some patients) Chronic sinusitis Varicella Variola Myxedema Nephrosis (some patients) Foreign protein injection Ionizing radiation Decreased In Hyperthyroidism Pregnancy Period after irradiation, chemotherapy, and glucocorticoid administration Acute phase of infection Causes of Monocytosis (>10% of differential count; absolute count >500/cu mm) Monocytic leukemia, other leukemias Other myeloproliferative disorders (myeloid metaplasia, polycythemia vera) Hodgkin's disease and other malignant lymphomas Lipid storage diseases (e.g., Gaucher's disease) Postsplenectomy Tetrachloroethane poisoning Recovery from agranulocytosis and subsidence of acute infection Many protozoan infections (e.g., malaria, kala-azar, trypanosomiasis) Some rickettsial infections (e.g., Rocky Mountain spotted fever, typhus) Certain bacterial infections (e.g., SBE, TB, brucellosis) Chronic ulcerative colitis, regional enteritis, and sprue Sarcoidosis Collagen diseases (e.g., RA, SLE) Most common causes are indolent infections (e.g., mycobacteria, SBE) and recovery phase of neutropenia. Monocyte phagocytosis of RBCs in peripheral smears from earlobe is said to occur often in SBE. Plasma Cells Increased In Plasma cell leukemia Multiple myeloma Hodgkin's disease CLL Other neoplasias (cancer of liver, kidney, breast, prostate) Cirrhosis RA SLE Serum reaction Bacterial infections (e.g., syphilis, TB)
- 236. Parasitic infections (e.g., malaria, trichinosis) Viral infections (e.g., infectious mononucleosis, rubella, measles, varicella, benign lymphocytic meningitis) Decreased In Not clinically significant Causes of Eosinophilia (>250/cu mm; diurnal variation with highest levels in morning) Allergic diseases (e.g., bronchial asthma, hay fever, urticaria, drug therapy, allergic rhinitis, eczema) Parasitic infestation, especially with tissue invasion (e.g., trichinosis, Echinococcus disease, schistosomiasis, filariasis, fascioliasis) Mycoses (e.g., coccidioidomycosis) Some infectious diseases (e.g., scarlet fever, erythema multiforme, Chlamydia infection) Collagen-vascular diseases (e.g., periarteritis nodosa, SLE, RA, scleroderma, dermatomyositis, Churg-Strauss syndrome) Some diffuse skin diseases (e.g., pemphigus, dermatitis herpetiformis) Some hematopoietic diseases (e.g., PA, chronic myelogenous leukemia, AML, polycythemia, Hodgkin's disease, T-cell lymphomas, eosinophilic leukemia); postsplenectomy Some immunodeficiency disorders (e.g., Wiskott-Aldrich syndrome, graft-versus-host disease, cyclic neutropenia, IgA deficiency) Some gastrointestinal diseases (e.g., eosinophilic gastroenteritis, ulcerative colitis, regional enteritis, colon carcinoma) Some endocrine diseases (e.g., hypopituitarism, Addison's disease) Postirradiation Miscellaneous conditions Certain tumors (ovary, involvement of bone or serosal surfaces) Sarcoidosis Löffler's parietal fibroplastic endocarditis Familial conditions Poisoning (e.g., phosphorus, black widow spider bite) Drugs (e.g., aspirin sensitivity) Hypereosinophilic syndrome Highest levels occur in trichinosis, Clonorchis sinensis infection, and dermatitis herpetiformis. HEMATOLOGIC DISEASES ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS) See Chapter 15. AGAMMAGLOBULINEMIA, X-LINKED (BRUTON'S DISEASE) (X-linked recessive trait) See Table 11-6 and Table 11-7. Table 11-6. Comparison of Some Primary Immunodeficiency Diseases
- 237. Table 11-7. Classification of Primary Immunologic Defects Male patients experience severe recurrent pyogenic infections (commonly due to Streptococcus pneumoniae, Haemophilus influenzae; also Streptococcus pyogenes and S. aureus) after age 4–6 mos. Often have persistent viral infections (e.g., chronic, progressive, fatal CNS infection with echoviruses) or parasitic infections. Giardia lamblia leads to chronic diarrhea. Large joint arthritis probably due to Ureaplasma urealyticum. Not unusually susceptible to viral infections except fulminant hepatitis. wInability to make functional antibody is the distinguishing feature; antibody responses to immunization are usually absent. Live virus vaccination may cause severe disease (e.g., paralytic polio). wSerum levels of all immunoglobulins are very low (IgG <100 mg/dL; IgA, IgM undetectable). wB cells in peripheral blood are absent or found in very low numbers. wT cell numbers and function are intact. Plasma cells in lymph nodes and GI tract are absent or found in very low numbers. No markers exist for detection of heterozygotes. Hypoplasia of tonsils, adenoids, lymph nodes. Thymus appears normal with Hassall's corpuscles and abundant lymphoid cells. Increased frequency of lymphoreticular malignancy (£6%). Prone to develop connective tissue diseases (e.g., dermatomyositis, RA-like disorder) and allergic disorders (e.g., rhinitis, asthma, eczema, drug rash) Female carriers can be identified by examination of B cells. AGRANULOCYTOSIS wIn acute fulminant form, WBC is decreased to £2000/cu mm, sometimes as low as 50/cu mm. Granulocytes are 0–2%. Granulocytes may show pyknosis or vacuolization. wIn chronic or recurrent form, WBC is decreased to 2000/cu mm with less marked granulocytopenia. Relative lymphocytosis and sometimes monocytosis are seen. wBone marrow shows absence of cells in granulocytic series but normal erythroid and megakaryocytic series. ESR is increased. Hb, RBC count and morphology, platelet count, and coagulation tests are normal. Laboratory findings due to infection. Due To Peripheral destruction of PMNs (often drug related) Overwhelming sepsis More generalized bone marrow failure (see Anemia, Aplastic) ALDER-REILLY ANOMALY wHeavy azurophilic granulation of granulocytes and some lymphocytes and monocytes associated with mucopolysaccharidoses ( Table 13-12) are seen. Present in £90% of neutrophils in Hurler's syndrome. Inconstant in blood but always present in marrow mononuclear phagocytes. ALPHA HEAVY-CHAIN DISEASE (Mediterranean-type abdominal lymphoma; most common heavy-chain disease) w Diagnostic Criteria Serum protein shows distinctive increase in monoclonal IgA heavy chain (alpha chain) not associated with a light chain; causes an elevated broad peak in half the cases and is normal in the other cases. Same alpha chain in jejunal fluid, lymphocytes, or plasma cells. Low concentration of alpha chains in urine. Laboratory findings of severe malabsorption with chronic diarrhea and steatorrhea due to diffuse lymphoma-like proliferation in small intestine and mesentery. Rarely, respiratory tract involvement. Biopsy of small intestine shows marked infiltration with abnormal plasma cells. Bence Jones proteinuria is absent. Bone marrow is normal. ALPHA1-ANTITRYPSIN DEFICIENCY
- 238. (Autosomal recessive deficiency associated with familial pulmonary emphysema and liver disease. The heterozygous state occurs in 10–15% of the general population, who have serum levels of alpha1-antitrypsin ~60% of normal; homozygous state occurs in 1 in 2000 persons, who have serum levels ~10% of normal; there are many alleles of alpha1-antitrypsin gene.) See Table 11-8. Table 11-8. Alleles of the AAT Gene wAbsent alpha1 peak on serum protein electrophoresis. Should be confirmed by assay of serum alpha 1-antitrypsin (electroimmunoassay) and Pi phenotyping (isoelectric focusing on polyacrylamide; DNA analysis also permits prenatal diagnosis), and functional analysis of total trypsin inhibitory capacity (90% is due to alpha1-antitrypsin activity). Alpha1-Antitrypsin May Be Decreased In (Typically <50 mg/dL) Prematurity Severe liver disease Malnutrition Renal losses (e.g., nephrosis) GI losses (e.g., pancreatitis, protein-losing diseases) Exudative dermopathies Alpha1-antitrypsin deficiency should be ruled out in children with neonatal hepatitis, giant cell hepatitis, chronically abnormal liver chemistries, or juvenile cirrhosis and in adults with chronic hepatitis without serologic markers, cryptogenic cirrhosis, hepatoma. Alpha1-Antitrypsin Increased In (Is an acute-phase reactant) Acute or chronic infections Neoplasia (especially cervical cancer and lymphomas) Pregnancy Use of birth control pills mLiver biopsy supports the diagnosis and helps stage extent of liver damage. Shows characteristic intracytoplasmic inclusions (in both heterozygotes and homozygotes) that may be found in patients with emphysema without liver disease and in asymptomatic heterozygous relatives, but must be searched for and stained specifically, because the rest of the pathology in the liver is not specific. ~9% of adults with nonalcoholic cirrhosis are MZ phenotype. Hepatoma may occur in cirrhotic livers. Liver disease occurs in 10–20% of children with this deficiency. Clinical picture may be neonatal hepatitis (in 15% of those with ZZ phenotype), prolonged obstructive jaundice during infancy, or cirrhosis, or patient may be asymptomatic. 5–10% of infants with undefined cholestasis have alpha 1-antitrypsin deficiency. In ~25% of these patients, clinical and biochemical abnormalities become normal by age 3–10 yrs; ~25% have abnormal liver function tests with or without clinical cirrhosis; ~25% survive first decade with confirmed cirrhosis; 25% die of cirrhosis between 6 mos and 17 yrs of age. mPulmonary emphysema occurs in heterozygotes and homozygotes; occurs in family of 25% of patients. Causes 2% of cases of emphysema. Secondary bronchitis and bronchiectasis may occur. Associated with phenotypes Pi ZZ and probably Pi SZ but not Pi MZ. Purified alpha1-antitrypsin is now available for augmentation therapy. Indicated when alpha1-antitrypsin is severely deficient, abnormal lung function tests shows deterioration. Not indicated when lung function is normal even if there is alpha 1-antitrypsin deficiency with liver disease, or when pulmonary emphysema is associated with normal or heterozygous phenotypes. ANEMIA, ACUTE BLOOD LOSS RBC, Hb, and Hct level are not reliable initially because of compensatory vasoconstriction and hemodilution. They decrease for several days after hemorrhage ceases. RBC returns to normal in 4–6 wks. Hb returns to normal in 6–8 wks. Anemia is normochromic, normocytic. (If hypochromic or microcytic, rule out iron deficiency due to prior hemorrhages.) Reticulocyte count is increased after 1–2 days, reaches peak in 4–7 days (£15%). Persistent increase suggests continuing hemorrhage.
- 239. Blood smear shows no poikilocytes. Polychromasia and increased number of nucleated RBCs (up to 5:100 WBCs) may be found. Increased WBC (usually £20,000/cu mm) reaches peak in 2–5 hrs, becomes normal in 3–4 days. Persistent increase suggests continuing hemorrhage, bleeding into a body cavity, or infection. Differential count shows shift to the left. Platelets are increased (£1 million/cu mm) within a few hours; coagulation time is decreased. BUN is increased if hemorrhage into lumen of GI tract occurs. Serum indirect bilirubin is increased if hemorrhage into a body cavity or cystic structure occurs. Laboratory findings due to causative disease (e.g., peptic ulcer, esophageal varices, leukemia). ANEMIA, APLASTIC3 wPeripheral blood pancytopenia with variable bone marrow hypocellularity in the absence of underlying myeloproliferative or malignant disease. Neutropenia (absolute neutrophil count <1500/cu mm) is always present; often monocytopenia is present. Lymphocyte count is normal; reduced helper/inducer to cytotoxic/suppressor ratio. Platelet count <150,000/cu mm; severity varies. Anemia is usually normochromic, normocytic but may be slightly macrocytic. RDW is normal. Poikilocytes are not seen on peripheral blood smear. Bone marrow is hypocellular; aspiration and biopsy should both be performed to rule out leukemia, myelodysplastic syndrome, granulomas, tumor. Reticulocyte count corrected for Hct is decreased. Serum iron is increased. Flow cytometry phenotyping shows virtual absence of CD34 stem cells in blood and marrow. Laboratory findings represent the whole spectrum, from the most severe condition of the classic type with marked leukopenia, thrombocytopenia, anemia, and acellular bone marrow, to cases with involvement only of erythroid elements. In some cases, the marrow may be cellular or hyperplastic. wCriteria for severe aplastic anemia (International Aplastic Anemia Study Group) ³2 peripheral blood criteria plus either marrow criteria Peripheral blood criteria Neutrophils <500/cu mm Platelets <20,000/cu mm Reticulocyte count <1% (corrected for Hct) Marrow criteria Severe hypocellularity Moderate hypocellularity with <30% of residual cells being hematopoietic Due To Idiopathic in 50% of cases Chemicals (e.g., benzene family, insecticides) Cytotoxic and antimetabolite drugs Other drugs Antimicrobials (especially chloramphenicol, quinacrine), anticonvulsants (especially hydantoin), analgesics (especially phenylbutazone), antihistamines, antidiabetic drugs, sedatives, others (especially gold; NSAIDs, sulfonamides, antithyroid drugs) Immunologic disorders (e.g., graft-versus-host disease, thymoma and thymic carcinoma) Ionizing irradiation (x-rays, radioisotopes) Malnutrition (e.g., kwashiorkor) Viral infections in 10% of cases (especially seronegative hepatitis; EBV, CMV, HIV, parvovirus) Constitutional, inherited (e.g., Fanconi's anemia) Leukemia is the underlying disease in 1–5% of patients who present with aplastic anemia. 15% of aplastic anemia patients develop myelodysplasia and leukemia. Paroxysmal nocturnal hemoglobinuria develops in 5–10% of patients with aplastic anemia, and aplastic anemia develops in 25% of patients with paroxysmal nocturnal hemoglobinuria. ANEMIA, FANCONI'S (Simple autosomal recessive syndrome of pancytopenia and characteristic congenital anomalies of rudimentary thumbs, hypoplastic radii, short stature, renal anomalies, skin hyperpigmentation, chromosomal breaks) Pancytopenia usually noted at 4–10 yrs of age but may be from infancy to 20s. Anemia, leukopenia, and thrombocytopenia may not all be present at onset. Profound anemia may be macrocytic and hyperchromic or normochromic. Increased HbF (>28%). Decreased granulocytes. Atrophic bone marrow. Causes >20% of childhood cases of aplastic anemia. Increased incidence of leukemia in patients and relatives.
- 240. Cytogenetic studies show normal chromosome numbers but structural instability causing breaks, gaps, constrictions, rearrangements. Laboratory findings due to anemia, hemorrhage, infection, renal abnormalities. ANEMIA, HEMOLYTIC, ACQUIRED Laboratory findings due to increased destruction of RBCs RBC survival time differentiates intrinsic defect from factor outside RBC. Blood smear often shows marked spherocytosis. Anisocytosis, poikilocytosis, and polychromasia are seen. Slight abnormality of osmotic fragility occurs. Increased indirect serum bilirubin (<6 mg/dL) because of compensatory excretory capacity of liver). Urine urobilinogen is increased (may vary with liver function; may be obscured by antibiotic therapy altering intestinal flora). Bile is absent. Hemoglobinemia and hemoglobinuria are present when hemolysis is very rapid. Haptoglobins are decreased or absent in chronic hemolytic diseases (removed after combination with free Hb in serum). WBC is usually elevated. Laboratory findings due to compensatory increased production of RBCs Normochromic, normocytic anemia. MCV reflects immaturity of circulating RBCs. Polychromatophilia is present. Reticulocyte count is increased. Erythroid hyperplasia of bone marrow is evident. Laboratory findings due to mechanism of RBC destruction, e.g., Positive direct Coombs' test. Warm antibodies. Cold agglutinins. Biological false-positive test for syphilis may occur. Laboratory findings due to underlying conditions Malignant lymphoma Collagen diseases (e.g., SLE) DIC Idiopathic pulmonary hemosiderosis Infections, especially Mycoplasma infection; infectious mononucleosis, malaria, cholera Paroxysmal nocturnal hemoglobinuria Physical/chemical (e.g., burns, drugs, toxins [phenylhydrazine, benzene]) Antibody-induced Drug induced (e.g., quinidine, quinine, penicillins, cephalothin, alpha methyldopa) Autoantibody (warm, cold) Alloantibody (erythroblastosis fetalis, incompatible transfusion) Paroxysmal cold hemoglobinuria ANEMIA, HEMOLYTIC, MICROANGIOPATHIC (Traumatic intravascular hemolysis due to fibrin strands in vessel lumens) See Table 11-1, Table 11-9, Table 11-10 and Fig. 11-6. Fig. 11-6. Algorithm for workup of microcytic hypochromic anemia. (CBC = complete blood cell count; FEP = free erythrocyte protoporphyrin; Rx = therapy.) wPeripheral blood smear establishes the diagnosis by characteristic burr cells, schistocytes, helmet cells, microspherocytes. Nonimmune hemolytic anemia varies in severity depending on underlying condition (see Anemia, Hemolytic, Acquired). Laboratory findings of hemolysis, e.g., increased serum LD, decreased haptoglobin, hemosiderinuria; hemoglobinemia and hemoglobinuria are less common. Iron deficiency due to urinary loss of iron. Direct Coombs' test is usually negative. Laboratory findings due to causative disease Due To Renal disease (e.g., malignant hypertension, renal graft rejection) Cardiac valvular disease (e.g., intracardiac valve prostheses, bacterial endocarditis, severe valvular heart disease)
- 241. Severe liver disease (e.g., cirrhosis, eclampsia) DIC Autoimmune disorders (e.g., periarteritis nodosa, SLE) TTP Snakebite Some disseminated neoplasms ANEMIA, HEMOLYTIC, HEREDITARY NONSPHEROCYTIC (This heterogeneous group may be due to pyruvate kinase deficiency, variants of G-6-PD deficiency, Hb Zurich, other rare congenital enzyme defects [e.g., glutathione]) wCharacterized by persistent hemolysis without demonstrable autoantibodies, abnormal hemoglobins, altered RBC morphology, or other obvious findings indicating etiology. Hemolytic anemia may be severe; may begin in newborn; may be precipitated by certain drugs. RBCs show Howell-Jolly bodies, Pappenheimer bodies, Heinz bodies, basophilic stippling; slight macrocytosis may be present. Increase in reticulocyte count is marked, even with mild anemia. Bone marrow shows marked erythroid hyperplasia; normal hemosiderin is present. WBC, platelet count, Hb electrophoresis, osmotic fragility, and mechanical fragility are normal. Autohemolysis is present in some cases but not in others; reduction by glucose is less than in normal blood. ANEMIA, IRON-DEFICIENCY See Table 11-1, Table 11-9, Table 11-10, Fig. 11-3 and Fig. 11-6. Due To (Usually a combination of these factors) Chronic blood loss (e.g., menometrorrhagia; bleeding from GI tract, especially from carcinoma of colon; hiatus hernia; peptic ulcer; intestinal parasites; marathon runners) Decreased dietary intake (e.g., poverty, emotional factors) Decreased absorption (e.g., steatorrhea, gastrectomy, achlorhydria) Increased requirements (e.g., pregnancy, lactation) The cause of iron deficiency should always be ascertained to avoid overlooking occult carcinoma. In adults, iron deficiency usually means blood loss. If no GI or gynecologic cause is apparent, endoscopy must be performed. Laboratory Findings wDecreased serum ferritin is the most sensitive and specific test and is first test to reflect iron deficiency; decreased before anemia but may be increased when there is coexisting liver disease, inflammation, or other conditions that increase ferritin . Thus iron deficiency is suggested by serum ferritin <25 ng/mL in a patient with inflammation, <50 ng/mL in a hemodialysis patient, and <100 ng/mL in liver disease; <12 ng/mL always indicates iron deficiency. Serum ferritin >200 ng/mL generally indicates adequate iron stores regardless of underlying conditions. Ferritin usually distinguishes iron deficiency from thalassemia in uncomplicated cases. wHb is decreased (usually 6–10 gm/dL) out of proportion to decrease in RBC (3.5–5.0 million/cu mm); thus decreased MCV (<80 fL) is a sensitive indicator; MCH is decreased (<30 pg); decreased MCHC (25–30 gm/dL) is poor indicator as it is usually normal until anemia is severe. wIncreased RDW is found more often in iron deficiency than in thalassemia; increased RDW may be the first indication of iron deficiency; sensitivity = 89%; negative predictive value of normal RDW = 93%; positive predictive value = 45%; specificity = only 45%. wHypochromia and microcytosis parallel severity of anemia. Polychromatophilia and nucleated RBCs are less common than in PA or thalassemia. Diagnosis from peripheral blood smear is difficult and unreliable. Target cells may be present but are more common in thalassemias; basophilic stippling and polychromasia also favor thalassemia although absent in 50% of cases. Anisocytosis is less marked in thalassemia. wRatio of microcytic to hypochromic RBCs (measured with automated hematology analyzer) is <0.9 in iron deficiency but >0.9 in beta-thalassemia. wSerum iron is decreased (usually 40 µg/dL), TIBC is increased (usually 350–460 µg/dL), and transferrin saturation is decreased (<15%). TIBC may be normal or moderately increased in many patients with uncomplicated iron deficiency. Serum transferrin may be normal or increased (calculated transferrin = TIBC × 0.7). These have limited value in differential diagnosis because they are often normal in iron deficiency and abnormal in anemia of chronic disease and may be affected by recent iron therapy. wAs iron deficiency progresses, decreased serum ferritin is followed in order by anisocytosis, microcytosis, elliptocytosis, hypochromia, decreases in Hb, decreases in serum iron, and decreases in transferrin saturation. mSerum transferrin receptor assay increases only after iron stores are depleted (i.e., decline in serum ferritin below reference range and compensatory erythropoiesis begins) but before changes are seen in other markers of tissue iron deficiency (e.g., transferrin saturation, MCV, erythrocyte protoporphyrin). Particularly useful in differentiating iron-deficiency anemia from anemia of chronic disease and in diagnosing iron-deficiency anemia in patients with chronic disease. Increased sensitivity and specificity when combined with ferritin. wBone marrow shows normoblastic hyperplasia with decreased hemosiderin, later absent, and decreased percentage of sideroblasts. Decreased to absent iron is the gold-standard test for diagnosis of iron deficiency. Reticulocytes are normal or decreased, unless there is recent hemorrhage or administration of iron. mFree erythrocyte protoporphyrin is increased and is useful screening test because it can be done on fingerstick sample. Is increased before anemia. Also increased in lead poisoning, anemia of chronic disease, and most sideroblastic anemias but is normal in thalassemias. WBC is normal or may be slightly decreased in 10% of cases; may be increased with fresh hemorrhage. Serum bilirubin and LD are not increased. Platelet count is usually normal but may be slightly increased or decreased; often increased in children.
- 242. Coagulation studies are normal. RBC fragility is normal or (often) increased to 0.21%. RBC life span is normal. Laboratory finding may disclose causative factors (e.g., GI bleeding). wResponse to oral iron therapy is the final proof of diagnosis of iron deficiency but primary cause must be determined. Increased reticulocytes within 3–7 days with peak of 8–10% on fifth to tenth day; proportional to degree of anemia. Followed by increasing Hb (average 0.25–0.4 gm/dL/day) and Hct (average = 1%/day) during first 7–10 days; thereafter Hb increases 0.1 gm/dL/day to level ³11 gm/dL in 3–4 wks. Should be about half corrected in 3 wks and fully corrected by 8 wks. In older patients, increase of 1 gm/dL may take 1 mo, whereas in younger patients Hb increases 3 gm/dL and Hct increases 10%. Failure to respond suggests incorrect diagnosis, coexistent deficiencies (folic acid, vitamin B 12, thyroid), associated conditions (e.g., lead poisoning, bleeding, malabsorption, liver or kidney disease). Clinical utility is not yet established for RBC ferritin (also decreased in anemia of chronic disease) and serum transferrin receptor tests. Most difficult differential diagnosis is thalassemias and anemia of chronic disease. See Table 11-1, Table 11-9 and Table 11-10. In the United States, median Hb is ~ 1 gm/dL lower in blacks without iron deficiency than in whites. ANEMIA, MACROCYTIC, OF LIVER DISEASE wIncreased MCV (100–125 fL) in one-third to two-thirds of patients. Indices resemble those in other megaloblastic anemias. Low MCHC may indicate associated iron deficiency. wUniform round macrocytosis is the cardinal finding. Target cells and stomatocytes may be present. Hemolytic anemia or true folate deficiency is frequent in alcoholic liver disease. WBC and platelet count may be decreased or normal. ANEMIA, MACROCYTIC, OF SPRUE, CELIAC DISEASE, STEATORRHEA See Chapter 7. ANEMIA, MEGALOBLASTIC (Dyssynchronous nuclear and cytoplasmic maturation in all erythroid and myeloid cell lines due to aberrant DNA synthesis caused by deficiency of folate or vitamin B12) See Table 11-11, Table 11-12 and Fig. 11-7. Table 11-11. Laboratory Tests in Differential Diagnosis of Vitamin B 12 and Folic Acid Deficiencies Table 11-12. Pernicious Anemia (PA) (Vitamin B12 Deficiency) and Folate Deficiency
- 243. Fig. 11-7. Sequence of laboratory tests in macrocytic anemia. (HCYS = homocysteine; MMA = methylmalonic acid.) E.g., valproic acid, carbamazepine, phenytoin. Hematologic picture is identical to that in folate or vitamin B 12 deficiency but neurologic findings are absent in folate deficiency. Normochromic macrocytic anemia is a relatively late event; RBC may be as low as 500,000/cu mm. Degree of anemia does not correlate with severity of neurologic signs and symptoms, which may precede hematologic abnormalities. wRBC indices MCV is increased (95–110 fL with mild to moderate anemia, but may also be due to round macrocytes arising from nonmegaloblastic causes; 110–150 fL with more severe anemia). MCV increases many months before onset of anemia or clinical symptoms in almost all patients. MCV >95 fL should prompt further study. MCV >120 fL is most likely due to megaloblastic anemia. MCV may be normal in presence of coexisting iron deficiency, inflammatory disease, renal failure, or thalassemia trait. MCV normal in ~9% of megaloblastic patients. RDW is usually very increased due to marked anisocytosis/poikilocytosis but may be normal. MCH is increased (33–38 pg with moderate anemia; £56 pg with severe anemia). MCHC is normal. wLarge hypersegmented neutrophils (³5 lobes) are the earliest morphologic sign of megaloblastic anemia (rule out congenital hypersegmentation, which occurs in 1% of white persons, and uremia); more than two 5-lobed neutrophils is strongly suggestive and any with ³6 lobes is considered diagnostic. Occasionally moderate eosinophilia is present. Blood smear may show oval macrocytes, schistocytes, polychromatophilia, stippled RBCs, Howell-Jolly bodies, Cabot's rings, etc. Nucleated RBCs may be found with Hct <20%. Presence of macro-ovalocytes is a good clue, although these may also be seen in myelodysplasia in contrast to the presence of round macrocytes in nonmegaloblastic anemias. Poikilocytosis and anisocytosis are moderate to marked; always present in relapse. Reticulocyte count is usually decreased. Thrombocytopenia (<150,000/cu mm) is present in 12% of cases; abnormal and giant forms may be seen. Leukopenia is <4000/cu mm in 9% of cases. wMarrow shows megaloblastic and erythroid hyperplasia and abnormalities of myeloid and megakaryocytic elements. Erythroid megaloblastosis may be masked by concomitant iron deficiency but granulocytic megaloblastic changes persist. Not indicated if diagnosis is unequivocal or treatment has been started. wIn PA serum vitamin B12 is very low, usually <100 pg/mL; 100–150 pg/mL usually signifies early vitamin B 12 deficiency even without neuropathy or macrocytosis. May occur with neurologic symptoms but without anemia in one-third or fewer of patients with vitamin B 12 deficiency, especially in older persons. RBC folate is low in many patients with vitamin B12 deficiency. Serum Vitamin B12 May Also Be Decreased In Diet deficient in folic acid (low in 10–30% of patients with simple folate deficiency; corrected by folate therapy alone). £50% of patients with pure Vitamin B 12 deficiency have falsely low RBC folate values. Malabsorption Loss of gastric mucosa, e.g., partial or complete gastrectomy, atrophic gastritis, gastric irradiation. Annual assay of vitamin B 12 should be performed because 100% of patients with total resection and 10% with partial resection will be deficient within 5 yrs. Small bowel disease (e.g., Crohn's disease, scleroderma, lymphoma, ileal resection, tropical sprue, celiac disease, chronic pancreatic insufficiency, bacterial overgrowth). Primary hypothyroidism. (Almost 50% of patients have serum achlorhydria with intrinsic factor failure and low vitamin B 12; rarely megaloblastic anemia develops.) Parasites. 5% of persons infected with Diphyllobothrium latum. Blind-loop syndrome diagnosed by positive Schilling test that becomes normal after 2 wks of tetracycline therapy. Drug effects (e.g., long-term PAS or colchicine use, use of oral contraceptives, aspirin, alcohol) Pregnancy–progressive decrease during pregnancy (normal serum B12 in megaloblastic anemia of pregnancy) Impaired cell utilization Abnormal vitamin B12 carrier protein (transcobalamin II deficiency, abnormal protein) Enzyme deficiency (e.g., congenital methylmalonicacidemias) Prolonged nitrous oxide exposure One-third of patients with multiple myeloma Other conditions Iron deficiency Vegetarian diet Smoking 15–30% of aged persons Cancer Aplastic anemia Folate deficiency Hemodialysis
- 244. Ingestion of high doses of vitamin C Artifactual Antibiotics (with microbiologic assays) Diagnostic radioisotopes for other tests (with RIA assays) Serum Vitamin B12 May Be Increased In Myeloproliferative diseases Leukemia–acute and chronic myelogenous; about one-third of the cases of chronic lymphatic; some cases of monocytic. Normal in stem cell leukemia, multiple myeloma, Hodgkin's disease. Polycythemia vera Leukocytosis Some cases of carcinoma (especially with liver metastases) Liver disease (acute hepatitis, chronic hepatitis, cirrhosis, hepatic coma) Ingestion of vitamin A, vitamin C, estrogens, anticonvulsants Uremia Serum folate is normal or increased. Decreased serum folate in folate deficiency. Decreased RBC folate in both folate and B 12 deficiency. (See Table 11-3.) Serum Folic Acid May Be Decreased In Nutritional (may fall relatively quickly) Alcoholism is most common cause. Infancy, prematurity, elderly. Chronic disease. Hemodialysis. Anorexia nervosa. Increased requirements due to marked cellular proliferation Pregnancy Hyperthyroidism Neoplasia (e.g., acute leukemia, metastatic carcinoma) Hemolytic anemias (e.g., sickle cell, thalassemias, hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria) Ineffective erythropoiesis (PA, sideroblastic anemia) Exfoliative dermatitis, e.g., psoriasis Malabsorption Small bowel disease (e.g., celiac disease, tropical sprue, Crohn's disease, lymphoma, amyloidosis, small bowel resection) Defect in utilization due to certain enzyme deficiencies Drug effects–folic acid antagonists (e.g., methotrexate, trimethoprim, pyrimethamine), anticonvulsants, oral contraceptives, aspirin Decreased liver stores (e.g., cirrhosis, hepatoma) Idiopathic Artifactual Improper specimen storage (folate is labile) Radioactivity in blood (affects radioassays) Antibiotic therapy (affects microbiologic assays) Serum folate serves to distinguish combined deficiency from vitamin B12 deficiency alone. Low serum folate indicates only negative folate balance, not folate deficiency. Decreased serum folate is not evidence of tissue deficiency, for which RBC folate should be assayed. RBC Folate Reflects folate status at time RBCs were produced; therefore more reliable indicator of tissue folate deficiency as it is not subject to daily variation due to diet, etc. Decreased in folate or vitamin B12 deficiency. RBC folate does not fall below normal until all body stores are depleted. Thus, all three parameters should be measured simultaneously in suspected cases of megaloblastic anemia. RBC folate should always be measured in suspected cases of megaloblastic anemia when serum folate and vitamin B12 are assayed (see Table 11-11). Usual normal range is 5–15 ng/mL; is associated with normal hematologic findings. 3–5 ng/mL is borderline; is associated with variable hematologic findings. <3 ng/mL is associated with positive hematologic findings. Serum Folic Acid May Be Increased In PA (or may be normal) Period after folic acid administration or eating
- 245. Vegetarians Blood transfusion Some cases of blind-loop syndrome (due to folate synthesis by bacteria in gut) False elevation in hemolyzed specimens (due to folate in RBCs) Falsely increased to normal in some patients with severe iron deficiency (for unknown reason) wIron deficiency is present in one-half of patients with folate deficiency and one-third with vitamin B12 deficiency. If iron deficiency is more severe than folate deficiency, results of serum and RBC folate tests are normal, and diagnosis cannot be made from these tests; hypersegmentation of PMNs in blood smear is the only clue. wSerum methylmalonic acid and homocysteine become increased very early in course of vitamin B 12 deficiency. Patients with folate deficiency usually show only increase of homocysteine although some may have mild increase of methylmalonic acid. Are the most sensitive tests to detect early vitamin B 12 deficiency and become positive before obvious hematologic evidence of vitamin B 12 deficiency. Useful in patients with borderline vitamin B 12 levels (100–300 pg/mL). Should be positive in acute neurologic disease due to vitamin B 12 deficiency even when hematologic changes are absent. Remain positive for at least 24 hrs after onset of vitamin B12 therapy in cases in which therapy is begun before blood was drawn for vitamin B 12 levels. Urine methylmalonic acid may be useful when serum methylmalonic acid is falsely high in renal insufficiency or intravascular volume depletion. Tests should be requested in cases of unexplained hematologic or neuropsychiatric abnormalities with low or borderline serum vitamin B 12 levels. (Reference ranges: methylmalonic acid = 70–279 nmol/L, homocysteine = 5–15 µmol/L.) wSerum antibodies Intrinsic factor (IF) antibody Type I autoantibodies block binding of vitamin B 12 to intrinsic factor; found in serum in 70% of PA patients. Type II autoantibodies bind to site remote from vitamin B 12 binding site; found in ~40% of PA patients; rarely occur in absence of type I antibodies. Positive test strongly supports diagnosis of PA and therefore should be performed in patients with low serum B 12; positive test combined with low serum B12 is virtually pathognomonic of PA; however, a negative test does not rule out PA because almost one-fourth of PA patients are negative for this antibody. More often found in gastric juice than in serum. False-positive results are rare (high serum B 12 causes false-positive results). Parietal cell antibodies Found in 90% of patients with PA but frequency decreases with duration of PA. Found in ~30% of their nonanemic first-degree relatives and in patients with autoimmune endocrinopathies; occur frequently in chronic gastritis. Found in 2% of normal population (third decade) increasing to >9% in eighth decade. Intrinsic antibodies are more specific but less sensitive. wSchilling test is diagnostic of PA (shows very decreased absorption of radiolabeled B 12, which is corrected only by simultaneous administration of gastric intrinsic factor). Differentiates PA from other causes of vitamin B12 deficiency (commonplace injection of vitamin B12 may make serum level temporarily normal for many weeks) and can establish the functional absence of intrinsic factor before serum B 12 deficiency or anemia are present or after patient has received vitamin B 12 treatment. (See Table 11-13.) Table 11-13. Interpretation of schilling Test Fasting patient is given oral vitamin B 12 tagged with 58 Co and vitamin B12 tagged with 57 Co bound to intrinsic factor. In 1–2 hrs, a flushing dose of 1 mg of nonradioactive B12 is injected to saturate B12 binding sites, and a 24-hr urine specimen is collected. In PA, the 58 Co in urine is low (usually <5% of the administered dose) but the 57 Co B12 bound to intrinsic factor is normally absorbed and excreted (>10% of the administered dose). A simpler method uses 1 µg of radiocobalt-labeled cobalamin followed within 1 hr by the flushing dose. In intestinal malabsorption, 58 Co and 58 Co in the urine are equally low (<5%). Both become normal if underlying cause is treated (e.g., antibiotic treatment in patients with bacterial overgrowth, administration of exogenous pancreatic enzyme in patients with pancreatic insufficiency). For test to be valid, patient must have normal renal function, normal intestinal mucosal absorption, complete 24-hr urine collection. Some patients (e.g., after partial gastrectomy or vagotomy) cannot absorb dietary vitamin B12 but can absorb crystalline vitamin B12 used in test, which gives false-normal result. Can probably be replaced by very high serum gastrin values 4 (see Zollinger-Ellison Syndrome). mIncreased serum gastrin with low serum vitamin B12 suggests PA. Vitamin B12 level does not predict either degree of anemia or MCV. wAchlorhydria occurs even after administration of pentagastrin; this is virtually essential for diagnosis of PA; presence of gastric acid rules out PA. Decreased volume of gastric juice, high pH (>3.5), and decreased or absent pepsin and rennin are also found. Achlorhydria and gastric changes are rarely found in children. mSerum holotranscobalamin II (circulating protein carrier of vitamin B 12) falls before vitamin B12. wRecently developed deoxyuridine (dU) suppression test: patient's marrow cells are cultured with radiolabeled thymidine; in normal marrow, labeled thymidine uptake is suppressed on addition of unlabeled dU because dU can be converted to deoxythymidine, but suppression does not occur when patient is folate or B 12 deficient due to inability to convert dU; adding either folate or B 12 to the medium indicates specific cause. May be useful when other test results are masked by recent therapy or are equivocal. Limited availability at present but may become gold standard of megaloblastic states. Serum iron, TIBC, ferritin, and marrow iron are almost always increased during relapse unless complicating iron deficiency is present. Serum ALP is decreased; increases after treatment. Serum cholesterol is moderately decreased. Cholinesterase activity in RBC, plasma, and whole blood is decreased. Laboratory findings due to hemolysis RBC survival is decreased. Serum LD is markedly increased (principally LD-1 and LD-2 with LD-1>LD-2).
