YR1 Lecture 1H - Pathological Effects of Diabetes - Dr Heok P'ng - 2022 PDF

The Pathological Effects of Diabetes Dr Chow Heok P’ng ICPMR, Westmead Hospital Western Sydney University Overview Diabetes in Australia Definition and criteria Pancreas – anatomy and function Glucose homeostasis Classification Pathogenesis of diabetic complications Long-term pathological complicati...

The Pathological Effects of Diabetes Dr Chow Heok P’ng ICPMR, Westmead Hospital Western Sydney University Overview Diabetes in Australia Definition and criteria Pancreas – anatomy and function Glucose homeostasis Classification Pathogenesis of diabetic complications Long-term pathological complications Concluding remarks Diabetes in Australia 280 Australians develop diabetes every day. That’s one person every five minutes. Diabetes is Australia’s fastest growing chronic disease ie. >120000 Australians have developed diabetes in the past year. Nearly 1.8 million Australians have diabetes. This includes all types of diagnosed diabetes (1.4 million known and registered) as well as silent undiagnosed type 2 diabetes (up to 500,000 estimated). 3.3 million Australians estimated to have diabetes by 2031. Diabetes in Australia 6th leading cause of death in Australia >$10 billion financial cost to the community Indigenous population – More than 3X as likely as non-indigenous population to have diabetes – Prevalence 12% in 2004-2005 (likely higher due to undiagnosed disease) – 55-64 year olds : proportion to diabetes deaths is 4x greater than non-indigenous individuals Definition Group of metabolic disorders with impaired glucose utilization Characterized by hyperglycaemia Depending on the aetiology of DM, factors contributing to hyperglycaemia may include reduced insulin secretion, decreased glucose usage, and increased glucose production Criteria for the Diagnosis of DM Symptoms of diabetes plus random blood glucose concerntration ≥ 11.1mmol/L (200mg/dL) or Fasting plasma glucose ≥ 7.0mmol/L (126mg/dL) or Two-hour plasma glucose ≥ 11.1mmol/L (200mg/dL) during an oral glucose tolerance test (after ingestion of 75g oral glucose load) FPG < 6.1 mmol/L (110mg/dL) is considered normal Impaired glucose tolerance = FPG < 7.0mmol/l and 2 hour plasma glucose ≥ 7.8 (140mg/dl) and < 11.1mmol/l Impaired fasting glucose = FPG ≥ 6.1 mmol/L (110mg/dL) and < 7.0mmol/L (126 mg/dL) and 2 hour plasma glucose 30) and up to 80% of patients are obese No evidence of A.I. or HLA linkage Deficiency of insulin is mild relative to that of type 1 DM Characterised by 3 pathophysiologic abnormalities : impaired secretion of insulin, peripheral insulin resistance and excessive hepatic glucose production Secondary diabetes Hyperglycaemia is associated with identifiable causes of islet destruction or insulin dysfunction Genetic defects of B cell function or insulin processing/insulin action Diseases of the exocrine pancreas (pancreatitis, haemochromatosis, cystic fibrosis) Endocrinopathies causing insulin resistance (acromegaly, Cushing’s syndrome, islet cell tumours) Drug or chemical induced (steroids, Infections (CMV, rubella) Genetic syndromes (Down’s syndrome, Turner’s syndrome) Gestational diabetes Mechanisms of complications Non-enzymatic glycosylation of proteins leading to advanced glycosylation end products (AGEs) Intracellular hyperglycaemia with disturbances in polyol pathways Activation of protein kinase C Nonenzymatic glycosylation Nonenzymatic glycosylation results from the interaction of glucose with amino groups on proteins leading to AGEs Reversible for days to weeks eg. Glycosylated hemoglobin (HbA1c) After weeks, irreversible advanced glyosylation end products (AGEs) accumulate over lifetime of blood vessels Nonenzymatic glycosylation AGEs shown to cross-link proteins (eg. collagen, extracellular matrix proteins), accelerate atherosclerosis (trapping nonglycated proteins eg. LDL, albumin), induce endothelial dysfunction (induction of procoagulant