Approach to macrocytic anemia
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This document provides an overview of macrocytic anemia, focusing on deficiencies in cobalamin and folate. It describes the etiology, absorption, clinical features, hematologic findings, diagnosis, and other causes of macrocytic anemia. Cobalamin and folate deficiencies can result in megaloblastic changes in the bone marrow and ineffective hematopoiesis. Diagnosis involves measuring serum levels of cobalamin, folate, methylmalonic acid and homocysteine, along with tests to determine the underlying cause of deficiency. Other potential causes of macrocytic anemia include vitamin B6 deficiency, acute infections, drugs, toxins, acute myeloid leukemia, and genetic disorders.
Approach to macrocytic anemia
- 1. Dr. Bikal Lamichhane Internal Medicine Resident Approach to Macrocytic Anemia
- 2. The megaloblastic anemias are a group of disorders characterized by the presence of distinctive morphologic appearances of the developing red cells in the bone marrow. Bone marrow usually produces large, structurally abnormal, immature red blood cells due to impaired DNA synthesis. The marrow is usually hypercellular and the anemia is based on ineffective erythropoiesis.
- 3. Etiology
- 4. Cobalamin Has a cobalt atom at the center of a corrin ring. Adocobalamin and methylcobalamin forms are major natural cobalamin. Minor amounts of hydroxocobalamin to which methyl- and adocobalamin are converted rapidly by exposure to light.
- 5. Absorption of Cobalamin Two mechanism, 1) Passive, occurring equally through buccal, duodenal, and ileal mucosa; it is rapid but extremely inefficient, with <1% of an oral dose being absorbed by this process. 2) Active; it occurs through the ileum and is efficient for small (a few micrograms) oral doses of cobalamin, and it is mediated by gastric intrinsic factor (IF).
- 9. Folate Folic (pteroylglutamic) acid is a yellow, crystalline, water- soluble substance. The highest concentrations are found in liver, yeast, spinach, other greens, and nuts (>100 μg/100 g). Folate is easily destroyed by heating, particularly in large volumes of water. Total body folate in the adult is ~10 mg, with the liver containing the largest store.
- 10. Daily adult requirements are ~100 μg, and so stores are sufficient for only 3–4 months in normal adults. Folates are absorbed rapidly from the upper small intestine.
- 12. Clinical Features Many symptomless patients are detected through the finding of a raised mean corpuscular volume (MCV) on a routine blood count. Anorexia is usually marked, and there may be weight loss, diarrhea, or constipation. Glossitis, angular cheilosis, a mild fever in more severely anemic patients, jaundice (unconjugated), and reversible melanin skin hyperpigmentation also may occur.
- 13. Neurologic Manifestations Vitamin B12 is needed for the myelination of the central nervous system. Its deficiency may cause a bilateral peripheral neuropathy or degeneration (demyelination) of the cervical and thoracic posterior and lateral (pyramidal) tracts of the spinal cord and, less frequently, of the cranial nerves and of the white matter of the brain. Optic atrophy and cerebral symptoms including dementia, depression, psychotic symptoms, and cognitive impairment may be prominent.
- 14. MRI may show the “spongy” degeneration of the cord. Loss of proprioception and vibration sensation with positive Romberg and Lhermitte signs. Gait may be ataxic with spasticity (hyperreflexia). Autonomic nervous dysfunction can result in postural hypotension, impotence, and incontinence Cobalamin deficiency in infancy:poor brain development,impaired intellectual development,feeding difficulties, lethargy, coma,convulsions and myoclonus.
- 15. Cardiovascular Disease: severe homocystinuria (blood levels ≥100 μmol/L) due to deficiency of one of three enzymes, methionine synthase, MTHFR, or cystathionine synthase ischemic heart disease, cerebrovascular disease, or pulmonary embolus or deep vein thrombosis in young.
- 16. HEMATOLOGIC FINDINGS PERIPHERAL BLOOD : Oval macrocytes, with anisocytosis and poikilocytosis The MCV is usually >100 fL. Neutrophils are hypersegmented (more than five nuclear lobes). Leukopenia due to a reduction in granulocytes and lymphocytes. Platelet count may be moderately reduced.
