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Pathology of Diabetes
 

Pathology of Diabetes

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Medical school lecture for preclinical students. Updated Jul 2013.

Medical school lecture for preclinical students. Updated Jul 2013.

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    Pathology of Diabetes Pathology of Diabetes Presentation Transcript

    • Strength, it is that we want so much in this life, for what we call sin & sorrow have all one cause, and that is our weakness. With weakness comes ignorance, and with ignorance comes misery. - - Swamy Vivekananda
    • CPC 3.2: Ms. ML, 18y, Thrush.  Recurrent thrush*, boils*, tired*, (months)  Obese*, junk food, no exercise*,  polyuria, polydipsia* , Abd. Striae*,  Mom, Granny DM2*, smoker 30/d, social drinker,  Dipstick: Nitrate +, WCC 3+, Blood 2+, Prot. 2+, Glucose 2+  MSU: Ecoli >108, swab: Candida 4+, RBGL 35. • ? Key points: • ? DD: Thrush, UTI, PID, Preg, DM 1, 2, 1.5, MODY, LADA* • ? Next step:
    • ? Pathogenesis of DM “recurrent infections” 1 2 3 4 5 0% 0% 0%0%0% 1. Associated AIDS 2. Hyperglycemia 3. Cell starvation. 4. Blood Vessel damage. 5. All of the above.
    • Features supporting diagnosis of DM2 ? 1. On & off for long time. 2. Always drinking. 3. Obesity. 4. Recurrent boils. 5. Mom has DM2 1 2 3 4 5 0% 0% 0%0%0%
    • Significance of Nitrite in Urine? 1. Ketone bodies. 2. Gram -ve bacteria 3. Lymphocytes 4. Neutrophils 5. Gram +ve bacteria. 1 2 3 4 5 0% 0% 0%0%0%
    • Etiology of Thrush ? 1. Proteinuria 2. Bacterial infection 3. Glycosuria 4. Trichomoniasis 5. Candidiasis 1 2 3 4 5 0% 0% 0%0%0%
    • II NIDDM II GDM I IDDM Sec IDDM Sec IDDM I LADA Sec IDDM I IDDM LADA MODY Most likely .. What type of DM ? 1. 56 year male obese 2. 30 year female following pregnancy 3. 8 year old boy, poor growth, DKA. 4. 24 year female Cushing‟s sy 5. 68 Year male following Ca. pancreas. 6. 32 male, DM, BMI 18, Anti-GAD +ve. 7. 34 year male, extensive tuberculosis. 8. 12 year old female following viral fever 9. 41y DM2, BMI 17.1, HbA1c 14.1, DKA 10.15y male, BMI 16.2, recurrent infect.
    • DM Questions  Definition? types common? Diagnosis?  Primary & Sec? Congenital? Gestational?  Monogenic? MODY, LADA, drugs?  List functions of Insulin? Antagonists?  Etiology & Pathogenesis of Type 1 & 2.  Stages of DM & their pathological basis?  Obesity & Insulin resistance * • FFAs, PKC, Adipkines, PPARγ • Inflammation & Insulin resistance.  Mechanism of β cell destruction type 1, 2.  Islet Amyloid PolyPeptide (IAPP)?
    • DM Questions  MODY & LADA – pathogenesis, subtypes.  Pathogenesis of Complications: • Mechanism: AGEs, Activate of PKC, & Polyols. • Infections – common & pathogenesis. • Foot ulcer, Retinopathy (prol & non-prol), • Neuropathy? Central, peripheral, autonomic… • Difference Angiopathy Micro & Macro? MI, Stroke. • Diabetic Nephropathy – albuminuria, KW lesion, Papillary Necrosis, Pyelonephritis, CRF. • Hypertension, Cataract,  Metabolic: Diabetic Coma, DKA, HONK **
    • CPC32-Diabetes:  Pathology Major CLI: • Diabetes Overview & Classification. • Complications Micro & Macroangiopathy. Retinopathy, nephropathy, neuropathy, dermatopathy. • Metabolic complications (ketoacidosis etc) • Laboratory diagnosis of diabetes. (GTT, HBA1c, etc)  Pathology Minor CLI: • Metabolic Syndrome (Syndrome X). • Hypoglycemia syndromes, Insulinoma, (glucoganoma) • MODY, LADA, type 1.5, Gestational & Secondary DM. • Bronze Diabetes.
