Pathology of Diabetes

More people would learn from their mistakes if they weren't so busy denying them. -Harold J. Smith

Molly is a 15 year old Y10 student comes to ED with her Aunty Ada, community health worker. Ada says Molly has ‘wee’ problem. Molly : ‘I’m going to the toilet often to pass wee and it is sore and itchy afterwards’ Problem Analysis: ? Key points: ? Differential Diagnosis: ? Further questions:

CPC4.3.2 – Molly. Frequency: Passing urine every 2 – 3 hours. Duration: ‘ long time ’ Dysuria: terminal Duration: one day –‘Aunty brought me here’ Haematuria: no Itch: all the time, ‘quite sore from scratching’ Duration: ‘has been there on and off for long time, worse in last three days’ Menstrual hx: menarche age 12 years; irregular K LMP: 3/52 ago, normal K Pelvic pain: no Vaginal discharge: whitish Sexual history : never been sexually active

CPC4.3.2 – Molly. Thirst: Aunty Ada: Molly always seems to drinking ’ Appetite: normal Weight: Ada : ‘Since she has put on a lot of weight ’ Bowels: No change/normal All other systems questions : negative SH Lives with Aunty Ada; mum on TI with rest of family. Doing well at school, plans to study nursing. Non smoker, no alcohol PMH 2005 recurrent boils axilla + groin , settled with antibiotics; Ear infection as a young child PSH nil Meds nil Immunisations up to date

CPC4.3.2 – Molly. ? Key points, ? DD, Pathogenesis / importance of, Polyuria, Polydipsia, Polyphagia? Recurrent Infections? Weight gain? DM What type? How to confirm? Investigations? Complications? Prognosis? Management – advice / therapy ?

Diagnostic points (for DM type) ? On & off for long time. Always drinking. Put on weight. Recurrent boils. Mom has DM type 2

?Pathogenesis: “ recurrent multisite infections” Associated AIDS Hyperglycemia Ischemia Immunodeficiency Multifactorial

Miss ML: Most likely diagnosis: DM Type 1 DM Type 2 MODY 1 MODY 2 Gestational DM

?Pathogenesis: Whitish vaginal discharge. Proteinuria Bacterial infection Glycosuria Trichomoniasis Candidiasis

Most likely .. What type of DM ? 56 year male obese 30 year female following pregnancy 8 year old boy, poor growth. 24 year female Cushing’s sy 68 Year male following Ca. pancreas. 34 year male, extensive tuberculosis. 12 year old female following viral fever . II NIDDM II GDM I IDDM Sec IDDM Sec IDDM Sec IDDM I IDDM

In this world, Be like the tongue in the midst of the teeth, carefully, confidently & courageously going about its task, without getting bitten..! - Baba Divine Discourse on the Bhagavad Gita, 1984

“ Nothing great in the world has ever been accomplished without passion” - - CHRISTIAN FRIEDRICH HEBBEL

Pathology of Diabetes Dr. Venkatesh M. Shashidhar Assoc. Prof. & Head of Pathology

What is Diabetes? “… .a wonderful but not very frequent affection among men, being a melting down of the flesh and limbs into urine …Life is short, offensive, and distressing, thirst unquenchable, death inevitable…” -- Aretaeus of Cappadocia (AD 81-3) 150 AD – Aretaeus, named "diabetes“ Greek word for "siphon” 1788 – Cawley – damaged pancreas in DM. 1921 – Banting & Best, Insulin

Introduction Diabetes mellitus (sweet urine) 3% of world population, 100m. Incidence increasing alarmingly (259m  2025) Most Common non communicable disease. High Morbidity & mortality. DM shortens life span by 15 years. Leading cause of blindness and Kidney dis. Pacific Islands – leaders in DM & Obesity…! Aus: 7 th leading cause of death, 1M.. half of whom may be unaware of their disease.

Diabetes Mellitus - Definition 2 nd Century, Greek physician, Aretus named Diabetes from diabainein, “to flow through or siphon & Mellitus meaning sweet/Honey . * insipidus  tasteless – dilute urine. Disorder of metabolism (Carb, Prot & Fat) Absolute/Relative deficiency of insulin. Characterized by hyperglycemia. P olyuria, P olydypsia, P olyphagia.