- 246. Serum indirect bilirubin is increased (<4 mg/dL). Urine urobilinogen and coproporphyrin I are increased. Stool urobilinogen is increased. 50% of PA patients have thyroid antibodies. Increased frequency of gastric adenocarcinoma and gastric carcinoids. wCharacteristic Response of Laboratory Tests to Specific Treatment of PA or Folate Deficiency RBC count reaches normal between 8th and 12th week regardless of severity of anemia; Hb concentration may rise at a slower rate, producing hypochromia with microcytosis. Peripheral blood is normal in 1–2 mos. Characteristic reticulocyte response is proportional to severity of anemia. Reticulocyte count begins to rise by 4th day after treatment and reaches maximum on 8th to 9th day; returns to normal by 14th day. Daily injection of 200 µg of folinic acid or citrovorum factor causes a reticulocyte response in patients with folate deficiency but not in those with B12 deficiency. Megaloblasts disappear from marrow in 24–48 hrs followed by reversal of megaloblastic changes in myeloid cells a few days later. Serum folate decreases (in PA) at the same time reticulocytosis takes place. Serum iron decreases to normal or less than normal at the same time reticulocytosis takes place. Serum uric acid increases; peak precedes maximum reticulocyte count by ~24 hrs; remains increased as long as rapid RBC regeneration goes on. Serum LD decreases but is not yet normal by eighth day. Serum bilirubin becomes normal. Serum ALP increases to normal. Serum cholesterol rises to greater than normal levels; most marked at peak of reticulocyte response. Increased urinary urobilinogen and coproporphyrin I immediately revert to normal, preceding reticulocyte response. Achlorhydria persists. RBC cholinesterase activity increases. In Children Adult type PA (very rare condition of gastric atrophy with lack of intrinsic factor production at birth; antibodies to intrinsic factor are present; parietal cell antibodies in 50% of cases; corrected by administration of intrinsic factor; frequent endocrine dysfunction such as hypoparathyroidism and hypoadrenalism) Congenital absence of intrinsic factor (PA develops at age 12–18 mos; corrected by exogenous gastric intrinsic factor; normal gastric mucosa and acid secretion, no antibodies to intrinsic factor or parietal cells, no associated endocrine deficiency) Imerslund-Graesbeck syndrome (rare autosomal recessive defective ileal receptor of B 12 prevents absorption; ileum is normal histologically; normal gastric and endocrine function; proteinuria and renal tubular dysfunction are present; decreased folate and normal B 12 concentrations; responds to parenteral B12 therapy) ANEMIA, MEGALOBLASTIC, OF PREGNANCY AND PUERPERIUM Anemia may have been present during previous pregnancy with spontaneous remission after delivery. Hematologic abnormalities are less marked than in PA. If achlorhydria is present, it often disappears after delivery. Therapeutic response to folic acid but usually not to vitamin B 12 Urinary excretion of formiminoglutamic acid is increased. ANEMIA, MEGALOBLASTIC, REFRACTORY TO FOLIC ACID OR VITAMIN B12 Due To Inborn errors of metabolism Transcobalamin II deficiency (absence of transport protein for vitamin B 12 with profound megaloblastic anemia in infancy; serum B12 is usually normal; may respond to huge doses of parenteral B12) Intrinsic factor deficiency (juvenile PA) Enzyme defects (e.g., congenital methylmalonicacidemia, congenital homocystinemia, 5-methyltetrahydrofolate transferase deficiency, hereditary orotic aciduria) Drug effects Antifolate drugs (e.g., methotrexate, trimethoprim) Interference with absorption of folate (e.g., anticonvulsants, oral contraceptives, alcohol) or vitamin B 12 (e.g., colchicine, PAS, phenformin) Inactivation of vitamin B12 by nitrous oxide Antimetabolites Mild megaloblastic anemia Purine inhibitors (e.g., 6-mercaptopurine, azathioprine [Imuran]) Pyrimidine inhibitors (e.g., 5-fluorouracil)
- 247. Severe megaloblastic anemia Deoxyribonucleotide inhibitors (e.g., cytosine arabinoside, hydroxyurea) Intercalating agents (e.g., doxorubicin) Refractory macrocytic anemia–myelodysplastic syndromes with or without 5q(–) acquired chromosomal abnormality. ANEMIA, MYELOPHTHISIC Anemia is usually mild; not more than moderate. Increased nucleated RBCs and normoblasts in peripheral smear, often without reticulocytosis, are out of proportion to the degree of anemia and may be found even in the absence of anemia. Polychromatophilia, basophilic stippling, and increased reticulocyte count may also occur. WBC may be normal or decreased; occasionally it is increased up to a leukemoid picture; immature WBCs may be found in peripheral smear. Platelets may be normal or decreased, and abnormal forms may occur. Abnormalities may occur even when WBC is normal. wBone marrow demonstrates primary disease. Metastatic carcinoma of bone marrow (especially breast, lung, prostate, thyroid) Hodgkin's disease, leukemia Multiple myeloma (5% of patients) Gaucher's disease, Niemann-Pick disease, and Hand-Schüller-Christian disease Osteopetrosis Myelofibrosis mMild anemia with normoblastemia should arouse suspicion of infiltrative disease of marrow. mNonhemolytic normocytic anemias with no obvious cause characterized by marked RBC changes on blood smear should arouse suspicion of malignancy or marrow fibrosis. ANEMIA OF CHRONIC DISEASES See Table 11-1, Table 11-9 and Fig. 11-6. Due To Subacute or chronic infections (especially TB, bronchiectasis, lung abscess, empyema, bacterial endocarditis, brucellosis, osteomyelitis) Neoplasms RA (anemia parallels activity of arthritis) Rheumatic fever, SLE Uremia (BUN >70 mg/dL) Chronic liver diseases Hypothyroidism Chronic adrenal insufficiency Laboratory Findings wAnemia is usually mild (Hb >9 gm/dL) but may be as low as 5 gm/dL in uremia when other factors are present. Is insidious over 3–4 wk period, then not progressive. May be due to multiple mechanisms, e.g., failure of erythropoiesis, decreased RBC survival, iron deficiency, etc. wAnemia is usually normocytic, normochromic. RDW and indices are usually normal. Hypochromic and/or microcytic in one-fourth to one-third of these patients, in which case it is always less marked than in iron-deficiency anemia. Moderate anisocytosis and slight poikilocytosis are present. Reticulocytosis, polychromatophilia, and nucleated RBCs are absent (may be present with severe anemia or uremia). wSerum iron and TIBC are decreased. If TIBC is elevated, presence of iron deficiency must be ruled out, but TIBC is not sufficiently sensitive or specific to distinguish this from iron-deficiency anemia. Transferrin saturation is usually normal; >10% if decreased; <10% implies iron deficiency. wSerum ferritin is increased or normal in contrast to iron deficiency. In RA, liver disease, or neoplasms, normal serum ferritin does not exclude concomitant iron deficiency. Free erythrocyte protoporphyrin is increased. Bone marrow cellular elements are generally morphologically normal. Hemosiderin is increased or normal; sideroblasts are decreased. Myeloid/erythroid ratio is usually normal. RBC survival is slightly decreased in patient (80–90 days) but not in normal recipient. Platelet count is normal. Increased WBC, ESR, and other acute-phase reactants (e.g., CRP, fibrinogen, ceruloplasmin) are disproportionate to anemia and may be a useful clue to distinguish this from iron-deficiency anemia. Hypothyroidism wOccurs in one-third to two-thirds of patients with hypothyroidism; usually mild (Hct >35%). May be secondary to hypopituitarism.
- 248. Normochromic, normocytic or macrocytic (if hypochromic, rule out associated iron deficiency) No anisocytosis or poikilocytosis Reticulocyte count is not increased. Serum iron is usually decreased and responds only to treatment of hypothyroidism unless concomitant iron deficiency is present. Decreased total blood volume and plasma volume. Normal RBC survival Concurrent iron-deficiency anemia or PA may be present. Hypogonadism Normochromic, normocytic; only occurs in men. Hypoadrenalism Hct is pseudonormal at presentation due to plasma volume depletion; corticosteroid therapy unmasks anemia. Is corrected by 1–2 mos of therapy. Chronic Renal Disease Blood smear frequently shows burr cells or schistocytes. Usually normochromic, normocytic; hypochromic microcytosis may be due to chronic disease or iron deficiency. Severity of anemia roughly parallels severity of renal disease but when dialysis is required, anemia is almost always severe. Decreased serum iron and transferrin. Serum iron, TIBC, and ferritin often are not helpful and bone marrow specimen stained for iron may be necessary for diagnosis of iron deficiency. Concurrent iron deficiency due to GI tract blood loss may be present. Anemia responds to erythropoietin therapy. Bone marrow usually shows erythroid hypoplasia. Decreased serum erythropoietin. Decreased RBC survival by chromium 59 (59 Cr) studies. Chronic Liver Disease mIncreased MCV (100–125 fL) in one-third to two-thirds of patients. Indices resemble those in other megaloblastic anemias. Low MCHC may indicate associated iron deficiency. wUniform round macrocytosis is the cardinal finding. Target cells and stomatocytes may be present. Presence of hypochromic macrocytes or microcytes may suggest misleading diagnosis of iron deficiency. Spur cell (acanthocyte) hemolysis may be due to abnormal lipid metabolism. Hemolytic anemia or true folate deficiency is frequent in alcoholic liver disease. Reticulocyte count is usually increased. Serum iron, TIBC, and ferritin are often not helpful, and bone marrow specimen stained for iron may be necessary for diagnosis of iron deficiency. Decreased RBC survival by 59 Cr studies. ANEMIA, PATHOGENESIS CLASSIFICATION Anemias may be classified according to pathogenesis, which is convenient for understanding the mechanism or according to RBC indices and peripheral blood smear and reticulocyte count (see Fig. 11-3), which is convenient for workup of a clinical problem. Marrow hypofunction with decreased RBC production Marrow replacement (myelophthisic anemias due to tumor or granulomas [e.g., TB]). In absence of severe anemia or leukemoid reaction, nucleated RBCs in blood smear suggest miliary TB or marrow metastases. Marrow injury (hypoplastic and aplastic anemias) Nutritional deficiency (e.g., megaloblastic anemias due to lack of vitamin B 12 or folic acid) Endocrine hypofunction (e.g., pituitary, adrenal, thyroid; anemia of chronic renal failure) Marrow hypofunction due to decreased Hb production (hypochromic microcytic anemias) Deficient heme synthesis (iron-deficiency anemia, pyridoxine-responsive anemias) Deficient globin synthesis (thalassemias, hemoglobinopathies) Excessive loss of RBCs Hemolytic anemias due to genetically defective RBCs Abnormal shape (hereditary spherocytosis, hereditary elliptocytosis) Abnormal Hb (sickle cell anemia, thalassemias, HbC disease) Abnormal RBC enzymes (G-6-PD deficiency, congenital nonspherocytic hemolytic anemias) Hemolytic anemias with acquired defects of RBC and positive Coombs' test
- 249. Autoantibodies, as in SLE, malignant lymphoma Exogenous allergens, as in penicillin allergy Excessive loss of normal RBCs Hemorrhage Hypersplenism Chemical agents (e.g., lead) Infectious agents (e.g., Clostridium welchii, Bartonella, malaria) Miscellaneous diseases (e.g., uremia, liver disease, cancers) Physical agents (e.g., burns) Mechanical trauma (e.g., artificial heart valves, tumor microemboli). Blood smear shows fragmented bizarre-shaped RBCs in patients with artificial heart valves. Anemias are often multifactorial; the resultant characteristics depend on which factor predominates. The diagnosis must be reevaluated after the apparent causes have been treated. ANEMIA, PYRIDOXINE-RESPONSIVE Severe hypochromic microcytic anemia is present. Blood smear shows anisocytosis, poikilocytosis with many bizarre forms, target cells, hypochromia. Polychromatophilia and reticulocytosis are not increased. Serum iron is increased; TIBC is somewhat decreased; transferrin saturation is markedly increased. Marrow sideroblasts and blood siderocytes are increased. Marrow and liver biopsy show increased hemosiderin. Bone marrow usually shows normoblastic hyperplasia; occasionally it is megaloblastic. Response to pyridoxine is always incomplete. Even when Hb becomes normal, morphologic changes in RBCs persist. Tryptophan tolerance test demonstrates pyridoxine deficiency. It may be positive in pyridoxine-responsive anemia, or it may be normal. A positive test produces abnormally large urinary excretion of xanthurenic acid. ANEMIA, SIDEROBLASTIC (Miscellaneous group of diseases characterized by increased sideroblasts [erythroblasts containing iron inclusions] in marrow) See Table 11-9. Hereditary (X-linked transmission) Usual onset in young adulthood but may be in childhood or infancy Anemia is usually severe, hypochromic, microcytic; smear shows anisocytosis, poikilocytosis, elliptocytes, target cells, basophilic stippling mixed with normal-appearing RBCs (dimorphic RBC population). WBC and platelets are usually normal. wBone marrow shows erythroid hyperplasia with normoblastic maturation; 10–40% of normoblasts are ringed sideroblasts; normal or increased iron. Megaloblastic changes indicate complicating folate deficiency. Transferrin saturation is increased. <50% of patients respond to pyridoxine therapy. Idiopathic Refractory Usual onset in older adulthood (rarely <50 yrs) wDimorphic anemia is usually moderate, normocytic, or macrocytic with a small population of hypochromic RBCs on blood smear, some of which show marked stippling. Reticulocytes are usually not increased. WBCs are variable but usually normal. WBCs may show morphologic changes (hypogranular, Pelger-Huët–like neutrophils). Blasts are <1%. Platelet counts are variable. Abnormal thrombopoiesis with abnormal morphology (e.g., hypogranular, large platelets or fragments, large nuclei). Bone marrow shows erythroid hyperplasia; 45–95% of normoblasts are ringed sideroblasts; excessive hemosiderin. Megaloblastic changes due to complicating folate deficiency are found in 20% of patients. Dysgranulopoiesis and dysmegakaryopoiesis may be evident. Serum ferritin and iron stores are increased due to ineffective erythropoiesis. Transferrin saturation is increased (>90% in 33% of patients). However, some patients may be iron deficient or have normal iron status. Iron overload is principal feature that determines long-term prognosis. Acute leukemia develops in ~10% of patients. Secondary Due To
- 250. Drugs (e.g., isoniazid, chloramphenicol, alcohol, lead, cytotoxic drugs such as nitrogen mustard and azathioprine) Diseases Hematologic (e.g., leukemia, polycythemia vera, megaloblastic anemia, hemolytic anemia) Neoplastic (e.g., lymphoma, myeloma, carcinoma) Inflammatory (e.g., infection, RA, SLE, polyarteritis nodosa) Miscellaneous (uremia, myxedema, thyrotoxicosis, porphyria, copper deficiency) Hereditary (pyridoxine responsive or pyridoxine refractory) Idiopathic (pyridoxine responsive or pyridoxine refractory) ANEMIA IN PARASITIC INFESTATIONS Anemia due to blood loss, malnutrition, specific organ damage Malaria: hemolytic anemia D. latum (fish tapeworm): macrocytic anemia Hookworm: hypochromic microcytic anemia due to chronic blood loss Schistosoma mansoni: hypochromic microcytic anemia due to blood loss from intestine; macrocytic anemia due to cirrhosis of schistosomiasis Amebiasis: due to blood loss and malnutrition ANEMIA IN PREGNANCY This is a normal physiologic change due to hemodilution—total blood volume and plasma volume increase more than red cell mass. Onset is at eighth week; full development by 16–22 wks; rapid return to normal in puerperium. Hb averages 11 gm/dL; Hct value averages 33%. RBC morphology is normal. RBC indices are normal. mIf Hb is <10 gm/dL or hypochromic microcytic indices are abnormal, rule out iron-deficiency anemia, which may occur frequently during pregnancy. ANEMIAS (HEMOLYTIC), CLASSIFICATION5 See Fig. 11-1 and Fig. 11-2. A useful approach to the diagnosis of hemolytic anemias may be based on the following: Site of RBC destruction (intravascular or extravascular) Site of etiologic defect (intracellular RBC or extracellular) Nature of defect (acquired or hereditary) Hemoglobin Disorders Intrinsic Autosomal Sickle cell (SS) disease Common Thalassemias Common HbC, HbD, HbE disease Common Unstable hemoglobins Very rare Membrane Disorders Intrinsic Congenital or familial (usually autosomal dominant) Hereditary spherocytosis Common (~0.02% of Northern European population) Hereditary elliptocytosis Rare Hereditary stomatocytosis Very rare Acanthocytosis (abetalipoproteinemia) Very rare Hereditary pyropoikilocytosis Very rare Acquired—paroxysmal nocturnal hemoglobinuria Rare Extrinsic Acquired Isoimmune (blood transfusion reaction, hemolytic disease of newborn) Autoimmune hemolytic anemia (Coombs' test usually positive; spherocytes may be present) Rare Warm antibody 70% of autoimmune hemolytic anemia Idiopathic Secondary to disease (e.g., lymphomas/leukemia, infectious mononucleosis, SLE) Cold agglutinin syndrome Idiopathic Secondary (e.g., Mycoplasma pneumoniae infection, infectious mononucleosis, viral infection, lymphoreticular neoplasms)
- 251. Paroxysmal cold hemoglobinuria Rare Idiopathic Secondary (viral illnesses, syphilis) Atypical autoimmune hemolytic anemia Coombs' test negative Combined cold and warm autoimmune hemolytic anemia Drug induced (e.g., penicillin, methyldopa) Common wNonimmune (usually Coombs'test negative and morphologic changes in blood smear) Physical or mechanical Prosthetic heart valves Microangiopathic hemolytic disease, including DIC, TTP, hemolytic uremic syndrome, etc. March hemoglobinuria Severe burns Snakebite Osmotic–distilled water used in prostate resection Infectious Protozoan (e.g., malaria, toxoplasmosis, leishmaniasis) Bacterial (e.g., sepsis, clostridial toxins, bartonellosis) Viral (e.g., echovirus) Metabolic Disorders Intrinsic G-6-PD deficiency Common Pyruvate kinase deficiency Rare Hexokinase deficiency Phosphofructokinase deficiency Aldolase deficiency Defects in nucleotide metabolism Erythropoietic porphyria Extrinsic Drug effects with normal RBCs or in G-6-PD deficiency Marked hypophosphatemia (<1 mg/dL) may predispose to hemolysis. Other conditions (e.g., lead poisoning, Wilson's disease) w15–20% of acquired immune hemolytic anemias are related to drug therapy. ~3% of patients taking penicillins and cephalosporins develop positive direct Coombs' test; hemolysis is infrequent and usually extravascular. ~10% of patients taking methyldopa develop positive direct Coombs' test after 3–6 mos but <1% develop hemolysis. Serologic findings cannot be distinguished from those of idiopathic warm-antibody autoimmune hemolytic anemia. APLASIA, CONGENITAL PURE RED CELL (DIAMOND-BLACKFAN ANEMIA) (Rare familial anemia associated with congenital anomalies of kidneys, eyes, skeleton, heart; usual onset before age 12 mos; present at birth in 25% of patients. Spontaneous remissions in ~20% of patients after months or years.) mSevere normochromic, often macrocytic, anemia that is refractory to all treatment except transfusion and sometimes prednisone. Reticulocytes are invariably decreased or absent. WBC and differential blood count are normal or WBC is slightly decreased. Platelet count is normal or slightly increased. m Bone marrow usually shows marked decrease in erythroid precursors. Myeloid cells and megakaryocytes are normal. m Increased erythropoietin level m Adenosine deaminase and purine nucleoside phosphorylase activity in RBCs are characteristically increased. No evidence of hemolysis is found. Normal serum folic acid, vitamin B12, liver function tests, RBC life span; negative Coombs' test Normal serum iron with increased saturation level Laboratory changes due to effects of therapy, e.g., Hemosiderosis Steroid effects (e.g., infections, diabetes mellitus, gastric ulcer) ATAXIA-TELANGIECTASIA (Autosomal recessive multisystem disorder of humoral and cellular defects. Cerebellar ataxia is apparent when child starts to walk. Oculocutaneous telangiectasias develop between 3 and 6 yrs of age.) See Table 11-7. wSerum AFP is almost always increased. mSelective absence of IgA in 50–80% of patients. IgE is usually low. Other immunoglobulins may be abnormal. Decreased total T cells (CD3) and helper cells (CD4) with normal or increased suppressor cells (CD8). mRecurrent infections in 80% of cases, usually bacterial sinopulmonary but not viral.
- 252. Delayed cutaneous anergy indicates impaired cell-mediated immunity. ATRANSFERRINEMIA (Very rare autosomal recessive isolated absence of transferrin) Hypochromic, microcytic, iron-deficiency anemia is unresponsive to therapy. TIBC is low (<85 µg/dL). wAbsence of transferrin (normal = 200–400 mg/dL) is demonstrated by nephelometry or immunoelectrophoresis (see Transferrin, Serum). wSerum protein electrophoresis shows marked decrease in beta globulins and absence of transferrin band. Hemosiderosis with involvement of adrenals, heart, etc., is present. BISALBUMINEMIA wTwo albumin bands are present on serum protein electrophoresis in clinically healthy persons. Homozygotes or carriers CHÉDIAK-HIGASHI SYNDROME (Rare autosomal recessive lysosomal storage disease that causes hypopigmentation of skin, hair, and uvea) See Table 11-6. wNeutrophils contain coarse, deeply staining, peroxidase-positive, fused large granulations in cytoplasm, which are present less frequently in other WBCs. Most prominent in marrow cells. wLysosomal inclusions also found in liver, spleen, Schwann cells. Pancytopenia appears during the (accelerated) lymphoma-like phase. m Laboratory findings due to frequent severe pyogenic infections and hemorrhage (which cause death by age 5 years) or to lymphoreticular malignancy in teens Marked deficiency of natural killer cell function. wHeterozygous carriers identified by a granulation anomaly in PMNs. Treated by bone marrow transplant. CHEMICALS, HEMATOLOGIC EFFECTS (Especially benzene; also trinitrotoluene and others) In order of decreasing frequency Anemia Macrocytosis Thrombocytopenia Leukopenia Other (e.g., decreased lymphocytes, increased reticulocytes, increased eosinophils) Varying degrees of severity up to aplastic anemia Hemolytic anemia is sometimes produced. CRYOFIBRINOGENEMIA wPlasma precipitates when oxalated blood is refrigerated at 4°C overnight. Due to fibrinogen-fibrin complexes that show reversible cold precipitability in anticoagulated blood. May cause erroneous WBC when electronic cell counter is used. May be associated with increased alpha1-antitrypsin, haptoglobin, alpha2 macroglobulin (by immunodiffusion technique), and plasma fibrinogen. Not associated with cryoglobulins. Has been reported in association with many conditions, especially Hematologic and solid neoplasms Thromboembolic conditions CRYOGLOBULINEMIA6 (Presence of proteins that precipitate spontaneously and reversibly at less than body temperature within 3 days; insoluble at 4°C and may aggregate up to 30°C; can fix complement and initiate inflammatory reaction; 500–5000 mg/dL in serum; normal = <80 mg/dL) Type I (monoclonal immunoglobulin, especially IgM kappa type) Causes 25% of cases. Most commonly associated with multiple myeloma and Waldenström's macroglobulinemia; other lymphoproliferative diseases with M components; may be idiopathic. Often present in large amounts (>5 mg/dL serum). Blood may gel when drawn. Severe symptoms (e.g., Raynaud's disease, gangrene without other causes). Type II (monoclonal immunoglobulin mixed with at least one other type of polyclonal immunoglobulin, most commonly IgM and polyclonal IgG; always with RF) Causes up to 25% of cases.
- 253. Associated with lymphoproliferative and autoimmune disorders, chronic HCV infection, Sjögren's syndrome, syndrome of essential mixed cryoglobulinemia, immune-complex nephritis (e.g., membranoproliferative GN, vasculitis). High-titer RF without definite rheumatic disease. C4 levels decreased. Type III (mixed polyclonal immunoglobulin, most commonly IgM-IgG combinations, usually with RF) Causes ~50% of cases. Usually present in small amounts (<1 mg/dL serum) in normal persons. Most commonly associated with lymphoproliferative disorders, connective tissue diseases (e.g., SLE); vasculitis and/or nephritis in chronic inflammatory diseases of bowel or liver or rheumatic diseases or persistent infections (e.g., bacterial endocarditis, HCV, fungal, parasitic). Recurrent purpura may occur. wHyperviscosity syndrome is likely at IgM >4.0 gm/dL; clinically unpredictable at 2.0–4.0 gm/dL; therefore serum viscosity should be measured. Viscosity increases exponentially with IgM concentration. m Cryoprecipitate may be seen in serum. m May cause erroneous WBC when electronic cell counter is used. m Rouleaux formation may occur. ESR may be increased at 37°C but is normal at room temperature. Laboratory findings of associated conditions Liver disease—e.g., serologic evidence of viral hepatitis. Renal disease—e.g., immune glomerular disease. Renal failure develops in ~50%, and marked proteinuria occurs in ~25%. Skin biopsy showing cutaneous vasculitis. ELLIPTOCYTOSIS, HEREDITARY (Autosomal dominant trait affecting 1 in 2500 persons in United States. >10 variants are known.) wBlood smear shows 25–100% elliptical RBCs. In healthy individuals, £10% of RBCs may be elliptical. Also seen frequently in thalassemias, hemoglobinopathies, iron deficiency, myelophthisic anemias, megaloblastic anemia; these must be ruled out to establish the diagnosis in a congenital hemolytic anemia with marked elliptocytosis. Only a few abnormal RBCs are present at birth with gradual increase to stable value after ~3 mos of age. Hemolysis is rare in newborns. Splenectomy does not relieve elliptocytosis despite clinical improvement. Severity of disease varies from severe hemolytic disease to asymptomatic carrier status. Degree of hemolysis does not correlate with proportion of abnormal RBC. Elliptocytes are the only hematologic abnormality seen in ~85% of patients; such patients are asymptomatic. Spherocytes are present in some forms. Mild normocytic normochromic anemia (Hb = 10–12 gm/dL) in 10–20% of patients. ~12% of patients show a chronic congenital hemolytic anemia (Hb <9 gm/dL) with decreased RBC survival time, moderate anemia, increased serum bilirubin, increased reticulocyte count, increased osmotic fragility, and autohemolysis. Severe in ~5% of patients (homozygous)—transfusion-dependent anemia with misshapen RBCs resembling hereditary pyropoikilocytosis. wElliptocytes are found in at least one parent and may be present in siblings. Mechanical fragility is increased. Osmotic fragility and autohemolysis are normal in patients without hemolytic anemia. Hb electrophoresis is normal. Laboratory findings due to complications (e.g., gallstones, hypersplenism). ERYTHROCYTE PYRUVATE KINASE DEFICIENCY (Congenital autosomal recessive nonspherocytic hemolytic anemia showing wide range of clinical and laboratory findings from severe neonatal anemia requiring transfusion to fully compensated hemolytic process in healthy adults; due to deficiency of pyruvate kinase [10–25% of normal] in RBCs) wAssay of RBC pyruvate kinase activity demonstrates heterozygous carrier state in persons who are hematologically normal. Beyond early childhood Hb is usually 7–10 g/dL. Peripheral smear shows no characteristic changes (i.e., few or no spherocytes, occasional tailed poikilocytes, macrocytosis, reticulocytosis). Abnormal autohemolysis test is poorly corrected by glucose. Normal osmotic fragility. If an infant has been transfused, the assay should be performed 3–4 mos later. mDiagnosis is difficult to make. May be suggested by increased Hb oxygen affinity (P50) due to elevated 2,3-diphosphoglycerate. Laboratory findings due to complications (e.g., cholelithiasis, hemosiderosis) Other rare deficiencies of RBC enzymes also exist. ERYTHROCYTOSIS, CLASSIFICATION Polycythemia vera Hereditary erythrocytosis (rare conditions) High oxygen-affinity hemoglobinopathies Decreased RBC 2,3-diphosphoglycerate (due to high RBC adenosine triphosphate or autosomal recessive diphosphoglycerate mutase deficiency) Increased production of erythropoietin (autosomal recessive)
- 254. Erythropoietin-receptor mutations (autosomal dominant) Unknown causes Secondary polycythemia Relative polycythemia Neonatal thick blood syndrome Factitious polycythemia (due to blood doping or ingestion of steroids by athletes) GLUCOSE 6-PHOSPHATE DEHYDROGENASE (G-6-PD) DEFICIENCY IN RBC (Inherited sex-linked disorder. Is the most frequent inherited RBC enzyme disorder.) May be associated with several different clinical syndromes. Classes 2 and 3 represent 90% of cases. Classes 4 and 5 show no clinical findings. Class 1 (<5% of normal RBC enzyme activity)—rare, chronic, congenital, nonspherocytic hemolytic anemia worsened by oxidant drugs or febrile illness. Not improved by splenectomy. Class 2 (<10% of normal RBC enzyme activity)—episodic acute hemolytic crises induced by some oxidant drugs (e.g., primaquine, sulfonamides, acetanilid) or acidosis. Splenectomy is not helpful. Class 3 (RBC G-6-PD activity = 10–60% of normal)—oxidant drugs or infection (e.g., pneumonia, infectious hepatitis) induce acute self-limited (2–3 days) hemolysis in persons without previously recognized hematologic disease. Also reported in hepatic coma, hyperthyroidism, myocardial infarction (after first week), megaloblastic anemias, and chronic blood loss. Many other genetic and clinical variants. wAfter standard dose of primaquine in adult, intravascular hemolysis is evidenced by the following: Decreasing Hct usually begins in 2–4 days; reaches nadir by 8–12 days. Heinz bodies and increased serum bilirubin occur during first few days of hemolysis. Reticulocytosis begins at about fifth day; reaches maximum in 10–20 days. Hemolysis subsides spontaneously even if primaquine is continued. wIn vitro tests of Heinz body formation when patients' RBCs are exposed to acetylphenylhydrazine. Hb varies from 7 gm/dL to normal; is lower when due to exogenous agent; is usually normochromic, normocytic. Peripheral smear shows varying degree of nucleated RBCs, spherocytes, poikilocytes, crenated and fragmented RBCs, and Heinz bodies but is not distinctive. wDiagnosis is established by RBC assay for G-6-PD (using fluorescence); heterozygotes have two RBC populations and proportions of each determine degree of deficiency detected. mScreening test using fluorescent spot test is available. In Newborn 5% develop neonatal jaundice after first 24 hrs (in contrast to erythroblastosis fetalis). Serum indirect bilirubin usually reaches peak at third to fifth day (often >20 mg/dL). When jaundice appears late in first week, peak serum level may occur during second week of life. In Asian and Mediterranean infants, neonatal jaundice and kernicterus is more common. Significant portions of the bilirubin may be conjugated. In American black infants at term, incidence of neonatal jaundice is not increased; occurs after exposure to certain drugs (e.g., synthetic vitamin K, naphthalene). Decreased In American black males (13%) American black females (3%; 20% are carriers) Some other ethnic groups (e.g., Greeks, Sardinians, Sephardic Jews) All persons with favism (but not all persons with decreased G-6-PD have favism) Increased In PA to three times normal level; remains elevated for several months, even after administration of vitamin B 12. Idiopathic thrombocytopenic (ITP; Werlhof's disease); becomes normal soon after splenectomy. GRAFT-VERSUS-HOST DISEASE (Due to small lymphocytes [mature marrow T cells] in transplant of donor organs or tissues to immunocompromised host [e.g., bone marrow transplant recipients, infants with congenital immunodeficiency syndromes, but not AIDS patients]) Acute (Within days but <1–2 mos after transplantation) wLaboratory findings due to selective epithelial damage involving Liver: increased serum bilirubin, ALP, AST; may progress to liver failure with encephalopathy, ascites, coagulation disorders. Intestine: bloody diarrhea, paralytic ileus. Positive biopsy of liver, skin, colon, upper GI tract. Acute condition causes persistent severe immunoincompetence with profound immunodeficiency and susceptibility to infection. Transfusion-associated graft-versus-host disease often causes bone marrow aplasia with pancytopenia; is usually severe in contrast to graft-versus-host disease after bone marrow transplant. Chronic
- 255. w >100 days but occasionally as early as 40–50 days after transplantation). Liver: changes of chronic cholestasis (in 80% of cases); often resembles acute graft-versus-host disease; rarely progresses to cirrhosis. Abnormalities of cellular immunity (e.g., decreased B cells, defects in number and function of CD4+ T cells, increased number of nonspecific suppressor cells, impaired antibody production against specific antigens). Thrombocytopenia. Skin changes resemble lichen planus and, later, scleroderma. Biopsy shows changes in affected organs. In a recent report serum catalase showed sensitivity of 100%, specificity of 88% compared to 88% and 28%, respectively, for 5'-NT. 7 GRANULOMATOUS DISEASE, CHRONIC (Rare heterogeneous disorder characterized by chronic recurrent suppurative infections by catalase-positive organisms [e.g., S. aureus, Aspergillus spp.; also seen frequently are Serratia marcescens, Pseudomonas cepacia, Klebsiella spp., Escherichia coli, Nocardia, Chromobacterium violaceum], which usually have low virulence [e.g., Salmonella, Candida albicans]. Due to abnormality of nicotinamide-adenine dinucleotide phosphate oxidase system, PMNs and monocytes ingest normally but fail to kill certain bacteria and fungi; ~60% are X-linked membrane abnormalities, ~40% due to autosomal recessive inheritance (most are cytosol abnormalities), 5% are membrane abnormalities, <1% due to autosomal dominant inheritance.) wFailure of these cells to reduce nitroblue tetrazolium to purple formazan on slide test provides a simple rapid diagnosis in patients and in heterozygotes for the X-linked form (carriers). Nitroblue tetrazolium test now replaced by flow cytometry respiratory burst assay. wOther confirmatory tests in reference laboratory for absent (or severely reduced) production of oxygen radicals include measurement of oxygen consumption, hydrogen peroxide or superoxide production, and chemiluminescence of phagocytes. wPrenatal diagnosis has been established using nitroblue tetrazolium test on fetal blood leukocytes. Fetal DNA from chorionic villus or amniocytes can also be analyzed for specific mutation. WBCs show morphologically normal appearance and granules on routine Wright's- and Giemsa-stained smears. Serum complement and immunoglobulin levels are normal. Laboratory findings due to infection (leukocytosis, anemia, increased ESR, elevated gamma globulin levels) Laboratory findings due to abscesses of lung, liver, osteomyelitis Laboratory findings due to granulomas causing obstruction (e.g., GI tract, GU tract) HEAVY-CHAIN DISEASES Gamma (Rare disorder with excessive production of heavy-chain proteins, producing homogeneous serum and/or urine protein spike) wSerum protein electrophoresis/immunofixation Monoclonal gamma heavy chain in serum, which may be broad or hypogammaglobulinemia. Localized spikes or bands may be absent. Normal immunoglobulins are usually decreased. Gamma globulin almost absent. Serum tests Normal level of total serum protein but increased globulin (>2 gm/dL) and decreased albumin. Increased uric acid (>8.5 mg/dL). Increased BUN (30–50 mg/dL). Urine tests Trace to 1+ protein (0.5–20 gm/day). Negative for Bence Jones protein. Gamma heavy chain identical to that of abnormal serum protein varies from undetectable to 20 gm/day (usually <1 gm). Hematologic findings Normocytic, normochromic anemia (usually Coombs'-positive autoimmune hemolytic), leukopenia, and thrombocytopenia common (probably due to hypersplenism). Eosinophilia sometimes marked; relative lymphocytosis. Vacuolated mononuclear cells sometimes seen. Bone marrow and lymph nodes contain increased numbers of plasma cells, lymphocytes, and many atypical lymphoplasmacytoid cells. In terminal phase is similar to plasma cell leukemia. mHistologic findings of associated lymphoma, e.g., extranodal non-Hodgkin's lymphoma in ~75% of cases. ~50% of cases were preceded by or associated with neoplasias (e.g., lymphoma, leukemia, carcinoma), autoimmune disorders (especially RA), or other disorders (e.g., infections, hypogammaglobulinemia, Down syndrome) Marked susceptibility to bacterial infection. Mu (Usually associated with CLL or a lymphoma) wDiagnostic Criteria Serum protein electrophoresis immunofixation shows monoclonal Mu heavy chain. Hypogammaglobulinemia with a monoclonal peak in 40% of patients. Bence Jones proteinuria in two-thirds of patients; most excrete large amounts of kappa light chains. Bone marrow shows vacuolated plasma cells.
- 256. HEMOGLOBIN C (HbC) DISEASE HbC Disease wHb electrophoresis demonstrates the abnormal hemoglobin. Significant hypochromic hemolytic anemia is present. mBlood smear shows many target cells, variable number of microspherocytes, occasional nucleated RBCs, a few tetragonal crystals within RBCs that increase after splenectomy. Reticulocyte count is increased (2–10%). Osmotic fragility is decreased. Mechanical fragility is increased. RBC survival time is decreased. HbF is slightly increased. Increase in serum bilirubin is minimal. Normoblastic hyperplasia of bone marrow is present. HbC Trait (Occurs in 2% of American blacks, less frequently in other Americans.) wHb electrophoresis demonstrates the abnormal Hb. Blood smear shows variable number of target cells. No other abnormalities are seen. HbC–Beta-Thalassemia Resembles HbCC but different concentration of HbC on electrophoresis. Usually asymptomatic but moderate hemolysis may occur if HbA is absent, in which case family studies may be needed to differentiate from HbCC. HbSC Disease HEMOGLOBIN D (HbD) DISEASE Homozygous HbD Disease wHb electrophoresis demonstrates the abnormal Hb at acid pH. Mild microcytic anemia Target cells and spherocytes Decreased RBC survival time Heterozygous HbD Trait wHb electrophoresis demonstrates the abnormal hemoglobin at acid pH. No other laboratory findings are characteristic. HEMOGLOBIN E (HbE) DISEASE (Occurs almost exclusively in Southeast Asia; found in 3% of population in Vietnam and up to 35% in Laos; migrates like HbA2 on electrophoresis.) Homozygous HbE Disease Mild hypochromic hemolytic anemia or no anemia mMarked microcytosis (MCV = 55–70 fL) and erythrocytosis (~5.5 million/cu mm) mSmear shows predominant target cells (25–60%), which differentiates from HbE trait and microcytes. wElectrophoresis shows 95–97% HbE and the rest is HbF. Electrophoretic mobility same as HbA 2 but concentration is higher (15–30%). Heterozygous HbE Trait Asymptomatic persons found during family studies or screening programs. Normal Hb concentration Slight to moderate microcytosis (MCV = 65–80 fL) Erythrocytosis (RBC = 5.0–5.34 million/cu mm) wElectrophoresis shows 30–35% HbE.
- 257. HbE–Beta-Thalassemia Is most common symptomatic thalassemia in Southeast Asia. mHemolytic anemia varies in severity from moderate to marked (thalassemia major or intermedia phenotype). mSmear shows severe hypochromia and microcytosis, marked anisopoikilocytosis with many teardrop and target forms. Nucleated RBCs and basophilic stippling may be present. HbE–Alpha-Thalassemia Analogous to alpha-thalassemia 1 and 2 and HbH In American blacks, 28% have mild alpha-thalassemia without microcytosis, 3% have homozygotic alpha-thalassemia with microcytosis, 1% have microcytosis due to beta-thalassemia. Median Hb is ~ 1 gm/dL lower in blacks without iron deficiency than in whites. Alpha- or beta-thalassemia or HbE occur in ~50% of Southeast Asians and causes microcytosis. HEMOGLOBIN F (HbF), HEREDITARY PERSISTENCE Inherited persistence of increased HbF in adult without clinical manifestations due to many different genetic lesions (probably autosomal dominant). Incidence is <0.2%. Decreased MCV and MCHC wHb electrophoresis shows increased HbF (20–30%) and 60–70% HbA. wMay be pancellular (HbF is increased in all RBCs) or heterocellular (HbF is increased only in some RBCs), as distinguished by Kleihauer-Betke stain of peripheral blood smear. May be associated with other hemoglobinopathies but is different from the increase of HbF that is found in some hemoglobinopathies. HEMOGLOBINOPATHIES, LABORATORY SCREENING Normocytic normochromic RBC except in Thalassemia syndromes—microcytic hypochromic HbC, HbD, HbE diseases—microcytic normochromic Osmotic fragility—normal or decreased (especially in thalassemia) Symmetric shift in HbC, HbD, HbE, diseases Asymmetric shift in other hemoglobin diseases Target cells—in many of hemolytic diseases due to hemoglobinopathies; 50% of RBCs in HbC, HbD, HbE diseases Sickle cell test (Hb solubility test may be negative with <10% HbS; or monoclonal antibody test)—recognizes HbS Supravital stain (e.g., brilliant cresyl blue test for inclusion bodies [Heinz bodies])—these Heinz bodies may confirm suspicion of alpha-thalassemia minor in patient with microcytic anemia with normal Hb electrophoresis. Hb electrophoresis Distinguish sickle cell anemia and trait. Usually cellulose acetate at alkaline pH confirmed by agar at acid pH or isoelectric focusing. Electrophoresis of separated globin chains can substantiate alpha-chain abnormality. Distinguish various types of Hb. Alkali denaturation for HbF Kleihauer-Betke stain of blood smear identifies RBCs containing HbF. Flow cytometry Isopropanol precipitation test screen for unstable hemoglobins, which may not be detected on routine electrophoresis because they migrate with HbA. wReference laboratory tests Measurement of globin-chain synthesis ratios for confirmation of alpha- and beta-thalassemias. DNA analysis can detect gene deletions and point mutations, which disclose most types of alpha- and beta-thalassemia). Prenatal diagnosis during first trimester using DNA from chorionic villi or, after 16th week, from fetal cells by amniocentesis. HEMOGLOBINS, UNSTABLE (E.g., Hb Koln, Hb Zurich) Usually autosomal dominant inheritance mLaboratory evidence of episodes of hemolytic anemia of varying degrees of severity precipitated by infection or drugs (e.g., antimalarials, sulfonamides, acetanilid, nitrofurantoin, nalidixic acid, toluidine blue) Peripheral blood smear shows hypochromia, macrocytosis, anisocytosis, poikilocytosis, increased reticulocytes Supravital stain shows preexistent Heinz bodies (precipitation of abnormal Hb); may be few or absent if spleen is present. Excess precipitation of Hb at 37°C in 17% isopropanol compared to normal. Hb electrophoresis is often normal.