    • “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
    • 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 for "siphon” “Sweet” • 1788 – Cawley – damaged pancreas in DM. • 1921 – Banting & Best, Insulin unite for diabetes world diabetes day 14 November
    • Introduction  Most Common non communicable disease (3%)  Incidence increasing alarmingly (259m 2025)  Asia Pacific – maximum Increasing incidence.  High Morbidity & mortality.  Shortens life (15y) – HTPN, MI, Stroke, CRF.  7th top cause of death, 50% unaware (Au)
    • World Statistics:
    • Diabetes Mellitus - Definition  2nd 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.  Polyuria, Polydypsia, Polyphagia.
    • Criteria for the Diagnosis of Diabetes 1. Random blood glucose - 11.1mmol/L or high, 2. Fasting glucose - 7mmol/L or high 3. HbA1C of > 6.5% • On more than one occasion + classical signs & symp. 4. OGTT for borderline cases (5.5 - 6.9 mmol/L), >11mmol/L at 2 hours after a 75 gm of oral glucose.  Why Oral GTT - not IV..? *  What is normal blood glucose..? <7..?  Why glucose needs tight control..?
    • Pancreas Normal Anatomy:
    • Normal Pancreas:
    • Normal Pancreas: Islet of Langerhans (Endocrine Pancreas) Pancreatic acini (Exocrine Pancreas)
    • Normal Pancreatic Islet: (ipx stain) α cells 20% (Glucagon) ß cells 70% (Insulin) ßα Other Cells in Islets: δ cells - Somatostatin PP Cells - pancreatic polypeptide D1 cells – Vasoactive Intestinal Polypeptide Enterochromaffin – Seratonin.
    • Blood Glucose & Hormones Hormones  Insulin  Glucortocoids  Glucagon  Growth Hormone  Epinephrine Action  Glucose  Glucose  Glucose  Glucose  Glucose Maintained within 3.5-5.5 mmol/l.
    • Insulin secretion:
    • Insulin Anabolic Steroid GLUT4 * only these tissue….!
    • Insulin - Anabolic Steroid  Transmembrane transport of glucose (Liver, muscle & adipose tissue. Maintain metabolism: • Striated Muscle glucose uptake • Adipose tissue lipogenesis • Hepatic gluconeogenesis.  Protein & triglyceride synthesis  Nucleic acid & Protein synthesis  In DM Insulin  glucose & catabolism (glycolysis, lipolysis, proteolysis)
    • Obesity & Diabetes: Relationship  Excess free fatty acids (FFAs): Increased FFAs increase insulin resistance.  Inflammation: FFAs result in release from macrophages and β cells of IL-1β – Pro-Infl.  Adipokines: Adipocytes release pro inflammatory cytokines in response to increased FFAs. (Also release adipnectins – anti inflammatory)  Peroxisome proliferatory-activated receptor-γ (PPARγ): activation of PPARγ improves insulin sensitivity. (thiazolidinediones - antidiabetics Pioglitazone).
    • Obesity & Insulin resistance. Diabetes is a state of inflammation
    • 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%
    • New in DM Pathogenesis: Incretins.  Insulin release through Incretins (from intestine) in response to glucose intake. • Glucagon-Like Peptide-1 (GLP-1) • Glucose-dependent Insulinotropic Polypeptide (GIP)  Stimulate β cells (Insulin) & Inhibit α (glucagon)  Destroyed by dipeptidyl peptidase (DPP).  Dysregulation in DM2 (early breakdown).  Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [DPP 4 inhibitor] – Approved for PBS.  http://www.medscape.com/infosite/dia/article-3
    • GIP : glucose-dependent insulinotropic polypeptide (GIP) GLP-1: glucagon-like peptide-1 (GLP-1) DPP 4: enzyme dipeptidyl peptidase-4 (DPP-4) – breaks down GIP & GLP-1
    • Insulin Resistance: JCU Research…!