activity & increased vascular permeability), reduce proteolysis and alter extracellular matrix composition and structure Intracellular hyperlycaemia with distubances in polyol pathways Some tissues (nerve, lens, kidney, blood vessels) that don’t require insulin for glucose transport developed increased intracellular glucose which is metabolized to sorbitol and then fructose. This increased osmotic load leading to influx of H2O and osmotic cell injury Increased sorbitol affects cellular physiology (decreased myoinositol, altered redox potential) and may lead to cellular dysfunction Activation of protein kinase C Intracellular glucose increases formation of diacyglycerol leading to activation of certain isoforms of protein kinase C (PKC) which affects cellular events leading to DM complications – ↑ vascular endothelial growth factor (VEGF) leading to neovascularisation eg. in retina – ↑ TGF-B stimulating basement membrane production of collagen and fibronectin by mesangial cells leading to increased deposition of ECM and BM material – Alter gene transcriptions for fibronectin, type IV collagen, ECM proteins – Altering enzyme function Long term complications Multiple organs affected Vascular complications Non-vascular complications – Gastroparesis, sexual dysfunction and skin changes Diabetes : Late complications Morphological changes in the pancreas Variable : Reduction in size of the pancreas and number of islets (especially type 1 DM) Beta cell degranulation and fibrosis of islets Amyloid deposition in the islets and leukocytic infiltration, especially insulitis (lymphocytic infiltrate within and about islets Insulitis Amyloid Vascular complications Vascular complications further divided into Macrovascular complications – Atherosclerosis increasing risk of coronary artery disease, peripheral vascular disease, cerebrovascular disease & renal insufficiency – Hyaline arteriosclerosis associated with hypertension is more prevalent and severe in diabetics Microvascular complications – Retinopathy – Neuropathy – Nephropathy – Peripheral vascular disease Atherosclerosis Atherosclerosis Fatty streak Fibrofatty plaque Complicated plaque Atherosclerosis Trichome stain Atherosclerotic plaque with thrombosis and rupture Coronary artery disease Coronary artery disease 4 day old infarct Histology – coagulative necrosis with neutrophilic infiltrate Coronary artery disease Post myocardial infarct rupture of left ventricular free wall Histology Cerebrovascular disease Peripheral vascular disease Diabetic microangiopathy Diffuse thickening of basement membrane of small arteries and capillaries occurs in all patients and is related to hyperglycaemia and AGEs Most evident in capillaries of the skin, skeletal muscle, retina, renal glomeruli and renal medulla Affects nonvascular structures, such as renal tubules, peripheral nerves and placenta Capillaries are more leaky than normal to plasma proteins Diabetic ocular complications Diabetic retinopathy classified into 2 stages – Non proliferative retinopathy Intraretinal and preretinal haemorrhages Exudates Cotton wool spots Edema Thickening of retinal capillaries Microaneurysms – Proliferative Process of neovascularization leading to vitreous hemorrhage and fibrosis of the retina leading to retinal detachment Other complications – cataracts, glaucoma, decreased visual acuity & blindness Pathophysiology of diabetic retinopathy Small blood vessels in eyes vulnerable to poor blood glucose control Accumulation of glucose and or fructose damages small blood vessels in the retina Result of microvascular retinal changes Hyperglycaemia induced intramural pericyte death and thickening of basement membrane leads to incompetence of the vascular walls – Alteration in blood-retinal barrier – Increased vascular permeability Diabetic retinopathy Pathogenesis of diabetic retinopathy Consequences of chronic leakage Location of lesions in background diabetic retinopathy Signs of