- 258. HEMOGLOBINS WITH ALTERED OXYGEN AFFINITY High-oxygen-affinity hemoglobins cause left shift in oxygen dissociation curve with less oxygen delivered to tissues; autosomal dominance. Erythrocytosis without splenomegaly Low P50 (see Polycythemia) Due to unstable Hb (e.g., Koln, Zurich, Gun Hill) or stable Hb (e.g., Yakima, Rainer, Bethesda) wMay be difficult to separate from normal Hb by electrophoresis in conventional media, isoelectric focusing mThese hemoglobinopathies are discovered in patients with unexplained erythrocytosis whose Hb shows a high oxygen affinity (oxygen tension at 50% saturation). Usually <20 mm Hg (normal = 27.5 mm Hg). Serum erythropoietin may be normal but increases after therapeutic phlebotomy. Low-oxygen-affinity hemoglobins cause right shift in oxygen dissociation curve with more oxygen delivered to tissues; autosomal dominance; cyanosis. •Mild hemolytic anemia in some cases. •High P50. w•Identify Hb by gel electrophoresis or measure absorption spectrum at 450–750 nm. •Due to unstable Hb (e.g., Torino, Seattle) or stable Hb Kansas. HEMOGLOBINURIA, PAROXYSMAL COLD Due To Original cases were due to syphilis; followed exposure to cold environment. Presently reported cases are not related to exposure to cold. May be idiopathic or associated with convalescence from an acute viral illness (e.g., mumps, measles, infectious mononucleosis). wLaboratory findings of acute, transient, nonrecurring hemolytic anemia with sudden hemoglobinuria, hemoglobinemia, spherocytosis, anisocytosis, poikilocytosis, nucleated RBCs. wCold autohemolysin (IgG antibody against P blood group system) is present (Donath-Landsteiner test—only if blood is chilled and then brought to 37°C in presence of complement and type O RBCs). Direct Coombs' test may be only weakly positive during the attack due only to complement as IgG readily elutes from RBCs. HEMOGLOBINURIA, PAROXYSMAL NOCTURNAL (MARCHIAFAVA-MICHELI SYNDROME)8 (Acquired clonal stem cell disorder; RBC deficiency of glycosylphosphatidylinositol-anchoring proteins causing increased sensitivity to complement-mediated lysis) mInsidious slowly progressive hemolytic anemia (mild to moderate, often macrocytic) and cytopenia mEvidence of hemolysis, e.g., Hemoglobinuria (black urine) is evident on arising. Urine contains Hb, hemosiderin (in WBCs and epithelial cells of sediment), and increased urobilinogen. Hemoglobinemia is present; increases during sleep. Methemalbuminemia. Increased serum LD and indirect bilirubin. Serum haptoglobin is absent during an episode. Stool urobilinogen is usually increased. Severity of hemolysis depends on number of affected RBCs, which coexist with normal cells (chimerism). Mild hemolysis with <20% complement-sensitive RBCs Sleep-related hemolysis with 20–50% affected RBCs Continuous hemolysis with >50% affected RBCs wFlow cytometry is superior to and replaces Ham's test. Demonstrates deficiency of glycosylphosphatidylinositol-anchored protein in RBCs and granulocytes. Permits concomitant diagnosis of paroxysmal nocturnal hemoglobinuria in ~20% of patients with myelodysplasia. CD59 analysis available commercially. Demonstration of increased RBC sensitivity to complement Ham's test (RBC fragility is increased in acid medium and in hydrogen peroxide); amount of change is related to clinical severity. Sucrose hemolysis test is said to be more sensitive but less specific than Ham's test. Autohemolysis is increased. Negative direct Coombs' test. Osmotic fragility is normal. Serum iron may be decreased. Platelet count usually shows mild to moderate decrease. WBC is usually decreased. Blood smear is not characteristic and often shows hypochromasia and polychromatophilic macrocytes (reticulocytes). Bone marrow is not diagnostic; most often shows normoblastic hyperplasia with adequate myeloid and megakaryocytic cells, but cellularity may be decreased or aplasia may be present. Stainable iron is often absent. Leukocyte ALP activity is decreased (as in other marrow stem cell disorders, e.g., chronic myelogenous leukemia and myelodysplastic syndromes).
- 259. RBC acetylcholinesterase activity is decreased. Develops in 5–10% of patients with aplastic anemia, and aplastic anemia develops in 25% of patients with paroxysmal nocturnal hemoglobinuria. Laboratory findings due to m•Recurrent arterial and venous thromboses, especially of GI tract, in ~30% of patients (e.g., hepatic, portal, splenic); cerebral, skin. · Hemorrhage. · Infection—causes death in ~10% of patients. m•Renal findings similar to those in sickle cell disease (e.g., papillary necrosis, multiple infarcts). · Spontaneous clinical remission in ~15%, including negative Ham's test. mDiagnosis should be considered in any patient with Coombs'-negative acquired chronic hemolysis, especially if hemoglobinuria, pancytopenia, or thrombosis is present. Bone marrow transplantation is definitive therapy. HEMOLYSIS Autoimmune, Extravascular, Warm Due To Primary (idiopathic)—55% of cases Secondary Lymphoproliferative neoplasms (e.g., chronic lymphatic leukemia, Hodgkin's and non-Hodgkin's lymphoma)—20% of cases Drugs—20% of cases Viral infections Connective tissue diseases Insidious onset of normochromic, normocytic anemia; nucleated RBCs, polychromasia, reticulocytosis, spherocytes; fragmented RBCs may be present. wDiagnosis by positive direct antiglobulin test (negative in £4% of cases) RBC coating by IgG alone in 20–40% of cases (makes SLE unlikely); by complement alone in 30–50% of cases; by both in 30–50% of cases Indirect antiglobulin test is positive in 60% of cases. Laboratory findings due to hemolysis Intravascular Hemolysis wAnemia varies from mild (Hb = 11.5 gm/dL) to severe (Hb = 2 gm/dL). MCV is usually 80–110 fL; MCV <70 fL in normochromic anemia suggests hemoglobinopathy or paroxysmal nocturnal hemoglobinuria; MCV >115 fL suggests macrocytic anemia. Peripheral smear shows macrocytes, nucleated RBCs, polychromatophilia. Spherocytes suggest hereditary spherocytosis or autoimmune hemolytic anemia. Microspherocytes suggest HbC disease, ABO erythroblastosis, burns. RBC cell fragments suggest DIC, prosthetic valves, hemolytic uremic syndrome. Target cells suggest hemoglobinopathies, postsplenectomy state. wIncreased reticulocyte count is a major criterion for hemolytic anemia. Plasma haptoglobin level decreases ~100 mg/dL in 6–10 hrs and lasts for 2–3 days after analysis of 20–30 mL blood. Test is relatively reliable and very sensitive. Plasma Hb increases transiently with return to normal in 8 hrs; lacks accuracy and precision. mHemoglobinuria occurs 1–2 hrs after severe hemolysis and lasts £24 hrs. It is a transient finding and is relatively insensitive. False-positive is due to myoglobinuria or to lysis of RBCs in urine. mUrine hemosiderin occurs 3–5 days after hemolysis with positive Prussian blue staining of renal tubular epithelial cells. It may be difficult to detect a single episode. Urine hemosiderin is commonly found in paroxysmal nocturnal hemoglobinuria. mSchumm's test for methemalbuminemia becomes positive 1–6 hrs after hemolysis of 100 mL blood and lasts 1–3 days. Methemalbuminemia also occurs in hemorrhagic pancreatitis. Serum bilirubin increase depends on liver function and amount of hemolysis. With normal liver function, it is increased 1 mg/dL in 1–6 hrs to maximum in 3–12 hrs after hemolysis of 100 mL blood. Increased serum total LD; isoenzymes may be useful to confirm RBC source. Extravascular hemolysis may cause increased serum indirect bilirubin and LD and decreased serum haptoglobin. In compensated hemolysis, little or no increase is seen in serum LD, bilirubin, Hb, or urine hemoglobin as in acute hemolytic anemia, but urine hemosiderin may be present. Increased urine and fecal urobilinogen are insensitive and unreliable as an index of hemolysis. Bone marrow shows marked normoblastic erythroid hyperplasia. Iron stains show marked increase; absence of iron suggests paroxysmal nocturnal hemoglobinuria. Combined Cold and Warm Antibody (Autoimmune Hemolytic Anemia) In ~8% of cases of autoimmune hemolytic anemia, serologic findings satisfy criteria for both warm and cold autoimmune hemolytic anemia. SLE occurs in >25% of these cases.
- 260. Severe hemolytic anemia. Autoimmune, Intravascular Cold Due To Primary (idiopathic) cold agglutinin syndrome–50% of cases Due to monoclonal cold antibody, usually IgM kappa anti-I (titer >1:1000), that reacts over wide temperature range and is active at skin temperature of 30–32°C. Secondary cold agglutinin syndrome Usually due to polyclonal cold antibodies with low titer and narrow thermal range. Monoclonal IgM anti-I antibodies (sometimes in high titer) are associated with Mycoplasma pneumonia (>80% of cases), infectious mononucleosis and some viral infections. Monoclonal IgM mu, kappa antibodies (sometimes in high titer) are associated with lymphoreticular disease (e.g., non-Hodgkin's lymphoma, Waldenström's macroglobulinemia, CLL). Polyclonal anti-I antibodies in low titer (<1:64) can be found in healthy persons. wDiagnosis by demonstrating cold antibody in serum. wAgglutination at room temperature that prevents performing RBC count or making blood smears should arouse suspicion of this condition. wArtifactual increased MCV and decreased RBC count due to clumps. MCH markedly increased. mChronic hemolysis with exacerbations, especially when patient is chilled. Stable mild to moderate anemia with polychromasia, rare spherocytes, occasional erythrophagocytosis. RBC morphology is less abnormal than in warm-antibody autoimmune hemolytic anemia. mDirect antiglobulin test is positive due to complement. Note difference between cold agglutinins and cryoglobulins. Cold agglutinins are immunoglobulins that bind RBC antigens best at 4°C; most are not cryoglobulins. Cryoglobulins are immunoglobulins that precipitate at low temperature; most do not bind RBC antigens. HEMOLYTIC DISEASE OF THE NEWBORN (ERYTHROBLASTOSIS FETALIS) Probability of isoimmunization of Rh-negative woman by a single Rh-incompatible pregnancy is ~17%. If mother and fetus are ABO incompatible, a protective effect on Rh isoimmunization occurs (due to immediate destruction of fetal RBCs by maternal AB antibodies). An Rh-positive infant occurs in ~10% of Rh-negative white women, 5% of black women, and 1% of Asian women. Prevalence has been markedly reduced due to prompt therapy with Rh immune globulin after abortion or delivery. Prenatal Screening and Diagnosis wBlood ABO and Rh type should be ascertained at first prenatal visit early in pregnancy. Indirect Coombs' test should always be performed regardless of Rh type because of ABO or irregular antigens. wFetal Rh D genotyping can be determined in DNA extracted from plasma buffy coat of Rh D-negative pregnant women. Occasional false-negatives occur in first trimester of pregnancy.9 Rh-negative women should be given anti-D immunoglobulin (RhIg) at end of second trimester and again within 72 hrs of delivery of Rh-positive baby. RhIg is also given when fetal RBCs can enter maternal circulation. Prevalence of hemolytic disease of the newborn has been markedly reduced due to prompt RhIg therapy. wMonitor anti-D titer in maternal serum periodically to detect sensitization (titer >1:8). If increased, serial amniotic fluid indirect bilirubin is performed to determine infant's risk in severe cases, and lung maturity is determined by lecithin/sphingomyelin ratio and other studies. wAmniocentesis in sensitized mothers is more reliable than anti-D titer to assess severity of disease. Indirect bilirubin reflects hemolysis. Determine prenatal umbilical vein Hct; if <18%, transfuse type O, Rh-negative RBCs in utero, which may cause infant to be typed as Rh-negative. DNA analysis of amniotic fluid by PCR can determine D-antigen status of fetus. wAt birth, determine cord blood Hb and bilirubin, and perform direct (Coombs') antiglobulin test on infant's RBCs. Positive direct antiglobulin test means probable later exchange transfusions. If test results indicate fetal-maternal hemorrhage >30 mL of fetal whole blood, additional RhIg should be given. wFetal-maternal hemorrhage may be indicated by Rosette test: antibody binds to fetal Rh-positive RBCs, forming rosette; detects 5 mL Rh-positive fetal RBCs (10 mL Rh-positive whole blood); negative with <2.5 mL Rh-positive fetal RBCs. Kleihauer-Betke test detects HbF; is least sensitive. Enzyme-linked antiglobulin test detects <12.5 mL (and as little as 3 mL) of Rh-positive whole blood. Flow cytometry detects 0.1% Rh-positive RBCs equivalent to fetal-maternal hemorrhage of 15 mL whole blood. Postnatal Diagnosis and Therapy wSerum indirect bilirubin shows rapid rise to high levels. May rise 0.3–1.0 mg/hr to level of 30 mg/dL in untreated infants to maximum in 3–5 days unless they die. Increased urine and fecal urobilinogen parallels serum levels. wDirect Coombs' test is strongly positive on cord blood RBCs when due to Rh, Kell, Kidd, Duffy antibodies but is usually negative or weakly positive when due to anti-A antibodies. It becomes negative within a few days of effective exchange transfusion, but may remain positive for weeks in untreated infants. Indirect Coombs' test on cord blood may be positive because of “free” immune antibody. At birth little or no anemia is seen. Anemia may develop rapidly (RBCs may decrease by 1 million/cu mm/day) in severe cases to maximum by third or fourth day. MCV and MCH are increased; MCHC is normal. Nucleated RBCs in peripheral blood are markedly increased (10,000–100,000/cu mm) during first 2 days (normal = 200–2000/cu mm) and are very large. They tend to decrease and may be absent by third or fourth day. Normoblastosis is mild or absent when due to antigens other than RhO. Peripheral smear shows marked polychromatophilia and anisocytosis, macrocytic RBCs, increased reticulocyte count (>6% and up to 30–40%). In ABO incompatibility, spherocytosis may be marked with associated increased osmotic fragility; spherocytosis is slight or absent in Rh incompatibility. HbF is decreased and adult Hb is increased. WBC is increased (usually 15,000–30,000/cu mm).
- 261. Platelet count is usually normal; may be decreased in severe cases but returns to normal after 1 wk. With decreased platelets, increased bleeding time, poor clot retraction, and purpura may be found. Prothrombin and fibrinogen deficiencies may occur. Disease terminates in 3–6 wks after elimination of maternal antibodies from infant's serum. Late anemia occurs during second to fourth week of life in 5% of those receiving exchange transfusions. Reticulocyte count is low, and marrow may not show erythroid hyperplasia. Hypoglycemia occurs in >15% of infants with cord Hb <10 gm/dL; often asymptomatic. Exchange Transfusion Use mother's serum for cross match. Use indirect Coombs' test for cross match. Use Rh-negative donor unless both mother and baby are Rh-positive. For subsequent transfusions, use blood compatible with that of mother and infant. Monitor infant's glucose level during exchange with heparinized blood and after exchange with citrated blood, as high glucose content of citrated blood may cause infant hypoglycemia 1–2 hrs later. Monitor infant's blood pH, because pH of donor is low; therefore prefer fresh heparinized blood. In infants, Hb of 15 gm/dL corresponds to RBC volume of 30 mL/kg body weight. Transfusion of 6 mL of whole blood equals 2 mL of packed RBCs. Destruction of 1 gm of Hb produces 35 mg of bilirubin. Infant with blood volume of 300 mL can have decrease in Hb of 1 gm/dL that may be undetected but produces 105 mg of bilirubin. wINDICATIONS FOR EXCHANGE TRANSFUSION See Table 11-14. Table 11-14. Criteria for Performing Exchange Transfusion Birth Weight Is (gm) Serum Bilirubin Is (mg/dL) <1000 10.0 1001–1250 13.0 1251–1500 15.0 1501–2000 17.0 2001–2500 18.0 >2500 20.0 Transfuse at one step earlier in presence of Serum protein <5 gm/dL Metabolic acidosis (pH <7.25) Respiratory distress (with O2 <50 mm Hg) Certain clinical findings (e.g., hypothermia, CNS or other clinical deterioration, sepsis, hemolysis) Other criteria for exchange transfusion are suddenness and rate of bilirubin increase and when it occurs; e.g., an increase of 3 mg/dL in 12 hrs, especially after bilirubin has already leveled off, must be followed with frequent serial determinations, especially if it occurs on the first or seventh day rather than on third day. Beware of rate of bilirubin increase >1 mg/dL during first day. Serum bilirubin of 10 mg/dL after 24 hrs or 15 mg/dL after 48 hrs in spite of phototherapy usually indicates that serum bilirubin will reach 20 mg/dL. Rate of bilirubin increase is not as great as in ABO hemolytic disease as in Rh disease; if danger level for exchange transfusion is not reached by third day, it is unlikely that it will be reached. Laboratory Complications of Exchange Transfusion Electrolytes—hyperkalemia, hypernatremia, hypocalcemia, acidosis Clotting—overheparinization, thrombocytopenia Infection—bacteremia, serum hepatitis Other—hypoglycemia Phototherapy of Coombs'-positive infants decreases exchange transfusions (from 25% to 10% of these infants); follow effect of therapy with serum bilirubin every 4–8 hrs. Phototherapy is not usually begun until serum bilirubin is 10 mg/dL. Skin color is disguised by phototherapy, so serum bilirubin determination is even more important. Beware of untreated in these infants occurring in 1–8 wks due to short survival time of Coombs“-positive RBCs. wPhototherapy is contraindicated in infants with congenital erythropoietic porphyria and with significant direct-reacting bilirubinemia to avoid bronze-baby syndrome. Serum, urine, and skin become bronze (bronze-black) due to some unknown pigment. Onset several hours or more after phototherapy; patient usually recovers without sequelae.
- 262. Most patients have some preexisting liver disease. Amniocentesis, Indications Prior immunized pregnancy with maternal antibody titer >1:8 in albumin History of hemolytic disease of newborn After the first amniocentesis at 24th week, repeat every 2–3 wks to measure presence and increase in bilirubin pigments; the rise in these pigments according to age of fetus correlates with severity of disease and is indication for intrauterine transfusion, repeat examination, or immediate delivery. Lecithin/sphingomyelin ratio should also be measured to determine pulmonary maturity (see Chapter 14). ABO hemolytic disease alone does not cause fetal loss and therefore is not an indication for amniocentesis. Indications for Selection of Patients for Immunosuppression of Rh Sensitization 10 (Passive immunization using RhIg anti-D, which should be administered within hours of delivery. Less protective for £13 days.) Nonimmunized mother must be RhO. (D) negative and weak D (D+W [formerly Du .]) negative regardless of ABO blood group. 1.8% of Rh-negative women become sensitized late in pregnancy. D+W women are classified as Rh positive and are not considered at risk for Rh immunization. Other indications (unless the father or fetus is known and documented to be Rh negative) (because of prenatal typing errors £3%) include: Abortion (spontaneous, therapeutic, threatened) Abruptio placentae Abdominal trauma during pregnancy Administration of whole blood, RBCs, granulocytes, or platelet concentrates from Rh-positive donors to Rh-negative patients of childbearing age Amniocentesis Ectopic pregnancy External cephalic version Chorionic villus sampling Death in utero Manual removal of placenta Percutaneous umbilical blood sampling Placenta previa Trophoblastic disease or neoplasm (not complete hydatiform mole) Tubal ligation Immune thrombocytopenic purpura Whenever a positive D+W test is found in a woman known to be D+W negative before delivery, the postpartum blood should be tested to confirm fetal-maternal hemorrhage and to quantify the volume of fetal cells in maternal circulation. Maternal serum must have no Rh antibodies. If antenatal RhIg has been administered, mother's postpartum serum will contain anti-D (usually weakly reactive [direct antiglobulin test] low titer [£4]), which does not indicate existing immunization, and she should receive postpartum immunoprophylaxis. Baby must be RhO (D) positive or D+W positive and have negative direct Coombs' test (cord blood). Protocol to determine postpartum candidacy for RhIg administration: Test mother to determine if she is Rh negative; do not perform D+W test. If mother is Rh negative, test cord RBCs; if these are Rh positive or D+W positive, mother is a candidate. Even if baby (cord RBCs) is Rh O negative, D+W typing is still necessary as D+W–positive cord RBCs can cause Rh sensitization. Quantitate fetal-maternal hemorrhage to determine dose of RhIg. Use microscopic D+W test for routine screening to detect Rh-positive fetal cells; detects fetal-maternal hemorrhage of ~35 mL of fetal blood in a woman of average size. This is often omitted due to difficulty in reading test and low predictive value of positive test. RhIg half-life is 21–30 days (standard dose). Thus most women have positive antibody screen. Records must be kept of antenatal RhIg to avoid classifying this as active immunization. Erythroblastosis, ABO ABO incompatibility causes approximately two-thirds of cases; Rh incompatibility causes less than one-third of cases, and the latter are more severe. Minor blood factors (e.g., c, E, Kell) cause 2% of cases. wMother is group O with group A1 or B infant; rarely is mother group A2 with group A1 or B infant. wInfant's serum shows positive indirect Coombs' test with adult RBCs of same group varying up to moderately positive, but positive test is not dependable. Infant's RBCs show a negative direct Coombs' test (by standard methods) due to antibody derived from mother that has crossed placenta. Both Coombs' reactions have disappeared after the fourth day. Marked microspherocytosis is present. Osmotic fragility is increased. Anti-A or anti-B titer in mother's serum is not useful because no correlation exists between the occurrence of hemolytic disease and the presence or height of the titer. If mother's serum does not hemolyze RBCs of same type as infant's, the diagnosis should be questioned. Rapidly developing anemia is rare; serial bilirubin determinations are indicators for exchange transfusion to prevent a level of 20 mg/dL. Infants may show jaundice in first 24 hrs but rarely require exchange transfusion for anemia or hyperbilirubinemia. For exchange transfusion, use group O, Rh-type–specific blood or group O, Rh-negative blood. Infants born subsequently to same parents do not have more serious disease, and they may have less serious disease.
- 263. HEMORRHAGE, NEONATAL See Table 11-15. Table 11-15. Comparison of Neonatal Acute and Chronic Blood Loss in Fetal-Maternal Hemorrhage Internal Hemorrhage (E.g., intracranial, large cephalohematoma, rupture of liver or spleen, retroperitoneal hemorrhage) Anemia without associated jaundice in first 1–3 days Indirect hyperbilirubinemia appears after third day. Twin-to-Twin Hemorrhage (Occurs in ~15% of monochorial twin pregnancies.) wHb difference >5 gm/dL in identical twins. wRecipient twin shows. Erythrocytosis with Hb £30 gm/dL and Hct up to 82% Increased indirect bilirubin Laboratory findings due to congestive heart failure, venous thrombosis, respiratory distress, kernicterus wDonor twin shows anemia with Hb as low as 4 gm/dL, increased reticulocyte count, increased number of nucleated RBCs. Fetal-Maternal Transfusion Anemia varies from mild to severe. Polychromatophilia, increased reticulocyte count, increased number of nucleated RBCs Serum bilirubin is not increased. Coombs' test is negative. If chronic, then findings due to iron deficiency may occur. wDiagnosis is established only by demonstrating fetal RBCs in maternal blood (e.g., Kleihauer-Betke test, flow cytometry). This condition can be found in ~50% of mothers but in only 1% of pregnancies is infant anemic. May not be found if there is major group incompatibility between mother and infant, in which case buffy coat smears of maternal blood may show erythrophagocytosis; or perform serial anti-A or anti-B titers in mother's blood for several weeks after birth. Concurrent hemolytic disease of the newborn and intraplacental hemorrhage should also be ruled out. In maternal-to-fetal transfusion, infant may show same findings as for recipient twin in twin-to-twin hemorrhage. HISTIOCYTOSIS X (LANGERHANS CELL GRANULOMATOSIS) (Proliferative abnormalities of macrophages) Eosinophilic Granuloma wBiopsy of bone is diagnostic. Blood is normal; eosinophilia is unusual. Leukopenia and thrombocytopenia suggest poorest prognosis. Letterer-Siwe Disease (Rapidly progressive fatal malignant disease primarily of children) Progressive normocytic normochromic anemia Hemorrhagic manifestations due to thrombocytopenia wDiagnostic biopsy (e.g., bone, skin, lymph nodes) shows characteristic lesions.
- 264. Hand-Schüller-Christian Disease (Reactive proliferation of macrophages of uncertain etiology) wDiagnosis by biopsy of involved tissues (especially bone) Anemia, leukopenia, and thrombocytopenia may be present. Diabetes insipidus may occur. HODGKIN'S DISEASE AND OTHER MALIGNANT LYMPHOMAS wDiagnosis is established by histologic findings of biopsied lymph node. Blood findings may vary from completely normal to markedly abnormal. Moderate normochromic normocytic anemia occurs, occasionally of the hemolytic type; may become severe. wSmall lymphocytic and follicular lymphomas often have malignant lymphocytes in peripheral blood; leukemic phase in 5–15% of patients. Cytopenias occur, commonly due to hypersplenism, immune effect, or lymphoma effect on marrow. wBone marrow involvement at time of diagnosis in <10% of patients with Hodgkin's disease; 50% of patients with diffuse, small cleaved lymphoma and mixed cell type; 70–80% of patients with follicular, small cleaved cell lymphoma; less frequent in those with large cell lymphomas. Patients with large intermediate-grade lymphoma and serum LD >500 U/L are less likely to be cured. Serum protein electrophoresis: Albumin is frequently decreased. Increased alpha 1 and alpha2 globulins suggest disease activity. Decreased gamma globulin is less frequent in Hodgkin's disease than in lymphosarcoma. Gamma globulins may be increased, with macroglobulins present and evidence of autoimmune process (e.g., hemolytic anemia, cold agglutinins). Monoclonal gammopathy in ~20% of small lymphocytic lymphomas. ESR and CRP are increased during active stages in ~50% of cases; may be normal during remission. ESR >30 mm/hr after radiotherapy may predict relapse. Hodgkin's Disease Peripheral blood changes are common (~25% of cases at time of diagnosis) but not specific. WBC may be normal, decreased, or slightly or markedly increased (25,000/cu mm). Leukopenia, marked leukocytosis, anemia are bad prognostic signs. Eosinophilia occurs in ~20% of patients. Relative and absolute lymphopenia may occur. If lymphocytosis is present, look for another disease. Neutrophilia may be found. Monocytosis may be found. These changes may all be absent or may even be present simultaneously or in various combinations. Rarely, Reed-Sternberg cells are found in marrow or peripheral blood smears in advanced disease. Platelets may be decreased or increased. Patients commonly have abnormal T-cell function with deficiencies of cell-mediated immunity and increased susceptibility to bacterial, fungal, and viral infections (especially herpes zoster and varicella); these persist even after cure. Serum immunoglobulins are usually normal. >50% of cases show evidence of EBV in Reed-Sternberg cells. Non-Hodgkin's Lymphoma Patients often have abnormalities of humoral immunity; hypogammaglobulinemia in 50% of cases and monoclonal gammopathy in ~10% of cases of small lymphocytic lymphomas. Autoimmune hemolytic anemia and thrombocytopenia may occur. Increased serum CA 125 in ~40% of cases indicates pleuropericardial or peritoneal involvement, may be useful for staging. Return of increased value to normal indicates therapeutic response with sensitivity of 100% and specificity >87%. Laboratory findings due to involvement of other organ systems (e.g., liver, kidney, CNS) Testicular non-Hodgkin's lymphoma is often aggressive and associated with CNS and bone marrow disease. Laboratory findings due to effects of treatment (e.g., radiation, chemotherapy, splenectomy), including acute and long-term toxicity, gonadal dysfunction, peripheral neuropathy, and second neoplasms (especially acute myelogenous leukemia). Occurs frequently in AIDS patients and shows rapid course, poor prognosis, frequent extranodal and CNS involvement. Post–organ transplantation malignant lymphomas in ~2% of cases; median time ~6 mos and two-thirds within 10 mos. Occurs in 0.8% of recipients of renal allografts, 1.6% of liver allografts, 5.9% of heart allografts. Compared to spontaneous lymphomas, these tend to be more aggressive, frequently large cell type in extranodal sites, especially CNS; many are immunoglobulin negative. wGene Rearrangement Use In follicular lymphomas bcl-2 gene rearrangement is molecular counterpart of t(14;18)(q32:q21) reciprocal translocation; found in >80% by cytogenic analysis and virtually all by molecular testing and differentiates this from reactive lymph nodes. Monitor for residual lymphoma during chemotherapy, confirm remission, detect minimal residual disease, detect marrow or distant site involvement, monitor patients undergoing marrow transplantation, diagnose relapse earlier. In B-cell diffuse lymphoma, patients positive for bcl-2 are less likely to have complete remission. Detection by PCR after bone marrow has been purged before marrow transplant is indicator to predict relapse. See Burkitt's lymphoma, Table 11-16.
