Pathology of Diabetes

"Never offer the devil a ride. He will always want to be in the driving seat…!" BK. Pathology of Diabetes Dr. Venkatesh M. Shashidhar Associate Professor of Pathology Fiji School of Medicine Diabetes Mellitus    Disorder of metabolism (Carb, Prot & Fat) Due to Absolute/relative deficiency of insulin. Characterized by hyperglycemia. Clinically : Polyuria, Polydypsia, Polyphagia.  Introduction       Diabetes mellitus (sweet urine) 3% of world population, 100 million people Incidence is increasing alarmingly (40% in the past decade, more in future. 259 m by 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…! World Statistics: Normal Pancreatic Islet: ß α ß cells (Insulin) α cells (Glucagon) δ cells (Somatostatin) pp Cells (pan prot) Insulin - Anabolic Steroid        Transmembrane transport of glucose Liver, muscle & fat   blood glucose Liver & skeletal muscle -  glycogen Converts glucose to triglycerides Nucleic acid & Protein synthesis Diabetes  Increased catabolism. Hyperglycemia,  protein synthesis, Liplysis, wasting, weight loss. Blood Glucose & Hormones Hormone Action  Insulin   Glucose  Glucortocoids   Glucose  Glucagon   Glucose  Growth Hormone   Glucose  Epinephrine   Glucose Cellular Glucose Uptake Insulin Requiring  Striated Muscle  Cardiac Muscle  Fibroblasts  FAT Non-Insulin Requiring  Blood Vessels  Nerves  Kidney  Eye Lens Pathology in Diabetes:  Low glucose inside cell  decreased cell metabolism (muscle, liver)  High glucose outside  Glycosylation damage (BV)  Polyol products – osmotic damage* Classification  Primary DM – (primary - no other disease)     Type I – IDDM / Juvenile – 10%. Type II – NIDDM /Adult onset – 80%. MODY – 5% maturity onset - Genetic Gestational Diabetes Pancreatitis/tumors/Hemochromatosis. Infectious – congenital rubella, CMV. Endocrinopathy, downs. Drugs – Corticosteroids.  Secondary DM – (secondary to other dis.)     Pathogenesis of Type I DM Genetic HLA-DR3/4 • • • • • Environment Viral infe..? Autoimmune Insulitis PS Glomerulonephritis Ab to ß cells/insulin Graves, Hashimoto thyroiditis. Rheumatic heart disease SLE, Collagen vascular disease Rheumatoid arthritis. ß cell Destruction Type I / IDDM Insulin deficiency Progression of Type I Pathogenesis of Type II DM Genetic / ß cell defect Obesity / Life style ? Abnor. Secretion Insulin Resistance IDDM ß cell exhaustion Relative Insulin Def. Type II NIDDM “Things may come to those who wait, but only the things left by those who hustle.” – Abraham Lincoln What type? 1. 2. 3. 4. 5. 6. 56 year male obese 30 year female following pregnancy 8 year old boy. 24 year female with Cushing’s sy 68 Year male following Carcinoma of pancreas. 34 year male with extensive tuberculosis. II NIDDM II GDM I IDDM Sec IDDM Sec IDDM Sec IDDM Type-I         Type-II     Less common Children < 25 Years Insulin- Dependent Duration: Weeks Acute Metabolic complications Autoantibody: Yes Family History: No Insulin levels: very low Islets: Insulitis 50% in twins         More common Adult >25 Years Insulin Independent * Months to years Chronic Vascular complications. No Yes Normal or high * Normal / Exhaustion 60-80% in twins Insulitis – Type I Insulinitis Islets in Type II Diabetes: Loss of ß cells, replaced by Amyloid deposits (hyalinization) Islets in Type II Diabetes: Loss of ß cells, replaced by Amyloid deposits (hyalinization) 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. 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     Glucose Glycosylation BM damage leak ‘AGE’ deposition Diabetic Neuropathy   Sensory  Motor (myelin) Peripheral Neuropathy    Bilateral, symmetric Progressive, irreversible Paraesthesia, pain, muscle atrophy Cranial nerve – diplopia, Bell palsy GIT- constipation, diarrhoea CVS – orthostatic hypotension  Visceral neuropathy    Neuropathy Myelin loss in nerve Chronic Polyneuropathy Claw foot – Dermopathy & Neuropathy Diabetic Amyotrophy Painful muscle wasting Diabetic Neuropathic ulcer 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 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 Hyaline nodules Diabetic Glomerulosclerosis Normal Retina Non Proliferative Retinopathy     Venous dilation and small red dots posterior retinal pole - capillary micro-aneurysms. Dot and blot retinal hemorrhages and deep-lying edema and lipid exudates impair macular function. Late generalized diminution of vision due to ischemia and macular edema - common cause of visual defect (best detected by fluorescein angiography) 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. Proliferative Retinopathy       Neovascularization - which grows into the vitreous cavity. In advanced disease, neovascular membranes can occur, resulting in a traction retinal detachment. Vitreous hemorrhages may result. sudden severe loss of vision can occur when there is intravitreal hemorrhage. Poor visual prognosis if severe retinal ischemia, extensive neovascularization, or extensive fibrous tissue formation. Panretinal photocoagulation may diminish or eliminate proliferative retinopathy Retinopathy  Non Proliferative      Microaneurysms, Dot blot hemorrhages Hard and soft exudates Cotton wool – infarcts Macular edema. Neovascularization Large hemorrhages Retinal detachment.  Proliferative.    Diabetic Retinopathy Neovascularization Cotton wool spots Diabetic Retinopathy Dot blot – Hemorrhages (Microaneurysms) Diabetic Retinopathy Pre retinal Hemorrhage - detachment Diabetic Retinopathy Advanced fibrous plaques “The past cannot be changed, but the future can.. by actions in the present time.” --BK Past is history, Future is mystery Present is the gift…! Label the diagram. 1. Hard dep. 2. Optic disc 3. Macula 4. Blot hem 5. Cotton wool Macroangiopathy Atherosclerosis     Dyslipidemia  HDL Non-Enzymatic Glycosylation  Platelet Adhesiveness      Thromboxane A2  Prostacyclin Endothelial damage  Atherosclerosis MI, CVA, Gangrene of Leg (PVD), Renal Insufficiency Atherosclerosis: Slide Show Diabetic Gangrene Fungal infections: Candidiasis Macrosomia With Polycythemia Blood vessel calcification: Amputated thumb Cataract Acanthosis Nigricans Insulin resistance… Acanthosis Nigricans Insulin resistance… Label the diagram. 1. Capillary 2. Nodule – AGE 3. Bowman caps 4. Hyaline arteriolo sclerosis in arteriole. Infections in Diabetes:       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.   Points to remember:    Disorder of metabolism – Insulin Type-I Children, Acute, Metabolic compl. Type-II Adults, Chronic, Vascular compl.  Angiopathy (micro/macro),  Heart, Brain, Kidney, Retina, Skin, BV.     Increased Infections – know reasons. Hypoglycemia is more dangerous. Not hyper Glucose control is critical * FBS, GTT & HbA1C. Questions..         How – Ketoacidosis? How – hypoglycemia ? Angiopathy – Macro & Micro ? Infections in Types of retinopathy ? Diabetes insipidus ? Nephrotic / Nephritic syndrome ? Kidney damage in Diabetes ? The best gift of Nature to man is the briefness of his life…! Latin quote “It's not that I'm so smart, it's just that I stay with problems longer” --Albert Einstein