Criteria for the Diagnosis of Diabetes Symptoms + unexplained weight loss + RBS > 11.1 mmol/L. OR Fasting(>8h) pl.glucose > 7.0 mmol/L OR 2h pl.glucose > 11.1 mmol/L during an 75g oral glucose tolerance test (OGTT).

Normal Pancreas: Islet of Langerhans (Endocrine Pancreas) Pancreatic acini (Exocrine Pancreas) Duct

Normal Pancreatic Islet: (ipx stain) α cells 20% (Glucagon) ß cells 70% (Insulin) δ cells (Somatostatin) pp Cells (pan prot) ß α

Blood Glucose & Hormones Hormones Insulin Glucortocoids Glucagon Growth Hormone Epinephrine Action  Glucose  Glucose  Glucose  Glucose  Glucose Maintained within 3.5-6.5 mmol/l .

Insulin - Anabolic Steroid Transmembrane transport of glucose (Liver, muscle & adipose tissue. Maintain metabolism: Skeletal Muscle glucose uptake Adipose tissue lipolysis Hepatic gluconeogenesis.  glycogen &  gluconeogenesis.  lipolysis  Lipogenesis.  Protein & triglyceride synthesis  Nucleic acid & Protein synthesis Diabetes   glucose   catabolism

Cellular Glucose Uptake Insulin Requiring Striated Muscle Cardiac Muscle Liver Adipose Tissue Glucose deficiency Low glucose: Liver: Gluconeogenesis Adipose: Lipolysis  FFA Muscle: depressed metabolism. Non-Insulin Requiring Blood Vessels Nerves Kidney Eye Lens Polyol damage Excess glucose: Glucose  Aldehyde dehydrogenase  Sorbitol

Diabetes Classification : (not a single disease) Primary DM Type I – IDDM / Juvenile – 10%. Type II – NIDDM /Adult onset – 80%. MODY – 5% Maturity Onset Diabetes of Youth Genetic, sub types MODY 1 – MODY 11, Gestational Diabetes Mellitus. Type 1.5 – latent autoimmune DM in adults (LADA ) Other. Secondary DM Excess hyperglycemic stimulus. Cushings, Phaeochromocytoma, acromegaly, Steroid therapy. Beta cell destruction: Pancreatitis/tumors/Hemochromatosis Infectious – congenital rubella, CMV, TB, Endocrinopathy, Downs Sy.

Metabolic Syndrome (X) - IDF criteria Central Obesity >90cm male, >80 fem – Asian, chinese, Jap. >94cm male, >80 fem – Europ, Africa, Arab. + Any two of the following. Raised triglycerides >1.7mmol/l or treat. Reduled HDL-C <1.03mmol/l or treat. Hypertension 130/85 or treat. Fasting plasma glucose >5.6mmol/l or DM2. Australia prevalence 2005 – 30.7% 10 Year CVD risk - 23.4%

LADA: Late onset Autoimmune DM Features of both type 1 and type 2. Younger, Rapid onset & progression to insulin dependency. Immune markers like type 1 diabetes, may lack ketoacidosis symptoms. Incidence: - 6-10% (UK). Diagnosis: Elevated pancreatic autoantibodies Risk factors: Metabolic Syndrome LADA + Metabolic syndrome = DM Type 1.5. Complications of both type 1 & 2. (metabolic, Macro & Microangiopathy etc).

Your life should rest on morality and truth. Base your life on truth & love for all. - Sai - Summer Showers, 1973 Money and goes but morality comes and grows.

Pathogenesis of Type I DM Genetic HLA-DR3/4 Environment Viral infe..? Insulin deficiency Autoimmune Insulitis Ab to ß cells/insulin ß cell Destruction Other Autoimmune disorders: PS Glomerulonephritis Graves, Hashimoto thyroiditis. Rheumatic heart disease SLE, Collagen vascular disease Rheumatoid arthritis. Secondary DM Inflammation, Tumor, Infection Trauma Pancreatitis Antibodies: Islet cell Ab - ICA Insulin Auto Ab - IAA Glut. Acid Decarb - GAD65

Insulitis – Type I Lymphocytes.