- 265. Table 11-16. Non-Hodgkin's Lymphoma HYPEREOSINOPHILIC SYNDROME w Diagnostic Criteria Eosinophilia >1500/cu mm for >6 mos No other cause for eosinophilia Organ dysfunction, e.g., Cardiovascular in 50–75% of cases (e.g., valve insufficiency, heart failure, mural thrombi cause systemic embolization in 5% of cases) Pulmonary in one-third of cases (e.g., pleural effusion, diffuse interstitial infiltrates) Neurologic in 35–75% of patients Cutaneous in 50% of patients Liver function abnormalities in 15% of cases Abnormal urine sediment in 20% of patients Total WBC is usually <25,000 but may be >90,000/cu mm with 30–70% eosinophils. Abnormalities in count and morphology of platelets, WBC, and RBC. Mild anemia in ~50% of cases. Thrombocytopenia in one-third of cases. Hypercellular bone marrow with 25–75% eosinophils. May be difficult to distinguish from eosinophilic leukemia. HYPERIMMUNOGLOBULINEMIA E SYNDROME (Very rare autosomal dominant condition shows recurrent infections, chronic candidiasis, skeletal and dental abnormalities) See Table 11-6. wIncreased eosinophils in blood (in >90% of cases), sputum, and sections of tissues. Not correlated with serum IgE. wVery high serum IgE with substantial fluctuations over time. Other immunoglobulins are usually normal. Normal count of lymphocytes and subsets. HYPERIMMUNOGLOBULINEMIA M SYNDROME (Heterogeneous group of disorders) Male patients have history of pyogenic infections resembling those in X-linked agammaglobulinemia. Also susceptible to opportunistic infections, especially due to Pneumocystis carinii. wSerum usually has very low concentration of IgG (<150 mg/dL) and undetectable IgA and IgE. IgM is high normal and may be ³1000 mg/dL; IgD is also increased. wB lymphocytes are normal in number but have only surface IgM and IgD; surface IgG and IgA are virtually absent. Increased frequency of autoimmune disorders; neutropenia is most important and may be recurrent, severe, and prolonged; autoimmune hemolytic anemia, thrombocytopenia. In second decade of life, IgM-producing polyclonal plasma cells may show marked proliferation with extensive invasion of GI tract, liver, and gall bladder that may be fatal. Increased risk of abdominal cancers. HYPOALBUMINEMIA, HYPOANABOLIC (Inherited disorder present from birth, without kidney or liver disease) Growth and development are normal. The patient is unaffected except for periodic peripheral edema. wSerum albumin is <0.3 gm/dL. wTotal globulins are 4.5–5.5 gm/dL. Serum cholesterol is increased. Albumin synthesis is decreased, with decreased catabolism of IV-injected albumin. HYPOGAMMAGLOBULINEMIA, COMMON VARIABLE (OR “ACQUIRED”) (Heterogeneous immunodeficiency syndrome; can result from three different immunologic causes: intrinsic B-cell defects, immunoregulatory T-cell imbalances, or autoantibodies to T or B cells)
- 266. See Table 11-6. Clinically, may resemble X-linked agammaglobulinemia but infections are less severe, sex distribution is equal. Or patients may have unusual infections (e.g., P. carinii, various fungi); recurrent HSV and HZV infections in ~20% of patients. Untreated cases present with chronic lung disease and bronchiectasis and infections elsewhere due to other organisms. Many have sprue-like syndrome due to G. lamblia. wDiagnosis by exclusion of other causes of humoral immune defects. Serum IgG is decreased (<250 µg/µL); IgA and IgM are usually decreased. Associated with increased incidence (~20%) of autoimmune diseases (e.g., PA occurs in ~10% of patients, SLE, RA) and malignancy (especially intestinal lymphomas and gastric adenocarcinoma) Reactive follicular hyperplasia of lymph nodes, tonsil, spleen, and small bowel (may cause malabsorption) but lack plasma cells. Sterile noncaseating granulomas can occur in liver, spleen, lung, skin. T lymphocyte function may be impaired. Number of peripheral blood B cells may be low or high but fail to differentiate into immunoglobulin antibody–secreting cells. IMMUNODEFICIENCY, CELLULAR, WITH NORMAL IMMUNOGLOBULINS (NEZELOF'S SYNDROME) See Table 11-7. wLymphopenia, neutropenia, eosinophilia wMarked deficiency of total T cells and T-cell subsets; normal helper/suppressor (CD4/CD8) ratio (in contrast to AIDS patients, who show marked deficiency of CD4 with reverse of ratio) Normal or increased serum immunoglobulins; some show selective IgA deficiency, increased IgD, and marked increase in IgE. Infants may show recurrent or chronic pulmonary infection, failure to thrive, candidiasis, gram-negative sepsis, GU tract infection, progressive varicella, etc. Decreased lymphoid tissue with depletion of paracortical lymphocytes Hypoplastic thymus shows abnormal architecture with no Hassall's corpuscles, few lymphocytes, poor corticomedullary distinction. Few patients have associated enzyme deficiency causing low or absent serum uric acid. IMMUNODEFICIENCY, CLASSIFICATION Primary See Table 11-6, Table 11-7 and Table 11-17. Table 11-17. Some Infectious Agents in Various Immune Deficiency Disorders Primary B-cell (antibody) deficiency disorders X-linked agammaglobulinemia (block in maturation of pre-B cells) Common variable immunodeficiency (block in differentiation of B cells to plasma cells) Selective IgA deficiency (block in differentiation to a specific isotype) Selective IgG subclass deficiency (block in differentiation to a specific isotype) Hyperimmunoglobulinemia M syndrome Primary T-cell deficiency DiGeorge syndrome (lack of thymus development causes block in T-cell maturation) Chronic mucocutaneous candidiasis (probable absence of T-cell clones that respond to Candida infections) Hyperimmunoglobulinemia E syndrome Combined T-cell/B-cell deficiency Severe combined immunodeficiency disease (defect in adenosine deaminase or purine nucleoside phosphorylase enzymes) Wiskott-Aldrich syndrome Ataxia-telangiectasia Secondary, Associated With Virus infections (e.g., HIV, CMV, EBV infection, measles)
- 267. Metabolic disorders (e.g., uremia, malnutrition, diabetes mellitus) Protein deficiency (e.g., nephrotic syndrome) Immunosuppression (e.g., drugs, neoplasms, splenectomy) Respiratory tract disorders Anatomic (e.g., tracheoesophageal fistula, cleft palate, gastroesophageal reflux Other (e.g., cystic fibrosis, immotile cilia, allergy) Prematurity IMMUNODEFICIENCY, SCREENING TESTS See Fig. 11-8 and Table 11-17. Fig. 11-8. Algorithm for workup of recurrent infections. (G-6-PD = glucose-6-phosphate dehydrogenase; hyper-IgE = hyperimmunoglobulinemia E; Ig = immunoglobulin; NBT = nitroblue tetrazolium.) Cell mediated HIV serology. Total lymphocyte count (lymphopenia usually indicates T-cell dysfunction because most circulating lymphocytes are T cells). T lymphocyte subsets. T cell–deficient patients tend to have chronic recurrent Candida infection of scalp, nails, mucous membranes. Anergy skin tests (purified protein derivative [tuberculin], Candida). B-cell deficiency should be suspected with recurrent, complicated, or severe pyogenic infections. Humoral immunity Antibody defects Serum IgG, IgM, IgA, anti-A, anti-B isohemagglutinins Serum IgG antibody titers before and after vaccinations (e.g., diphtheria, tetanus, Pneumococcus, H. influenzae type b) Complement defects CH50 C1-4 deficiencies associated with pyogenic infections and autoimmunity C3, C5-9 deficiencies associated with neisserial infections Phagocyte defects WBC and differential counts Serum IgE Nitroblue tetrazolium test now replaced by flow cytometry respiratory burst assay IMMUNOGLOBULIN A (IgA) DEFICIENCY, SELECTIVE (Immunodeficiency syndrome with lack of IgA-producing cells in intestinal lamina propria) See Table 11-6 and Table 11-7. wSerum IgA is very low (<5 mg/dL). wSerum IgM and IgG are usually normal. Serum antibodies to IgA in >40% of patients; therefore IV or IM blood products that contain IgA (e.g., immune serum globulin) are contraindicated. Peripheral blood lymphocytes bearing IgA, IgM, and IgG are normal. Plasma cells producing IgA are absent in GI and respiratory epithelium. Clinical—asymptomatic or recurrent pyogenic respiratory infections; increased incidence of allergic disease (e.g., asthma, eczema), autoimmune diseases (e.g., RA, SLE), GI complications (e.g., celiac disease, malabsorption, chronic giardiasis). Found in >1 in 400 persons in general population. IRRADIATION, HEMATOLOGIC EFFECTS
- 268. (Depends on amount of irradiation received) Severe Severe leukopenia with infection. Thrombocytopenia and increased vascular fragility, causing hemorrhage; begins in 4–7 days, peak severity in 16–22 days. Aplastic anemia if patient survives 3–6 wks; laboratory findings due to complications, such as hemorrhage, infection, dehydration. Mild (<300 R) Increased neutrophils within a few hours with onset of irradiation sickness. Decreased lymphocytes after 24 hrs, causing decrease in total WBC. No anemia unless dose of radiation is greater; may appear in 4–8 wks. ( Early appearance of anemia with greater irradiation is due to hemorrhage and changes in fluid homeostasis rather than marrow injury.) Platelets slightly decreased (some patients). Chronic (occupational) Decreased granulocytes Increased lymphocytes, relative or absolute Varying degrees of leukocytosis and leukemoid reactions Varying degrees of anemia, normocytic or macrocytic; erythrocytosis Thrombocytopenia Late Increased incidence of leukemia (e.g., in survivors of atomic bomb explosions) Increased incidence of visceral malignancy (e.g., liver cancer due to Thorotrast, bone cancer due to radium) JORDANS ANOMALY wHarmless rare anomaly of fatty inclusions in cytoplasm of all neutrophils, most monocytes, some basophils and eosinophils, occasional lymphocytes. w3–10 vacuoles/neutrophil stain with Sudan III. Fewer vacuoles are found in marrow myeloid cells beginning with promyelocytes. LEUKEMIA, ACUTE In adults 20% of acute leukemias are lymphocytic (ALL) and 80% are nonlymphocytic (AML). wIn children, 75% of cases are ALL and 25% are AML or chronic; >80% show clonal chromosomal abnormalities. With specific genetic abnormalities, PCR can identify as few as 1 malignant cell per 10 6 normal cells and minimal residual leukemia in >90% cases of childhood ALL. wPeripheral blood. WBC is rarely >100,000/cu mm. It may be normal and is commonly less than normal. Peripheral smear shows many cells that resemble lymphocytes; it may not be possible to differentiate the very young forms as lymphoblasts or myeloblasts, and special cytochemical stains may be used (blast cells are positive for peroxidase, Sudan black B, and nonspecific esterase in AML but negative in ALL; cytoplasmic acid phosphatase may be positive in T-cell ALL). Auer rods are diagnostic of AML; seen in 10–20% of cases. Special immunologic markers distinguish T-cell, B-cell, and non–T-, non–B-cell types of ALL, which is important because of different prognosis and relapse patterns in the three types. Prognosis is poorer in older children and adults >35 yrs and those with high initial WBC, with chromosome translocations (e.g., 9,22 in Ph 1 chromosome and 4,11-positive ALL). Favorable response to treatment is more likely if B-cell lymphoblasts are CALLA positive (common ALA antigen) but cytoplasmic mu-chain negative. Presence of leukemic lymphoblasts that express myeloid antigens is associated with an unfavorable prognosis. Anemia is almost always present at clinical onset. Usually normocytic and sometimes macrocytic, it is progressive and may become severe. Normoblasts and polychromatophilia are common. Platelet count is usually decreased at clinical onset and becomes progressively severe. May show poor clot retraction, increased BT, positive tourniquet test, etc. wBone marrow Blast cells are present even when none are found in peripheral blood. (This finding is useful to differentiate from other causes of pancytopenia.) Progressively increasing infiltration with earlier cell types (e.g., blasts, myelocytes) is seen. The myeloid-erythroid ratio is increased. Erythroid and megakaryocyte elements are replaced. Cultures (bacterial, fungal, viral) should be performed routinely as they may be the first clue to occult infection. wQuantification of leukemic cells by molecular methods (e.g., PCR or antibody detection) in minimal residual disease ALL 11, 12 and 13 Combinations of surface antigens semispecific for leukemic clone detect level of 10 -4 cells. Various PCR techniques have limit of detection of 10 -2 to 10-6 leukemic cells. After end of induction chemotherapy, level of minimal residual disease is useful for prognosis. >10 -2 cells (which is below detection limit with conventional microscopic examination of bone marrow) or >10-3 cells at later time is associated with very high probability of relapse; <10 -5 (<0.01% nucleated cells) is associated with very low probability of relapse. If <10-3 cells in bone marrow, sampling error may be significant because of multifocal clones; therefore use peripheral blood or multiple marrow samples. Considered in remission after cytotoxic therapy, <1010 leukemic cells and leukemic cells cannot be identified by conventional techniques. With 1011 to 1012 leukemic cells, clinical symptoms are present. With 1013 leukemic cells, death results. DIC may be present at onset (especially with M3; also with M4 and M5; less commonly with other forms). Serum uric acid is frequently increased. Tumor lysis syndrome may cause hyperphosphatemia, hypokalemia, hypocalcemia, hypomagnesemia, etc. (See Chapter 17.) Increased serum creatinine and BUN reflect infiltration of kidneys, impairing renal function. In AML serum LD is frequently but inconstantly increased; normal to slight increase in serum AST, ALT is seen. LD >400 U/L predicts shorter survival in elderly
- 269. patients. Urine lysozyme may be increased in acute nonlymphocytic leukemia (M4 and M5). wLaboratory findings due to complications Meningeal leukemia occurs in 25–50% of children and 10–20% of adults with acute leukemia; CSF shows pleocytosis and increased pressure and LD. CSF should be examined routinely as “sanctuary” for leukemic cells during chemotherapy and to rule out occult infection. Cranial irradiation may be indicated if leukemic cells in CSF, WBC ³100,000/cu mm, or Ph1 chromosome is present. With large leukemic cell burden, hyperuricemia (may have urate nephropathy), hyperkalemia, hyperphosphatemia with secondary hypocalcemia are common. Infection causes 90% of deaths. Most important pathogens are enteric gram-negative rods (especially Pseudomonas aeruginosa, E. coli) and S. aureus. With cumulative immunosuppression, fungi (especially C. albicans), viruses (especially VZV and other herpesviruses), and P. carinii. Hemolytic anemia. Laboratory findings due to predisposing conditions Inherited syndromes Genetic (e.g., Down syndrome, Bloom's syndrome, Klinefelter's syndrome, Fanconi's anemia) Immunodeficiency (e.g., ataxia-telangiectasia, common variable immunodeficiency, severe combined immunodeficiency, Wiskott-Aldrich syndrome) Ionizing radiation (therapeutic or accidental) Chemotherapeutic drugs (e.g., alkylating agents) Toxins (e.g., benzene) Complete remission is possible with drug therapy (e.g., prednisone in ALL). WBC falls (or rises) to normal in 1–2 wks with replacement of lymphoblasts by normal PMNs and return of RBC and platelet counts to normal; bone marrow may become normal. Maximum improvement in 6–8 wks. Laboratory findings due to toxic effect of therapeutic agents Amethopterin toxicity causes a macrocytic type of anemia with megaloblasts in marrow, rather than blast cells in marrow as with leukemic normocytic anemia. Cyclophosphamide can cause hematuria. L-Asparaginase can cause coagulopathies, hyperglycemia, etc. Daunorubicin can cause cardiac toxicity with fibrosis. In childhood ALL, 7× increase in all cancers and 22× increase in CNS tumors. LEUKEMIA, HAIRY CELL (LEUKEMIC RETICULOENDOTHELIOSIS) (Rare condition of splenomegaly and infrequent lymphadenopathy with characteristic pathologic changes in marrow and spleen) wDiagnosis is established by finding the characteristic mononuclear cells (that show long delicate cytoplasmic projections) in the peripheral blood (vary from 0%–90%) or bone marrow, which show a characteristic diffuse intense histochemical reaction of tartrate-resistant acid phosphatase (isoenzyme 5) activity (mild to moderate staining of leukocytes may be seen in Sézary syndrome, CLL, infectious mononucleosis, and in various histiocytes). Cells bear B lymphocyte markers. Isoenzyme 5 may also be increased in the serum. Hairy cells increased to frankly leukemic levels in £ 20% of cases. Hypersplenism with pancytopenia in >50% of cases Thrombocytopenia (in 75% of cases), usually <80,000/cu mm Anemia (usually normochromic), usually 7–10 gm/dL Leukopenia (in >60% of cases), usually <4000/cu mm Abnormal platelet function may be found. ESR may be increased. wBone marrow reticulin fibrosis causes dry tap requiring core biopsy; hairy cells are readily seen. Leukocyte ALP activity is markedly increased in some patients. Laboratory findings due to infection (e.g., pyogenic bacteria, opportunistic organisms) LEUKEMIA, LYMPHOBLASTIC, ACUTE (ALL) Primarily affects children; comprises >85% of childhood leukemias. Children with Down syndrome have 15× higher incidence of leukemia (especially ALL). Increased incidence also in immunodeficiency syndromes (e.g., ataxia-telangiectasia), osteogenesis imperfecta, Poland's syndrome, and sibs of ALL patients. High relapse rate. In adults, 80% of ALL cases are B-cell and 20% are T-cell lineage. Classified as L-1, L-2, L-3 (French-American-British [FAB] classification system) based on cell morphology; cannot be differentiated by cytochemical stains. ~25% of cells in L-1 and L-2 have T-cell antigens; rest are null cells (B-lineage ALL that lack CD10 expression). L-3 cells usually have B-cell (Burkitt's) antigens. L-1 is more common in childhood ALL and L-2 is more common in adult ALL. wWBC increased; may be >100,000/cu mm but normal or low in some patients. Moderate to severe thrombocytopenia. Variable degree of anemia. wMarrow usually shows >50% lymphoblasts. mHigh incidence of meningeal involvement; CSF may show increased protein and cells (some recognized as leukemic). mPh1 chromosome is present in ~20% of adults and <5% of children. Uniformly poor prognostic sign. Most commonly in non–T-cell, non–B-cell ALL; never in T-cell ALL. Serum LD, uric acid, ESR often increased. LEUKEMIA, LYMPHOCYTIC, CHRONIC (CLL) (30% of all leukemias in United States; <5% are T-cell type)
- 270. See Table 11-18. Table 11-18. Comparison of Chronic Lymphocytic Leukemias Diagnostic Criteria wLymphocyte count >15,000/cu mm in absence of other causes and marrow infiltration >30% for >6 mos. Have characteristic immunophenotype. wDemonstration of monoclonality in the proper clinical context confirms the diagnosis regardless of absolute lymphocyte count. Monoclonality is determined by demonstration of light-chain restriction in B-cell lymphocytosis and rearranged T-cell receptor genes in T-cell lymphocytosis; natural killer cells do not rearrange T-cell receptor genes. wPeripheral blood WBC is increased (usually 50,000–250,000/cu mm) with 90% lymphocytes, which are uniformly similar, producing a monotonous blood picture of small, mature-looking lymphocytes with minimal cytoplasm indistinguishable from normal. Frequent smudge cells. Blast cells are uncommon. Granulocytopenia. Neutropenia is a late occurrence. Autoimmune hemolytic anemia and thrombocytopenia in 25% of patients. Hb <11 gm/dL and/or thrombocytopenia (<100000/cu mm), diffuse bone marrow infiltration, and lymphocyte doubling time <1 yr correlate with marked decrease in survival time. Progress with rising WBC but may be absent with WBC >50,000/cu mm. Platelet count is less likely to increase with therapy than in myelogenous leukemia. wBone marrow Infiltration with earlier lymphocytic cell types is progressively increased. There is replacement of erythroid, myeloid, and megakaryocyte series, which show normal morphology and maturation. wLymph node biopsy shows pattern of diffuse lymphoma with well-differentiated, small, noncleaved cells; aspirate or imprint shows increased number of immature leukocytes, predominantly blast cells. Serum enzyme levels are less frequently increased and show a lesser increase than in chronic myelogenous leukemia. Even serum LD is frequently normal. Direct Coombs' test is positive in up to one-third of patients. Hypogammaglobulinemia occurs in two-thirds of cases depending on duration of disease; monoclonal gammopathy (most often IgM) is found in <1% of cases. Uric acid levels are not increased but may become so during therapy. Ph1 chromosome is not found. Chromosomal abnormalities in ~50% of patients, most often chromosomes 12 (especially trisomy 12) and 14 (especially 14q+). Laboratory findings due to secondary infection (e.g., encapsulated bacteria, herpes zoster, opportunistic organisms) Progression to more aggressive cancers in ~10% of cases, e.g., large B-cell lymphoma, prolymphocytic leukemia (>30% of cells are prolymphocytes), ALL, multiple myeloma LEUKEMIA, MYELOGENOUS, CHRONIC (Malignant clonal disorder of stem cells; 20% of all leukemias in United States; 90% of cases occur in adults, 10% in children) See Table 11-19, Fig. 11-9. Table 11-19. Differential Diagnosis of Chronic Myelogenous Leukemia
- 271. Fig. 11-9. Transformation of myeloproliferative syndromes. (CML = chronic myelogenous leukemia.) Types of chronic myeloid leukemias Chronic myelogenous leukemia Chronic myelomonocytic leukemia Mast cell leukemia (rare) Chronic monocytic leukemia (rare) Chronic eosinophilic leukemia (rare) Classified into chronic, accelerated, and blast crisis phases. Chronic Phase wWBC is usually 50,000–300,000/cu mm when disease is discovered, predominantly neutrophils and myelocytes with no leukemic hiatus. In earlier stages the more mature forms predominate, with sequentially fewer younger forms and only an occasional blast cell; later the younger cells predominate. Absolute basophilia is invariably present; may precede clinical symptoms by many years. Eosinophilia may be present but has less diagnostic utility than basophilia. Absolute monocytosis but relative monocytopenia is typical. Lymphocytes are normal in absolute number but relatively decreased. Decreased leukocyte ALP score in 95% of untreated cases. Leukocyte ALP score can rise to normal or high levels with infection, inflammation, or secondary malignant disease, after splenectomy, during remission due to chemotherapy, or at onset of blast crisis. mAnemia is usually normochromic, normocytic; absent in early stage and severe in late stage. Blood smear shows few normoblasts, slight polychromatophilia, occasional stippling. Reticulocyte count is usually <3%. Anemia is due to myelophthisis; also due to bleeding (skin and GI tract), hemolysis, and insufficient compensatory hematopoiesis. Degree of anemia is a good index of extent of leukemic process and therefore of prognosis. mPlatelet count is increased in 30–50% of cases; may be normal; decreased in terminal stages with findings of thrombocytopenic purpura. Low count may increase with therapy. Bleeding manifestations are usually due to thrombocytopenia. Megakaryocytes in blood in ~25% of cases. wBone marrow Hyperplasia of granulocytic elements occurs, with increase in myeloid/erythroid ratio. Myeloblasts <5% of all cells initially. Granulocytes are more immature than in the peripheral blood. Number of eosinophils and basophils is increased. Megakaryocytes may be increased. Hemosiderin deposits are increased. Focal or diffuse reticulin fibrosis in approximately one-third of cases. Macrophages (pseudo-Gaucher's cells) in approximately one-third of cases. wPhiladelphia chromosome t(9;22)(q34q11)(Ph1 ) due to chimeric bcr-abl gene on chromosome 22 is found in 95% of early chronic-phase cases; persists in chronic stable phase when marrow and blood appear normal. Presence of Ph1 affects response to therapy and survival. Persists during blast phase when additional abnormalities may appear in £ 8% of cases (e.g., chronic myelomonocytic leukemias). Other cytogenic abnormalities occur in one-third of the 5% of patients who are Ph1 -negative. Ph1 chromosome has also been found in ~20% of adults with ALL, 2% of adults with AML, 5% of children with ALL. Ph 1 chromosome in acute leukemia indicates a poor prognosis. Ph1 is present in granulomonocytic, erythroid, and megakaryocytic lines as well as some B lymphocytes. If karyotyping is negative, Ph 1 may be revealed by Southern blot, fluorescence in situ hybridization, or RT-PCR, which are more sensitive. PCR can detect 1 Ph 1 -positive cell in 105 to 106 normal cells. Needle aspiration of spleen Number of immature leukocytes is increased. Normoblastosis is present. Megakaryopoiesis is increased. Serum and urine uric acid are increased, especially with high WBC and antileukemic therapy. Urinary obstruction may develop because of intrarenal and extrarenal uric acid crystallization. Serum LD is increased; rises several weeks before relapse and falls several weeks before remission. LD is useful for following course of therapy. Increased serum AST and ALT show less increase than in acute leukemia; are normal in half of patients. Serum protein electrophoresis shows decreased albumin with increased alpha and gamma globulins. Direct Coombs' test is positive in £ 20% of patients at some time in course of disease; overt hemolysis in ~25% of these patients. Laboratory findings due to leukemic infiltration of organs (e.g., kidney [hematuria common; uremia rare], heart, liver). With increasing survival in blast crisis, meningeal leukemia has become more frequent (up to 40%) with leukemic cells in CSF indicative of need for intrathecal chemotherapy. Serum vitamin B12 level is increased (often >1000 µg/mL); B12-binding capacity is increased. Peripheral blood remission due to drugs–decreased WBC to nearly normal levels (decrease in spleen size is usually parallel) with only rare immature cells, correction of anemia, control of thrombocytosis, and occasional rise of LAP score to normal; marrow continues to show granulocytic hyperplasia and Ph 1 chromosome. Thyroid uptake of radioactive iodine is normal.
- 272. Accelerated Phase (Experienced by ~50% of patients before a blast crisis) wCombination of various criteria described in literature Rapidly increasing WBC (>50,000/cu mm) (doubling time <5 days) showing increasing immaturity and increased number of blasts (>5–15% in marrow, >15% in blood), basophilia (>10% in marrow, >20% in blood). Hb <7.0 g/dL not due to therapy. Platelets <100,000/cu mm not due to therapy or >1 million/cu mm despite therapy. Increased leukocyte ALP score. New karyotypic abnormalities (e.g., trisomy 8, trisomy 18, additional Ph 1 chromosomes). Myelofibrosis in some cases. Associated with clinical symptoms. Increasing doses of drugs are needed to lower neutrophil count. Blast Crisis (Occurs abruptly without an accelerated phase in 50% of cases) wDiagnosed by >30% blasts in marrow or peripheral blood or extramedullary proliferation of blasts (chloroma), or large foci of blasts in bone marrow biopsy. Approximately one-third of patients with CML in blast crisis have lymphoid transformation (cells show morphologic, antigenic, enzymatic [TdT], and other lymphoid characteristics). Patients are increasingly refractory to therapy in blast phase and die of acute leukemia or complications in 3–6 mos. Platelet count <15,000 or >1 million/cu mm, blasts in peripheral blood, absence of Ph 1 , and moderate to marked myelofibrosis at time of diagnosis are poor prognostic signs. WBC <25,000/cu mm or Hb >14 gm/dL are good prognostic signs. Juvenile Chronic Myelogenous Leukemia14 Differs from adult CML Aggressive disease. 95% of patients are <4 yrs old. Leukocytosis (usually <100,000/cu mm) with absolute monocytosis (>450/cu mm). Immature myeloid cells in peripheral blood in >70% of cases. <25% marrow blasts. Absent Ph1 . Increased HbF (typically 20–80%); is only leukemia with this increase. Lymphadenopathy in 20% of cases. Skin involvement with monocytic infiltrate is very common; may be preceded by neurofibromatosis. Viral studies (CMV, EBV, rubella) are usually negative. Leukocyte ALP is not useful; may be normal, low, or increased. LEUKEMIA, PLASMA CELL wWBC usually >15,000, with >20% plasma cells or >2000/cu mm in peripheral blood varying from typical plasmacytes to immature and atypical forms; absolute plasma cell count >2000/cu mm. Occasionally, special studies (cytochemical stains, cell surface and cytoplasmic markers, electron microscopy) are needed to confirm identity of plasma cells. wPlasma cell monoclonality. ~60% of cases are primary and the rest occur in 2% of previously diagnosed cases of multiple myeloma. Primary cases have smaller M protein peak in serum, higher platelet count, younger age, and longer survival. Other findings (see Myeloma, Multiple) LEUKEMIA, PROLYMPHOCYTIC (Rare variant of CLL; may occur de novo or from CLL) Compared to CLL, is characterized by more rapid clinical course, poorer prognosis, slightly older patient age, larger spleen, less frequent lymphadenopathy, higher prolymphocyte count (>55%), and immunologic differences (mouse erythrocytes, rosettes, surface immunoglobulin staining). WBC >100,000/cu mm in 65% of patients. ~80% are B-cell and 20% are T-cell type, which show different chromosomal abnormalities. LEUKEMIA, RISK FACTORS Ionizing radiation Oncogenic viruses Chemical agents (e.g., benzene compounds) Genetic disorders (e.g., trisomy 21, Fanconi's syndrome, Bloom's syndrome, ataxia-telangiectasia) Advanced maternal age LEUKEMIAS, NONLYMPHOCYTIC, ACUTE15,16 wFrench-American-British (FAB) Classification Has 85% concordance. Based on morphology and cytochemistry. Advances in immunophenotyping and cytogenetics provide additional essential information. M-1, M-2, M-3 leukemias are predominantly granulocytic.
- 273. M-0 Acute Myelogenous Leukemia Incidence: ~5% of AML cases ³ 30% blasts Minimal differentiation. M-1 Acute Myeloid Leukemia with Minimal Maturation Incidence: 20% of AML cases >90% of nonerythroid nucleated cells are blasts, predominantly type 1. <10% of nonerythroid nucleated cells are of maturing granulocytic lineage. Occasional Auer rods may be present M-2 Acute Nonlymphocytic Leukemia with t(8;21) Incidence: 30% of AML cases Patient age: young (mean = 28 yrs) Clinical findings: splenomegaly in 28%; chloromas, especially of face area, in 20% Morphology: myeloblasts often with Auer rods (90%) are heterogeneous, hypogranular, and frequently show pseudo-Pelger-Huët abnormalities. Sum of type I and II blast cells is 30–89% of nonerythroid cells (differs from M-1 in which the sum of type I and II blast cells is >90% of nonerythroid cells and ³ 3% of these are peroxidase or Sudan black positive); monocytic cells are <20%; granulocytes from promyelocytes to polynuclear types are >10%. Maturation toward granulocytes is often abnormal; eosinophil precursors are frequently increased and may contain Auer rods. Histochemistry: cells contain granulocyte but not monocyte enzymes; Sudan black and myeloperoxidase is abnormal (punctate rather than diffuse). Karyotype: t(8;21)(q22;q22); critical region 21q translocated to 8q; frequent loss of sex chromosome. Increased predilection for this leukemia in Down syndrome (trisomy 21). Oncogenes: c-ets-2 translocates from 21q to 8q but expression data for the gene are unknown; c- mos remains at 8q and c-myc translocates to 21q but both are probably not important. Prognosis: 75–85% complete remission rate after chemotherapy but median survival (9.5 mos) is of average duration. M-3 Acute Promyelocytic Leukemia Incidence: 10% of AML cases Patient age: median of 31 yrs Clinical findings: typically present with bleeding diathesis; £ 47% die of early fatal hemorrhage. DIC in £ 80% of cases. Morphology: <30% blasts in most cases. Predominantly neoplastic promyelocytes with coarse azurophilic granules and multiple Auer rods; a variant ( M-3V is ~30% of M-3 cases) shows hypo/microgranular promyelocytes on electron microscopy. Leukemic cell count in peripheral blood is usually not high (5000–15,000/cu mm). Unusual feature: blast cells occasionally can be induced to differentiate into mature granulocytes or macrophages by various agents. Karyotype: t(15;17)(q22;q12) occurs frequently. Oncogene: none known M-4 Acute Myelomonocytic Leukemia Incidence: 25% of AML cases Marrow morphology: ³ 30% of nonerythroid nucleated cells are myelomonocytic blasts; 2–80% of these are of granulocytic lineage and 20–80% are of monocytic lineage. Peripheral blood typically shows myelomonocytic blasts and >500/cu mm monocytes; serum lysozyme is often elevated. A variant (M-4Eo) shows 1–30% abnormal eosinophils (precursors). Histochemistry: very weak staining for nonspecific esterase; can be distinguished from granulocytic types by monoclonal antibodies demonstrating specific antigens. Karyotype: almost all patients show inversion of chromosome 16 [inv(16)(p13;q22)]; <10% show balanced translocation between short arm of one chromosome 16 and long arm of other chromosome 16 [t(16;16)(p13.1;q22)]. Oncogene: unknown Molecular oncology: disruption of metallothionein genes by the chromosomal abnormality Prognosis: 70–90% complete remission rate, probably with prolonged median duration (>18 mos). More than one-third have relapse in CNS including myeloblastomas (compared with 5% of all patients with acute nonlymphocytic leukemia, who rarely show CNS myeloblastomas). M-5 Acute Monocytic Leukemia with t(9;11) Incidence: 10% of acute monoblastic leukemia patients Patient age: often children and young adults Clinical findings: leukemic cells may infiltrate skin or gums; serum lysozyme is often elevated. Morphology: >30% of nonerythroid nucleated cells are blasts; >80% are of monocytic lineage. Can be distinguished from granulocytic types by monoclonal antibodies
- 274. demonstrating specific antigens. M-5a: poorly differentiated variant is 4% of AML cases; >80% of monocytic cells are blasts. M-5b: well-differentiated variant is 6% of AML cases; <80% of monocytic cells are blasts. Karyotype: t(9;11)(p22;q23) Oncogene: c-ets-1 translocated to 9p22 in region of interferon-alpha gene; expression data not known. M-6 Erythroleukemia Incidence: 6% of AML cases Marrow morphology: ³ 50% of all nucleated cells are erythroblasts. ³ 30% of nonerythroid nucleated cells are myeloblast cells (if <30%, the diagnosis is myelodysplastic syndrome). Erythroid hyperplasia and marked dyserythropoiesis (e.g., megaloblasts, ringed sideroblasts, Howell-Jolly bodies) are common. Nucleated RBCs in peripheral blood smear and anemia are common. Immunologic abnormalities are more frequent in this form, e.g., positive Coombs' test, ANA, positive RF, increased serum gamma globulins, hemolytic anemia. M-7 Acute Megakaryocytic Leukemia Incidence: 1% of AML cases Marrow morphology: myelofibrosis present in almost all patients; 20–40% present with acute myelofibrosis, making blast count impossible. Blast cells are highly polymorphic and are often classified as undifferentiated. Myeloblasts and megakaryoblasts are ³ 30% of all cells. Increased numbers of maturing megakaryocytes may be present. Megakaryocyte fragments and micromegakaryocytes and blasts are frequently present in peripheral blood. Histochemistry: no myeloperoxidase or nonspecific esterase reaction. Unlike all other FAB subtypes, diagnosis is based on electron microscope identification of platelet peroxidase or on specific monoclonal antibodies to megakaryocyte antigens. Karyotype: abnormalities of chromosome 21 have been reported but specificity is still uncertain. High serum LD Prognosis: preliminary reports of poor response to conventional anthracycline-cytarabine–based therapy M-0 Acute Myeloid Leukemia without Differentiation Blasts do not fulfill FAB morphologic and cytochemical classification criteria. Not included in current FAB classification. Acute Undifferentiated Leukemia No evidence of either myeloid or lymphoid lineage. <1% of all acute leukemia cases. Not included in current FAB classification. Acute Mixed-Lineage Leukemia Myeloid and lymphoid lineages in same clone. 5–10% of all acute leukemia cases. 5–10% of acute leukemias convert from one lineage to another. Not included in current FAB classification. Therapy-Related Leukemia Clinical findings: >70% have a preleukemic phase lasting ~11 mos; occurs several years (median = 4 yrs) after chemotherapy (most frequently with an alkylating agent, especially melphalan, chlorambucil, or cyclophosphamide) or radiation for another disease such as Hodgkin's disease (by comparison, ~20% of all acute nonlymphocytic leukemias have a preleukemic phase). Risk is 3–10% 10 yrs after therapy but may be greater after age 40. Highest risk after combined radiation and alkylating therapy; develop AML. Risk of 5–20× after exposure to nontherapeutic compounds (e.g., benzene). Unexplained pancytopenia; infection and hemorrhage. Karyotype: >75% show deletion of chromosome 5/5q– and/or 7/7q–. Prognosis: shorter survival compared to de novo leukemias; often refractory to therapy. LEUKEMIAS AND LYMPHOMAS, DIAGNOSTIC METHODS wBased on combination of Microscopic examination of blood, bone marrow and/or lymph nodes Cytochemical and immunohistochemical staining Immunophenotyping by flow cytometry Cytogenetics Molecular analysis Clinical features Chromosome Abnormalities See Table 11-20.
- 275. Table 11-20. Chromosomal Translocations in Hematologic Malignancies At initial diagnosis, routine cytogenetic studies show chromosomal abnormality in >50% of cases. Acute nonlymphocytic leukemia 54% Acute lymphocytic leukemia 41% Chronic granulocytic leukemia 94% Myelodysplastic syndrome 39% Lymphoma 71% Cytogenetic studies show structural abnormalities including translocations, deletions, isochromosomes, inversions, duplications, and numeric anomalies (e.g., trisomies, monosomies). In contrast, molecular tests may detect only one or a few specific translocations. If an abnormal chromosome clone is not observed, the analysis should be considered nondiagnostic. 17 Risk assessment in ALL patients Of children <1 yr old for whom prognosis is poor, 70–80% have MLL gene rearrangements. In adolescents and adult patients, high frequency of MLL rearrangements and bcr-abl fusion is associated with poor prognosis. Favorable genetic abnormalities are hyperdiploidy (>50 chromosomes/cell), which is also associated with low WBC count, and ETV6-CBFA2 (TEL-AML1) fusion, which manifests mainly at age 1–9 yrs. Markedly hypodiploid or near-haploid leukemic cells usually indicate poor prognosis regardless of age of WBC count. Leukemic cells with bcr-abl fusion usually indicates high-risk. LEUKEMIA/LYMPHOMA SYNDROME, ADULT HUMAN T CELL (Recently described syndrome found chiefly in black men in United States and elsewhere with acute onset, aggressive clinical course) wIncreased antibody titers to HTLV-I. In Japan, ~25% of healthy persons are antibody positive. wLeukemic phase with WBC count £ 190,000/cu mm, large or mixed small and large cell immunoblastic types, typical “flower” cells with indented nuclei; infrequent anemia and thrombocytopenia. Bone marrow involvement in 50% of patients, correlates poorly with extent of peripheral blood involvement. wHypercalcemia in ~75% of patients is characteristic; may occur without bone involvement. May be very high. wBiopsy shows lymphomatous involvement of affected sites (e.g., lymph nodes, liver, spleen, bone, skin, etc). wHTLV-I can be isolated from malignant lymphoma or leukemia cells. Laboratory findings due to involvement of various organs or systems (e.g., liver, CNS). Marked immunosuppression with opportunistic infections (e.g., cryptococcal meningitis, P. carinii pneumonia) LYMPHADENOPATHY, ANGIOIMMUNOBLASTIC (Rare lymphoproliferative disorder arising from mature postthymic T lymphocytes with sudden onset of constitutional symptoms and lymphadenopathy; very poor prognosis) wDiagnosis requires a lymph node biopsy, which shows characteristic changes, but these alone do not permit diagnosis and the clinical findings are required. Nonspecific polyclonal hypergammaglobulinemia in 75% of cases. Coombs-positive hemolytic anemia in 50% of cases. Leukocytosis with lymphopenia Thrombocytopenia High frequency of autoantibodies and often associated with other autoimmune syndromes, especially SLE. Death usually due to infection associated with T-cell immune deficiency (e.g., CMV, EBV, HSV, P. carinii, mycobacteria, opportunistic fungi). Lymphomas (B- or T-cell type or rarely Hodgkin's disease) develop in 5–20% of cases. Serologic tests for HIV are negative. LYMPHOCYTOSIS (INFECTIOUS), ACUTE Markedly increased WBC (³ 40,000/cu mm) is due to lymphocytosis (normal appearing, small-sized lymphocytes). Heterophil agglutination is negative. LYMPHOMA, CUTANEOUS T-CELL (Derived from postthymic T helper cells) Sézary Syndrome wSyndrome of skin lesions due to infiltration of Sézary cells associated with presence of these cells in peripheral blood wIncreased peripheral blood lymphocyte count, >15% of which are atypical lymphocytes (Sézary cells) Total WBC often increased. ESR, Hb, and platelet counts usually normal.
- 276. Bone marrow, lymph nodes, and liver biopsy usually normal. Mycosis Fungoides wBiopsy of lesion (usually skin) shows microscopic findings that parallel clinical findings. Repeated periodic biopsies may be needed before diagnosis is established. Laboratory findings are generally not helpful. Bone marrow may show increase in RE cells, monoblasts, lymphocytes, plasma cells. Peripheral blood may occasionally show increased eosinophils, monocytes, and lymphocytes. wMycosis fungoides cells in peripheral blood or marrow suggest extensive disease. Laboratory findings due to involvement of virtually any other organ. LYMPHOPROLIFERATIVE (AUTOIMMUNE) SYNDROME18 (Recently defined inherited disorder arising in early childhood that includes massive persistent lymphadenopathy, splenomegaly, and autoimmune features due to failure of apoptosis of lymphocytes) wAbsolute increase of B-cell and T-cell counts with polyclonal expansion of T cells, 25% of which are double negative. wAutoimmune disease. Hemolytic anemia ITP Autoimmune neutropenia Polyclonal hypergammaglobulinemia Others (e.g., GN, primary biliary cirrhosis, Guillain-Barré syndrome) wCirculating autoantibodies. Positive direct Coombs' test Anticardiolipin antibody Others (e.g., ANA, RF) wBiopsy of lymph nodes or spleen shows characteristic benign lymphoid hyperplasia and plasmacytosis. Marked increase in plasma interleukin-10 values Laboratory changes due to infection after splenectomy for hypersplenism MACROGLOBULINEMIA (PRIMARY; WALDENSTRÖM'S) (Due to monoclonal proliferation of plasmacytoid lymphocytes and lymphocytoid plasma cells of B-cell origin producing an IgM M protein) wElectrophoresis/immunofixation of serum shows an intense sharp peak in globulin fraction, usually in the gamma zone, identified as IgM by immunoelectrophoresis (75% are kappa). The pattern may be indistinguishable from that in multiple myeloma. IgM protein ³3.0 gm/dL. Associated decrease in normal immunoglobulins. wTotal serum protein and globulin are markedly increased. mESR is very high. mRouleaux formation is marked; positive Coombs' reaction; difficulty in cross-matching blood. mSevere anemia, usually normochromic normocytic; usually due to hemodilution, occasionally hemolytic. Increased plasma volume may contribute an artifactual component. WBC is decreased, with relative lymphocytosis but no evidence of lymphocytic leukemia; monocytes or eosinophils may be increased. wBone marrow biopsy is always hypercellular and shows >30% involvement by pleomorphic infiltrate with atypical “lymphocytes” and also plasma cells. Increased number of mast cells. Similar spleen and liver involvement occurs in ~50% of patients. Marrow aspirate is often hypocellular. wLymph node may show malignant lymphoma, usually well-differentiated lymphocytic lymphoma with plasmacytoid features. mFlow cytometry shows that £50% of patients have circulating monoclonal B lymphocyte population. m50% of patients with Waldenström's macroglobulinemia have hyperviscosity syndrome due to coagulation abnormalities caused by large IgM molecule. (Normal serum viscosity = £ 1.8 centipoise.) Causes persistent oronasal hemorrhage in ~75% of patients, neurologic and visual disturbances, hypervolemia, and congestive heart failure. IgM may also cause cryoglobulinemia. Bence Jones proteinuria is found in 10% of cases. Monoclonal light chain in 70–80% of cases. Coagulation abnormalities: There may be decreased platelets and abnormal BT, coagulation time, PT, prothrombin consumption, etc. Serum uric acid may be increased. Impaired renal function is much less common than in myeloma. Amyloidosis is rare. wDiffers from multiple myeloma by absence of lytic bone lesions and of hypercalcemia. Macroglobulinemia may also be associated with neoplasms, collagen diseases, cirrhosis, chronic infections. MARROW TRANSPLANTATION, COMPLICATIONS Acute graft-versus-host disease develops in 25–30% of recipients and is fatal in 8%. Chronic graft-versus-host disease develops in 20–30% of patients who survive >6 mos. Most infections occur within 6 mos. Interstitial pneumonia occurs in 16% of those conditioned by cyclophosphamide and up to 50% of those conditioned with
- 277. whole-body irradiation; mortality is 40–50%; one-half of cases are due to CMV and one-half are of unknown cause. MAY-HEGGLIN ANOMALY (Rare autosomal dominant abnormality of WBCs and platelets) wLarge, poorly granulated platelets are associated with large abnormal Döhle's bodies in cytoplasm of most granulocytes and all neutrophils in absence of infection. (Döhle's bodies may also be found in neutrophilic response to infection.) In absence of infection, these Döhle's bodies are pathognomonic. wDiagnosis is confirmed by finding Döhle's bodies in a parent or sibling. Variable thrombocytopenia with prolonged BT and impaired clot retraction. ~50% have abnormal bleeding. METAPLASIA, AGNOGENIC MYELOID (IDIOPATHIC MYELOFIBROSIS) (Classified as a myeloproliferative stem cell disease stimulating marrow fibroblasts) w Diagnostic Criteria Bone marrow shows fibrosis without apparent cause. Repeated bone marrow aspirations often produce no marrow elements. Surgical biopsy of bone for histologic examination shows fibrosis of marrow that is usually hypocellular. Normocytic anemia due to hemolysis and decreased production Leukoerythroblastic peripheral blood (see Tumor of Bone Marrow); tailed cells (dacryocytes) present. Splenomegaly and osteosclerosis wPeripheral smear shows characteristic anisocytosis and marked poikilocytosis with teardrop RBCs (dacryocytes), polychromatophilia, and occasional nucleated RBCs. Rarely seen in other hematologic conditions. Reticulocyte count is increased (£10%). Hypersplenism may cause thrombocytopenia and leukopenia. WBC may be normal (50% of patients) or increased (usually £30,000/cu mm), and abnormal forms may occur. Immature cells (£15%) are usual. Basophils and eosinophils may be increased. Platelets may be normal, increased, or decreased, and abnormal and large forms may occur. Deficient platelet aggregation after collagen or epinephrine may occur. wNeedle puncture of spleen and a lymph node shows extramedullary hematopoiesis involving all three cell lines. Leukocyte ALP score is usually increased (in contrast to CML); may be marked. Serum uric acid is often increased. Prolonged PT is found in 75% of patients. Serum vitamin B12 is often increased. Some patients have trisomies of 8, 9, and 21 (appearance during treatment is a poor prognostic sign) but Ph 1 is rare. Laboratory findings due to complications Hemorrhage Hemolytic anemia Infection DIC (occurs in 20% of patients) Rule out other myeloproliferative diseases, especially CML. May arise with prior polycythemia vera. METHEMOGLOBINEMIA (>1.5 gm/dL methemoglobin) Due To Most common is acquired form due to drugs and chemicals, especially aniline derivatives (e.g., acetanilid, phenacetin, certain sulfonamides, various clothing dyes), nitrites, nitrates, local anesthetics (e.g., benzocaine, lidocaine), antimalarials, dapsone. Abnormal HbM (several different types)—autosomal dominant mutation in globin chains Autosomal recessive deficiency of methemoglobin reductase Laboratory Findings Normal arterial oxygen saturation in presence of apparent clinical cyanosis that does not respond to oxygen administration suggests methemoglobin level >15%. 30–40% is associated with symptoms of anoxia; >50% indicates severe toxicity; >70% is often fatal. wFreshly drawn blood is chocolate-brown; does not become red after exposure to air. wReduced nicotinamide adenine dinucleotide (NADH) diaphorase activity is decreased in congenital but normal in toxic states. wStarch-block electrophoresis identifies the HbM. wSpectroscopic absorption analysis—band at 630 µ disappears on addition of 5% potassium cyanide. RBC count is slightly increased; no other hematologic abnormalities are found; no jaundice is present. G-6-PD deficiency enhances HbM production.
- 278. Oxygen dissociation curve shifted to right, causing more oxygen delivery to tissues Patient is cyanotic clinically but in apparent good health. (Clinical cyanosis >5.0 gm/dL deoxyhemoglobin.) wIn newborns with cyanosis, methemoglobin level is usually >10% and may reach 60–70% in severe cases. Persistent methemoglobinemia in spite of IV methylene blue (1–2 mg/kg) suggests abnormal HbM. Recurrence of methemoglobinemia without reexposure to chemicals suggests inherited enzyme deficiency. Cyanosis without dyspnea in previously pink infant suggests acquired methemoglobinemia due to chemicals, but cyanosis from birth suggests inherited enzyme deficiency or abnormal HbM. HbM causes cyanosis from birth only if it is alpha-chain type; cyanosis of beta-chain type appears at age 2–4 mos. MONOCLONAL GAMMOPATHIES, CLASSIFICATION (Clonal disorders of atypical cells of RE system. Each is a homogeneous product of a single clone of proliferating cells and is expressed as a monoclonal gammopathy.) Monoclonal proteins consist of two heavy polypeptide chains of the same class (e.g., gamma, alpha, mu) and subclass, and two light polypeptide chains of the same type (either kappa or lambda); may be present in serum, urine, and CSF. Heavy-chain disease is production of only heavy chains without accompanying light chains; light-chain disease is the reverse. Identified by protein electrophoresis, immunoelectrophoresis, immunofixation. Idiopathic monoclonal gammopathy of unknown significance Benign (IgG, IgA, IgD, IgM; rarely free light chains). Associated with neoplasms of cells now known to produce M proteins. Biclonal gammopathies. Only two-thirds of patients with monoclonal gammopathy are symptomatic. Malignant Multiple myeloma (IgG, IgA, IgD, and Bence Jones gammopathies are associated with classic picture) Symptomatic Smoldering (asymptomatic and indolent) Plasma cell leukemia Nonsecretory Osteosclerotic Plasmacytoma Solitary of bone Extramedullary Malignant lymphoproliferative diseases Waldenström's macroglobulinemia Malignant lymphoma Heavy-chain diseases Gamma Alpha Mu Delta (very rare) Amyloidosis Secondary to multiple myeloma (no monoclonal protein in other secondary types) Primary Unknown significance Idiopathic Others (e.g., ~10% of patients with chronic HCV liver disease) MONOCLONAL GAMMOPATHY, IDIOPATHIC (“BENIGN,” “ASYMPTOMATIC”) (PLASMA CELL DYSCRASIA OF UNKNOWN SIGNIFICANCE; MONOCLONAL GAMMOPATHY OF UNKNOWN SIGNIFICANCE)19 (Found in 0.5% of healthy persons >30 yrs, 3% >70 yrs, and £10% at 80 yrs) See Table 11-21. Table 11-21. Comparison of Multiple Myeloma and Monoclonal Gammopathy of Unknown Significance (MGUS) wThe following changes are present for a period of >5 yrs. Monoclonal serum protein concentration usually <3 gm/dL and does not increase during follow-up; IgG type in 73% of patients, IgM in 14%, IgA in 11%, biclonal in 2%; normal immunoglobulins may be depressed. In contrast, multiple myeloma always shows depression of background immunoglobulins and higher monoclonal serum protein (>3 gm/dL). Normal serum albumin. Usually <10% plasma cells in bone marrow.