    • The foundation of lasting self- confidence and self esteem is excellence, mastery of your work. - Brian Tracy
    • Diabetes Classification: (not a single disease) • Type I – IDDM / Juvenile – 5-10%. • Type II – NIDDM /Adult onset – 90-95%. • MODY – 5% Maturity Onset Diabetes of Youth □ Genetic, sub types MODY 1–6 (3 & 2 common), • LADA – Latent Autoimmune Diabetes in Adults (LADA) • Gestational Diabetes Mellitus. • Other. (neonatal diabetes, – Insulin gene defects) Endocrinopathy, Downs Sy. • Excess hyperglycemic stimulus (drugs & disease). □ Cushings, Phaeochromocytoma, acromegaly, Steroid therapy. • Beta cell destruction: □ Pancreatitis/tumors/Hemochromatosis – Bronze diabetes. □ Infectious – congenital rubella, CMV, TB,
    • MODY: Maturity Onset Diabetes of Young.  5% of DM in Young*, non obese, insulin release defect*  Like DM2, non-ketotic hyperglycemia, no DM Antibodies.  Auto. Dom. - Monogenic – Genetic testing*.  Treatment is specific to type. Unlike type 1 or 2  Subtypes: 1,2,3,4,5,6 – type 3 & 2 common.  1,3,4,5,6 – Insulin transcription defect  HNF.  Type 2 – Enzyme glucokinase, defective β cell response. Type 2 in children
    • LADA: Late onset Autoimmune DM  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.  Features & complications of both type 1 & 2. Type 1 in Adults
    • One machine can do the work of fifty ordinary men. No machine can do the work of one extraordinary man. - - Elbert Hubbard
    • Pathogenesis of Type I DM Genetic HLA-DR3/4 Environment Viral infe..? Insulin deficiency Autoimmune Insulitis Ab to ß cells/insulin ß cell Destruction Secondary DM Inflammation, Tumor, Infection Trauma Pancreatitis Antibodies: Islet cell Ab - ICA Insulin Auto Ab - IAA Glut. Acid Decarb - GAD65
    • Type-1 clinical course
    • Type II Pathogenesis Relative Insulin Def. β cell dysfunction ? Β cell ExhaustionIDDM
    • Progression of Type II Years ..
    • 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 (only in late stage…!)
    • Being a good 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 like burning coal*  Glucose is highly reactive - damages proteins, cells & tissues.  Insulin - safely uses & stores glucose. – mom..!*  Diabetes is state of insulin deficiency.  Hyperglycemia  PPP  Tissue damage  Complications.  Clinical symptoms & signs are mainly due to complications.  Acute: metabolic - DKA / HONK.  Chronic: BV - Kidney, CNS & immune system.
    • Diabetes Complications:  Short term Complications: (metabolic) • Hypoglycemia • Diabetic Ketoacidosis DKA • Hyper Osmolar Non Ketotic coma HONK  Long term Complications: (Angiopathy) • Microngiopathy - Retinopathy, Nephropathy, Neurophathy, der matopathy. • Macroangiopathy – Atherosclerosis.
    • Pathogenesis of complications:  Insulin dependant tissue: Striated muscle, adipose tissue & Liver. • Low glucose inside cell decreased cell metabolism. Starvation. • High glucose outside Glycosylation damage (AGE), cross linking, trap plasma proteins, LDL, cholesterol* - “diabetic pathy‟s”  Insulin independent tissue: BV, nerve, (kidney, eye, CNS) • Excess glucose □ Sorbitol, Polyol  osmotic damage* □ Activation of Protein Kinase C  Inflam. angiogenesis, fibrosis.
    • DM2: Pathogenesis of complications Insulin Requiring Cells  Striated Muscle  Liver  Adipose Tissue Intra cellular hypoglycemia  Low glucose:  Liver: Gluconeogenesis  Adipose: Lipolysis  FFA Extracellular hyperglycemia:  Acute: DKA, HONK.  Chronic: AGE deposition, glycosylation of cells, matrix, proteins - Vascular & tissue damage, micro & macro angiopathy, ischemia, infarction, …* Non-Insulin Requiring Cells  Blood Vessels  Nerves & Brain  Kidney, Eye Lens  Intracellular Hyperglycemia  Excess glucose:  Glucose  Aldose reductase  Sorbitol (Polyol)  Osmotic cell swelling and dysfunction.  Activation of Protein Kinase C – Inflam. - IL-β
    • The best gift of Nature to man is the briefness of his life…! -- Latin quote
    • DM: Complications:
    • Macroangiopathy:  Atherosclerosis.  Glycosylation of BM
    • DM Microangiopathy – pathogenesis Normal Diabetic  Glucose  Glycosylation  BM damage leak  „AGE‟ deposition PATHOGENESIS OF DM COMPLICATIONS: 1. Chronic Hyperglycemia. 2. Glycosylation of BV B. membrane 3. Leakage of proteins, excess BM matrix. 4. Narrow, thick, fragile, Leaky BV + Inflam. 5. Leakage of LDL, protein, angiogenesis. • Ischemia • Proteinuria (kidney) • Micro Aneurysms (retina) • Atherosclerosis.