background diabetic retinopathy Microaneurysms usually temporal to fovea Hard exudates frequently arranged in clumps or rings Intraretinal dot and blot haemorrhages Retinal oedema seen as thickening on biomicroscopy Preproliferative diabetic retinopathy Signs Cotton-wool spots Venous irregularities Dark blot haemorrhages Intraretinal microvascular abnormalities (IRMA) Treatment - not required but watch for proliferative disease Consequences of retinal ischaemia Proliferative diabetic retinopathy Affects 5-10% of diabetics IDD at increased risk (60% after 30 years) Neovascularization Flat or elevated Severity determined by comparing with area of disc Neovascularization of disc = NVD Neovascularization elsewhere = NVE Diabetic retinopathy Normal vision Vision in diabetic retinopathy Diabetic nephropathy Glomerular changes Vascular changes Interstitial changes Pyelonephritis Papillary necrosis Normal Glomerulus Diabetic glomerulosclerosis Diabetes : Glomerular Pathology Diffuse increase in mesangial matrix (PAS) Diffuse thickening of basement membrane Nodular glomerulosclerosis Capillary loop microaneurysms / mesangiolysis Insudative lesions (fibrin cap, capsular drop) Hyaline arteriolosclerosis – afferent and efferent IF: Linear IgG and albumin along GBM and TBM EM: GBM thickening. Increase in mesangial volume Changes in Types 1 and 2 diabetes similar, though may be more heterogeneous in Type2 Diabetic glomerular changes – Diffuse mesangial sclerosis Diabetic glomerulosclerosis Ultrastructural finding – thickened glomerular basement membrane Ultrstructural finding : mesangial matrix expansion Nodulular glomerulosclerosis – Kimmelstiel Wilson nodules PAS stain Diabetes : Vascular changes Diffuse thickening of vascular basement membrane, with hyaline arteriosclerosis & arteriolar hyalinosis Diabetes : Tubulointerstitial change Thickened tubular basement membrane Protein resorbtion droplets in PCT Ischaemic injury: Interstitial fibrosis and tubular atrophy Vessels - hyaline arteriolosclerosis - large vessel disease and effects (eg atheroembolism) Interstitial inflammation common. Note DD DIABETES: TUBULOINTERSTITIAL CHANGE Diabetic glomerulosclerosis DIABETIC RENAL DISEASE Clinical Pathology Microalbuminuria Progressive proteinuria – becoming less selective with time Nephrotic syndrome Impaired renal function Microscopic haematuria not uncommon Pyelonephritis Pyelonephritis – Autonomic neuropathy leading to bladder dysfunction – Increased frequency of instrumetation – Increased susceptibility to infections Acute pyelonephritis – gross findings Papillary necrosis Pathogenesis – combination of 3 factors – 1. Acute pyelonephritis – 2. Obstruction to urine blow as with a neurogenic bladder in diabetics – 3. Compromised blood supply as with DM NB. Combination of ischaemia and infections. Ischaemia in DM results from microangiopathy and DM are more prone to infections Papillary necrosis Papillary necrosis - histology Low power view Medium power view DIABETIC RENAL DISEASE Clinical Significance Diabetes mellitus is the leading cause of ESKD in Australia Diabetes is the most common cause of kidney disease in Australia Diabetic renal disease develops in approximately 1/3 of people with diabetes > 1 million Australians have diabetes with Type 2 diabetes accounting for 85-90% of cases Kidney Health Australia www.kidney.org.au DIABETIC RENAL DISEASE Pathogenesis 1 Metabolic defects Insulin deficiency / hyperglycaemia – changes in GBM (increase in type IV collagen and fibronectin, and reduction in heparan sulfate) – reduction in charge Non-enzymatic glycosylation of proteins – increase in glycation end-products (AGE’s) which bind to RAGE – induction of VCAM – initiation of endothelial injury DIABETIC RENAL DISEASE Pathogenesis 2 Haemodynamic changes Probably important in disease initiation and progression Hyperfiltration, increase in glomerular capillary pressure, glomerular hypertrophy, increase in glomerular filtration