- 279. Absence of Bence Jones protein (or <50 mg/day), anemia, myeloma bone lesions, lymphoproliferative disease, hypercalcemia, renal insufficiency. Monoclonal light-chain proteinuria may occur (up to 1 gm/24 hrs). May be associated with aging, cholecystitis, neoplasms, many chronic diseases (most often RA) and infections (e.g., TB). wPeriodic reexamination is essential because many patients develop myeloma (16%), macroglobulinemia (3%), or primary amyloidosis (3%) within 5 yrs and 25% at 10 yrs; lymphoproliferative disorders develop in 17% at 10 yrs, and 33% of patients at 20 yrs; no definite predictive factors permit recognition of this group, but more likely to become malignant if the following criteria are present and converse if these criteria are absent: IgG >200 mg/dL, or either IgA or IgM >100 mg/dL or IgD or IgE paraprotein is found at any concentration. Immunoglobulin fragments in urine (usually Bence Jones protein) or serum. Progressive increase in paraprotein concentration. Low levels of polyclonal immunoglobulin. One study20 in a general hospital showed the following: Paraproteinemia by electrophoresis was found in 730 of 102,000 samples (0.7%). 375 had paraprotein ³200 mg/dL (2 g/L) 114 of these were B lymphocytic malignancy 96—multiple myeloma 4—Waldenström's macroglobulinemia 8—chronic lymphatic leukemia 6—non-Hodgkin's lymphoma 261 were monoclonal gammopathy of undefined significance ~50 of post–progenitor cell transplant patients for £2 yrs; usually low-level IgG MYELODYSPLASTIC (PRELEUKEMIC) SYNDROMES wClonal proliferative disorders of bone marrow that show peripheral blood cytopenias and dysmyelopoiesis; 30–40% of cases progress to acute nonlymphocytic leukemia, 60–80% of patients die of complications (e.g., acute infection, hemorrhage) or associated diseases, 10–20% remain stable and die of unrelated causes. No detectable cause, but prior chemotherapy (especially with alkylating agents) or radiation in some. Partial or complete loss of chromosome 5 and/or 7 and trisomy 8 are very common. French-American-British (FAB) Classification wRefractory anemia Persistent anemia refractory to treatment with vitamin B12, folate, or pyridoxine, with decreased reticulocytes, variable dyserythropoiesis. Anemia may be macrocytic, normocytic, or dimorphic with hypochromasia with changes in size and shape of RBCs. <1% blasts in peripheral blood. <5% blasts in marrow. <15% ringed sideroblasts in marrow (bone marrow normoblasts). Hypercellular marrow with erythroid hyperplasia and/or dyserythropoiesis. Normal megakaryocytes and granulocytes. Dysgranulopoiesis is infrequent. 5% of patients present with these findings but without anemia. wRefractory anemia with ringed sideroblasts (same as acquired idiopathic sideroblastic anemia) Refractory anemia (see previous section); bimorphic RBCs—oval macrocytes and hypochromic microcytes; many siderocytes >15% ringed sideroblasts <1% blasts in peripheral blood <5% blasts in marrow >10% develop acute myelocytic leukemia wRefractory anemia with excess blasts (poor prognosis; usually progresses to acute leukemia within a year) Cytopenia affecting ³2 cell lines <5% blasts in peripheral blood and 5–20% blasts in marrow; granulocytic maturation is present; <1% marrow sideroblasts Variably cellular marrow with granulocytic or erythroid hyperplasia Dysgranulopoiesis, dyserythropoiesis, and/or dysmegakaryocytopoiesis wRefractory anemia with excess blasts in transformation (from myelodysplasia to overt acute nonlymphocytic leukemia) >5% blasts in peripheral blood and/or 20–30% blasts in marrow (>30% blasts constitutes acute nonlymphocytic leukemia). <1% marrow sideroblasts. Auer rods present in myeloid precursors. Does not fit into FAB M1–M7 categories. 75% develop acute myelocytic leukemia. wChronic myelomonocytic leukemia Same as refractory anemia with excess blasts but with >100 monocytes/µL in peripheral blood. Neutrophilia; mature granulocytes may be increased. <5% blasts in peripheral blood and usually 5–20% blasts in marrow. <1% marrow sideroblasts. Increased monocyte precursors in marrow (may need special stains). Abnormal and asynchronous maturation of different cell series is defined as: w•Dyserythropoiesis Anisocytosis, poikilocytosis, oval macrocytes, nucleated RBCs, and normochromia are most common changes in RBCs on peripheral smear. RBC population may be dimorphic. Erythroid maturation defects with bizarre (e.g., multinucleated) forms and megaloblastic features unresponsive to folic acid, vitamin B 12, and iron. w•Dysgranulomonopoiesis Increased or decreased numbers or abnormal nuclei or granulation in blood, acquired Pelger-Huët anomaly. Variable increase in mature granulocyte precursors (usually myelocytes) and monocytosis occur frequently in marrow.
- 280. w•Dysmegakaryocytopoiesis. Increased or decreased number. Atypical, bizarre, or giant platelets, often with giant abnormal granules, are seen in most cases. Marrow megakaryocytes are often atypical or bizarre. Platelet function defects with prolonged BT and aggregation abnormalities are very common. Other clinicopathologic forms include refractory anemias of various types, pure red cell aplasia, paroxysmal nocturnal hemoglobinuria, chronic idiopathic neutropenia, chronic idiopathic thrombocytopenia, etc. Low granulocyte or platelet count or elevated bone marrow blast count are independent indicators of poor outcome. 5q– karyotype is often found in refractory anemia and carries a relatively good prognosis. Monosomy 7 and trisomy 8 are frequently found in other subclasses of myelodysplasia and are associated with poor prognosis. Poor prognosis is indicated by (in decreasing order of importance) >5% blasts in marrow, circulating blasts, abnormal karyotypes, granulocytopenia (<1000/cu mL), monocytopenia, thrombocytopenia (<140,000/cu mL), ineffective erythropoiesis, presenting Hb of <9.0 gm/dL, hemolysis, <20% ringed sideroblasts in marrow, abnormal localization of blasts in center of marrow rather than in subendostial areas, circulating CD34 + cells. MYELOMA, MULTIPLE See Table 11-22, Table 11-23 and Table 11-24. Table 11-22. Comparison of Diseases with Monoclonal Immunoglobulins Table 11-23. Immunochemical Frequency of Monoclonal Gammopathies Table 11-24. Comparison of Immunoproliferative Disorders w Diagnostic Criteria Bone marrow shows sheets or >20% plasma cells and Abnormality of immunoglobulin formation (monoclonal spike >4 gm/dL or Bence Jones proteinuria >0.5 gm/24 hrs) If monoclonal spike is <4 gm/dL, then substitute criteria: Reciprocal depression of normal immunoglobulins or Panhypogammaglobulinemia and osteolytic bone lesions or Plasmacytosis not due to other causes (see Plasma Cells) Very increased serum total protein is due to increase in globulins (with decreased albumin/globulin ratio [A/G]) in one-half to two-thirds of the patients. Serum protein immunoelectrophoresis or immunofixation characterizes protein as monoclonal (i.e., one light-chain type) and classifies disease by identifying specific heavy chain. It reveals abnormal immunoglobulins in 80% of patients. A serum or urine monoclonal paraprotein can be identified in £99% of patients with multiple myeloma. Percent of Patients Immunoelectrophoresis or Immunofixation Shows £99% Monoclonal protein in serum or urine 90% Serum monoclonal spike 20% Both serum and urine monoclonal protein 20% Monoclonal light chains in urine only <2% Hypogammaglobulinemia only without serum or urine paraprotein
- 281. 60% IgG myeloma protein 20% IgA myeloma protein 10% Light chain only (Bence Jones proteinemia) Very rare IgE myeloma protein <1% IgD myeloma protein* *IgD myeloma is difficult to recognize because serum levels are relatively low, specific antiserum is required to demonstrate IgD; on electrophoresis, IgD is often included in beta globulin peak, and clinical features are the same as in other types of myeloma. Bence Jones proteinuria is almost always present, and total protein is often normal. wBence Jones proteinuria occurs in 35–50% of patients. >50% of IgG or IgA myeloma and 100% of light-chain myelomas have Bence Jones proteinuria. ·Dipstick tests for urine protein will miss Bence Jones protein, and heat precipitation is not a reliable test. wElectrophoresis/immunofixation of both serum and urine is abnormal in almost all patients. If only serum electrophoresis is performed, kappa and some lambda light-chain myelomas will be missed. 10% of patients have hypogammaglobulinemia (<0.6 gm/dL). Free immunoglobulin light chains are rapidly filtered by glomerulus and found only in urine. Intact monoclonal Ig is identified only in serum. wBone marrow aspiration usually shows 20–50% plasma cells or myeloma cells, usually in sheets; abnormal plasma cells may be found (flaming cells, morular cells, Mott cells, thesaurocytes); multiple sites may be required. Hematologic findings · Anemia (normocytic, normochromic; rarely macrocytic) in 60% of patients. · Usually normal WBC and platelet count; 40–55% lymphocyte frequently present on differential count, with variable number of immature lymphocytic and plasmacytic forms. Decreased WBC and platelet counts are seen in ~20% of patients, usually with extensive marrow replacement. Eosinophilia may be found. m•Rouleaux formation (due to serum protein changes) in 85% of patients, occasionally causing difficulty in cross-matching blood. m•Increased ESR in 90% of patients and other abnormalities due to serum protein changes. May be normal in light-chain myeloma. >100/hr is rare in any condition other than myeloma. •Cold agglutinins or cryoglobulins. mHyperviscosity syndrome is characteristic of IgM and occurs in 4% of IgG and 10% of IgA myelomas and may be the presenting feature. Symptoms are usually present when relative serum viscosity = 6–7 cP (normal = <1.8 cP). mClinical amyloidosis occurs in 15% of cases of multiple myeloma, but monoclonal spikes are present in urine in most, if not all, cases of primary amyloidosis. IgD myeloma and light-chain disease are associated with amyloidosis and early renal failure more frequently than in other types of myeloma. Amyloidosis is indistinguishable from primary type. Serum beta2-microglobulin is increased in proliferative disorders in which rapid cell multiplication or increased tumor burden is present. >6 µg/mL indicates poor prognosis (normal = <2 µg/mL); may also be increased by renal failure. Chromosome analysis frequently shows translocation t(11;14)(q13;q32). Laboratory findings of repeated bacterial infections, especially those due to Streptococcus pneumoniae, S. aureus, and E. coli. See bone diseases of calcium and phosphorus, Table 13-6. Serum calcium is markedly increased in 25–50% of cases. Corrected calcium (mg/dL) = serum calcium (mg/dL) – serum albumin (gm/dL) + 4.0. Serum phosphorus is usually normal. Serum ALP is usually normal or slightly increased. Increase may reflect amyloidosis of liver or bone disease. Hypercalciuria causing dehydration and tubular dysfunction. See Myeloma Kidney. mPresymptomatic phase (may last many years) may show only · Unexplained persistent proteinuria · Increased ESR ·Myeloma protein in serum or urine · Repeated bacterial infections, especially pneumonias (6× greater incidence) · Amyloidosis wHigh tumor mass (clinical stage III) is present when any of the following are present. · Hb <8.5 gm/dL ·Corrected calcium >12 mg/dL · Serum IgG >7 gm/dL · Serum IgA >5 gm/dL ·Bence Jones proteinuria >12 gm/day · Advanced lytic bone lesions wLow tumor mass (stage I) is present when all of the following are present. ·Hb >10 gm/dL. · Normal corrected calcium. ·Serum IgG <5 gm/dL. · Serum IgA <3 gm/dL. · Bence Jones proteinuria <4 gm/day. ·Generalized lytic bone lesions are absent. Stage II has intermediate values Subclassified as A if serum creatinine <2 mg/dL or B if >2 mg/dL Survival varies from 61 mos for stage IA patients to 15 mos for stage IIIB patients. Serial measurement of serum globulins and/or Bence Jones proteinuria are excellent indications of efficacy of chemotherapy; decrease in Bence Jones proteinuria occurs before decrease in abnormal serum globulin peak. Lowered AG in IgG myeloma only (due to cationic IgG paraproteins causing retention of excess chloride ion) Increased incidence of other neoplasms (not known if related to chemotherapy) Acute myelomonocytic leukemia, often preceded by sideroblastic refractory anemia, is increasingly seen. 20% of patients develop adenocarcinoma of GI tract, biliary tree, or breast. MYELOMA, MULTIPLE, SMOLDERING (~15% of multiple myeloma patients who are asymptomatic when diagnosed) wSerum M protein >3 gm/dL; uninvolved immunoglobulins are decreased. wBone marrow shows >10% atypical plasma cells.
- 282. Plasma cell labeling index is very low. Urine frequently contains a small amount of M protein. No anemia, renal insufficiency, or bone lesions; condition remains stable. MYELOMA, NONSECRETORY w1% of multiple myeloma patients in whom no M protein in serum, urine, or monoclonal protein can be identified in plasma cells by immunofluorescence or immunoperoxidase. MYELOMA, OSTEOSCLEROTIC wDiagnosis based on biopsy from single or multiple osteosclerotic bone lesions Bone marrow aspiration shows <5% plasma cells Lambda M protein is usually present. Absence of anemia, hypercalcemia, renal insufficiency Erythrocytosis and thrombocytosis may occur. CNS protein is increased. Syndrome of POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin pigmentation) is rare disorder. NEUTROPENIA, PERIODIC (CYCLIC) (Rare autosomal dominant condition) wRegular periodic occurrence of neutropenia every 10–35 days, lasting 3–4 days. WBC is 2000–4000/cu mm, and granulocytes are as low as 0%. Monocytosis may occur. Eosinophilia may occur during recovery. Bone marrow during episode may show hypoplasia or maturation arrest at myelocyte stage. NEUTROPHILIA, HEREDITARY GIANT (Very rare innocuous autosomal dominant anomaly) w1–2% of neutrophils are ~2× normal size and contain 6–10 nuclear lobes. In females drumstick appendages are often duplicated. No associated anomalies. Acquired form may occur in myeloproliferative disease, AML, treatment with alkylating agents. NEUTROPHILS, HEREDITARY HYPERSEGMENTATION (Harmless autosomal dominant condition) wHypersegmentation of neutrophils resembles that seen in PA but is a permanent abnormality. Most neutrophils have ³4 lobes. ³5 lobes in 10% of heterozygotes and 30% of homozygotes. A similar condition exists that affects only the eosinophilic granulocytes (hereditary constitutional hypersegmentation of the eosinophil). An inherited giant multilobed abnormality of neutrophilic leukocytes is also seen. Hypersegmentation is also found in almost every patient with chronic renal disease with BUN >30 mg/dL for >3 mos. OROTIC ACIDURIA, HEREDITARY (Very rare childhood disorder of pyrimidine metabolism due to a defect in the conversion of orotic acid to uridylic acid) wSevere megaloblastic anemia refractory to vitamin B12 and folic acid but responsive to oral prednisone and yeast extract containing uridylic and cytidylic acids. Marked anisocytosis. Leukopenia is present with increased susceptibility to infection. wLarge amounts of orotic acid in urine; crystals precipitate when urine stands at room temperature. wRBC orotidylic decarboxylase activity is decreased (<5.5 U). Iatrogenic orotic aciduria occurs during cancer chemotherapy with 6-azauridine. PANCYTOPENIA wAnemia plus wLeukopenia—absolute myeloid decrease may be associated with relative lymphocytosis or with lymphocytopenia plus wThrombocytopenia Laboratory findings due to causative disease Due To
- 283. Hypersplenism Congestive splenomegaly Malignant lymphomas Histiocytoses Infectious diseases (TB, kala-azar, sarcoidosis) Primary splenic pancytopenia Diseases of marrow Metastatic carcinoma Multiple myeloma Aleukemic leukemia Osteopetrosis Myelosclerosis, myelofibrosis, etc. Systemic mastocytosis Aplastic anemias Physical and chemical causes (e.g., ionizing irradiation, benzol compounds) Idiopathic causes (familial or isolated; “isolated” accounts for 50% of all cases of pancytopenia) Megaloblastic anemias (e.g., PA) Paroxysmal nocturnal hemoglobinuria (rare) PELGER-HUËT ANOMALY (Autosomal dominant, usually heterozygous, anomaly of WBCs) wNuclei of >80% of granulocytes lack normal segmentation but are shaped like pincenez eyeglasses, rods, dumbbells, or peanuts; present in peripheral blood and bone marrow. Coarse chromatin is evident in nuclei of granulocytes, lymphocytes, and monocytes and in marrow metamyelocytes and bands. Sex chromatin body is not found in affected women. Acquired Pelger-Huët anomaly is less predominant; may occur in acute and chronic myeloproliferative disorders (may be a premonitory feature) and may be transient in various acute infections, leukemoid reactions, and reactions to certain drugs (e.g., colchicine, sulfonamides, alkylating agents). Not found in acute and rarely in chronic lymphatic leukemias. PLASMACYTOMA, SOLITARY wDiagnosis is based on histologic finding of single tumor of plasma cells, which are identical to those of multiple myeloma. No criteria of multiple myeloma are present. wBone marrow shows no evidence of multiple myeloma. wRadiographs and bone scans are negative for other myeloma bone lesions. Myeloma proteins are at low or normal concentration in serum or concentrated urine by immunofixation. Nonmyeloma immunoglobulin concentration in serum is generally normal. Paraprotein is detectable in 80–90% of cases of solitary plasmacytoma of bone, often at very low concentrations. IgG kappa is most common; IgA and Bence Jones protein have been described. Solitary plasmacytoma of bone is considered to represent the earliest stage of multiple myeloma, and 50–60% of cases progress to multiple myeloma within 5 yrs. 15% remain solitary; 12% develop local recurrence; 15% develop new distant lesions. After local radiotherapy, level of any myeloma protein is reduced and level of nonmyeloma immunoglobulins may be increased above normal. ~30% remain free of disease for >10 yrs; other patients develop multiple myeloma after median of 3 yrs. CSF total protein, albumin, and IgG may be increased if a vertebral lesion extends into the spinal canal. Extramedullary plasmacytoma may occur, chiefly (80%) in upper respiratory tract. ~20% of patients have low level monoclonal immunoglobulin (not IgM) in urine or serum. Diagnosis is based on histologic examination of tumor and same criteria as previous section. Development of multiple myeloma is infrequent. POLYCYTHEMIA, FACTITIOUS wNormal oxygen saturation. wSerum erythropoietin is low in autotransfusion but increased by exogenous erythropoietin. Due To Use of androgens by athletes to increase muscle mass and strength Intentional by blood doping (athlete is phlebotomized and later transfused with own stored blood before competitive event to improve performance) or administration of erythropoietin POLYCYTHEMIA, RELATIVE (STRESS ERYTHROCYTOSIS) (Recent literature questions existence of this entity21 ) Relative polycythemia is not secondary to hypoxia but results from decreased plasma volume due to unknown mechanism or to decreased fluid intake and/or excess loss of body fluids (e.g., due to diuretics, dehydration, burns) with high normal RBC mass. Increased RBC (usually <6 million/cu mm), Hb, and Hct Normal WBC, platelet, and reticulocyte counts
- 284. Findings of secondary polycythemia (e.g., decreased oxygen saturation) are not present (see next section). Serum erythropoietin is normal. Leukocyte ALP score is normal or mildly increased. Bone marrow shows normal cellularity and megakaryocyte count; no myelofibrosis; iron may be absent. Hypercholesterolemia is frequent. Laboratory findings due to complications (e.g., thromboembolism) POLYCYTHEMIA, SECONDARY mDiagnosis is suggested by erythrocytosis without increased WBC, platelets, or splenomegaly; causes listed below should be sought. Hct is slightly increased. Leukocyte ALP score is normal or slightly increased. Increased plasma cholesterol is frequent. Serum erythropoietin is usually increased or normal. Due To Physiologically Appropriate Hypoxia with decreased arterial oxygen saturation Decreased atmospheric pressure (e.g., high altitudes). Chronic heart disease. Congenital (e.g., pulmonary stenosis, septal defect, patent ductus arteriosus) Acquired (e.g., chronic rheumatic mitral disease) Arteriovenous aneurysm. Impaired pulmonary ventilation. Alveolar-capillary block (e.g., Hamman-Rich syndrome, sarcoidosis, lymphangitic cancer). Alveolar hypoventilation (e.g., bronchial asthma, kyphoscoliosis). Restriction of pulmonary vascular bed (e.g., primary pulmonary hypertension, mitral stenosis, chronic pulmonary emboli, emphysema). Abnormal hemoglobin pigments (methemoglobinemia or sulfhemoglobinemia due to chemicals, such as aniline and coal tar derivatives) or high-oxygen-affinity hemoglobinopathies (50% of hemoglobinopathy cases show an abnormality on standard Hb electrophoresis). ( Hb oxygen affinity [P50] is the oxygen tension at which Hb becomes 50% saturated. Normal = 27.5 mm Hg. Usually <20 mm Hg in these conditions. Decreased P50 indicates increased oxygen affinity and increased P50 indicates decreased oxygen affinity. May be increased by high-affinity hemoglobinopathies, carboxyhemoglobinemia, decreased RBC 2,3-diphosphoglycerate, alkalosis. May be decreased by hemoglobinopathies, increased RBC 2,3-diphosphoglycerate, acidosis.) Carboxyhemoglobinemia (“smoker's erythrocytosis”) can be detected by oximetry but not from P50. Physiologically Inappropriate Increased erythropoietin secretion, e.g., Associated with tumors and miscellaneous conditions (may be first sign of an occult curable tumor) Renal disease (hypernephroma, benign tumors, hydronephrosis, cysts, renal artery stenosis, long-term hemodialysis; occurs in up to 5% of renal cell carcinomas; occurs in £17% of kidney transplant recipients) Hemangioblastoma of cerebellum (occurs in 15–20% of cases) Uterine fibromyoma Hepatocellular carcinoma (5–10% of cases) Others Increased androgen Pheochromocytoma Cushing's syndrome (adrenocortical hyperplasia or tumor) Masculinizing ovarian tumor (e.g., arrhenoblastoma) Factitious (use of androgens by athletes) POLYCYTHEMIA VERA See Table 11-25, Fig. 11-9 and Fig. 11-10. Table 11-25. Comparison of Polycythemia Vera, Secondary Polycythemia, and Ralative Polycythemia
- 285. Fig. 11-10. Sequence of laboratory tests in the diagnosis of erythrocytosis. (2,3-DPG = 2,3-diphosphoglycerate.) w Criteria for Diagnosis22 A1 + A2 + A3; if A3 is absent, then two of four criteria from B must be present. A1: Increased RBC mass (³ 36 mL/kg in men; ³ 32 mL/kg in women) A2: Normal arterial oxygen saturation (³ 92%) A3: Splenomegaly (occurs in ~75% of cases) B1: WBC >12,000/cu mm (occurs in ~60% of cases) B2: Platelet count >400,000/cu mm (occurs in >60% of cases) B3: Increased leukocyte ALP score (occurs in ~70% of cases) in absence of fever or infection B4: Increased serum vitamin B12 (>900 pg/mL) (occurs in ~30% of cases) or B12-binding capacity (>2200 pg/mL) (occurs in ~75% of cases) False-positive rate ~0.5% due to combination of smokers' polycythemia (causing increased RBC mass) and alcoholic hepatitis (causing splenomegaly, increased B 12, WBC, leukocyte ALP). False-negative may occur in patients with (1) recent bleeding, (2) concomitant decreased arterial oxygen saturation due to concomitant chronic lung disease, (3) early or minimal polycythemia vera, (4) increased RBC mass associated with increased plasma volume resulting in normal Hb and Hct. False-negative cases may present with portal vein thrombosis, Budd-Chiari syndrome, or unexplained thrombocytosis, leukocytosis, splenomegaly. RBC is increased; often = 7–12 million/cu mm; may increase to >15 million/cu mm. Increased Hb = 18–24 gm/dL in males and >16 gm/dL in females residing at altitude <2000 ft, in 71% of cases. Increased Hct >55% in 83% of cases; >60% indicates increased RBC mass but <60% may be associated with normal RBC mass. MCV, MCH, and MCHC are normal or decreased. Increased 51 Cr RBC mass is reported essential for diagnosis; blood volume is increased; plasma volume is variably normal or slightly increased. RBC mass may be difficult to perform reliably if not done frequently, and some experts omit this test when other criteria are present, especially if serum erythropoietin is decreased and marrow erythroid colony growth occurs in absence of exogenous erythropoietin. Increased platelet count >400,000/cu mm in 62% of cases; often >1 million/cu mm. Increased PMNs >12,000/cu mm in ~60% of cases; usually >15,000 cu mm; sometimes a leukemoid reaction is seen. Mild basophilia in ~60% of cases. Oxygen saturation of arterial blood is normal in 84% of cases. Increased leukocyte ALP score >100 in 79% of cases. Increased serum vitamin B12 >900 pg/mL in ~30% of cases. Increased vitamin B12-binding capacity >2200 pg/mL in ~75% of cases. wErythropoietin in plasma or serum is usually decreased (but occasionally normal) in polycythemia vera; usually remains normal during phlebotomy therapy. Usually increased (but may be normal) in secondary polycythemia; overlap between these. Normal level is not helpful but increased level rules out polycythemia vera and requires search for cause of secondary erythrocytosis. Increases may be intermittent; therefore a single normal level is unreliable. Usually normal in relative polycythemia. ESR is decreased. Blood viscosity is increased. Osmotic fragility is decreased (increased resistance). Peripheral blood smear may show macrocytes, microcytes, polychromatophilic RBCs, normoblasts, large masses of platelets, neutrophilic shift to the left. Reticulocyte count >1.5% in 44% of cases. mBone marrow shows general hyperplasia of all elements. Cellularity >75%, especially with megakaryocytic hyperplasia in presence of erythrocytosis, is strong evidence for polycythemia vera. (Mean cellularity <48% in normal persons and 48–55% in secondary cases.) Mild myelofibrosis may be present; iron may be decreased or absent. wSpontaneous erythroid colony formation occurs in in vitro culture of marrow erythroid progenitors in polycythemia vera without addition of exogenous erythropoietin (seen less commonly in other myeloproliferative disorders) but not in secondary polycythemia or normal persons; test only available in special labs. Serum uric acid increased in ~50% of cases.
- 286. Serum total bilirubin slightly increased in ~50% of cases. Serum iron decreased in ~50% of cases. Serum potassium may be increased (artifactual due to thrombocytosis). BT and coagulation time are normal, but clot retraction may be poor. Urine may contain increased urobilinogen, and occasionally albumin is present. Laboratory findings of associated diseases (e.g., gout, duodenal ulcer, cirrhosis, hypertension). Laboratory findings due to complications such as thromboses (e.g., cerebral, portal vein), intercurrent infection, peptic ulcer, hemorrhage, myelofibrosis, myeloid metaplasia (develops in 3–10% of patients), chronic myelogenous leukemia (develops in 20% of patients), acute leukemia (develops in 1% of patients). PYROPOIKILOCYTOSIS, HEREDITARY wRare congenital severe hemolytic anemia with virtually all RBCs markedly misshapen (especially fragments, spheres, elliptocytes, pyknotic forms). MCV is low (55–74 fL). Increased osmotic fragility Increased autohemolysis with or without glucose Splenectomy greatly lessens hemolysis. Rhnull DISEASE Mild to moderate chronic hemolytic anemia with characteristic stomatocytosis wAbsence of all Rh antigens on RBCs Shortened RBC life span Increased osmotic fragility HbF may be increased. SEVERE COMBINED IMMUNODEFICIENCY DISORDERS (SCID) (Rare disorders of many genetic causes that show congenital absence of all immune functions, with death due to infection before age 1–2 yrs. Failure to thrive. Diverse immunologic, hematologic, enzymatic, and genetic features. May be cured with bone marrow transplant.) Autosomal Recessive SCID wMarked lymphopenia (<1000 lymphocytes/cu mm) with lack of T and B cell function; very low T-cell count but CD4/CD8 ratio is rarely reversed as in AIDS. T and B cell counts very low in most autosomal recessive forms. Eosinophilia and monocytosis are prominent features. mDecreased serum immunoglobulins; no antibody formation after immunization. mDelayed cutaneous anergy; cannot reject transplants. mRecurrent infections due to opportunistic organisms (persistent thrush or diaper Monilia rash or P. carinii pneumonia; viral infection from VZV, HSV, adenovirus, CMV, measles virus, progressive vaccinia) finally causes wasting and death. Graft-versus-host disease may develop. Very small thymus (<1 gm) that fails to descend from neck shows few lymphocytes, no corticomedullary distinction, and usually no Hassall's corpuscles, but thymic epithelium appears normal. Lymph nodes show lymphocyte depletion in both follicular and paracortical areas; tonsils, adenoids, Peyer's patches are absent or very underdeveloped. wEnzyme deficiency (e.g., adenosine deaminase, purine nucleoside phosphorylase) occurs in ~40% of autosomal recessive SCID patients. Adenosine deaminase deficiency causes severe depletion of both T and B cells and lack of both cell-mediated and humoral immunity. Purine nucleoside phosphorylase deficiency preferentially affects T cells; severe defect in cell-mediated immunity but humoral immunity is intact. RBCs show adenosine deaminase deficiency and increased deoxyadenosine triphosphate and deoxyadenosine diphosphate. SCID is most commonly X linked. Defective Expression of Major Histocompatibility Complex Antigens Persistent diarrhea in early infancy Malabsorption Susceptibility to opportunistic infection Hypogammaglobulinemia with decreased IgM and IgA Poor or absent antibody production Moderate lymphopenia; decreased T-cell function; normal B cell percentage Absent plasma cells in tissues Severe hypoplasia of thymus and lymphoid tissues
- 287. SCID with Leukopenia (Very rare condition in infants) Total lack of lymphocytes Tiny thymus (<1 gm) shows no Hassall's corpuscles or lymphocytes. SICKLE CELL DISEASE23 See Table 11-26. Sickling of RBCs Sickling should be confirmed with hemoglobin electrophoresis and genetic studies. Occurs In Sickle cell disease Sickle cell trait HbC-Harlem HbC-Georgetown HbI False-Positive In First 4 mos after transfusion with RBCs having sickle cell trait Mixture on slide with fibrinogen, thrombin, gelatin (glue) Excessive concentration of sodium metabisulfite (e.g., ³4% instead of 2%) Drying of wet coverslip preparation Poikilocytosis False-Negative In First 4 mos after transfusion with normal RBCs Heating, bacterial contamination, or prolonged washing with saline of RBCs Newborn because HbF is high during first months of life Sickle Solubility Test Sodium dithionate is added to lysed RBCs to reduce the Hb. Solution is turbid when HbS is present but remains clear with other Hb. Does not differentiate between sickle cell anemia, sickle cell trait, and other HbS genetic variants. False-Negative Results May Occur With Patient's Hb is <5 g/dL. Phenothiazine drugs. Unreliable for newborn screening because of high HbF. False-Positive Results May Occur With Lipemic specimens Abnormal gamma globulins Polycythemia Increased number of Heinz bodies (e.g., postsplenectomy) Increased number of nucleated RBCs Inadequate for genetic counseling because does not detect carriers of HbC and beta-thalassemia. Sickle Cell Trait (Heterozygous sickle cell or HbAS disease; occurs in ~10% of American blacks) wHb electrophoresis: HbS is 20–40%, and HbA is 60–80%; normal amounts of HbA2 and HbF (£2%) may be present. wSickle cell preparation is positive. Blood smear shows only a few target cells; sickled cells are not seen. CBC and indices are normal; no anemia or hemolysis or jaundice is present. Anoxia may cause systemic sickling (see following section, Sickle Cell Anemia). HbS concentration is too low for sickling to occur under most conditions but beware anesthesia, airplane flights, etc.
