Pathology of Diabetes

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

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

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

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

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

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

7. ?Pathogenesis: “ recurrent multisite infections” <ul><li>Associated AIDS </li></ul><ul><li>Hyperglycemia </li></ul><ul><li>Ischemia </li></ul><ul><li>Immunodeficiency </li></ul><ul><li>Multifactorial </li></ul> ?Pathogenesis: “ recurrent multisite infections” <ul><li>Associated AIDS </li></ul><ul><li>Hyperglycemia </li></ul><ul><li>Ischemia </li></ul><ul><li>Immunodeficiency </li></ul><ul><li>Multifactorial </li></ul>

8. Miss ML: Most likely diagnosis: <ul><li>DM Type 1 </li></ul><ul><li>DM Type 2 </li></ul><ul><li>MODY 1 </li></ul><ul><li>MODY 2 </li></ul><ul><li>Gestational DM </li></ul> Miss ML: Most likely diagnosis: <ul><li>DM Type 1 </li></ul><ul><li>DM Type 2 </li></ul><ul><li>MODY 1 </li></ul><ul><li>MODY 2 </li></ul><ul><li>Gestational DM </li></ul>

9. ?Pathogenesis: Whitish vaginal discharge. <ul><li>Proteinuria </li></ul><ul><li>Bacterial infection </li></ul><ul><li>Glycosuria </li></ul><ul><li>Trichomoniasis </li></ul><ul><li>Candidiasis </li></ul> ?Pathogenesis: Whitish vaginal discharge. <ul><li>Proteinuria </li></ul><ul><li>Bacterial infection </li></ul><ul><li>Glycosuria </li></ul><ul><li>Trichomoniasis </li></ul><ul><li>Candidiasis </li></ul>

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

11. . 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

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

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

14. . <ul><li>What is Diabetes? </li></ul><ul><li>“… .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…” </li></ul><ul><li>-- Aretaeus of Cappadocia (AD 81-3) </li></ul><ul><li>150 AD – Aretaeus, named &quot;diabetes“ Greek word for &quot;siphon” </li></ul><ul><li>1788 – Cawley – damaged pancreas in DM. </li></ul><ul><li>1921 – Banting & Best, Insulin </li></ul>

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

16. . World Statistics:

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

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

19. . Pancreas Normal Anatomy:

20. . Normal Pancreas:

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

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

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

24. . Normal Insulin secretion:

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

26. . Insulin Functions:

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

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

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

30. . LADA: Late onset Autoimmune DM <ul><li>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. </li></ul><ul><li>Incidence: - 6-10% (UK). </li></ul><ul><li>Diagnosis: Elevated pancreatic autoantibodies </li></ul><ul><li>Risk factors: Metabolic Syndrome </li></ul><ul><li>LADA + Metabolic syndrome = DM Type 1.5. </li></ul><ul><li>Complications of both type 1 & 2. (metabolic, Macro & Microangiopathy etc). </li></ul>

31. . 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.

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

33. . Insulitis – Type I Lymphocytes.

34. . DM1 Course:

35. . Progression of Type II Years ..

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

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

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

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

40. . Diagnosis: (WHO)

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

42. . 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.

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

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

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

46. 47. DM: Complications:

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

48. 49. Microangiopathy Pathogenesis: <ul><li>Hyperglycemia chronic. </li></ul><ul><li>Glycosylation of basement membrane proteins  Leaky blood vessels. </li></ul><ul><li>Excess deposition of proteins – glycosylation cycle. </li></ul><ul><li>Thick and Leaky blood vessels. </li></ul><ul><li>Narrow lumen </li></ul><ul><li>Ischemic Organ damage... </li></ul>

49. 50. Diabetic Microangiopathy Normal Diabetic <ul><li>Glucose </li></ul><ul><li>Glycosylation </li></ul><ul><li>BM damage leak </li></ul><ul><li>‘ AGE’ deposition </li></ul>

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