Progression of Type II Years ..

Pathogenesis of Type II DM Relative Insulin Def. ß cell Exhaustion (IDDM)

DM2 Islets: Normal early  amyloid late:  Normal. Loss of ß cells ( only in late stage ) replaced by Amyloid protein deposit (hyalinization).

Type-I Type-II Less common (10%) Children < 25 Years Insulin- Dependent Duration: Weeks Acute Metabolic complications Autoantibody: Yes Family History: No Insulin levels: low Islets: Insulitis 50% in twins More common (90%) Adult >25 Years NIDDM* Months to years Chronic Vascular complications. No Yes Normal or high * Normal / Exhaustion ~100% in twins

Type-I Type-II Insulitis: Lymphocytic infiltrate within islets. Islet Hyalinization: Central hyaline deposits replacing dead beta cells

New in DM: Incretins. Incretin harmones by enteroendocrine cells of intestine in response to glucose. G lucagon- l ike p eptide-1 (GLP-1) G lucose-dependent I nsulinotropic P olypeptide (GIP) Inhibit α cells, stimulate β cells  Insulin. Destroyed by dipeptidyl peptidase (DPP). Dysregulation of these in DM2. Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [DPP 4 inhibitor] – Approved for PBS. Medscape online video: http://www.medscape.com/infosite/dia/article-3

Being true human is maintaining complete harmony between thought, word and deed. Divergence between thought, word and deed is the cause of all our problems…! - BABA.

DM Complications: Glucose is highly reactive - damages tissues. Glucose absorption, storage & use – Timely Insulin release - critical. Diabetes is state of insulin deficiency. Absolute/Delayed/inappropriate insulin response Glucose excess – Hyperglycemia. Neo-glucogenesis – Proteolysis, lipolysis Clinical symptoms & signs are mainly due to complications. Complications: Acute Metabolic & Chronic Vascular. Damage to BV, Kidney, CNS & immune system.

Diabetes Complications: Short term Complications: (metabolic) Hypoglycemia Diabetic Ketoacidosis Non Ketotic hyperosmolar diabetic coma Lactic acidosis Long term Complications : (Angiopathy) Microngiopathy - Retinopathy, Nephropathy, Neurophathy, dermatopathy. Macroangiopathy – Atherosclerosis.

Pathogenesis of complications: Insulin dependant tissue: Skeletal muscle, adipose tissue Low glucose inside cell decreased cell metabolism High glucose outside Glycosylation damage (AGE) - * Insulin independent tissue: BV, nerve, (kidney, eye, CNS) Excess glucose  Polyol  osmotic damage*

The best gift of Nature to man is the briefness of his life…! Latin quote

Microangiopathy Pathogenesis: Hyperglycemia chronic. Glycosylation of basement membrane proteins  Leaky blood vessels. Excess deposition of proteins – glycosylation cycle. Thick and Leaky blood vessels. Narrow lumen Ischemic Organ damage...

Diabetic Microangiopathy Normal Diabetic Glucose Glycosylation BM damage leak ‘ AGE’ deposition

Neuropathy Sensory  Motor (myelin) Peripheral Neuropathy Bilateral, symmetric Progressive, irreversible Paraesthesia, pain, muscle atrophy Visceral neuropathy Cranial nerve – diplopia, Bells palsy GIT- constipation, diarrhoea CVS – orthostatic hypotension

DM-Neuropathy – Myelin stain Myelin loss in nerve Normal

Neuropathic ulcer Etiology: peripheral sensory neuropathy, Trauma & deformity. Factors: Ischemia, callus formation, and edema.

Neuropathic ulcers FEATURES: Painless, surrounded by callus At pressure points. associated with good foot pulses May not be associated with gangrene

Neuropathic Arthropathy: Charcot’s foot. Acute, swollen, red, warm Minimal or no pain. No or minimal h/o trauma. Pathogenesis: Neuropathy  osteoporosis  # Chronic - Foot deformity. Normal Charcot

DM Amyotrophy - Painful muscle wasting Pain & weakness of lower limb muscles. Neuropathy. Muscle wasting. Minimal sensory loss. Loss of knee reflex. Inflammation in spinal cord.