- 288. Hematuria without any other demonstrable cause may be found. Hyposthenuria may occur. Sickle cells are found postmortem regardless of cause of death. Sickle Cell Anemia (Homozygous HbSS disease; occurs in 1 in 625 American blacks) wHb electrophoresis: HbS is 80–100%, and HbF comprises the rest (see Hemoglobin, Fetal); HbA is absent. wSickle cell preparation is positive; because other Hb variants migrate with HbS on electrophoresis, confirming Hb as a sickle type is important. Sickle solubility test is positive but does not differentiate anemia from other HbS genetic variants and may be falsely negative if Hb <5 g/dL. wBlood smear shows a variable number of RBCs with target cells (especially in HbSC disease), abnormal shapes, nucleated RBCs, Howell-Jolly bodies, spherical cells, polychromasia. Sickle cells in smear when RBCs contain >60% HbS (except in HbS-persistent HbF). After autosplenectomy, basophilic stippling, Pappenheimer bodies, nucleated RBCs also present. Normocytic normochromic anemia (Hb = 5–10 gm/dL; normal MCV). Reticulocyte count is increased (5–30%); may cause slight increase in MCV. WBC is increased (10,000–30,000/cu mm) during a crisis, with normal differential or shift to the left. Infection may be indicated by intracellular bacteria (best seen on buffy coat preparations), Döhle's bodies, toxic granules, and vacuoles of WBCs, Westergren ESR >20 mm/hr. Platelet count is increased (300,000–500,000/cu mm), with abnormal forms. Bone marrow shows hyperplasia of all elements. mDecreased ESR becomes normal after blood is aerated. ESR in normal range may indicate intercurrent illness or crisis. Osmotic fragility is decreased (more resistant RBCs). Mechanical fragility of RBCs is increased. RBC survival time is decreased (17 days in HbSS, 28 days in HbSC). Laboratory findings of hemolysis (e.g., increased indirect serum bilirubin [£6 mg/dL], increased urobilinogen in urine and stool, but urine is negative for bile). Hemosiderin appears in urine sediment. Hematuria is frequent. Renal concentrating ability is decreased, leading to a fixed specific gravity in virtually all patients after the first few years of life. Serum uric acid may be increased. Serum ALP is increased during crisis, representing vaso-occlusive bone injury as well as liver damage. Leukocyte ALP activity is decreased. Laboratory findings due to complications ·Infections due to immunocompromised status (functional asplenia); e.g., Salmonella osteomyelitis occurs more commonly in sickle cell syndromes; marked increase in susceptibility to pneumococcal and H. influenzae sepsis and meningitis, E. coli and meningococci infections, staphylococcal osteomyelitis, M. pneumoniae. · Vaso-occlusive crisis, e.g., infarction of lungs, brain, bowel; spleen completely infarcted by middle age, causing Howell-Jolly bodies, target cells. Bone marrow necrosis causing fat emboli syndrome; bone disorders (e.g., avascular necrosis of hip; dactylitis). · Kidney (see Nephropathy, Sickle Cell, Chapter 14). · Stasis and necrosis of liver—increased direct serum bilirubin £40 mg/dL, bile in urine, other findings of obstructive type of jaundice. · Hyperhemolytic crisis—superimposed further hemolysis due to bacterial or viral infections; Hb falls from usual 6–10 g/dL to £5 g/dL in a few days with increasing reticulocyte count. When hemolysis is present, G-6-PD deficiency should be ruled out as this is also common in blacks. ·Aplastic crisis—acute, self-limited episode of erythroid aplasia lasting 5–10 days due to parvovirus B19; falling Hct and reticulocyte count may require prompt transfusion. Recovery is marked by return of reticulocytosis, usually with resolution of infection. · Hypoplastic crisis—infection or inflammation causes brief suppression of bone marrow with accentuated brief drop in Hct and reticulocyte count. ·Splenic sequestration crisis—seen mostly in children age 5 mos to 5 yrs (before fibrosis of spleen has occurred); enormous enlargement of spleen associated with precipitous drop in Hct and hypovolemic shock. Over age 2 yrs, occurs more often with other HbS syndromes. · Megaloblastic crisis—rare occurrence of sudden cessation of erythropoiesis due to folate depletion in persons with inadequate folate (e.g., due to pregnancy, alcoholism, poor diet). · Bilirubin gallstones in 30% of patients by age 18 and 70% by age 30, may cause cholecystitis or biliary obstruction. w·Anemia and hemolytic jaundice are present throughout life after age 3–6 mos; hemolysis and anemia are increased only during hematologic crises. wNewborn screening by Hb electrophoresis on cord blood or filter paper spot. · In newborns with HbSS, anemia is rarely present. May cause unexplained prolonged jaundice. May be difficult to distinguish HbSS from HbAS in neonates because of large amount of HbF, which may obscure the HbA. HbA is also not produced in HbS–beta 0 -thalassemia, so an FS pattern on electrophoresis may indicate either. HbS–beta+ -thalassemia usually has an FSA phenotype, which requires careful differentiation from sickle cell trait (phenotype FAS). Percent of RBCs that will sickle is much lower in newborn (as low as 0.5%) than in older children. Diagnosis of HbSS is excluded by HbA on Hb electrophoresis of infant's blood or if mother has negative sickle cell preparation. In newborn, cellulose agar electrophoresis is useless to detect HbS because of the small amount present, and acidic citrate agar gel is needed. For exchange transfusion, sickle cell test must be performed on donor blood from blacks because these RBCs may sickle in presence of hypoxia as in RDS. Hb solubility tests (e.g., Sickledex) are usually not suitable on cord blood because a positive result may be easily obscured by a large amount of HbF. Most children are anemic and symptomatic by age of 1 yr; anemia and hemolysis are present throughout life. wAntenatal diagnosis is possible as early as 7–10 wks' gestation by gene analysis of fetal DNA on amniotic fluid cells or chorionic villi. Also detects HbSC disease. Diagnosis can also be made by fetal blood sampling. HbSC Disease (Occurs in 1 in 833 American blacks) wHb electrophoresis: HbA is absent; HbS and HbC are present in approximately equal amounts (30–60%); HbF is usually not seen (2–15%). wBlood smear shows tetragonal crystals within RBC in 70% of patients; RBCs tend to be microcytic with MCV usually low or low normal but high MCHC; rare true sickle cells, occasional spherocytes, typical distorted RBCs in which Hb is concentrated more in one area of cell than another. mA valuable diagnostic aid is the presence of target cells with normal MCV. wOther findings are the same as for sickle cell anemia, but there is less marked destruction of RBCs, anemia, etc., and the disease is less severe clinically. Hematologic crises may cause a more marked fall in RBC than occurs in HbSS disease. Sickle Cell–Beta-Thalassemia Disease
- 289. (Occurs in 1 in 1667 American blacks) wHb electrophoresis: HbS is 20–90%; HbF is 2–20%. In one syndrome, HbS may be very high and HbA synthesis is suppressed, causing a more severe disease. In the other (milder) syndrome, HbA is 25–50%; HbA 2 is increased. Anemia is hypochromic microcytic with decreased MCV; target cells are prominent; serum iron is normal. Other findings resemble those of sickle cell anemia. mValuable diagnostic aids are: the presence of target cells with normal MCV, microcytosis or splenomegaly in patients with mild to moderate sickle cell syndrome, apparent increase in HbA2 (HbC migrates in HbA2 position on gel electrophoresis), microcytosis in one parent. Sickle Cell–Persistent High Fetal Hemoglobin (Occurs in 1 in 25,000 American blacks) Hb electrophoresis: HbF is 20–40%; absent HbA and A2; HbS is ~65%. Findings are intermediate between those of sickle cell anemia and sickle cell trait, but sickle cells do not form. Normally HbF is evenly distributed among RBCs on Kleihauer-Betke stain. In contrast, sickle cell–thalassemia patients may have high HbF values but HbF is seen in only relatively few RBCs. Sickle Cell–HbD Disease (Occurs in 1 in 20,000 American blacks) Findings are intermediate between those of sickle cell anemia and sickle cell trait. Clinically mild syndrome. wHb electrophoresis demonstrates the abnormal hemoglobin at acid pH. SPHEROCYTOSIS, HEREDITARY (Defective RBC membrane due to spectrin deficiency; deficiency ~30% of normal in severe cases to 80% of normal in mildest cases.) Autosomal dominant form in ~70% of cases with moderately severe disease in which one parent and half the siblings are affected; ~20% have mild compensated hemolysis; may be sporadic and occur without a family history or may show recessive inheritance. ~10% of patients have severe debilitating disease with severe anemia that makes them transfusion dependent, with gallstones in childhood and bone changes. wAbnormal peripheral blood smear is most suggestive finding. Many microspherocytes are present. Anisocytosis may be marked; poikilocytosis is slight. RBCs show Howell-Jolly bodies, Pappenheimer bodies, Heinz bodies. Polychromatophilic reticulocytes and microspherocytes are present. wHemolytic anemia is moderate (RBC = 3–4 million/cu mm), microcytic (MCV = 70–80 fL), and hyperchromic (increased MCHC = 36–40 gm/dL). MCHC >36% means congenital spherocytic anemia if cold agglutinins and hypertriglyceridemia have been excluded. wOsmotic fragility is increased; increase generally reflects clinical severity of disease; when normal in some patients, the incubated fragility test shows increased hemolysis. Diagnosis is not established without abnormal osmotic fragility. Increased osmotic fragility does not distinguish hereditary spherocytosis from autoimmune hemolytic disease with spherocytosis but latter shows much less increased fragility with incubation. Autohemolysis (sterile defibrinated blood incubated for 48 hrs) is increased (10–50% compared to normal of <4% of cells); very nonspecific test. May sometimes be found also in nonspherocytic hemolytic anemias. Abnormal osmotic fragility and autohemolysis are reduced by 10% glucose; false-negative test may occur with concomitant diabetes mellitus. wDirect Coombs' test must be negative (in contrast to immune hemolytic conditions in which spherocytosis is common and direct Coombs' test is positive). Mechanical fragility is increased. WBC and platelet counts are usually normal; may be increased during hemolysis. wEvidence of hemolysis Degree of reticulocytosis (usually 5–15%) is greater than in other hemolytic anemias with similar degrees of anemia. Bone marrow shows marked erythroid hyperplasia except during aplastic crisis; moderate hemosiderin is present. Increased serum LD and indirect bilirubin. Haptoglobins are decreased or absent. Hemolytic crises usually precipitated by infection (especially parvovirus) cause more profound anemia despite reticulocytosis and increased jaundice and splenomegaly. Stool urobilinogen is usually increased. Hemoglobinemia and hemoglobinuria only during hemolytic crises. Laboratory findings due to complications, e.g., gallstones, aplastic crises Diagnosis should be questioned if splenectomy does not cause a complete response. Age at diagnosis is related to severity of hemolysis; more severe forms are diagnosed early in life. In neonates is associated with jaundice in ~50% of cases. Serum indirect bilirubin may be >20 mg/dL. Anemia is usually mild (Hb ³10 gm/dL) during first week of life. Spherocytes are present in infant and one parent and may be present in siblings. Reticulocyte count is usually 5–15%. SPLEEN, DECREASED FUNCTION (HYPOSPLENISM) Due To Congenital absence Splenectomy or autoinfarction (e.g., sickle cell anemia)
- 290. Infiltration (e.g., amyloidosis) Nontropical sprue, dermatitis herpetiformis, ulcerative colitis, regional ileitis (30% of patients), but overwhelming sepsis is rare. Irradiation Graft-versus-host disease wHowell-Jolly bodies (is the most consistent abnormality; good indicator of asplenic state), pocked cells, and target cells are seen in peripheral blood smears; also Pappenheimer bodies, a few acanthocytes, nucleated RBCs. Some Heinz bodies can be seen with special stains. Decreased osmotic fragility may be found. Increased risk of overwhelming infection by encapsulated bacteria (50% are due to Streptococcus pneumonia; another 25% are due to H. influenzae, Neisseria meningitidis, and group A streptococcus; Staphylococcus, Pseudomonas, and other gram-negative organisms are rarer). High mortality with massive bacteremia. Risk of infection is greater in infants less than 2 yrs old, within 2 yrs of splenectomy, or if underlying disorder is primary hematologic or splenic disease. Postsplenectomy Absence of RBC changes may suggest an accessory spleen in postsplenectomy patients. Increased WBC (granulocytosis) for several weeks in 75% of patients and indefinitely in 25%. Lymphocytosis and monocytosis occurs in several weeks in 50% of patients; some of these may show increased eosinophils or basophils. Platelet, WBC, and reticulocyte counts may increase to peak in 5–14 days in postoperative period, then become high normal. SPLEEN, INCREASED FUNCTION (HYPERSPLENISM) wDiagnosis is made by exclusion. wVarious combinations of anemia, leukopenia, thrombocytopenia are associated with bone marrow showing normal or increased cellularity of affected elements (includes primary splenic pancytopenia and primary splenic neutropenia). Decreased platelet count is moderate to severe (100,000 to 30,000/cu mm). Normochromic anemia (Hb = 9.0–11.0 g/dL) may occur. WBCs may be decreased with a normal differential count. Bone marrow is normal or shows increased cellularity of all lines with normal maturation. Peripheral blood smear may reflect the underlying cause. Spherocytes in hereditary spherocytosis Target cells in liver disease Atypical lymphocytes in infectious mononucleosis or chronic infection Leukoerythroblastosis, nucleated RBCs, and immature granulocytes in myeloid metaplasia with extramedullary hematopoiesis Teardrop and hand-mirror RBCs in myelofibrosis Direct Coombs' test is negative. 51Cr-tagged RBCs from normal person or from patient are rapidly destroyed after transfusion, and radioactivity accumulates in spleen. (Normal spleen/liver ratio = 1.0; in hypersplenism ratio is 1.5–2.0; in hemolysis ratio is >3.0.) Laboratory findings due to underlying disease that can cause splenomegaly, e.g., Congestion (e.g., cirrhosis with portal hypertension) Hematologic disorders (e.g., lymphoma/leukemia) Infiltration (e.g., lipid storage disease) Inflammation and infections (e.g., SBE, TB, sarcoidosis, collagen diseases, Felty's syndrome) Splenic tumors and cysts STOMATOCYTOSIS, HEREDITARY wRare condition of morphologic abnormality of >35% of RBCs in which one or more slit-like areas of central pallor produce a mouth-like appearance. Normally <5% of RBCs are stomacytic. £20% of RBCs are stomacytic in many acquired disorders (e.g., alcoholism, drug-induced hemolytic anemia, various neoplasms, hepatobiliary disease). Findings resemble hereditary spherocytosis with variable degree of hemolytic anemia, but splenectomy may cause partial or no remission. SULFHEMOGLOBINEMIA (>0.5 gm/dL sulfhemoglobin) Due To Drugs, especially phenacetin (including Bromo-Seltzer) and acetanilid Laboratory Findings wSpectroscopic absorption analysis—band at 618 µ does not disappear on addition of 5% potassium cyanide. Laboratory findings due to associated bromide intoxication. Bromide intoxication and sulfhemoglobinemia may be due to excessive intake of Bromo-Seltzer. THALASSEMIAS See Table 11-1, Table 11-9 and Table 11-27. Beta-chain synthesis is normally low at birth because HbA becomes predominant only after the first few months. Clinical and laboratory findings correspond to this;
- 291. thus neonatal anemia occurs only with alpha- but not with beta-thalassemia. Beta-Thalassemia Minima Silent carrier of beta-thalassemia trait Normal RBC morphology and Hb electrophoresis wCan only be demonstrated by reduced rate of beta-globin synthesis with increased alpha/betaglobin chain ratio. Beta-Thalassemia Trait wIn uncomplicated cases, Hb is normal or only slightly decreased (11–12 gm/dL), whereas RBC is increased (5–7 million/cu mm). Most nonanemic patients with microcytosis have thalassemia minor. wMicrocytic anemia with Hb <9.3 gm/dL is unlikely to be thalassemia minor. MCV is <75 fL whereas Hct is >30%; MCV may be as low as 55 fL. Microcytosis may be difficult to detect morphologically. wRatio of microcytic to hypochromic RBCs is >0.9 but <0.9 in iron deficiency. MCHC >31%. Blood smear changes are less than in thalassemia major. Anisocytosis is less marked than in iron-deficiency anemia. Poikilocytosis is mild to moderate; more striking than iron-deficiency anemia with Hb = 10–12 gm/dL. Target cells and oval forms may be numerous. Occasional RBCs show basophilic stippling in beta-thalassemia minor (rare in blacks but common in patients of Mediterranean descent). Reticulocyte count is increased (2–10%). Serum iron is normal or slightly increased; transferrin saturation may be increased. TIBC and serum ferritin are normal. Cellular marrow contains stainable iron. Osmotic fragility is decreased. wHb electrophoresis shows increased HbA2 (>4%); normal value does not rule out this diagnosis. Beta-Thalassemia Minor (>50 forms are recognized by gene cloning) See Table 11-28. Table 11-28. Differentiation of Microcytic Anemias of Iron Deficiency and Thalassemia Minor Slight or mild anemia. Most important differential diagnosis is iron deficiency. MCV usually <75 fL and Hct >30%; RBC is often increased. Normal iron, TIBC, serum ferritin wIncreased HbA2 (3–6%) on starch or agar electrophoresis and a slight increase in HbF (2–10%). HbA 2 is often decreased in iron deficiency; thus HbA 2 level may be normal in concomitant iron deficiency and beta-thalassemia minor, and the diagnosis of beta-thalassemia trait cannot be made until iron deficiency has been treated. HbA2 and HbF are absent in alpha-thalassemia. No specific laboratory identification of alpha-thalassemia trait (carrier). Thus, normal Hb electrophoresis and England-Fraser formula value < –6 in the absence of iron deficiency implies alpha-thalassemia minor; mild alpha-thalassemia is a clinical diagnosis. Thalassemia Intermedia (2–10% of thalassemia cases; may be homozygous delta-beta, beta0 , or beta+ , with or without an alpha gene or double heterozygous with an abnormal Hb such as S or E) Less severe clinical and laboratory findings than in thalassemia major and occur at later age. Hb is usually >6.5 g/dL. Combination of HbE and beta-thalassemia results in wide spectrum of clinical disorders varying from thalassemia to much milder that do not require transfusions. Thalassemia Major (Cooley's Anemia, Mediterranean Anemia) Several Hb electrophoretic patterns are characteristic (see Table 11-27). wClassification of beta-thalassemia syndromes:
- 292. · Homozygous beta0 —HbA is absent; HbF and HbA2 are present. · Homozygous beta+ —HbA, HbA2, and HbF are all detected. · HbF = 10–90%; HbA is decreased; HbA2 may be normal, low, or high. wMarked hypochromic microcytic regenerative hemolytic anemia is present. Often Hb = 2.0–6.5 g/dL, Hct = 10–24%, RBC = 2–3 million, indices are decreased. wBlood smear shows marked anisocytosis, poikilocytosis, target cells, spherocytes, and hypochromic, fragmented, and bizarre RBCs; also many nucleated RBCs—basophilic stippling, Cabot's ring bodies, siderocytes. Reticulocyte count is increased. WBCs are often increased, with normal differential or marked shift to left. Platelets are normal. Bone marrow is cellular and shows erythroid hyperplasia and increased iron. Serum iron and TIBC are increased. After age 5 yrs, iron-binding capacity is usually saturated. Laboratory findings of hemolysis and liver dysfunction (e.g., increased serum LD, AST, ALT, and indirect bilirubin [1–3 mg/dL], urine and stool urobilinogen; serum haptoglobin and hemopexin are very decreased or absent). Liver dysfunction causing disturbance of factors V, VII, IX, XI, prothrombin RBC survival time is decreased. Osmotic fragility is decreased. Mechanical fragility is increased. Laboratory findings due to complications, e.g., · Secondary hypersplenism (usually occurs between age 5–10 yrs, detected when transfusion requirement is >200–250 mg/kg body weight, at which time splenectomy is indicated). m•Hemosiderosis (hepatic fibrosis and cirrhosis; endocrinopathies with hypofunction of pituitary, thyroid, etc.). Proteinuria, hyposthenuria, failure to acidify urine, and increased urobilin and urobilinogen with dark color may be present. mBeta-thalassemia trait demonstrated in both parents. wPrenatal diagnosis is possible at 16 wks' gestation in 85% of cases by DNA analysis of amniotic cells; the remaining cases can be diagnosed by alpha-/beta-chain ratios in fetal blood (obtained by fetoscopy). Alpha-Thalassemia 2 See Table 11-29. Table 11-29. Classification of Alpha-Thalassemia Syndromes mOne alpha allele is deleted, which causes asymptomatic but transmissible trait. Occurs in £30% of black populations. Coincident with sickle cell or HbC trait, reduces the proportion of HbS or HbC below the usual 35–40% (also slightly decreasing the clinical severity); thus <35% variant Hb is good evidence for coexisting alpha-thalassemia in such patients. No clinical or hematologic findings. wDefinitive diagnosis of older silent carrier depends on special techniques (globin synthesis rates). Alpha-Thalassemia 1 Two copies of alpha-globin gene are deleted from same chromosome. Minimal hypochromic, microcytic anemia, increased target cells, anisocytosis, resembling beta-thalassemia trait but without increased HbA 2 HbE–Alpha-Thalassemia HbH Disease Inheritance of alpha-thalassemia 1 from one parent and alpha-thalassemia 2 from other causing absence of three of four alpha-globin alleles and excess of beta-globins (HbH). May also be due to deletion of two alpha-globin genes and presence of alpha-chain variant Hb Constant Spring. Acquired form may occur during course of myeloproliferative disorders due to relative suppression of alpha-chain gene. Hypochromic, microcytic hemolytic anemia is moderate to mild (Hb = 7–11 gm/dL), accentuated by infection, drugs, pregnancy, etc. Most RBCs are microcytic, hypochromic; many target or deformed RBCs wCharacteristic patterns on RBC and platelet histograms due to very small RBCs; may cause inaccurate platelet count. mSupravital stain shows granular inclusions (precipitated beta chains), which are very marked after splenectomy wIsoelectric focusing is more sensitive than Hb gel electrophoresis for variants present in small amounts
- 293. May present with neonatal jaundice. Hydrops Fetalis Deletion of all four alpha-globin genes with no normal Hb causes stillbirth or prompt postnatal death due to severe hypoxemia (despite cord Hb £10 g/dL). wPrenatal diagnosis by Southern blot of amniotic fluid DNA or chorionic villus sample, or by PCR techniques. THICK BLOOD SYNDROME, NEONATAL wHct >64% in a heparinized sample or >67% in an unheparinized sample. wWhen Hct is 60–64%, diagnosis must be made with a microviscosimeter. If <60%, hyperviscosity is not found. Hyperbilirubinemia, hypoglycemia, platelet count <130,000/cu mm, or abnormal blood smear (burr cells, fragmented RBCs, increased erythroid elements) are found in ~50% of cases. Therapeutic replacement of blood with plasma exchange transfusion aims to reduce Hct to 50–60% range. Due To Transfusion (e.g., maternal-fetal, twin to twin) Hypoxemia (e.g., postmaturity, small-for-gestational-age neonates) Decreased deformability of RBC membranes (e.g., sickle cell anemia, spherocytosis) THYMIC HYPOPLASIA (DiGEORGE SYNDROME) (Hypoplasia or aplasia of thymus and parathyroid and anomalies of other structures formed at same time [e.g., cardiac defects, renal abnormalities, facial abnormalities such as cleft palate] due to chromosome band 22q11 deletions) See Table 11-6 and Table 11-7. w Proposed Diagnostic Criteria Involvement of two or more of the following organ systems: Thymus Parathyroid Cardiovascular Hypocalcemia may be transient; may cause neonatal seizures. Serum immunoglobulins are usually near normal for age but may be decreased, especially IgA. IgE may be increased. Decreased T cells and relative increase in B cell percentage. Normal ratio of helper and suppressor types. With complete syndrome, susceptible to opportunistic infection ( P. carinii, fungi, viruses) and to graft-versus-host disease from blood transfusion. In partial syndrome (with variable amount of hypoplasia), growth and response to infection may be normal. Thymus is often absent; when found, histology appears normal. Lymph node follicles appear normal, but paracortical areas and thymus-dependent areas of spleen show variable amount of depletion. Incidence of cancer and of autoimmune disease is not increased. TUMOR OF BONE MARROW (Due to leukemia, metastases, agnogenic myeloid metaplasia) “Leukoerythroblastic” peripheral blood picture WBC may be increased, decreased, or normal. Peripheral blood may show left shift in myeloid series, thrombocytopenia, nucleated RBCs, schistocytes, teardrop RBCs. wMay show tumor cells in peripheral blood (“carcinocythemia”), especially in patients receiving high-dose chemotherapy before autologous marrow transplant and in those receiving growth factor therapy. wBone marrow examination establishes diagnosis. TUMOR OF THYMUS (>40% of patients have parathymic syndromes noted in the following, which are multiple in one-third) mAssociated with Myasthenia gravis in ~35% of cases. May appear up to 6 yrs after excision of thymoma in 5% of cases. Thymoma develops in 15% of patients with myasthenia gravis. Acquired hypogammaglobulinemia. 7–13% of adults with this condition have an associated thymoma; does not respond to thymectomy. Pure red cell aplasia found in approximately 5% of thymoma patients. 50% of patients with pure red cell aplasia have thymoma, of whom 25% benefit from thymectomy; onset followed thymectomy in 10% of cases. May be accompanied or followed, but not preceded, by granulocytopenia or thrombocytopenia or both in one-third of cases; thymectomy is not useful therapy. Pure red cell aplasia occurs in one-third of patients with hypogammaglobulinemia and thymoma. Autoimmune hemolytic anemia with positive Coombs' test and increased reticulocyte count Cushing's syndrome
- 294. MEN (usually type I) SLE Miscellaneous disorders (e.g., giant cell myocarditis, nephrotic syndrome) Cutaneous disorders (e.g., mucocutaneous candidiasis, pemphigus) WISKOTT-ALDRICH SYNDROME (Rare immunologic X-linked recessive condition characterized by eczema, repeated infections, and thrombocytopenia with death by age 10 due to infection, hemorrhage, or lymphoma [12% incidence]. Severe impairment of humoral and cellular immunity) See Table 11-6 and Table 11-7. wPlatelet count is decreased (average 15,000–30,000/cu mL) and small appearance on smear is diagnostic. Bleeding tendency (skin, GI tract) with frequent death due to intracranial hemorrhage. Decreased survival time of patients' platelets. Megakaryocytes appear normal. Impaired maturation of hematopoietic stem cells. Marked susceptibility to high-grade encapsulated organisms and to opportunistic infections (e.g., bacteria, fungi, P. carinii, chronic viral infections) and autoimmune disease is seen. Highly variable immunoglobulin levels, even within the same patient; predominant pattern is decreased serum IgM, increased IgA and IgE, normal IgG. Normal levels of circulating T and B cells; severely impaired cell-mediated and humoral immunity that decreases with age. EBV-associated lymphoid cancers (especially B immunoblastic non-Hodgkin's lymphoma with predilection for CNS) and autoimmune disorders in older persons. wScanning electron microscopy of fetal lymphocytes from umbilical vein establishes prenatal diagnosis. Tests of Coagulation See Table 11-30, Table 11-31 and Table 11-32. Table 11-30. Comparison of Coagulation disorders with Platelet or Vascular Disorders Table 11-31. Screening Tests for Presumptive Diagnosis of Common Bleeding Disordersa Table 11-32. Summary of Coagulation Studies in Hemorrhagic Conditions ANTICOAGULANTS, CIRCULATING (Usually antibodies that inhibit function of specific coagulation factors, especially VIII or IX; occasionally V, XI, XIII, vWF)
- 295. May be acquired (antibodies) due to multiple transfusions for congenital deficiency of a coagulation factor, or spontaneous. Associated with Clinical Disorders FactorDisorder VIII, IXAfter replacement therapy for hereditary deficiency XI SLE—very rare IX SLE—rare VIII SLE, RA, drug reaction, asthma, pemphigus, inflammatory bowel disease, postpartum period, advanced age X Amyloidosis (tissue binding rather than circulating) V Associated with streptomycin administration, idiopathic X, V SLE—common II Myeloma, SLE XIII Associated with isoniazid administration, idiopathic Also associated with pregnancy, lymphoproliferative diseases, certain drugs (e.g., penicillin, sulfonamides, phenytoin) wAntiphospholipid-thrombosis syndrome* defined as one or more autoantibodies (anticardiolipin antibodies, lupus anticoagulant) and/or biological false-positive for syphilis found on two occasions at least 12 wks apart associated with appropriate clinical manifestations. Most patients have positive assay for both lupus anticoagulant and anticardiolipin antibodies. May be secondary to SLE or primary (i.e., without signs of connective tissue disease). Directed against phospholipids rather than against a specific factor ( Fig. 11-11). Fig. 11-11. Laboratory diagnosis of antiphospholipid syndromes. (dRVRVT = dilute Russell super venom time; ELISA = enzyme-linked immunosorbent assay.) *Love PE, Santoro SA. Antiphospholipid antibodies: Anticardiolipin and the lupus anticoagulant in SLE and in non-SLE disorders. Prevalence and clinical significance. Ann Int Med 1990;112:682. Bick RL. The antiphospholipid-thrombosis syndromes. Am J Clin Path 1993;100:470. Riley RS, Friedline J, Rogers JS. Antiphospholipid antibodies: Standardization and testing. Clin Lab Med 1997;17:395. Anticardiolipin Antibodies Detected by ELISA against IgG, IgM, and IgA. Common in SLE—correlates with laboratory features (e.g., thrombocytopenia, prolonged aPTT, positive direct and indirect Coombs' test); may not correlate with clinical manifestations in contrast to primary syndrome. Lupus Anticoagulant w 1. Prolonged phospholipid-dependent clotting time in a screening assay •Increased aPTT; 1:1 mixture with normal plasma with aPTT >4 secs longer than control aPTT establishes presence of inhibitor, but the increased aPTT is corrected if due to a clotting factor deficiency. Low factor activity increases toward normal with further dilution of test plasma. · Prolonged aPTT should be confirmed by a different phospholipid detection clotting system (e.g., dRVVT). · Abnormal dRVVT and tissue thromboplastin inhibition test. dRVVT is more specific for lupus anticoagulant than aPTT because not influenced by deficiency of intrinsic pathway factors or antibodies to factors VIII, IX, or XI. Heparin or warfarin can prolong dRVVT and most other tests. · Kaolin clotting time is increased; is sensitive test for lupus anticoagulant, especially when aPTT is normal or only slightly increased. w 2. Demonstration that abnormality is due to inhibitor rather than factor deficiency · Rosner index >15 indicates an inhibitor: · Prolonged incubation with normal plasma does not increase inhibitor effect. · Decrease in two or more factors (VIII, IX, XI, or XII) by one-stage assay but normal by two-stage assay. w 3. Confirmation of inhibitor specificity for phospholipid · Platelet neutralization procedure (addition of platelets shortens the prolonged aPTT and dRVVT due to lupus anticoagulant but not due to factor VIII inhibitors). · Cephalin phospholipid neutralization (shortening) of prolonged test confirms lupus anticoagulant. w 4. No evidence of another coagulopathy to account for abnormal coagulation reaction. PT is usually normal to slightly increased. Thrombin time is normal. ANTITHROMBIN III See Fig. 11-12. Fig. 11-12. Blood coagulation eascade.
- 296. Use To detect hypercoagulable state associated with episodes of venous thrombosis; decreased in ~4.5% of patients with idiopathic venous thrombosis. Functional tests are required because the antigen level may be normal in ~10% of cases of hereditary qualitative deficiency by immunologic method. Decreased In Hereditary familial deficiency (typically 40–60% of normal); autosomal dominant trait. Chronic liver disease (>80% of cases of cirrhosis); liver cancer Nephrotic syndrome Protein-wasting diseases Heparin therapy for >3 days L-Asparaginase therapy Active thrombotic disease (e.g., thrombophlebitis, deep venous thrombosis, pulmonary embolism) (not diagnostically useful) AMI DIC (not diagnostically useful) Oral contraceptive use (slightly) Last trimester of pregnancy (rarely <75% of normal) Newborns (~50% of adult level, which is attained by age 6 mos) Other conditions (e.g., acute leukemia, carcinoma, burns, postsurgical trauma, renal disease, gram-negative septicemia) Increased In Patients with increased ESR, hyperglobulinemia Coumadin anticoagulation BLEEDING TIME (BT)24 See Fig. 11-13. Fig. 11-13. Algorithm for prolonged bleeding time. (= bleeding time.) Mielke modification of Ivy method; should use a standardized technique: blood pressure cuff on upper arm is inflated to 40 mm Hg; two small standardized skin incisions are made on volar surface of forearm using a specially calibrated template. Normal = 4–7 mins. Longer in women than in men. Use BT is functional test of primary hemostasis. BT is best single screening test for platelet functional or structural disorders, acquired (e.g., uremia) or congenital. Normal BT without suggestive history usually excludes platelet dysfunction. However, a normal BT does not rule out a significant defect; with clinical suspicion, platelet aggregation should be performed. Useful as part of workup for coagulation disorders in patients who have history of excess bleeding (e.g., associated with dental extraction, childbirth, circumcision, tonsillectomy) even with a normal platelet count. Normal in all other disorders of coagulation except vWF deficiency and some cases of very low plasma fibrinogen (because platelets contain fibrinogen). May be useful to monitor treatment of active hemorrhage in patients with prolonged BT due to uremia, von Willebrand's disease, congenital platelet function abnormalities, or severe anemia. No value in performing BT if platelet count is <100,000/cu mm as BT is usually prolonged. Prolonged BT with platelet count >100,000/cu mm usually indicates impaired platelet function (e.g., due to aspirin) or von Willebrand's disease.
- 297. Not recommended for prediction of bleeding in myeloproliferative diseases or neonates receiving NSAIDs. Sensitivity, specificity, and predictive value of BT in perioperative hemorrhage are not known. Not recommended for routine preoperative screening because General surgery patients without obvious risk factors for bleeding rarely have clinically significant increase in BT. Even with a prolonged BT, blood loss does not exceed that of patients with normal BT. Prolonged BT does not necessarily cause increased bleeding. Therapeutic decisions are not likely to be changed by results of BT. Clinical history is the best preoperative screening. Not recommended for preoperative evaluation of patients receiving aspirin or NSAIDs, patients with liver disease, patients for coronary bypass. May be useful in preoperative screening of patients for eye, middle ear, brain, or knee surgery. Usually Prolonged In Thrombocytopenia Platelet count <100,000/cu mm and usually <80,000/cu mm before BT becomes abnormal and <40,000/cu mm before abnormality becomes pronounced. BT is almost always abnormal when platelet count is <60,000/cu mm except in conditions that have young supereffective platelets. BT may be normal in some patients with immune thrombocytopenic purpura with marked decrease in platelet count. When platelet count = 80,000/cu mm, BT should be ~10 mins; when platelet count = 40,000/cu mm, BT should be ~20 mins; when platelet count = <10,000/cu mm, BT should always be >30 mins if platelet function is normal. If results are beyond these values, patient may also have a qualitative platelet abnormality. Platelet function disorders Hereditary Defect in plasma proteins von Willebrand's disease (especially 2 hrs after ingestion of 300 mg of aspirin) Deficient release of platelet glycoproteins Glanzmann's thrombasthenia Bernard-Soulier syndrome Defective release mechanisms Gray platelet syndrome Aspirin-like defect Storage pool deficiency Others, e.g., Wiskott-Aldrich syndrome Chédiak-Higashi syndrome Oculocutaneous albinism (Hermansky-Pudlak syndrome) Hereditary hemorrhagic telangiectasia Ehlers-Danlos syndrome Acquired Abnormal plasma factors Drugs Aspirin, NSAIDs (indomethacin, ibuprofen, phenylbutazone, etc.). Ingestion with £7 days is the most common cause of prolonged BT. Aspirin may double the baseline BT, which may still be within normal range. 325 mg of aspirin increases BT of most persons. Antimicrobials (especially high dose beta-lactam, e.g., carbenicillin; cephalosporins, nitrofurantoin, hydroxychloroquine) Anticoagulants (e.g., heparin, prostacyclin, streptokinase-streptodornase) Tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline) Phenothiazines (e.g., chlorpromazine, promethazine, trifluoperazine) Anesthetic (e.g., halothane, local) Methylxanthines (e.g., caffeine, theophylline, aminophylline) Others (e.g., dextrans, calcium channel–blocking agents, radiographic contrast agents, beta-adrenergic blockers, alcohol, aminocaproic acid, nitroglycerin) Uremia (may be corrected with vasopressin or cryoprecipitate) Fibrin degradation products (e.g., DIC, liver disease, fibrinolytic therapy) Macromolecules (e.g., dextran, paraproteins [myelomas, Waldenström's macroglobulinemia) Other immune thrombocytopenias Myeloproliferative diseases, including myelodysplastic syndrome, preleukemia, acute leukemia, hairy cell leukemia) Vasculitis Others (e.g., amyloidosis, viral infections, scurvy, after circulating through an oxygenator during cardiac bypass surgery) Vascular disorders Increased BT or BT increased out of proportion to platelet count suggests von Willebrand's disease or qualitative platelet defect. Usually Normal In Hemophilia Severe hereditary hypoprothrombinemia Severe hereditary hypofibrinogenemia CLOT RETRACTION Use Reflects platelet number and function. Poor test of clotting function Little value for detection of mild to moderate bleeding disorders May Occur In Various thrombocytopenias
- 298. Thrombasthenia COAGULATION (CLOTTING) TIME (LEE-WHITE CLOTTING TIME) Use See Table 11-33. Table 11-33. Effect of Anticoagulant Drugs on Coagulation Tests Former routine method for control of heparin therapy but now replaced by aPTT. It is not a reliable screening test for bleeding conditions because it is not sensitive enough to detect mild conditions but only detects severe ones. Normal coagulation time does not rule out a coagulation defect. Many variables exist in the technique of performing the test. Routine preoperative bleeding and coagulation times are of little value for routine preoperative screening. Prolonged In Severe deficiency (<6%) of any known plasma clotting factors except factor XIII (fibrin-stabilizing factor) and factor VII Afibrinogenemia Presence of a circulating anticoagulant (including heparin) Normal In Thrombocytopenia Deficiency of factor VII Von Willebrand's disease Mild coagulation defects due to any cause Interferences Increased In Anticoagulants Tetracyclines Decreased In Corticosteroids Epinephrine FIBRINOGEN DEGRADATION PRODUCTS (Latex agglutination rapid test kit detects increased level [10 µg/mL] in serum and parallels results with hemagglutination inhibition [HAI] method. Detects major breakdown products of fibrin or fibrinogen. Does not distinguish between fibrinolysis and fibrinogenolysis.) Use Aid in diagnosis of DIC Increased in Serum DIC In association with fibrinolytic therapy Thromboembolic events Pulmonary embolism—peak values may be transient. Postoperative deep venous thrombosis. AMI during first 24–48 hrs. Certain disorders of pregnancy. Small increases with exercise, anxiety, stress, severe liver disease. Increased in Urine
- 299. Kidney disease UTI—increased in infection of upper tract but not of bladder. Proliferative GN—level falls during response to drug therapy. Rejection of renal transplant. Conditions causing increased serum level (see previous paragraph) Interferences RF may cause false-positive. HEPARIN, PLASMA Use Monitor heparin therapy in selected situations. Combined heparin and warfarin therapy Combined heparin and recombinant tissue plasminogen activator therapy Heparin resistance in presence of a circulating anticoagulant Altered plasma clotting proteins (e.g., increased factor I or VIII or platelet factor 4 or decreased antithrombin III) When aPTT appears to be unsatisfactory for heparin therapy control (e.g., overwhelming infections, myocardial infarction, severe liver disease) Use of low-molecular-weight heparins To prove unrecognized heparin administration (e.g., indwelling catheter) PARTIAL THROMBOPLASTIN TIME, ACTIVATED (aPTT) See Table 11-33, Fig. 11-14, Fig. 11-15 and Fig. 11-16. Fig. 11-14. Algorithm for isolated prolonged activated partial thromboplastin time (aPTT). Fig. 11-15. Algorithm for acquired coagulation disorders. (I = increased; N = normal; DIC = disseminated intravascular coagulation.) Fig. 11-16. Algorithm for hereditary coagulation disorders. (I = increased; N = normal; PT = prothrombin time; aPTT = partial thromboplastin time.) Use Monitor heparin therapy Screen for hemophilia A and B Detect clotting inhibitors aPTT is the best single screening test for disorders of coagulation; it is abnormal in 90% of patients with coagulation disorders when properly performed. Screens for
- 300. all coagulation factors that contribute to thrombin formation except factors VII and XIII. The test may not detect mild clotting defects (25–40% of normal levels), which seldom cause significant bleeding. Not recommended for preoperative screening of asymptomatic adult unless patient has specific clinical indication (e.g., active bleeding, known or suspected bleeding disorders [including anticoagulant use], liver disease, malabsorption, malnutrition, other conditions associated with acquired coagulopathies, in which procedure may interfere with normal coagulation). Prolonged By Defect in factors (assays <30% of normal; intrinsic pathway) I (fibrinogen) II (prothrombin) V (labile factor) VIII* IX* X (Stuart-Prower factor) XI* XII (Hageman factor) Presence of specific inhibitors of clotting factors * (most frequently antibody against factor VIII, which occurs in ~15% of multitransfused patients with severe hemophilia A and less frequently in mild/moderate hemophilia A; and against circulating lupus anticoagulant). Mixing equal parts of patient's plasma and normal plasma corrects aPTT (or PT) if due to coagulation factor deficiency but not if due to an inhibitor. Heparin Warfarin Lupus anticoagulant* *May cause isolated prolonged aPTT. Normal In Thrombocytopenia Platelet dysfunction Von Willebrand's disease (may be prolonged in some patients) Isolated defects of factor VII Interferences Very increased or decreased Hct (e.g., polycythemia) that alters citrate concentration or inadequate citrate in collection tube Specimen contamination with EDTA Clots in specimen Partially filled collection tube Values may be falsely very high if plasma is very turbid or icteric when photoelectric machines are used. Drugs other than heparin Hirudin analogues and argatroban, warfarin Less frequently (e.g., hematin, hydroxyethyl starch, suramin, Taularidine [an additive in some IV medications]) Drugs that may inhibit heparin action (e.g., antihistamines, digitalis, nicotine, penicillin (IV), protamine, tetracycline, phenothiazine) PLASMINOGEN (Normal adults = 76–124% for males, 65–153% for females; infants = 27–59%) Use Is one indicator of fibrinolytic activity Monitor fibrinolytic therapy with streptokinase or urokinase May Be Decreased In Some familial or isolated cases of idiopathic deep venous thrombosis; autosomal deficiency or dysplasminogenemia Diabetic patients with thrombosis DIC and systemic fibrinolysis Behçet's disease Cirrhosis of the liver PLATELET AGGREGATION STUDIES
- 301. (Platelet aggregation stimulated by certain agonistic drugs is measured in vitro by turbidimeter, shown graphically by wave patterns.) See Table 11-34. Table 11-34. Congenital Functional Platelet Disorders Use Classification of congenital qualitative platelet functional abnormalities of adhesion, release, or aggregation (e.g., storage pool disease, Glanzmann's thrombasthenia, Bernard-Soulier syndrome) Rarely useful to evaluate acquired bleeding disorders. Interferences Aspirin may produce characteristic abnormalities of release defects with decreased thromboxane A 2 synthesis. Myeloproliferative diseases and uremia: abnormal aggregation to epinephrine, adenosine diphosphate (ADP), and collagen Aggregation may also be abnormal due to dysproteinemia, lipemia, hemolysis, various drugs (e.g., NSAIDs), and cardiopulmonary bypass. Interpretation ADP and epinephrine produce primary and secondary waves of aggregation; collagen, arachidonic acid, and ristocetin produce only primary waves Disorder Decreased Aggregation Von Willebrand's disease, Bernard-Soulier syndrome Ristocetin Thrombasthenia All agents except ristocetin Release defects Storage pool disease See Table 11-34 Idiopathic ADP, epinephrine, collagen Abnormal thromboxane A2 synthesis Arachidonic acid, ADP, epinephrine, collagen Afibrinogenemia No primary or secondary waves to ADP Platelet Aggregation, Ristocetin-Induced (Not same as ristocetin cofactor assay) Increased In Von Willebrand's disease (type IIB) Platelet-type von Willebrand's disease Type I New York von Willebrand's disease Decreased In Von Willebrand's disease (types I, IIA, IIC, III) ITP Storage pool disease Bernard-Soulier syndrome Acute myeloblastic leukemia Aspirin ingestion Infectious mononucleosis Cirrhosis PLATELET COUNT See Table 11-34, Table 11-35, Table 11-36 and Fig. 11-17.