    • Neuropathy – glucose neurotoxicity  Glucose  polyol  sorbitol  fructose.  Uses NADPH, increased oxidative damage.  Loss of myelin (Sensory nerves).  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 Normal
    • Neuropathic ulcer Etiology:  peripheral sensory loss  Trauma  ulcer. Features:  Deep punched out.  callus around ulcer.  Intact circulation. no ischemia / gangrene*
    • Nephropathy  Deposition of „AGE‟ within glomerulus as nodules - Nodular Glomerulo Sclerosis (KW) later diffuse sclerosis.  Initial leakage  microalbuminuria  Nephrotic syndrome  macro albuminuria  End stage renal failure.  Atherosclerosis of RA.  Ischemia, infarctions.  Papillary necrosis  Infections – Pyelonephritis, abscess.  Tubular damage – BM thickening.
    • Diabetic Glomerulosclerosis B A A: Nodular glomerulosclerosis. B: Hyaline Arteriolosclerosis.  What is the pathogenesis? Small contracted Irregular, scarred Granular surface Thin cortex.
    • DM Kidney: thickening of BM (PCT) PCT DCT PCT: Proximal Convoluted Tubule, DCT: Distal Convoluted Tubule
    • Nephropathy Progression
    • Nephropathy Classes: I - IV
    • DM kidney: papillary necrosis: Papillary necrosis
    • Retinopathy:  Non Proliferative • Microaneurysms, • Dots & blots • Hard exudates - protein • Soft Cotton wool – infarcts • Macular edema.  Proliferative. • Neovascularization • Large hemorrhages • Retinal detachment.
    • Diabetic Retinopathy • Dots • Blots • Exudates • Infarcts • Neovascularisation • Hemorrhages • Retinal detachment • Fibrosis.
    • 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.
    • infections: Fungal - Candidiasis  Immunosuppression.  Not hyperglycemia ..!  Multifactorial.
    • Pathogenesis of Infections in DM: Multifactorial:  Impaired inflammation – BV thickening.  Decreased metabolism.  WBC & chemical mediator glycosylation.  Glycosylation of immunoglobulins.  Tissue damage: Ischemia & infarctions.  Increased glucose is not the cause*
    • You must learn to distinguish between good and bad, truth and untruth. You must use your education for the purpose of serving community. - Sai Baba
    • Summary  Glucose is burning charcoal - complications.  Glucose – Intestine - Incretins – B cells – tissues.  Type 1 – destruction of B cells  child - fast.  Type 2 – Insulin dysfunction - adult – slow.  Complications: excess glucose.  Acute – DKA, HONK  Chronic – BV & tissue damage. Micro & Macro angiopathy.  Immunosuppression,  Macro angiopathy – Atherosclerosis.  Microangiopathy – Artereolosclerosis.  Pathy.. Retino, Neuro, Dermo, Nephro etc..
    • New Developments:  Incretin pathway  GLP-1 & GIP  DPP-4 inhibitors – gliptins.  Or Incretin mimitics -
    • Always do your best. What you plant now, you will harvest later. - - Og Mandino
    • Macrosomia With Polycythemia
    • Acanthosis Nigricans Insulin resistance…
    • 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.
    • 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
    • Diabetic Xanthoma:  Reddish yellow, pruritic, painful,  High blood glucose & lipids (Lipemic serum)  Subcutaneous fat necrosis, foamy macrophages and free lipids.  Risk of Pancreatitis.  Control of glucose and lipids  resolution.  Erruptive Xanthoma – sudden crop of xanthomas * severe.
    • Complications Summary:
    • "Decision and determination are the engineer and fireman of our train to opportunity and success." -- Burt Lawlor
    • Laboratory Diagnosis:  Urine glucose - dip-stick –Screening  Fasting > 7mmol, Random >11mmol  If Fasting level is 5.5 to 7  OGTT  HbA1c - for follow-up, not for diagnosis  Fructosamine – similar to HbA1c - long term maintenance.  Antibodies – Type-1  Gene testing: MODY
    • 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.
    • 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.
    • Endocrinology Other : (Brief notes)  Tumours – adenomas of endocrine gl.  Cushings disease.  Pheochromocytoma.  Zollinger Ellison syndrome.  MEN Syndromes – MEN type 1 & 2.
    • HHNK  Slower Onset  Glucose 600-2000  No Acidosis  Normal Breath  Shallow Respirations DKA vs HHNK DKA  Faster Onset  Glucose 300-800  Acidosis  Fruity Breath  Kussmaul Respirations