Chronic Polyneuropathy Pathophysiology: (unknown) Polyol  Sorbitol  damage. Ishcemic injuty. Impaired Nerve growth factor. Autoimmune damage. Claw foot – Dermopathy & Neuropathy

Diabetic Amyotrophy Painful, proximal Asymmetrical, motor neuropathy. Poor diabetic control – hyperglycemia – AGE. Occlusion of capillaries of proximal lumbar plexus  nerve damage. (no myelin degeneration*) It is multiple mononeuropathy

Nephropathy Nodular Glomerulo Sclerosis. Common morbidity & mortality. Deposition of ‘AGE’ Advanced Glycosylation End-products as nodules. Nephrotic syndrome Pyelonephritis End stage renal failure

Diabetic Nephropathy Microangiopathy, atherosclerosis & infections: Diffuse or nodular diabetic glomerulosclerosis (Kimmelstiel Wilson Sy) Renal arteriolosclerosis & atherosclerosis Necrotizing renal papillitis. Pyelonephritis. End stage kidney.

Nodular Glomerulosclerosis – KW lesion.

Diabetic Glomerulosclerosis B A

Diabetic Glomerulosclerosis Hyaline nodule

DM with Infarction: Papillary necrosis

Retinopathy: Non Proliferative Microaneurysms, Dots & blots Hard and soft exudates Cotton wool – infarcts Macular edema. Proliferative. Neovascularization Large hemorrhages Retinal detachment.

Non Proliferative Retinopathy Venous dilation and small red dots posterior retinal pole - capillary microaneurysms . Dot and blot retinal hemorrhages and deep-lying edema and lipid exudates impair macular function. Cotton-wool spots (soft exudates) - microinfarcts due to ischemia. They are white and obscure underlying vessels. Hard exudates are caused by chronic edema . They are yellow and generally deep to retinal vessels. Late generalized diminution of vision due to ischemia and macular edema - common cause of visual defect (best detected by fluorescein angiography)

Proliferative Retinopathy Neovascularization – new capillaries grow into the vitreous cavity. hemorrhages may lead to sudden severe loss of vision. In advanced disease, neovascular membranes can occur, resulting in a traction & retinal detachment. Leading to permanent blindness. Panretinal photocoagulation may diminish or eliminate proliferative retinopathy

Diabetic Retinopathy Fluorescein angiogram of the eye of a diabetic patient. Note the numerous, small, dot-like capillary microaneurysms.

Diabetic Retinopathy Pre retinal Hemorrhage - detachment

Label the diagram. 1. 2. 3. 4. 5. Hard/waxy dep Optic disc Macula Blot hem Cotton wool / soft dep.

You must learn to distinguish between good and bad, truth and untruth. You must use your education for the purpose of serving community. - Sai - Summer Showers, 1973.

Macroangiopathy Atherosclerosis Dyslipidemia  HDL Non-Enzymatic Glycosylation  Platelet Adhesiveness  Thromboxane A 2  Prostacyclin Endothelial damage  Atherosclerosis MI, CVA, Gangrene of Leg (PVD), Renal Insufficiency

Fungal infections: Candidiasis

Blood vessel calcification: In digital arteries in DM Amputated Toe Calcified BV

Cataract – Sorbitol.. Polyol..osmotic.. Lens epithelium (Insulin independent) is exposed to Hyperglycaemia, excessive flux of glucose to sorbitol by the polyol pathway. The accumulation of intracellular sorbitol exerts osmoprotection and prevents cell shrinkage. The excessive accumulation of sorbitol, causes an increased osmotic load within the lens causing swelling, fibre breakdown, and opacification (the osmotic hypothesis). Other mechanisms, including glycation and oxidative stress, may also be responsible for lens opacification.