- 302. Table 11-35. Some Congenital Hemorrhagic Diseases due to Disorders of Platelet-Vessel Wall Table 11-36. Comparison of Congenital Disorders of Platelet Function Fig. 11-17. Evaluation of hemostatic abnormalities. (Prothrombin time and activated partial thromboplastin time—see Fig. 11-15 and Fig. 11-16.) (BT = bleeding time; DAT = direct antiglobulin test [Coombs‘]; DIC = disseminated intravascular coagulation; HUS = hemolytic uremic syndrome; ITP = idiopathic thrombocytopenic purpura; TTP = thrombic thrombocytopenic purpura.) Increased In (>450,000/cu mm; <1 million/cu mm in 97% of patients). Myeloproliferative disease (e.g., polycythemia vera, CML, agnogenic myeloid metaplasia, essential thrombocythemia) Malignancy, especially disseminated, advanced, or inoperable, accounts for ~13% of cases in hospital patients. Patients recently having surgery, especially splenectomy (accounts for ~19% of cases in hospital patients); or experiencing severe trauma, massive acute hemorrhage, or thrombotic episodes. Infections account for ~31% of cases in hospital patients. Chronic inflammation as in inflammatory bowel disease, collagen diseases, and RA Iron-deficiency anemia Miscellaneous disease states (e.g., cardiac disease, cirrhosis of the liver, chronic pancreatitis, ARDS in neonates, burns, hypothermia, preeclampsia, ethanol withdrawal, renal failure, splenectomy) ~50% of patients with “unexpected” increase of platelet count are found to have a malignancy. Decreased In (Thrombocytopenia) Acquired Decreased platelet production (e.g., aplastic anemia, myelophthisis, exposure to ionizing radiation, nutritional deficiencies [folate, vitamin B 12, etc.], drug effects [alcohol, chemotherapeutic agents, etc.]) Infections (e.g., AIDS, SBE, septicemia, typhus, rubella, infectious mononucleosis) may have several mechanisms. Increased platelet destruction. wAntiplatelet antibodies (IgG and IgM) may be found in plasma and by flow cytometry, may be detected on platelets in most patients with drug-induced thrombocytopenia (e.g., heparin, quinidine, procainamide, quinine) (sensitivity = 90%). 15–29% of patients with autoimmune thrombocytopenia have only platelet-associated IgM. Negative results in plasma and on platelets argues strongly against an immune cause of thrombocytopenia. Platelet-associated IgG may be seen in ITP, sepsis, aplastic anemia, acute leukemia, SLE, immune vasculitis, drugs. Drug-induced immune thrombocytopenia (e.g., quinidine, quinine, gold, sulfonamides, penicillins; heparin causes thrombocytopenia in £10% of patients, usually in
- 303. 5–10 days) Neonatal alloimmune thrombocytopenia—uncommon condition that may cause intracranial hemorrhage in utero or at birth with death or neurologic impairment. Due to maternal platelet-specific antibody against infant platelet antigen inherited from father but absent in mother. Unexplained petechiae/ purpura at birth, platelet count <100,000/cu mm. Treated by transfusion of mother's platelet concentrate. Lymphoproliferative disorders Posttransfusion (develops in 5–10 days; complement-fixing antibody for platelet antigen P1 A1 establishes diagnosis) Extracorporeal circulation Increased platelet consumption TTP DIC Septicemia Toxemia of pregnancy (£ 20% of cases) Massive blood loss Hypersplenism Cirrhosis Dilutional (e.g., after massive transfusion) Renal insufficiency Paroxysmal nocturnal hemoglobinuria Inherited Allport's syndrome Bernard-Soulier syndrome Chédiak-Higashi syndrome Ehlers-Danlos syndrome May-Hegglin anomaly Wiskott-Aldrich syndrome Glanzmann's thrombasthenia Hermansky-Pudlak syndrome TAR (thrombocytopenia, absent radius bones) syndrome When associated with anemia and microangiopathy on peripheral smear, rule out DIC, TTP, hemolytic-uremic syndrome, prosthetic valve dysfunction, malignant hypertension, eclampsia, vasculitis, leaking aortic aneurysm, disseminated metastatic cancer. Interferences Pseudothrombocytopenia diagnosis by examination of stained blood smear Platelet clumping induced by EDTA blood collection tubes is the most common cause. Platelet satellitosis. Platelet cold agglutinins. Giant platelets. RBC count >6.5 million/cu mm. Pseudothrombocytosis Cryoglobulinemia Malaria parasites Fragments of RBCs or WBCs Microspherocytes Howell-Jolly bodies, nucleated RBCs, Heinz bodies, clumped Pappenheimer bodies 50,000–150,000/cu mm—usually no bleeding 20,000–50,000/cu mm—minor spontaneous bleeding; postoperative bleeding <20,000/cu mm—may have more serious bleeding. 5000/cu mm—frequently has serious bleeding. Platelet transfusions are not used if >20,000/cu mm except preoperatively or when a specific bleeding lesion (e.g., peptic ulcer) is present. One unit of platelet concentrate increases the platelet count by 15,000/cu mm in the average 70-kg adult; therefore minimal dose to administer is six units. No increment in 60 mins suggests that alloimmunization has occurred (should use single-donor platelets); >5000/cu mm increment suggests that alloimmunization has not occurred. PLATELET FUNCTION DEFECTS, ACQUIRED Due To Uremia Fibrinogen degradation products (e.g., liver disease, DIC, primary fibrinolytic syndromes) Myeloproliferative syndromes may show any combination of platelet aggregation defects that are not characteristic. Paraprotein coating of platelet membranes (e.g., multiple myeloma, Waldenström's macroglobulinemia, essential monoclonal gammopathy) Autoimmune diseases (e.g., collagen vascular disease, antiplatelet antibodies, immune thrombocytopenias) Anemias (e.g., severe deficiency of iron, B12, or folate)
- 304. Drug effects Interference with platelet membrane receptors (e.g., amitriptyline, imipramine, doxepin, chlorpromazine, cocaine, lidocaine [Xylocaine], isoproterenol, propranolol, cephalothin, ampicillin, penicillin, others) Inhibition of prostaglandin pathways (e.g., aspirin, indomethacin, ibuprofen, phenylbutazone, naproxen, furosemide, verapamil, others) Inhibition of platelet phosphodiesterase activity (e.g., caffeine, aminophylline, theophylline, papaverine, others) Unknown mechanisms (e.g., dicumarol, heparin, chlortetracycline, glycerol guaiacolate, others) PLATELET VOLUME, MEAN (Limited value when measured by routine automated hematology instruments) Normal = 7.4–10.4 fL Use Indicates uniformity or heterogeneity of size of platelet population. Study of thrombocytopenic patients Increased mean platelet volume with thrombocytopenia indicates that thrombopoiesis is stimulated and platelet production is increased. Normal mean platelet volume with thrombocytopenia indicates impaired thrombopoiesis. Increased In Immune thrombocytopenic purpura Thrombocytopenia due to sepsis (recovery phase) Myeloproliferative disorders Massive hemorrhage Prosthetic heart valve Splenectomy Vasculitis Decreased In Wiskott-Aldrich syndrome PROTEIN C, PLASMA Normal range = 70–130% Use Detect hypercoagulable states associated with episodes of venous thrombosis Decreased In Hereditary (autosomal dominant) deficiency (heterozygote levels are usually 30–65%; found in screening in 1 in 300 persons; thrombosis is not usual if level >50%). Establishes the diagnosis of purpura fulminans, which is seen in homozygous infants (usually <1% of normal). Warfarin-induced skin necrosis is almost pathognomonic for protein C deficiency. Liver disease DIC (not diagnostically useful) Postoperative state Malignancy ARDS Pregnancy Oral contraceptive use High loading dose of warfarin causes transient rapid drop in protein C levels. L-Asparaginase therapy Decreases with age (~4% per decade). PROTEIN S, PLASMA Use Detect hypercoagulable states associated with episodes of venous thrombosis Should be assayed whenever protein C is assayed; both are vitamin K–dependent inhibitors of coagulation. Heterozygotes with levels of 30–60% may have episodes of recurrent thrombosis. Functional rather than immunologic tests are preferred to detect qualitative as well as quantitative deficiency.
- 305. Decreased In Pregnancy First month of life Oral anticoagulant or contraceptive use Acute-phase reaction DIC (not diagnostically useful) Nephrotic syndrome Liver disease L-Asparaginase therapy Deep venous thrombosis in some patients PROTHROMBIN CONSUMPTION Impaired by Any defect in phase I or phase II of blood coagulation Thrombocytopathies Thrombocytopenia Hypoprothrombinemia Hemophilias Circulating anticoagulants Other PROTHROMBIN TIME (PT) See Table 11-33 and Table 11-36. Use Primarily for three purposes: Control of long-term oral anticoagulant therapy with coumarins and indanedione derivatives. Evaluation of liver function—PT is the most useful test of impaired liver synthesis of prothrombin complex factors (factors II, VII, X, proteins C and S). Evaluation of coagulation disorders—screen for abnormality of factors involved in extrinsic pathway (factors V, VII, X, prothrombin, fibrinogen). Should be used with aPTT. Prolonged by Defect In (Assays <30% of normal; extrinsic pathway) Factor I (fibrinogen) Factor II (prothrombin) Factor V (labile factor) Factor VII (stable factor) Factor X (Stuart-Prower factor) Prolonged In Inadequate vitamin K in diet Premature infants Newborn infants of vitamin K–deficient mothers (hemorrhagic disease of the newborn) Poor fat absorption (e.g., obstructive jaundice, fistulas, sprue, steatorrhea, celiac disease, colitis, chronic diarrhea) Severe liver damage (e.g., poisoning, hepatitis, cirrhosis) Drugs (e.g., coumarin-type drugs for anticoagulant therapy, salicylates) Factitious ingestion of warfarin Idiopathic familial hypoprothrombinemia Circulating anticoagulants Hypofibrinogenemia (acquired or inherited) Heparin Lupus anticoagulant
- 306. Reporting PT should be reported as ratio of patient results to control rather than as percentage. PT may also be reported as INR (international normalized ratio) only for patients on oral anticoagulants for ³2 wks who have stable PTs and responded appropriately to the drug. INR = ratio of patient PT to mean of PT reference range for that laboratory raised to the power of the international sensitivity index (index is provided by the thromboplastin manufacturer). Is intended to take into account differences due to different methods or thromboplastin-instrument combinations in interpretation of results. Suggested INR range = 2.0–3.0 for standard-dose therapy for treatment or prophylaxis of venous thrombosis or pulmonary or systemic embolus. Suggested INR range = 2.5–3.5 for high-risk patients with mechanical heart valves. Note: INR is dependent on instrumentation. Sensitive thromboplastin (low international sensitivity index) leads to undertreatment and insensitive thromboplastin (high international sensitivity index) leads to overtreatment. RISTOCETIN COFACTOR ACTIVITY Use Differential diagnosis of von Willebrand's disease Decreased In Von Willebrand's disease type I Von Willebrand's disease type IIA Cirrhosis THROMBIN TIME Use Detects abnormal fibrinogen Increased In Fibrinogen levels that are very low (<80 mg/dL) or high (>400 mg/dL) Interference with polymerization of fibrin Fibrin degradation products, especially DIC. High concentrations of monoclonal immunoglobulins (e.g., myeloma, macroglobulinemia) interfere with fibrin monomer polymerization. Uremia. Dysfibrinogenemia (abnormal fibrinogen present). Heparin contamination of specimen is common cause in hospital patients; however, a reptilase test is normal in presence of heparin but prolonged by other causes listed in previous section. Antithrombin antibodies TOURNIQUET TEST Use Differential diagnosis of purpura Positive In Thrombocytopenic purpuras Nonthrombocytopenic purpuras Thrombocytopathies Scurvy DISORDERS OF COAGULATION See Table 11-35. AFIBRINOGENEMIA, CONGENITAL (Rare inherited autosomal recessive congenital condition) See Table 11-34, Table 11-35 Table 11-36. wPlasma fibrinogen is absent. BT is often increased (one-third of patients). PT, aPTT, and thrombin time are abnormal. Platelet-to-glass adhesiveness is abnormal unless fibrinogen is added. BERNARD-SOULIER SYNDROME (Rare autosomal recessive absence or dysfunction of platelet membrane glycoproteins Ib receptor, V, IX [AQ37] that enable platelets to bind vWF)
- 307. See Table 11-34, Table 11-35 and Table 11-36. mMild or moderate thrombocytopenia, usually 25,000–80,000/cu mm. Hemorrhage and increased BT are excessively severe for degree of thrombocytopenia. Normal clot retraction. Giant platelets on smear. Abnormal vWF adhesion and ristocetin aggregation; other aggregations normal. wPlatelet membrane analysis using monoclonal antibodies with flow cytometry allows definite diagnosis. COAGULATION DISORDERS, NEONATAL Severe forms of factor VIII and IX deficiency cause most hemorrhagic congenital coagulation problems in newborns. In severe forms, bleeding occurs within the first week in 50% of cases (especially due to circumcision). Congenital deficiency of factor XIII Hemorrhagic disease of the newborn may be associated with anticonvulsant drug therapy (e.g., phenytoin, phenobarbital) in mother, severe liver disease in infant. Water-soluble forms of vitamin K may precipitate hemolysis in newborns, especially in presence of G-6-PD. DIC In a child with excessive bleeding, the following six tests can usually be done on £ 2 mL of blood within 1 hr: platelet count, PT, PTT, fibrinogen level, BT, thrombin time. Presence of large numbers of platelets and especially clumps of platelets on smear excludes thrombocytopenia as cause of bleeding in newborns . Abnormal hemostasis is rare in the healthy full-term infant. Most of the bleeding disorders seen by primary care physicians are acquired rather than inherited abnormalities of coagulation and are expressions of underlying disease. Incidence of Inherited Congenital Coagulation Factors (Autosomal recessive except factors IX and VIII, which are X-linked recessive, and factor II) XI Rare IX 1 in 100,000 VIII 1 in 25,000 VII 1 in 500,000 X 1 in 500,000 V 1 in 1,000,000 II (prothrombin) Rare I (fibrinogen) Rare XIII Rare In the sick neonate, thrombocytopenia is the most common cause of abnormal hemostasis; less common are DIC, vitamin K deficiency, inadequate liver function. The cause of neonatal thrombocytopenia (e.g., sepsis, DIC) is discovered in only 40% of the cases. COAGULOPATHY DUE TO LIVER DISEASE Screening tests may include any combination of abnormal PTT, aPTT, thrombin time, euglobulin or whole-blood clot lysis times, increased fibrin degradation products. These are corrected by mixture of equal parts of patient and normal plasma, except thrombin time if large amounts of fibrin degradation products are present due to hyperplasminemia or if fibrin polymerization is faulty. Special tests may show decreased antithrombin III, decrease in any coagulation factor (except factor VIII:c, which is normal or increased in liver disease but decreased in DIC), decreased alpha 2-antiplasmin. DISSEMINATED INTRAVASCULAR COAGULATION (DIC)25 ,26 (Widespread fibrin thrombi in microcirculation with rapid concurrent consumption of platelets and coagulation proteins and activation of thrombin; more than one mechanism is often present) See Table 11-37, Table 11-38, Table 11-39, Table 11-40. Table 11-37. Disseminated Intravascular Coagulation (Consumption Coagulopathy)
- 308. Table 11-38. Comparison of Acute Disseminated Intravascular Coagulation (DIC) and Primary Fibrinogenolysis Table 11-39. Comparison of Acute and Chronic Disseminated Intravascular Coagulation (DIC) Table 11-40. Differential Diagnosis of Disseminated Intravascular Coagulation (DIC) Due To Incidence (% of Cases) ·Infections Sepsis is most common cause (Gram positive and negative) Meningococcemia Rocky Mountain spotted fever Viremia (CMV and HIV infection, hepatitis, varicella) 30–50% · Pregnancy and obstetric complications, e.g., Retained dead fetus syndrome (in 50% of cases with fetus retained 5 wks) Eclampsia (fulminant in 10–15% of patients) Amniotic fluid embolism Abruptio placentae Saline-induced abortion 50% ·Trauma with extensive tissue injury (e.g., crush injuries, burns, extensive surgery, shock, fat embolism) 50–70% · Metastatic neoplasms, especially prostate Necrosis due to chemotherapy or irradiation Acute leukemia, especially acute promyelocytic 10–15% 15% · Vascular disorders Giant hemangioma of Kasabach-Merritt syndrome Large aortic aneurism <1% Cardiac, peripheral 25% ·Connective tissue diseases · Toxins (e.g., snakebites, brown recluse spider bite, drugs) · Injury to platelets or RBCs (e.g., immunologic hemolytic anemias) · Prosthetic devices (e.g., aortic balloon, LeVeen shunt) · RE system injury—liver disease (e.g., acute hepatic failure, obstructive jaundice, cirrhosis, hepatitis), postsplenectomy wCriteria for specific diagnosis are not well defined. No single test is diagnostic, and diagnosis usually depends on combination of findings. Single normal level does not rule out DIC and a repeat test screen should be done a few hours later for changes in platelet count and fibrinogen . wRepeated aPTT and PT (if initially prolonged), platelet count, and fibrinogen levels are particularly useful for screening. Normal in 25% of cases of acute DIC. If any are abnormal, follow with tests for fibrinogen degradation products and D-dimer. wMost sensitive and specific tests Test for fibrin degradation products (FDP) in serum >20 µg/mL (may be >100 µg/mL; normal = 0–10 µg/mL); sensitivity = 85–100%, specificity = ~50%. Positive D-dimer assay is specific for fibrin and is more reliable indicator of DIC (~100% specificity) than FDP assay because D-dimer is negative in cases of primary fibrinolysis. Thus combination of FDP and D-dimer tests = 100% sensitive and specific. Declining serial fibrinogen levels to <150 µg/dL); specificity >95% but sensitivity only ~25%. Antithrombin III is useful for diagnosis and to monitor therapy but immunologic assay should not be used. Fibrinopeptide A is increased. Protamine sulfate or ethanol gelation (reflect fibrinogen degradation products but are less specific). A negative protamine test argues against ongoing DIC; ethanol test is less sensitive and may produce false-negative results. Less sensitive and specific tests PT (should be done serially if prolonged) aPTT (increased in 50–60% of acute DIC cases) Decreased platelet count (in ~90% of cases) and abnormal platelet function tests (e.g., BT, platelet aggregation) Thrombin time Least sensitive and specific tests Euglobulin clot lysis measures fibrinolytic activity in plasma
- 309. Peripheral blood smear examination In addition, the following abnormalities often occur: Schistocytes in the peripheral blood smear and other evidence of microangiopathic hemolytic anemia may be present (e.g., increased serum LD, decreased serum haptoglobin). Cryofibrinogen may be present. Observation of the blood clot may show the clot that forms to be small, friable, and wispy because of the hypofibrinogenemia. Plasma factors V, VIII, and XIII are usually significantly decreased but results are useless for diagnosis. Survival time of radioiodine-labeled fibrinogen and rate of incorporation of 14 C-labeled glycine ethyl ester into soluble “circulating fibrin” are sensitive indicators of DIC. Clotting time determinations are used to monitor heparin therapy. mSuspect clinically in patients with underlying conditions who show bleeding (frequently acute and dramatic), purpura or petechiae, acrocyanosis, arterial or venous thrombosis. DYSFIBRINOGENEMIA, CONGENITAL (Rare congenital, autosomal dominant heterogeneous group of disorders due to synthesis of abnormal fibrinogen molecules; patients may have no bleeding diathesis) Fibrin formation is abnormally slow with prolonged plasma thrombin time. wDysfibrinogenemia is present if immunologic fibrinogen is >2× functional fibrinogen. Other coagulation factors are normal. Dysfibrinogenemia may also occur in liver disease, cancer, fibrinolysis, DIC. FACTOR V DEFICIENCY (PARAHEMOPHILIA) (Inherited autosomal recessive deficiency syndrome or acquired in association with severe liver disease or DIC) PT and aPTT are increased but corrected by addition of absorbed plasma. Congenital Infrequent bleeding occurs only in the homozygote. Variable increase in PT, prothrombin consumption, and coagulation time is not corrected by administration of vitamin K. w Factor V assay FACTOR VII DEFICIENCY (Inherited form is autosomal recessive trait and is rare; acquired type may be due to liver disease, vitamin K deficiency, or dicumarol therapy) PT is increased but corrected by aged serum. aPTT is normal. wFactor VII assay FACTOR VII DEFICIENCY, CONGENITAL (With this infrequent autosomal trait, bleeding occurs when the gene is homozygous; heterozygotes have little or no manifestations.) Increased PT is not corrected by administration of vitamin K (PT is normal when viper venom is used as thromboplastin; this does not correct PT in factor X deficiency). BT, coagulation time, clot retraction, and prothrombin consumption are normal. wFactor VII assay FACTOR VIII (ANTIHEMOPHILIC GLOBULIN) DEFICIENCY (HEMOPHILIA) (X-linked recessive deficiency or abnormal synthesis of factor VIII) wClassic hemophilia (factor VIII assay <1%) shows increased coagulation time, prothrombin consumption time, and aPTT; prolonged BT in ~20% of patients (see Table 11-32). wModerate hemophilia (factor VIII assay 1–5%) shows normal coagulation time and normal prothrombin consumption time but increased aPTT. wIn mild hemophilia (factor VIII assay <16%) and “subhemophilia” (factor VIII assay 20–30%), these laboratory tests may be normal; patients seldom bleed except after surgery. Screening tests for factor VIII deficiency: normal PT and platelet count, prolonged aPTT, thrombin time, BT Secondary tests: factor VIII:C, factor VIII:Ag, platelet aggregation, platelet agglutination, ristocetin cofactor wSpecific factor assay is required to differentiate from factor IX deficiency (hemophilia B). Laboratory findings due to hemorrhage and anemia. “Acquired” hemophilia may occur when an inhibitor (autoantibody) is present, usually occurring spontaneously but may be associated with autoimmune or lymphoproliferative disorders, pregnancy and postpartum states, or allergy to drugs, especially penicillin. aPTT mixing studies distinguish factor deficiency from antibody: pooled normal plasma supplies missing factor and corrects clotting time in case of deficiency, but antibody inhibits normal plasma causing incomplete correction of aPTT.
- 310. Antibodies develop in ~20% of patients receiving repeated transfusion of factor VIII products, prolonging aPTT and lowering factor VIII activity of normal plasma. wPrenatal diagnosis during eighth to tenth week of pregnancy by DNA analysis of amniocytes or chorionic villus material or by analysis of fetal blood at 12–14 wks for VIII:C and VIII:Ag. Carrier status determination by pedigree analysis and laboratory studies is 95% accurate in ~80% of women. >75% of patients with severe hemophilia who received multiple doses of factor concentrate before 1985 are HIV positive; many have AIDS. High incidence of viral hepatitis seropositivity. FACTOR IX (PLASMA THROMBOPLASTIN COMPONENT) DEFICIENCY (CHRISTMAS DISEASE; HEMOPHILIA B) (Inherited recessive X-linked deficiency) In severe cases, increased coagulation time, BT, prothrombin consumption time, and aPTT are found. Defect is corrected by administration of frozen plasma just as well as by bank blood. w Factor IX assay FACTOR X (STUART-PROWER) DEFICIENCY (Rare autosomal recessive defect resembles factor VII deficiency; heterozygotes show mild or no clinical manifestations) Increased PT (not corrected by use of viper venom as thromboplastin) is not corrected by administration of vitamin K. Heterozygotes may have only slight increase in PT. w Factor X assay Acquired form may be associated with amyloidosis, coumarin anticoagulant therapy, vitamin K deficiency, liver trauma. FACTOR XI (PLASMA THROMBOPLASTIN ANTECEDENT) DEFICIENCY (Inherited autosomal recessive deficiency is usually mild; acquired forms are recognized) In mild form, coagulation may be normal, prothrombin consumption time is slightly increased. In severe cases, increased coagulation time, increased prothrombin consumption time. Postoperative bleeding may not begin until several days after surgery. w Factor XI assay FACTOR XII (HAGEMAN FACTOR) DEFICIENCY Coagulation time and prothrombin consumption time are increased. Specific factor assay is needed to distinguish from factor XI deficiency. No hemorrhagic symptoms occur. FACTOR XIII (FIBRIN-STABILIZING FACTOR) DEFICIENCY (Inherited autosomal recessive deficiency with severe coagulation defect) Congenital Results of all standard clotting tests appear normal. Patient's fibrin clot is soluble in 5M urea. Whole blood clot is qualitatively friable. Acquired Type May Occur In AML Liver disease Association with hypofibrinogenemia in obstetric complications Presence of circulating inhibitors GLANZMANN'S THROMBASTHENIA (Rare autosomal recessive absence or dysfunction of glycoprotein receptor GPIIb/IIIa that enable platelets to bind a family of integrins [to generate large platelet aggregates], of which fibrinogen is most important; variant forms exist) See Table 11-36. Prolonged BT. Impaired clot retraction. Normal in essential athrombia, in which other laboratory abnormalities are the same. Normal platelet count and morphology but unusually well dispersed on smear with no clumping. Normal coagulation time. wTotally absent primary platelet aggregation induced by ADP, thrombin, collagen, or epinephrine. Decreased maximum response to ristocetin.
- 311. wProthrombin consumption tests abnormal but corrected by adding platelet substitute. HELLP SYNDROME (hemolysis, elevated liver enzymes, low platelets) w Diagnostic Criteria Hemolysis (increased serum bilirubin >1.2 mg/dL, LD >600 U/L, abnormal peripheral blood smear) Abnormal liver enzymes (serum ALT >79 U/L) Platelet count <100,000/cu mm Hemolysis and thrombocytopenia are typically milder than in TTP/hemolytic uremic syndrome. Bone marrow shows excessive megakaryocytes. Normal PT, aPTT, fibrinogen, fibrinogen degradation products Occurs during pregnancy or within 48 hrs of delivery. HEMORRHAGIC DISEASE OF THE NEWBORN (Due to lack of vitamin K) See Table 11-41. Table 11-41. Comparison of Hemorrhagic Diseases of the Newborn PT is markedly increased. PTT is increased. Coagulation time is increased. BT is normal; may be slightly increased. Capillary fragility, prothrombin consumption, and platelet count are normal. Laboratory findings due to blood loss. Secondary Due to a variety of transient defects in clotting; more commonly seen in low-birth-weight premature infants and anoxic or septic neonates. HEMORRHAGIC DISORDERS, CLASSIFICATION Vascular abnormalities Congenital (e.g., hereditary hemorrhagic telangiectasia [Osler-Weber-Rendu disease]) Acquired (see Purpura, Nonthrombocytopenic) Infection (e.g., bacterial endocarditis, rickettsial infection) Immunologic (e.g., Schönlein-Henoch disease, allergic purpura, drug sensitivity) Metabolic (e.g., scurvy, uremia, diabetes mellitus) Miscellaneous (e.g., neoplasms, amyloidosis, angioma serpiginosum) Connective tissue abnormalities Congenital (e.g., Ehlers-Danlos syndrome) Acquired (e.g., Cushing's syndrome) Platelet abnormalities (see sections on thrombocytopenic purpura, thrombocythemia, thrombocytopathies) Most useful tests are platelet count, peripheral smear examination, BT, platelet aggregation, platelet lumi-aggregation (release), platelet IgG and IgM antibodies, platelet membrane glycoproteins (flow cytometry), cyclo-oxygenase. Platelet factor 4, beta-thromboglobulin, thromboxanes for hyperactive/prethrombotic platelets. Plasma coagulation defects Causing defective thromboplastin formation Factor VIII deficiency (hemophilia) Factor IX (plasma thromboplastin component) deficiency (Christmas disease) Factor XI (plasma thromboplastin antecedent) deficiency
- 312. Von Willebrand's disease Causing defective rate or amount of thrombin formation Vitamin K deficiency (due to liver disease, prolonged bile duct obstruction, malabsorption syndrome, hemorrhagic disease of the newborn, anticoagulant therapy) Congenital deficiency of factor II (prothrombin), factor V (proaccelerin, labile factor), factor VII (proconvertin, stable factor), factor X (Stuart factor) Decreased fibrinogen due to intravascular clotting and/or fibrinolysis Obstetric abnormalities (e.g., amniotic fluid embolism, premature separation of placenta, retention of dead fetus) Congenital deficiency of factor XIII (fibrin-stabilizing factor), congenital afibrinogenemia, hypofibrinogenemia, etc. Neoplasms (e.g., leukemia, carcinoma of prostate) Transfusion reactions Gram-negative septicemia, meningococcemia Circulating anticoagulants Heparin therapy Dysproteinemias, SLE, postpartum state, some cases of hemophilia, etc. HYPERCOAGULABLE STATE Due To Estimated Frequency Primary (inherited) risk factors w• Activated protein C resistance (Due to factor V Leiden mutation in >95% of cases; found in 5% of persons in the United States; confirmed by PCR-DNA testing.) Activated protein C added to normal plasma prolongs aPTT but not in patients with activated protein C resistance, who have ratio <2.0. Normal ratio is >2.4; 2.0–2.3 is indeterminate. Invalidated by use of oral anticoagulants with 7–14 days, other causes of prolonged clotting times (e.g., factor deficiencies or inhibitors), presence of platelets in test plasma. 25–50% • Abnormal/delayed fibrinolysis 10–15%* † • Protein C deficiency 2–5% • Protein S deficiency 2–5% • Antithrombin III deficiency 2–5%* • Plasminogen deficiency or dysplasminogen 1–2%* † • Dysfibrinogenemia 1%* † • Homocystinemia (homocysteine deposits damage endothelium) Unknown* † • Sickle cell anemia * † • Prothrombin gene mutation 3–6%* • Factor XII deficiency Rare Secondary risk factors (acquired), e.g., • Antiphospholipid antibody syndrome 10%* † • Pregnancy • Oral contraceptive use • Neoplasia • Surgery, trauma, or immobilization • Sepsis • Protein loss (e.g., nephrotic syndrome) • Myeloproliferative disorders (e.g., polycythemia vera, essential thrombocytosis, agnogenic myeloid metaplasia, paroxysmal nocturnal hemoglobinuria) • Hyperviscosity syndromes due to abnormal proteins or increased RBC mass • SLE • DIC • Antineoplastic drugs • Coumadin necrosis syndrome • Heparin-induced thrombocytopenia and thrombosis * Associated with venous thrombosis. † Associated with arterial thrombosis. Indications for Screening Recurrent or migratory venous thrombosis or thrombosis at unusual site (e.g., mesenteric, portal) or at age <45 yrs Familial thrombosis Arterial thrombosis at age <30 yrs Unexplained neonatal thrombosis Recurrent fetal loss HYPOFIBRINOGENEMIA, CONGENITAL (Inherited autosomal dominant condition) Plasma fibrinogen is moderately decreased (usually <80 mg/dL). Bleeding and coagulation times are normal. Blood clots are soft and small. PURPURA, ALLERGIC (Called Henoch's purpura when abdominal symptoms are predominant and Schönlein purpura when joint symptoms are predominant)
- 313. No pathognomonic laboratory findings Platelet count, BT, coagulation time, clot retraction, and bone marrow are normal. Tourniquet test may be negative or positive. WBC and neutrophils may be increased; eosinophils may be increased. ESR is usually normal or may be slightly increased. Stool may show blood. Urine usually contains RBCs and slight to marked protein. Chronic urine findings in 25% of cases. BUN and creatinine may be increased. Renal biopsy shows minimal change pattern in mild cases and diffuse proliferative GN in severe cases with IgA deposition. <4% of patients progress to end-stage renal disease. Serum complement is not decreased. PURPURA, IDIOPATHIC THROMBOCYTOPENIC (ITP; WERLHOF'S DISEASE), IMMUNE See Table 11-42. Table 11-42. Comparison of Acute and Chronic Forms of Immune Thrombocytopenia wDiagnosis By Exclusion of other causes of thrombocytopenia (e.g., SLE, leukemia, HIV infection, thyroid disorders, etc; Isolated low platelet count with quantitatively and qualitatively normal RBCs and WBCs Bone marrow—normal or increased number and volume of megakaryocytes but without marginal platelets Decreased platelet count (<100,000/cu mm) due to markedly diminished half-life; no bleeding until <50,000/cu mm; postoperative and minor spontaneous bleeding may occur at 20,000–50,000/cu mm. Significant bleeding is unusual until count is below ~5000/cu mm and even then does not occur in most adults. Routine platelet counts have discovered many asymptomatic patients. Normal blood count and blood smear except for decreased number of platelets; platelets may appear abnormal (small or large immature or deeply stained). Mean platelet volume is normal or increased. Positive tourniquet test Increased BT Poor clot retraction Normal PT, aPTT, and coagulation time Laboratory findings due to hemorrhage Increased WBC with shift to left Anemia proportional to hemorrhage, with compensatory increase in reticulocytes, polychromatophilia, etc. Platelet IgG and autoantibodies (in ~33% of ITP patients) to specific platelet-membrane glycoproteins are not important for diagnosis or treatment; platelet IgG found in £ 75% of patients with other immune-associated thrombocytopenias. mA palpable spleen is evidence against ITP. In children 80–90% of acute cases remit spontaneously in 6–12 mos; rest become chronic; in adults almost all are chronic. £ 80% of children have preceding viral infection. Two-thirds of children and 85% of adults with chronic ITP develop normal platelet count after splenectomy. Platelet transfusions are indicated in ITP if Platelet count <5000/cu mm, even if asymptomatic. Severe mucosal bleeding at any platelet count. Bleeding after splenectomy. Impending/actual CNS hemorrhage at any platelet count. Before major surgery (other than splenectomy) that requires platelet count >50,000/cu mm. PURPURA, NONTHROMBOCYTOPENIC
- 314. Due To Abnormal platelets (e.g., thrombocytopathies, thrombasthenia, thrombocythemia) Abnormal serum globulins (e.g., multiple myeloma, macroglobulinemia, cryoglobulinemia, hyperglobulinemia) Infections (e.g., meningococcemia, SBE, typhoid, Rocky Mountain spotted fever) Other diseases (e.g., amyloidosis, Cushing's syndrome, polycythemia vera, hemochromatosis, diabetes mellitus, uremia) Drugs and chemicals (e.g., mercury, phenacetin, salicylic acid, chloral hydrate) Allergic reaction (e.g., Schönlein-Henoch purpura, serum sickness) Diseases of the skin (e.g., Osler-Weber-Rendu disease, Ehlers-Danlos syndrome) Von Willebrand's disease Avitaminosis (e.g., scurvy) Miscellaneous (e.g., mechanical, orthostatic) Blood coagulation factors (e.g., hemophilia) PURPURA, THROMBOCYTOPENIC See Platelet Count, Decreased In PURPURA, THROMBOTIC THROMBOCYTOPENIC (TTP); HEMOLYTIC UREMIC SYNDROME wClassic pentad: consumptive thrombocytopenia, microangiopathic hemolytic anemia, neurologic involvement, fever, minor renal involvement. Diagnosis by excluding other known causes of these features: Diarrhea-associated form: related commonly to a verocytotoxin-producing strain of E. coli O157:H7 and to Shigella with gastroenteritis and bloody diarrhea. Non—diarrhea-associated form is associated with: Complications of pregnancy (e.g., eclampsia, abruptio placentae, amniotic fluid embolism) Drugs (e.g., oral contraceptives, phenylbutazone, cyclosporin, 5-fluorouracil, mitomycin C) Underlying systemic diseases (e.g., primary glomerulopathies, rejection of renal transplant, vasculitis, cryoglobulinemia, septicemia, hypertension, adenocarcinoma) Inherited disorder Nonenteric pathogens Closely related hemolytic uremic syndrome showing acute renal failure is associated with other conditions: Bone marrow transplant (10% of patients) Normal pregnancy (usually postpartum) Drugs (e.g., oral contraceptives, mitomycin, immunosuppressive agents) Carcinoma (e.g., prostate, pancreas) Autoimmune disorders Immune deficiency disorders BUN may rise 50 mg/dL/day; is often >100 mg/dL. Urine may show blood, protein, casts, or anuria. Progressive renal disease or recovery. Oliguria and acute renal failure are uncommon. Renal biopsy shows fibrin thrombi damaging primarily glomerular endothelium (usually in children, associated with gastroenteritis, bloody diarrhea) or primarily arterial changes (associated with scleroderma or malignant hypertension, and after mitomycin treatment). Severe thrombocytopenic purpura with normal or increased megakaryocytes in bone marrow. Platelet count generally <50,000/cu mm; usually becomes normal in a few weeks. Microangiopathic hemolytic anemia (normochromic, normocytic) is present at onset or within a few days. Hb usually <10 g/dL; is often <6 gm/dL; may fall 50% in 2 days. Numerous fragmented and misshapen RBCs (burr cells, schistocytes) on blood smear is virtually required for this diagnosis. Increased reticulocytes, nucleated RBCs, basophilic stippling, and polychromatophilia. Increased serum Hb, indirect bilirubin, and LD, and decreased serum haptoglobin. Negative Coombs' test. Increased or normal WBCs and neutrophils In contrast to DIC, PT and aPTT are usually normal or may be mildly increased, clotting and fibrinogen are normal or only slightly increased; fibrin split products are usually present in low levels. Bone marrow is hypercellular with erythroid and megakaryocytic hyperplasia in response to hemolysis and consumptive thrombocytopenia. Serum AST and ALT may be slightly increased. High initial BUN and creatinine, decreasing Hb, and failure of platelet count to increase are poor prognostic signs. Multiorgan microvascular platelet thrombi in various organ systems result in clinical manifestations, especially neurologic (in ~90% of cases) and hemorrhagic (in up to 70%). Presence in gingival biopsy supports the diagnosis but occurs in <50% of cases. Other sites (skin, liver, lymph nodes, bone marrow) are rarely useful. Serum complement is normal. STORAGE POOL DISEASE, HEREDITARY (Hereditary platelet function defect disorder)
- 315. See Table 11-36. BT is usually abnormal. Abnormal aggregation to collagen Absent second aggregation curve to ADP and epinephrine although primary waves are present. Normal ristocetin aggregation Arachidonate aggregation is usually normal. THROMBOCYTOSIS, PRIMARY (ESSENTIAL THROMBOCYTHEMIA) (Classified as a myeloproliferative disorder involving the thrombocytes; see Fig. 11-9) w Diagnostic Criteria Platelet count >600,000/cu mm on two occasions (>1 million/cu mm in 90% of cases). No cause for reactive thrombocytosis No iron deficiency (marrow contains stainable iron or <1 gm Hb increase after 1 mo of iron therapy) No evidence of leukemia in peripheral blood or marrow (and absent Ph 1 chromosome; abl-bcr rearrangement is not found). No evidence of polycythemia (normal Hb or RBC mass) Bone marrow Fibrosis must be minimal or absent to rule out agnogenic myeloid metaplasia, or in absence of both splenomegaly and leukoerythroblastosis, it must be less than one-third of area of biopsy specimen. Hypercellular with hyperplasia of all elements, with predominance of megakaryocytes and platelet masses, eosinophilia, basophilia; no evidence of masked polycythemia vera; no ring sideroblasts of myelodysplastic syndrome Platelets appear normal early in disease; later abnormal in size and shape, and changes in structure occur. Aggregation may be abnormal with epinephrine, ADP, thrombin. Mild anemia (10–13 gm/dL) in one-third of patients due to blood loss WBC usually >12,000/cu mm without cells earlier than myelocyte forms in £ 40% of patients; leukocyte ALP score is usually normal or may be increased. Increased serum LD, uric acid Artifactual increase in serum potassium, calcium, oxygen Thrombohemorrhagic disease (bleeding—skin, GI tract, nose, gums in 35% of patients but normal BT) and thromboses of major vessels, usually arterial, in £ 40% of patients THROMBOCYTOSIS, REACTIVE See Platelet Count, Increased In. TRANSFUSION OF BLOOD Adverse Effects27, 28 and 29 Occurs from ~1 in 1000 components transfused in the United States. ~1 in 12,000 transfusions are given to the wrong person. Immune Mediated Acute Frequency/unit Fatal acute hemolysis (ABO) (mortality ~3.3%) 1:633,000 Nonfatal acute hemolysis (ABO) 1:33,000 Febrile nonhemolytic reaction (WBC or cytokine induced) 1:200 Allergic transfusion reaction 1:333 Acute anaphylaxis 1:20,000–1:50,000 Acute lung injury >1:5000 Hemolytic transfusion reaction 1:200 Chronic Alloimmunization RBC hemolysis 1:1500 Platelet refractoriness 1:3300–1:10,000 Delayed hemolysis 1:4000 Graft-versus-host disease (transfusion associated) Unknown Posttransfusion purpura Rare to very uncommon Non—Immune Mediated Acute Volume overload 1:100–1:200 Nonimmune hemolysis (e.g., heat, cold, osmotic, mechanical) Infrequent Electrolyte imbalance (K+ , Mg++ , Ca++ ) Uncommon Chemical effects (e.g., citrate) Uncommon Coagulopathy (e.g., DIC; usually with massive transfusions) Uncommon Chronic Alloimmunization RBC hemolysis 1:1500 Platelet refractoriness 1:3300–1:10,000 Delayed hemolysis 1:4000 Graft-versus-host disease (transfusion associated) 1:400,000 Posttransfusion purpura Rare to very uncommon Transfusional hemosiderosis Uncommon Infections Viruses HAV Usually single case reports HBV 1:60,000 HCV 1:100,000
- 316. HIV-I 1:450,000–1:660,000 HIV-II Extremely rare HTLV-I/II 1:600,000 CMV 3 per 100 to 12 per 100 Parvovirus B19 Rare EBV Rare (i.e., 3/100–12/100) Bacteria Syphilis Not reported since 1976 Bacterial contamination—platelet units (e.g., S. aureus, Klebsiella pneumoniae, S. marcescens, Staphylococcus epidermidis) 1:12,000 Bacterial contamination—RBC units (e.g., S. epidermidis, Bacillus cereus, Yersinia enterocolitica are most common) <1:1,000,000 Parasites Plasmodium spp. <5:1,000,000 Babesia microti <1:1,000,000 Trypanosoma cruzi (see Chagas' disease) <1:1,000,000 Leishmania spp. <1:20,000,000 Borrelia burgdorferi (see Lyme disease) Few or no cases Toxoplasma gondii Few or no cases Wuchereria bancrofti (see Lymphatic Filariasis) Few or no cases Newly instituted nucleic acid tests may detect £ 2 HIV-infected and £ 100 HCV-infected units/yr that were previously undetected. Transfusion Reactions Hemolytic transfusion reactions occur in ~1 in 12,000 transfusions and are fatal in 1 in 600,000 transfusions; almost always due to ABO incompatibility (usually due to clerical error). Isoimmune Major Transfusion Reactions Immediate reaction ABO-incompatible blood Laboratory findings due to complications of hemolysis (e.g., DIC, acute renal failure, cardiovascular failure Alloimmune Minor Transfusion Reactions Due to sensitization of RBCs against foreign, minor, non-ABO antibodies Delayed (3–10 days) reaction of extravascular hemolysis producing milder clinical and laboratory findings Indications Red Cell Transfusion Hb <8 gm/dL (Hct <26%) and MCV within normal limits (81–100 fL; 70–125 fL if age 14 yrs or less) Hb <8 gm/dL (Hct <26%) in patients with acute bleed or high risk * Hb <11 gm/dL (Hct <36%) in clinically symptomatic patients* † Hb <11 gm/dL (Hct <36%) or bleeding >1 U/24 hrs Any Hb level in high-risk* patients with acute bleed Any Hb level in symptomatic* † patients with acute bleed Any Hb level in patients bleeding >2 U/24 hrs or >15% of blood volume in 24 hrs Death is unlikely until Hb falls to 3 gm/dL or Hct to 10%. After bleeding has stopped, one unit of packed RBCs typically increases recipient's Hct 3%; 2 U increase Hct ~6.4% and Hb ~2 gm/dL. * High risk: e.g., coronary artery disease, chronic pulmonary disease, cerebrovascular disease, or known anemia. † Symptomatic: e.g., patients with signs or symptoms of anemia (such as tachycardia, angina, ECG changes) or of respiratory distress; with known hemoglobinopathy, etc. Cryoprecipitate (Cryoprecipitated Antihemophilic Factor) Transfusion Received massive transfusions >8 units/24 hrs Received transfusion of >6 RBC units/case (e.g., open heart surgery) Bleeding or invasive procedure in patients with hypofibrinogenemia or DIC Deficient factor VIII or von Willebrand's disease (if desmopressin acetate or factor VIII are not effective or available), or abnormal or markedly decreased fibrinogen in bleeding patients or before surgery or invasive procedure Typical bag of cryoprecipitate contains 100 U of factor VIII (the amount normally present in 100 mL of plasma) Risk of viral transmission same as for 1 unit of packed RBCs Fresh Frozen Plasma Transfusion In actively bleeding patients or before surgery or invasive procedures documented by (1) increased PT >1.5× midnormal range (usually >18 sec) or (2) increased aPTT >1.5× upper normal range (usually >55–60 sec) (normal fibrinogen and no heparin in specimen) and (3) coagulation assay <25% activity: After massive blood transfusion (>1 blood volume within several hours with evidence of coagulation deficiency) Deficiency of various coagulation factors or von Willebrand's disease (if desmopressin acetate or factor VIII are not effective or available) Reverse warfarin effect for immediate hemostasis when PT >18 secs; INR >1.6)
- 317. Deficiency of antithrombin III (when concentrate is not available), protein C, protein S, heparin cofactor II Hypoglobulinemia (rarely) Plasma exchange for TTP or hemolytic uremic syndrome Contraindicated as volume expander Each unit increases any clotting factor by 2–3% in average adult. Platelet Transfusion Platelet count >50,000/cu mm: unlikely to be needed; bleeding unlikely due to low count. Platelet count <5000/cu mm Spontaneous bleeding is likely except in platelet destruction disorders; prophylactic use is indicated. Platelet count <10,000/cu mm Prophylactic with minor hemorrhage; fever Platelet count <20,000 in patients Without thrombotic or ITP or posttransfusion purpura or hemolytic uremic syndrome Prophylactic in leukemia in presence of coagulation disorders, during induction therapy Before minor surgical procedures Platelet count <50,000 in patients with Minor bleeding Preoperative for a minor procedure Prematurity High blast count Platelet count <90,000 in patients with Bleed requiring RBC transfusion Preoperative for a major procedure Received massive RBC transfusion (>8 U/24 hrs) BT >10 mins Received transfusion of >6 RBC unit/case (e.g., open heart surgery) (Unit of platelets = 5.5 × 1010 cu mm) VON WILLEBRAND'S DISEASE (Heterogeneous group of inherited [>20 subtypes] and acquired disorders of vWF with mucocutaneous bleeding due to abnormal vWF quantity or quality. Most common inherited hemostatic abnormality.) See Table 11-36 and Table 11-43. Table 11-43. Types of von Willebrand's Disease (vWD) Hereditary deficiency (types I and III) or qualitative defect (type II) of a high-molecular-weight plasma protein (vWF) that mediates adherence of platelets to injured endothelium. All show mild to moderate bleeding except type III, which is severe. Type I: decreased amount of vWF without qualitative abnormality. Type III: vWF completely or almost completely absent from plasma and platelets. Type II: qualitative abnormalities of vWF due to loss of various multimers. vWF circulates complexed to (carrier for) factor VIII:c, which also responds as an acute-phase protein. Pseudo–von Willebrand's disease is a rare platelet disorder in which platelet receptors have marked avidity for vWF, which causes spontaneous clumping, depletes the plasma of vWF, and may cause mild to moderate thrombocytopenia. Acquired von Willebrand's disease due to formation of autoantibodies (in association with autoimmune and lymphoproliferative disorders), decreased synthesis, or other mechanisms (e.g., in myeloproliferative, vascular, and congenital heart diseases), or idiopathic. Difficulty in diagnosis arises from temporal variation in clinical and laboratory findings in an individual patient as well as from patient to patient; because many patients do not have the classic laboratory findings, a number of clinical variants have been described. BT is prolonged using a calibrated template; in a few patients, may only be prolonged after administration of 300 mg of aspirin. aPTT is prolonged. Platelet adhesiveness to glass beads is decreased. Ristocetin-induced aggregation of platelets is abnormal if ristocetin cofactor activity is <30%; thus may be normal
- 318. in mild von Willebrand's disease. May not identify some mild cases in which activity is >30% but less than normal value of 50–150%. Platelet count is usually normal but may be mildly decreased in type IIB or platelet-type von Willebrand's disease. PT and clot retraction are normal. Tourniquet test may be positive. Factor VIII coagulant activity (VIII:c) may range from normal to severely reduced (indicated by direct assay, aPTT, or TGT tests). wFactor VIII–related antigen (vWF:Ag) measured by special electroimmunoassay is decreased. May be increased in endothelial cell injury (e.g., trauma, surgery, surgical graft failure, clotting). wTransfusion of normal plasma (or of hemophiliac plasma, cryoprecipitate, serum) causes a rise in factor VIII activity greater than the amount of factor VIII infused, which does not peak until 8–10 hrs and slowly declines for days; in contrast, hemophilia shows rapid peak and fall after infusion of normal plasma or cryoprecipitate. This response to transfusion is a good diagnostic test in patients in whom diagnosis is equivocal. Factor VIII levels may increase to normal during pregnancy or use of oral contraceptives with subsidence of hemorrhagic episodes, although BT is often unaffected. Therefore diagnostic evaluation should not be done in the presence of these two circumstances. Screening of family members may be useful in difficult diagnostic cases, even if they are asymptomatic and have no history of unusual bleeding. Laboratory findings due to complications, e.g., viral infections, development of antibodies to vWF (occurs in severe type III). Platelet-type von Willebrand's disease is distinguished from type IIB by mixing studies with normal platelets and plasma. Screening tests: aPTT, BT, platelet count Confirmatory tests: tests for VIII:c, vWF:Ag, vWF:RCoF Tests to confirm diagnosis and determine type: ristocetin-induced platelet aggregation (RIPA), plasma wWF multimer analysis Comparison of Hemophilia A and Von Willebrand's Disease Hemophilia A von Willebrand's Disease BT Normal Prolonged Factor VIII:Ag Normal Low Factor VIII:C Low Prolonged-normal Platelet adhesion Normal Retarded Platelet aggregation (RIPA) Normal Decreased Ristocetin cofactor Normal Deficient aPTT Prolonged Prolonged-normal 1 Brugnara C, et al. Reticulocyte hemoglobin. An integrated parameter for evaluation of erythrocyte activity. Am J Clin Pathol 1997;108:133. 2 Brugnara C, et al. Reticulocyte hemoglobin content to diagnose iron deficiency in children. JAMA 1999;281:2225. 3 Young NS. Acquired aplastic anemia. N Engl J Med 1999;282:271. 4 Fairbanks VF. CAP Today 1996;88. 5Brain MC. Hemolytic anemia. Postgrad Med 1978;64:127. 6 Kallemuchikkal U, Gorevic PD. Evaluation of cryoglobulins. Arch Pathol Lab Med 1999;123:119. 7Yasmineh WG, et al. Serum catalase as marker of graft-vs-host disease in allogeneic bone marrow transplant recipients: pilot study. Clin Chem 1995;41:1574. 8 Dunn DE, et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med 1999;131:401. 9 Lo YMD, et al. Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. N Engl J Med 1998;339:1734. 10 Hartwell EA. Use of RH immune globulin. ASCP practice parameter. Am J Clin Pathol 1998;1210:281. 11 Cave H, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer, Childhood Leukemia Cooperative Group. N Engl J Med 1998;339:591. 12Pui CH, et al. Acute lymphoblastic leukemia. N Engl J Med 1998;339:605. 13 Morley A. Quantifying leukemia. N Engl J Med 1998;339:627. 14Hess JL, Zutter MM, Castleberry RP, Emanuel PD. Juvenile chronic myelogenous leukemia. Am J Clin Pathol 1996;105:238. 15 Koeffler HP. Syndromes of acute nonlymphocytic leukemia. Ann Intern Med 1987;107:748. 16 Lauglin WR, Bick RL. Acute leukemias: FAB classification and clinical correlates. Lab Med 1994;25:11. 17 Dewald GW, et al. Chromosome abnormalities in malignant hematologic disorders. Mayo Clin Proc 1985;60:675. 18 Straus SE, et al. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med 1999;130:591. 19Kyle RA. Benign monoclonal gammopathy—after 20–35 years of follow-up. Mayo Clin Proc 1993;68:26. 20 Malacrida V, et al. Laboratory investigation of monoclonal gammopathy during 10 years of screening in a general hospital. J Clin Pathol 1987;40:793. 21Fairbanks VF, et al. Measurement of blood volume and red cell mass: re-examination of 51Cr and 125I methods. Blood Cells Mol Dis 1996;22:169. 22 Polycythemia Vera Study Group. Polycythemia vera. Semin Hematol 1976;12:13. 23Steinberg MH. Management of sickle cell disease. N Engl J Med 1999;340:1021. 24 Burns ER, Lawrence C. Bleeding time. A guide to its diagnostic and clinical utility. Arch Pathol Lab Med 1989;113:1219.