- 17. BONE MARROW : Hypercellular with an accumulation of primitive cells .Cells are larger than normoblasts, and an increased number of cells with eccentric lobulated nuclei or nuclear fragments. Giant and abnormally shaped metamyelocytes and enlarged hyperpolyploid megakaryocytes are characteristic.
- 18. CHROMOSOMES Proliferating cells in the body show : random breaks, reduced contraction, spreading of the centromere, and exaggeration of secondary chromosomal constrictions and overprominent satellites. INEFFECTIVE HEMATOPOIESIS : unconjugated bilirubin in plasma ,raised urine urobilinogen, reduced haptoglobins and positive urine hemosiderin,raised serum lactate dehydrogenase,weakly positive direct antiglobulin test due to complement.
- 19. DIAGNOSIS OF COBALAMIN AND FOLATE DEFICIENCIES COBALAMIN DEFICIENCY : Serum Cobalamin normal levels :160–200 ng/L to 1000 ng/L. In patients with megaloblastic anemia due to cobalamin deficiency, the level is usually <100 ng/L. Borderline :100 to 200 ng/L. Serum cobalamin level is sufficiently robust, cost- effective, and most convenient to rule out cobalamin deficiency . But where clinical indications of pernicious anemia( PA) are strong, a normal serum vitamin B12 does not rule out the diagnosis.
- 20. Folate deficiency, transcobalamin 1 deficiency, oral contraceptives, and multiple myeloma have all been associated with low serum B12 levels that do not indicate B12 deficiency. High serum B12 levels : serum transcobalamin 1 levels raised presence of liver, renal, or myeloproliferative diseases or to cancer of the breast, colon, or liver. Serum Methylmalonate(MMA) and Homocysteine: elevated. Serum homocysteine: raised but may be raised in chronic renal disease, alcoholism, smoking, pyridoxine deficiency, hypothyroidism,therapy with steroids, cyclosporine, and other drugs
- 21. Tests for the Cause of Cobalamin Deficiency : Only strict vegetarians, or people living on a totally inadequate diet will be B12 deficient because of inadequate intake. Tests to diagnose PA : serum gastrin,( raised) serum pepsinogen I (low) in PA (90–92%) and gastric endoscopy. Tests for IF and parietal cell antibodies Tests for individual intestinal diseases.
- 22. FOLATE DEFICIENCY : Serum Folate: Normal range 2 μg/L to 15 μg/L. The serum folate level is low in all folate-deficient patients Serum folate rises in severe cobalamin deficiency because of the block in conversion of MTHF to THF inside cells,also in intestinal stagnant loop syndrome Red Cell Folate :Test of body folate stores. Normal (160–640 μg/L) of packed red cells. Serum homocysteine elevated. Tests for the Cause of Folate Deficiency : Diet history Tests for transglutaminase antibodies for celiac disease /duodenal biopsy as needed.
- 23. HEMATOLOGICAL FINDINGS PERIPHERAL BLOOD Oval macrocytes, usually with considerable anisocytosis and poikilocytosis, are the main feature. The MCV is usually >100 Fl unless a cause of microcytosis (e.g., iron deficiency or thalassemia trait) is present. Some of the neutrophils are hypersegmented (more than five nuclear lobes).
- 24. There may be leukopenia due to a reduction in granulocytes and lymphocytes, but this is usually >1.5 × 109/L. platelet count may be moderately reduced, rarely to <40 × 109/L. The severity of all these changes parallels the degree of anemia.
- 25. OTHER CAUSES OF MACROCYTIC ANEMIA Vitamin B6 deficiency: assessed by a therapeutic trial of pyridoxine Acute viral infections, drug reactions, or chemical toxicity( transient). AML :20% blasts in the marrow Genetic diseases:genomic testing
- 27. References Harrison’s principles of Internal Medicine , 20th edition. Uptodate 2020.