Acanthosis Nigricans Insulin resistance…

Pathogenesis of Infections in DM: Decreased metabolism – low immunity. Decreased function of lymphocytes & neutrophils – glycosylation. Glycosylation of immune mediators. Ab Capillary thickening – impaired inflammation. Ischemia & infarctions. Increased glucose (alone is not the cause * ) Diabetes  State of immunosuppression.

Laboratory Diagnosis: Urine glucose - dip-stick –Screening Random or fasting blood glucose (<11) Fasting > 7mmol, Random >11mmol If Fasting level is between 7-11 then OGTT HbA1c - for follow-up, not for diagnosis Fructosamine - for long term maintenance.

“ It's not that I'm so smart, it's just that I stay with problems longer”…! --Albert Einstein

CPC-3.2– END–DM2 Pathology – Major Core Learning Issues: Pathology of Diabetes Overview & Classification. Pathological basis of clinical features. Details of Type 1 & 2 (Etiology, pathogenesis, morphology, clinical features) Complications of Diabetes: Micro & Macroangiopathy. Retinopathy, nephropathy, neuropathy, dermatopathy.. etc.. & Metabolic complications (ketoacidosis, coma etc) Laboratory diagnosis of diabetes. (GTT, HBA1c, etc) Pathology – Minor CLI: Metabolic Syndrome (Syndrome X). MODY, LADA, Gestational, childhood type 2, Secondary diabetes, Bronze diabetes. Hyperglycemia Syndromes: Cushings, drugs, etc. Hypoglycemia syndromes, Insulinoma. New research & developments

Case 1 A 29y woman BMI = 33 kg/m2. complains of declining visual acuity since 6 months. Fundoscopic examination shows peripheral retinal microaneurysms. Urinalysis reveals 3+ proteinuria and 3+ glucosuria. Serum albumin is low & cholesterol is high. These clinicopathologic findings are best explained by which of the following pathologic mechanisms of disease

Pathologic mechanism? Anti-insulin antibodies. Increased insulin uptake. Irregular insulin secretion. Peripheral insulin resistance. Serum Anti GAD-67 antibodies.

50y, male DM2, kidney biopsy. Likely nature of feature shown by arrow? Amyloid protein. AGE protein Basement mem protein. Fibrinoid necrosis. Inflammatory cells.

47y F, DM2 - foot ulcer: ? Diagnosis Fungal infection Neuropathic ulcer Venous ulcer Arterial ulcer Atypical TB in AIDS

Thickening of small BV in this patient is most likely related which pathologic mechansim? Glycosylation of hemoglobin. Inadequate inflammtion resp. Insulin resistance in tissues. Increased Atherosclersis. Microvascular disease.

57y M, DM2: Gross Kidney- arrow ? feature Benign nephrosclerosis. Glomerulonephritis Papillary necrosis Nodular glomerulosclerosis Renal artery Atherosclerosis

DM– Pancreatic Islet- ? Feature shown by arrow? Β cell exhaution . Amyloid deposits Lymphocytic Insulitis Pancreatic acinus Chronic Pancreatitis

47y F, DM2 – Kidney- arrow ? feature Nodular glomerulosclerosis. Artereolosclerosis Atherosclerosis AGE deposition Diffuse glomerulosclerosis

DM Kidney.Microscopy. ? Feature Arrow B Nodular sclerosis Artereolosclerosis Diffuse sclerosis Pyelonephritis Abscess formation B A

DM Kidney.Microscopy. ? Feature Arrow A Nodular sclerosis Artereolosclerosis Diffuse sclerosis Pyelonephritis Abscess formation B A

57y M, DM2 – Kidney- arrow ? feature Dot hemorrhage Hard exudate Soft cotton wool exudate Neovascularization Micro Aneurysm

57y M, DM2 – Eye ? Pathogenesis AGE deposition Glycosylation Collagen deposition Osmotic Polyol damage Artereolosclerosis

56y Fem, Anterior wall MI. 3+ proteinuria & FBG 19mmol/L. Image shows her pancreas. What complication she may develop? Gall stones. Chronic pancreatitis. Uric acid stones. Gangrene of foot. Pancreatic carcinoma

Label the diagram. 1. 2. 3. 4. Capillary Nodule – AGE Bowman cap. Hyaline arteriolo sclerosis in arteriole.