- 319. 25 Sirridge M. Laboratory evaluation of the bleeding patient. Clin Lab Med 1984;4:285. 26 Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:586. 27Simon TI, et al. Practice parameter for the use of red blood cell transfusions. Arch Pathol Lab Med 1998;122:130. 28 College of American Pathologists. Practice parameter for the recognition, management, and prevention of adverse consequences of blood transfusion, June 1997. 29Goodnough LT, et al. Transfusion medicine. First of two parts—blood transfusion. N Engl J Med 1999;340:438.
- 320. CHAPTER 12 METABOLIC AND HEREDITARY DISORDERS Interpretation of Diagnostic Tests CHAPTER 12 METABOLIC AND HEREDITARY DISORDERS Acid-Base Disturbances, Mixed Acidosis, Lactic Acidosis, Metabolic Acidosis, Respiratory Alkalosis, Metabolic Alkalosis, Respiratory Anion Gap Classification Deficiency, Copper Deficiency, Niacin (Pellagra) Deficiency, Riboflavin Deficiency, Thiamine (Beriberi) Deficiency, Vitamin A Deficiency, Vitamin B6 (Pyridoxine) Deficiency, Vitamin B12 and Folic Acid Deficiency Vitamin C (Scurvy) Deficiency (or Excess), Vitamin D Deficiency, Vitamin E Deficiency, Vitamin K Deficiency, Zinc Dehydration, Hypertonic Dehydration, Hypotonic Infant who Fails to Thrive, Laboratory Evaluation Intrauterine Growth Retardation Malnutrition, Protein-Calorie Nutritional Factors in Young Children, Laboratory Indicators Total Parenteral Nutrition (TPN), Metabolic Complications Vitamin Reference Ranges (Blood) Maternal Serum Sampling Amniocentesis Chorionic Villus Sampling Fetal Blood Sampling Fetal Biopsy Ultrasonography and Echocardiography Karyotype Analysis Molecular Diagnosis Isolation of Fetal Cells in Maternal Blood Chromosome Analysis (Karyotyping) Inherited Disorders that can be Identified by Molecular Genetics Metabolic Conditions (Inherited), Classification Newborn Screening for Metabolic Disorders Nuclear Sexing Sex Chromosome in Leukocytes Apolipoproteins, Serum Cholesterol, HDL (High-Density Lipoprotein), Serum Cholesterol, LDL (Low-Density Lipoprotein), Serum Cholesterol (Total), Serum Cholesterol Decision Levels Chylomicrons, Serum Lipoprotein Electrophoresis Lipoproteins, Serum Triglycerides, Serum Acid Lipase Deficiencies Primary Hyperlipidemias L-Carnitine Deficiency Lecithin-Cholesterol Acyltransferase Deficiency (Familial) Lipodystrophy (Total), Congenital Tangier Disease Secondary Hyperlipidemias Metabolic Errors Associated with Hyperammonemia in Children Metabolic Errors Causing Acidosis Aminoaciduria, Secondary Argininosuccinicaciduria Beta-Aminoisobutyricaciduria Citrullinemia Cystathioninuria Cystinuria Hartnup Disease Histidinemia Homocysteinuria/Homocysteinemia Hydroxyprolinemia Hyperglycinemia Hyperprolinemia Iminoglycinuria, Familial Joseph's Syndrome (Imminoglycinuria) Lesch-Nyhan Syndrome L-Glycericaciduria Maple Syrup Urine Disease (Ketoaciduria) Methylmalonicaciduria Oasthouse Urine Disease Organic Acidemias Ornithine Transcarbamylase Deficiency Phenylketonuria (PKU) Propionicacidemia Tyrosinemia Xanthinuria Alkaptonuria Fructose Intolerance, Hereditary Fructosuria, Essential Galactosemia Lactase Deficiency; Intestinal Deficiency of Sugar-Splitting Enzymes (Milk Allergy; Milk Intolerance; Congenital Familial Lactose Intolerance; Disaccharidase Deficiency) Mannoheptulosuria Pentosuria Sucrosuria Type I Glycogen Storage Disease; Glucose-6-Phosphatase Deficiency (von Gierke's Disease) Type IB Glycogen Storage Disease Type II Glycogen Storage Disease; Generalized Glycogenosis; Alpha-1,4-Glucosidase Deficiency (Pompe's Disease) Type III Glycogen Deposition Disease (Forbes' Disease; Debrancher Deficiency; Limit Dextrinosis) Type IV Glycogen Deposition Disease (Andersen's Disease; Brancher Deficiency; Amylopectinosis) Type V Glycogen Deposition Disease (McArdle's Disease; Myophosphorylase Deficiency) Type VI Glycogen Storage Disease (Hepatic Phosphorylase Deficiency) Type VII Glycogen Storage Disease (Muscle Phosphofructokinase Deficiency; Tarui's Disease) Type VIII Glycogen Storage Disease May be Positive due to (1) Congenital Erythropoietic Porphyria (2) Erythropoietic Protoporphyria (3) Porphyria Cutanea Tarda (4) Acute Intermittent Porphyria (5) Variegate Porphyria (6) Hereditary Coproporphyria (7) Hepatoerythropoietic Porphyria (8) ALA Dehydrase Deficiency Cystinosis Fabry's Disease (Alpha-Galactosidase a Deficiency) Gaucher's Disease GM1 Gangliosidosis (Landing's Disease, Systemic Late Infantile Lipidosis) I-Cell Disease (Mucolipidosis II) Krabbe's Disease (Globoid Cell Leukodystrophy; Galactosylceramide Lipidosis) Mucolipidosis III (N-Acetylglucosaminylphosphotransferase Deficiency; Pseudo–Hurler's Polydystrophy) Mucopolysaccharidoses, Genetic Niemann-Pick Disease Oligosaccharidoses with Increased Urinary Oligosaccharides Tay-Sachs Disease (GM2 Gangliosidosis) Batten Disease (Batten-Spielmeyer-Vogt Disease) D1 Trisomy (Trisomy 13; Patau's Syndrome) Down Syndrome (Trisomy 21; Mongolism) Dysautonomia, Familial (Riley-Day Syndrome) Fragile X Syndrome of Mental Retardation Mediterranean Fever, Familial (Familial Paroxysmal Peritonitis; “Periodic Disease”) Trisomy 18 ACID-BASE DISORDERS
- 321. In analyzing acid-base disorders, several points should be kept in mind: Determination of pH and blood gases should be performed on arterial blood. Venous blood is useless for judging oxygenation but offers an estimate acid-base status. Blood specimens should be packed in ice immediately; delay of even a few minutes causes erroneous results, especially if WBC is high. Determination of electrolytes, pH, and blood gases ideally should be performed on blood specimens obtained simultaneously, because the acid-base situation is very labile. Repeated determinations may often be indicated because of the development of complications, the effect of therapy, and other factors. Acid-base disorders are often mixed rather than in the pure form usually described in textbooks. These mixed disorders may represent simultaneously occurring diseases, complications superimposed on the primary condition, or the effect of treatment. Changes in chronic forms may be notably different from those in the acute forms. For judging hypoxemia, one must also know the patient's Hb or Hct and whether the patient was breathing room air or oxygen when the specimen was drawn. Arterial blood gas values cannot be interpreted without clinical information about the patient. Renal compensation for a respiratory disturbance is slower (3–7 days) but more successful than respiratory compensation for a metabolic disturbance but cannot completely compensate for pCO2 >65 mm Hg unless another stimulus for HCO3 – retention is present. Respiratory mechanism responds quickly but can only eliminate sufficient CO2 to balance the most mild metabolic acidosis. Most laboratories measure pH and pCO2 directly and calculate HCO3 – using the Henderson-Hasselbalch equation: Arterial pH = 6.1 + log [(HCO3 –) ÷ (0.03 × pCO2)] where 6.1 is the dissociation constant for CO 2 in aqueous solution and 0.03 is a constant for the solubility of CO 2 in plasma at 37°C. A normal pH does not ensure the absence of an acid-base disturbance if the pCO2 is not known. An abnormal HCO3 – means a metabolic rather than a respiratory problem; decreased HCO3 – indicates metabolic acidosis, and increased HCO 3 – indicates metabolic alkalosis. Respiratory acidosis is associated with a pCO 2 of >45 mm Hg, and respiratory alkalosis is associated with a pCO2 of <35 mm Hg. Thus mixed metabolic and respiratory acidosis is characterized by low pH, low HCO 3 –, and high pCO2. Mixed metabolic and respiratory alkalosis is characterized by high pH, high HCO 3 –, and low pCO2. See Table 12-1, Table 12-2 and Table 12-3. Table 12-1. Metabolic and Respiratory Acid-Base Changes in Blood Table 12-2. Illustrative Serum Values in Acid-Base Disturbances Table 12-3. Illustrative Serum Electrolyte Values in Various Conditions In severe metabolic acidosis, respiratory compensation is limited by inability to hyperventilate pCO2 to less than ~15 mm Hg; beyond that, small increments of H+ ion produce disastrous changes in pH and prognosis; thus patients with lung disorders (e.g., COPD, neuromuscular weakness) are very vulnerable because they cannot compensate by hyperventilation. In metabolic alkalosis, respiratory compensation is limited by CO2 retention, which rarely causes pCO2 levels >50–60 mm Hg (because increased CO2 and hypoxemia stimulate respiration very strongly); thus pH is not returned to normal. Base excess is a value that hypothetically “corrects” pH to 7.40 by first adjusting pCO 2 to 40 mm Hg, thereby allowing comparison of resultant HCO3 – with normal
- 322. value at that pH (24 mEq/L). Base excess can be calculated from determined values for pH and HCO 3 – by the following formula: Base excess (mEq/L) = HCO3 – + 10(7.40 – pH) – 24 Negative base excess indicates depletion of HCO3 –. Does not distinguish primary from compensatory derangement. See Table 12-1, Table 12-3, Table 12-4 and Table 12-5; section on metabolic and respiratory acid-base changes in blood. Table 12-4. Upper Limits of Arterial Blood pH and HCO3 – Concentrations (Expected for Blood pCO2 Values) Table 12-5. Summary of Pure and Mixed Acid-Base Disorders Pearls m Pulmonary embolus: Mild to moderate respiratory alkalosis is present unless sudden death occurs. The degree of hypoxia often correlates with the size and extent of the pulmonary embolus. pO2 of >90 mm Hg when patient breathes room air virtually excludes a lung problem. Acute pulmonary edema: Hypoxemia is usual. CO2 is not increased unless the situation is grave. Asthma: Hypoxia occurs even during a mild episode and increases as the attack becomes worse. As hyperventilation occurs, the pCO 2 falls (usually <35 mm Hg); a normal pCO2 (>40 mm Hg) implies impending respiratory failure; increased pCO 2 in a patient with true asthma (not bronchitis or emphysema) indicates impending disaster and the need to consider intubation and ventilation assistance. m COPD (bronchitis and emphysema): May show two patterns—“pink puffers” with mild hypoxia and normal pH and pCO2 and “blue bloaters” with hypoxia and increased pCO2; normal pH suggests compensation, and decreased pH suggests decompensation. m Neurologic and neuromuscular disorders (e.g., drug overdose, Guillain-Barré syndrome, myasthenia gravis, trauma, succinylcholine administration): Acute alveolar hypoventilation causes uncompensated respiratory acidosis with high pCO 2, low pH, and normal HCO3 –. Acidosis appears before significant hypoxemia, and rising CO2 indicates rapid deterioration and need for mechanical assistance. m Sepsis: Unexplained respiratory alkalosis may be the earliest sign of sepsis. It may progress to cause metabolic acidosis, and the mixed picture may produce a normal pH; low HCO3 – is useful to recognize this situation. With deterioration and worsening of metabolic acidosis, the pH falls. m Salicylate poisoning: Characteristically, poor correlation is seen between serum salicylate level and presence or degree of acidemia (because as pH drops from 7.4 to 7.2, the proportion of nonionized to ionized salicylate doubles and the nonionized form leaves the serum and is sequestered in the brain and other organs, where it interferes with function at a cellular level without changing blood levels of glucose, etc.). In adults salicylate poisoning typically causes respiratory alkalosis, but in children this progresses rapidly to mixed respiratory alkalosis–metabolic acidosis and then to metabolic acidosis (in adults, metabolic acidosis is said to be a rare and a near-terminal event). m Isopropyl (rubbing) alcohol poisoning: Produces enough circulating acetone to produce a positive nitroprusside test (it therefore may be mistaken for diabetic ketoacidosis; thus insulin should not be given until the blood glucose is known). In the absence of a history, positive serum ketone test associated with normal AG, normal serum HCO3 –, and normal blood glucose suggests rubbing alcohol intoxication. Acid-base maps (Fig. 12-1) are a graphic solution of the Henderson-Hasselbalch equation that predicts the HCO 3 – value for each set of pH/pCO2 coordinates. They also allow a check of the consistency of arterial blood gas and some chemical analyzer determinations, because the chemical analyzer determines the total CO 2 content, of which 95% is HCO3 –. These maps contain bands that show the 95% probability range of values for each disorder. If the pH/pCO 2 coordinate is outside the 95% confidence band, then the patient has at least two acid-base disturbances. These maps are of particular use when one of the acid-base disturbances is not suspected clinically. If the coordinates lie within a band, however, there is no guarantee of a simple acid-base disturbance.
- 323. Fig. 12-1. Acid-base map. The values demarcated for each disorder represent a 95% probability range for each pure disorder (N = normal). Coordinates lying outside these zones suggest mixed acid-base disorders. (Adapted from Goldberg M, et al. Computer-based instruction and diagnosis of acid-base disorders. JAMA 1973;223:269. Copyright 1973 American Medical Association.) ACID-BASE DISTURBANCES, MIXED (Must always be interpreted with clinical data and other laboratory findings) See Table 12-2. Respiratory Acidosis with Metabolic Acidosis Examples: Acute pulmonary edema, cardiopulmonary arrest (lactic acidosis due to tissue anoxia and CO 2 retention due to alveolar hypoventilation) Acidemia may be extreme with •pH <7.0 (H+ >100 mEq/L). m• HCO3 – <26 mEq/L. Failure of HCO3– to increase ³3 mEq/L for each 10 mm Hg rise in pCO2 suggests metabolic acidosis with respiratory acidosis. Mild metabolic acidosis superimposed on chronic hypercapnia causing partial suppression of HCO3 – may be indistinguishable from adaptation to hypercapnia alone. Metabolic Acidosis with Respiratory Alkalosis Examples: Rapid correction of severe metabolic acidosis, salicylate intoxication, septicemia due to gram-negative organisms, initial respiratory alkalosis with subsequent development of metabolic acidosis. m Primary metabolic acidosis with primary respiratory alkalosis with an increased AG is characteristic of salicylate intoxication in absence of uremia and diabetic ketoacidosis. pH may be normal or decreased. Hypocapnia remains inappropriate to decreased HCO3 – for several hours or more. Respiratory Acidosis with Metabolic Alkalosis Examples: Chronic pulmonary disease with CO2 retention in which patient develops metabolic alkalosis due to administration of diuretics, severe vomiting, or sudden improvement in ventilation (“posthypercapnic” metabolic alkalosis) m Decreased or absent urine chloride indicates that chloride-responsive metabolic alkalosis is a part of the picture. m In clinical setting of respiratory acidosis but with normal blood pH and/or HCO 3 – higher than predicted, complicating metabolic alkalosis may be present. Respiratory Alkalosis with Metabolic Alkalosis Examples: Hepatic insufficiency with hyperventilation plus administration of diuretics or severe vomiting; metabolic alkalosis with stimulation of ventilation (e.g., sepsis, pulmonary embolism, mechanical ventilation) that causes respiratory alkalosis w Marked alkalemia with decreased pCO2 and increased HCO3 – is diagnostic. Acute and Chronic Respiratory Acidosis Examples: Chronic hypercapnia with acute deterioration of pulmonary function causing further rise of pCO 2 m May be suspected when HCO3 – in intermediate range between acute and chronic respiratory acidosis (similar findings in chronic respiratory acidosis with superimposed metabolic acidosis or acute respiratory acidosis with superimposed metabolic alkalosis) Coexistence of Metabolic Acidoses of Hyperchloremic Type and Increased AG Type Examples: Uremia and proximal renal tubular acidosis, lactic acidosis with diarrhea, excessive administration of sodium chloride to patient with organic acidosis m May be suspected when plasma HCO3 – level is lower than is explained by the increase in anions (e.g., AG = 16 mEq/L and HCO 3 – = 5 mEq/L) Coexistence of Metabolic Alkalosis and Metabolic Acidosis Examples: Vomiting causing alkalosis plus bicarbonate-losing diarrhea causing acidosis m May be suggested by acid-base values that are too normal for clinical picture ACIDOSIS, LACTIC Indicates acute hypoperfusion and tissue hypoxia. m Should be considered in any metabolic acidosis with increased AG (>15 mEq/L). w Diagnosis is confirmed by exclusion of other causes of metabolic acidosis and serum lactate ³5 mEq/L (upper limit of normal = 1.6 for plasma and 1.4 for whole blood). Considerable variation in literature in limits of serum lactate and pH to define lactic acidosis. w Exclusion of other causes by Normal serum creatinine and BUN. (Increased acetoacetic acid [but not beta-hydroxybutyric acid] causes false increase of creatinine by colorimetric assay.) Osmolar gap <10 mOsm/L. Negative nitroprusside reaction. (Nitroprusside test for ketoacidosis measures acetoacetic acid but not beta-hydroxybutyric acid; thus blood ketone test may be
- 324. negative in diabetic ketoacidosis.) Urine negative for calcium oxalate crystals. No known ingestion of toxic substances. Laboratory findings due to underlying diseases (e.g., diabetes mellitus, renal insufficiency, etc.) Laboratory tests for monitoring therapy Arterial pH, pCO2, HCO3 –, serum electrolytes, every 1–2 hrs until patient is stable Urine electrolytes every 6 hrs Associated or compensatory metabolic or respiratory disturbances (e.g., hyperventilation or respiratory alkalosis may result in normal pH) Due To Type A due to clinically apparent tissue hypoxia, e.g., acute hemorrhage, severe anemia, shock, asphyxia; marathon running, seizures Type B without clinically apparent tissue hypoxia due to Common disorders (e.g., diabetes mellitus, uremia, liver disease, infections, malignancies, alkaloses). Drugs and toxins (e.g., ethanol, methanol, ethylene glycol, salicylates, metformin). Hereditary enzyme defects (e.g., methylmalonicaciduria, propionicaciduria, defects of fatty acid oxidation, pyruvate-dehydrogenase deficiency, pyruvate-carboxylase deficiency, multiple carboxylase deficiency, glycogen storage disease type I). Others (e.g., short-bowel syndrome). With a typical clinical picture (acute onset after nausea and vomiting, altered state of consciousness, hyperventilation, high mortality) Decreased serum bicarbonate. Low serum pH, usually 6.98–7.25. Increased serum potassium, often 6–7 mEq/L. Serum chloride normal or low with increased AG. WBC is increased (occasionally to leukemoid levels). Increased serum uric acid is frequent (up to 25 mg/dL in lactic acidosis). m Increased serum phosphorus. Phosphorus/creatinine ratio >3 indicates lactic acidosis either alone or as a component of other metabolic acidosis. Increased serum AST, LD, and phosphorus. See Table 12-3. ACIDOSIS, METABOLIC m With Increased Anion Gap (AG >15 mEq/L) Lactic acidosis—most common cause of metabolic acidosis with increased AG (frequently >25 mEq/L) (see previous section) Renal failure (AG <25 mEq/L) Ketoacidosis Diabetes mellitus (AG frequently >25 mEq/L) Associated with alcohol abuse (AG frequently 20–25 mEq/L) Starvation (AG usually 5–10 mEq/L) Drug effects Salicylate poisoning (AG frequently 5–10 mEq/L; higher in children) Methanol poisoning (AG frequently >20 mEq/L) Ethylene glycol poisoning (AG frequently >20 mEq/L) Paraldehyde treatment (AG frequently >20 mEq/L) m With Normal Anion Gap (Hyperchloremic acidosis) Decreased serum potassium Renal tubular acidosis Acquired (e.g., drugs, hypercalcemia) Inherited (e.g., cystinosis, Wilson's disease) Carbonic anhydrase inhibitors (e.g., acetazolamide, mafenide) Increased loss of alkaline body fluids (e.g., diarrhea, loss of pancreatic or biliary fluids) Ureteral diversion (e.g., ileal bladder or ureter, ureterosigmoidostomy) Normal or increased serum potassium Hydronephrosis Early renal failure Administration of HCl (e.g., ammonium chloride) Hypoadrenalism (diffuse, zona glomerulosa, or hyporeninemia) Renal aldosterone resistance Sulfur toxicity m In lactic acidosis the increase in AG is usually greater than the decrease in HCO3 –, in contrast to diabetic ketoacidosis in which the increase in AG is identical to the decrease in HCO3 –. w Laboratory Findings
- 325. Serum pH is decreased (<7.3). Total plasma CO2 content is decreased; value <15 mEq/L almost certainly rules out respiratory alkalosis. Serum potassium is frequently increased; it is decreased in renal tubular acidosis, diarrhea, or carbonic anhydrase inhibition. Azotemia suggests metabolic acidosis due to renal failure. Urine is strongly acid (pH = 4.5–5.2) if renal function is normal. In evaluating acid-base disorders, calculate the AG (see below). ACIDOSIS, RESPIRATORY Laboratory findings differ in acute and chronic conditions. Acute Due to decreased alveolar ventilation impairing CO 2 excretion Cardiopulmonary (e.g., pneumonia, pneumothorax, pulmonary edema, foreign-body aspiration, laryngospasm, bronchospasm, mechanical ventilation, cardiac arrest) CNS depression (e.g., general anesthesia, drug effects, brain injury, infection) Neuromuscular conditions (e.g., Guillain-Barré syndrome, hypokalemia, myasthenic crisis) m Acidosis is severe (pH 7.05–7.10) but HCO 3 – concentration is only 29–30 mEq/L. Severe mixed acidosis is common in cardiac arrest when respiratory and circulatory failure cause marked respiratory acidosis and severe lactic acidosis. Chronic Due to chronic obstructive or restrictive conditions Nerve disease (e.g., poliomyelitis) Muscle disease (e.g., myopathy) CNS disorder (e.g., brain tumor) Restriction of thorax (e.g., musculoskeletal disorders, scleroderma, pickwickian syndrome) Pulmonary disease (e.g., prolonged pneumonia, primary alveolar hypoventilation) Acidosis is not usually severe. Beware of commonly occurring mixed acid-base disturbances Chronic respiratory acidosis with superimposed acute hypercapnia resulting from acute infection, such as bronchitis or pneumonia. Superimposed metabolic alkalosis (e.g., due to diuretics or vomiting) may exacerbate the hypercapnia. ALKALOSIS, METABOLIC Due To Loss of acid Vomiting, gastric suction, gastrocolic fistula Diarrhea in mucoviscidosis (rarely) Villous adenoma of colon Aciduria secondary to potassium depletion Excess of base due to Administration of absorbable antacids (e.g., sodium bicarbonate; milk-alkali syndrome) Administration of salts of weak acids (e.g., sodium lactate, sodium or potassium citrate) Some vegetarian diets Potassium depletion (causing sodium and H+ to enter cells) Gastrointestinal loss (e.g., chronic diarrhea) Lack of potassium intake (e.g., anorexia nervosa, administration of IV fluids without potassium supplements for treatment of vomiting or postoperatively) Diuresis (e.g., mercurials, thiazides, osmotic diuresis) Extracellular volume depletion and chloride depletion All forms of mineralocorticoid excess (e.g., primary aldosteronism, Cushing's syndrome, administration of steroids, ingestion of large amounts of licorice) Glycogen deposition Chronic alkalosis Potassium-losing nephropathy Hypoproteinemia per se may cause a nonrespiratory alkalosis. Decreased albumin of 1 gm/dL causes an average increase in standard bicarbonate of 3.4 mEq/L, an apparent base excess of +3.7 mEq/L, and a decrease in AG of ~3 mEq/L.1 w Laboratory Findings Serum pH is increased (>7.60 in severe alkalemia). Total plasma CO2 is increased (bicarbonate >30 mEq/L). pCO2 is normal or slightly increased.
- 326. Serum pH and bicarbonate are above those predicted by the pCO2 (by nomogram or Table 12-4). Hypokalemia is an almost constant feature and is the chief danger in metabolic alkalosis. Decreased serum chloride is relatively lower than sodium. BUN may be increased. Urine pH is >7.0 (£7.9) if potassium depletion is not severe and concomitant sodium deficiency (e.g., vomiting) is not present. With severe hypokalemia (<2.0 mEq/L), urine may be acid in presence of systemic alkalosis. m When the urine chloride is low (<10 mEq/L) and the patient responds to chloride treatment, the cause is more likely loss of gastric juice, diuretic therapy, or rapid relief of chronic hypercapnia. Chloride replacement is completed when urine chloride remains >40 mEq/L. When the urine chloride is high (>20 mEq/L) and the patient does not respond to sodium chloride treatment, the cause is more likely hyperadrenalism or severe potassium deficiency. See Table 12-4. ALKALOSIS, RESPIRATORY (Decreased pCO2 of <38 mm Hg) Due To Hyperventilation CNS disorders (e.g., infection, tumor, trauma, cerebrovascular accident [CVA]) Salicylate intoxication Fever Bacteremia due to gram-negative organisms Liver disease Pulmonary disease (e.g., pneumonia, pulmonary emboli, asthma) Mechanical overventilation Congestive heart failure Hypoxia (e.g., decreased barometric pressure, ventilation-perfusion imbalance) Anxiety-hyperventilation Laboratory Findings Acute hypocapnia—usually only a modest decrease in plasma HCO 3 – concentrations and marked alkalosis Chronic hypocapnia—usually only a slight alkaline pH (not usually >7.55) ANION GAP CLASSIFICATION (Calculated as Na – [Cl + HCO3]; typically normal = 8–16 mEq/L; if K is included, normal = 10–20 mEq/L; reference interval varies considerably depending on instrumentation.) Use Identification of cause of metabolic acidosis Supplement to laboratory quality control along with its components Increased In m Increased “unmeasured” anions Organic (e.g., lactic acidosis, ketoacidosis) Inorganic (e.g., administration of phosphate, sulfate) Protein (e.g., transient hyperalbuminemia) Exogenous (e.g., salicylate, formate, nitrate, penicillin, carbenicillin) Not completely identified (e.g., hyperosmolar hyperglycemic nonketotic coma, uremia, poisoning by ethylene glycol, methanol, salicylates) Artifactual Falsely increased serum sodium Falsely decreased serum chloride or bicarbonate Decreased unmeasured cations (e.g., hypokalemia, hypocalcemia, hypomagnesemia) m When AG >12–14 mEq/L, diabetic ketoacidosis is the most common cause, uremic acidosis is the second most common cause, and drug ingestion (e.g., salicylates, methyl alcohol, ethylene glycol, ethyl alcohol) is the third most common cause; lactic acidosis should always be considered when these three causes are ruled out. Decreased In m Decreased unmeasured anion (e.g., hypoalbuminemia is probably most common cause of decreased AG) m Artifactual “Hyperchloremia” in bromide intoxication (if chloride determination by colorimetric method) Hyponatremia due to viscous serum False decrease in serum sodium; false increase in serum chloride or HCO 3 – m Increased unmeasured cations Hyperkalemia, hypercalcemia, hypermagnesemia Increased proteins in multiple myeloma, paraproteinemias, polyclonal gammopathies (these abnormal proteins are positively charged and lower the AG)
- 327. Increased lithium, tris(hydroxymethyl)aminomethane buffer (tromethamine) m AG >30 mEq/L almost always indicates organic acidosis even in presence of uremia. AG of 20–29 mEq/L occurs in absence of identified organic acidosis in 25% of patients. AG is rarely >23 mEq/L in chronic renal failure. Simultaneous changes in ions may cancel each other out, leaving AG unchanged (e.g., increased chloride and decreased HCO3 –). AG may provide a clue to the presence of a mixed rather than simple acid-base disturbance. NUTRITIONAL DEFICIENCIES DEFICIENCY,