It is a matter of great satisfaction if you are educated on the right lines, become an example to others and accept positions of responsibility. In all these things, always keep “ Truth & Love for all ” as your goal. Then only you will get the Grace of God….! - Sai - Summer Showers, 1973.

Case 2 – 58y Fem Asymptomatic. She has a BMI of 29 and is on enalapril for hypertension. She has no symptoms of diabetes. A fasting glucose is 6.5mmol/L. Mother had DM type2. Should she be tested for DM? Indications? Yes. (IGTT, IFG, Aboriginals, High risk immig, Obese fem+, cardiac event, >45y+ BMI>30, FH of DM2 or HPTN). Diagnosis? next investigation for this patient? IFG, oGTT (FG 5.5-7, RG 7-11 mmol/L) How do you manage a IGT patient? Advice about Diet & excercise.

CPC-3.2– KFP Questions: DM – Definition, epidemiology Type I,II, NIDDM, IDDM, GDM, MODY. Etiology, Risk factors Pathogenesis of Clinical features – PPP Complications Acute – metabolic – ketoacidosis, coma Chronic – vascular – Micro/Macro Glycosylation, AGE, Polyols Lab Diagnosis – FBS, GTT, KFT, Lipids.

Summary Abnormal metabolic state characterised by glucose intolerance due to inadequate insulin action. Type I (juvenile onset) Autoimmune destruction of β-cells (Genetic + ? Virus + Autoimmunity); insulin-dependent – Treat by Insulin. Type II (maturity onset) - defective insulin action – peripheral resistance to insulin. treatment by life style change & oral hypoglycaemic agents. Complications: accelerated atherosclerosis, susceptibility to infections, and microangiopathy (retinopathy, neuropathy, dermatopathy, nephrophathy)

Points to remember/review: Diabetes is a state of hyper ketabolism. Increased fat & protein breakdown, wt loss. Blood vessel damage – arteriosclerosis is central to chronic complications. Increased Infections – why?. Glucose control is critical * why? Hypoglycemia is more dangerous. Not hyper FBS, GTT & HbA1C – interpretation.

Questions.. How – Ketoacidosis? How – hypoglycemia ? Macro Angiopathy ? – (atherosclerosis) Micro Angiopathy “Pathy” (arteriolosclerosis) Retinopathy – types, morphology, Nephropathy – types, morphology. Dermatopathy – morphology. Diabetic Amyotrophy - What is Diabetes insipidus ?

56y woman, nocturia 56y Fem, 3/12 nocturia excessive thirst and polyuria(1-4 times) disturbing her sleep. Recently noticed blurring of vision, & tingling sensation in her toes on both sides. Weight 94kg & height 1.71m. BMI 32. Hypertensive for several years. Mother diabetic type2. Glucometer capillary BS is 15mmol/L. What further Investigations? Ans: Twice..Lab RBS/FBS, GTT. Why not HbA1c for diagnosis? 60% of new diabetics have normal HbA1c. What other investigations should be done? Retina, urine, Lipid profile, Cardiac exam.

Site of action of Anti DM drugs:

Metabolic (short term) complications:

Diagnostic criteria for DM, IFG, and IGT

DECODE: increased 2-hour glucose is associated with increased mortality rate (adjusted for age, center, and gender).

Cumulative incidence of diabetes mellitus (based on American Diabetes Association criteria) according to study group in the DPP. * The incidence of diabetes differed significantly among the 3 groups (p <0.001 for each comparison. Reprinted with permission from Knowler et al. 13

Endocrinology Other : (Brief notes) Tumours – adenomas of endocrine gl. Cushings disease. Pheochromocytoma. Zollinger Ellison syndrome. MEN Syndromes – MEN type 1 & 2.

Diabetic Retinopathy Neovascularization Cotton wool spots

Diabetic Retinopathy Cotton wool Dot hem Blot hem Neovascul. Cotton wool

Diabetic Retinopathy Advanced fibrous plaques

Diabetic Retinopathy - Proliferative

MODY: Maturity Onset DM of Youth.

Pathology of Diabetes

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