area ? Other possible mediators of injury PDGF, TGF-B – podocyte damage Control of hyperglycaemia is of major importance Diabetic neuropathy Occurs in 50% of individuals with long standing DM Polyneuropathy – Commonly distal symmetric polyneuropathy presenting with distal sensory loss – Loss of myelinated fibres – Thickening of endoneurial arterioles, with hyalinsation Mononeuropathy – Less common than polyneuropathy presenting with pain and motor weakness in distribution of single nerve Autonomic neuropathy – Multiple organs affected (eg. GIT, CVS, genitourinary, metabolic) Diabetic lower extremity complications Cellulitis Deep skin and soft tissue infections, Foot ulcers Osteomyelitis Gangrene Peripheral vascular disease Diabetic foot complications Diabetic lower extremity complications - pathogenesis Neuropathy Sensory neuropathy interferes with normal protective mechanisms resulting in repeated trauma and damage Autonomic neuropathy leads to anhidrosis and drying of the skin in areas of pressure. Fissures develop and allow entry of micro-organisms Motor neuropathy leading to abnormal foot muscle mechanics and structural changes eg. hammer toe, claw toe, prominent metatarsal heads. This leads to altered weight distribution and pressure, causing abnormal pressure points, shoe wear and skin breakdown Diabetic lower extremity complications - pathogenesis High plantar pressures compromises blood supply at the microvascular level, leading to infections Impaired microvascular circulation impairs white cell migration into areas of infection and limits ability of antibiotics to reach the site of infection in an effective concentration Accelerated atherosclerosis leads to peripheral vascular disease Miscellaneous diabetic complicatons Liver disease Skin – Necrobiosis lipodica diabeticorum (NLD), atrophy of skin (secondary to steroid injection), granuloma annulare Breast – diabetic mastopathy Infections Liver disease Fatty liver disease – Steatosis – Steatohepatitis Cirrhosis Fatty liver disease Steatosis Steatohepatitis Cirrhosis Gross Histology Overview of late complications of diabetes Possible exam questions Write short notes on the late complications of diabetes Write short notes on the mechanisms of complications in diabetic patients Write short notes on the changes in diabetic renal disease What is the difference in pathogenesis between type 1 and type 2 DM MCQ 1. Which of the following is not a late complication of diabetes ? A. Peripheral vascular disease B. Diabetic ketoacidosis C. Proliferative retinopathy D. Diabetic glomerulosclerosis E. Atherosclerosis MCQ2. Which of the following is not considered a main mechanism contributing to diabetic complications A. Activation of the tyrosine kinase pathway B. Activation of protein kinase C C. Advanced glycosylation end products (AGEs) D. Intracellular hyperlgycaemia with disturbances in polyol pathways MCQ3. Which of the following is not a manifestation of diabetic renal disease A. Nodular glomerulosclerosis B. Thickened glomerular basement membrane C. Hyaline arteriosclerosis D. Interstitial nephritis E. Papillary necrosis MCQ4. What is the criteria for the diagnosis of diabetes A. Fasting plasma glucose ≥7.0mmol/L and 2 hr plasma glucose ≥11.1 (during oral glucose tolerance test) B. Fasting plasma glucose ≥7.7mmol/L and 2 hr plasma glucose ≥11.7 (during oral glucose tolerance test) C. Random blood glucose concentration ≥ 7.8mmol/l D. Fasting plasma glucose ≥ 11.0mmol/L MCQ5. Which of the following is true ? A. Type 1 DM is more common than type 2 DM. B. Diabetes is the leading cause of end stage kidney disease in Australia C. Diabetes is the 3rd leading cause of death in Australia D. The prevalence of diabetes in the indigenous population is less than nonindigenous individuals MCQ6. Which of the following is false ? A. Insulin is secreted by the islet cells in the pancreas B. Glucagon works by improving the uptake of glucose from the blood across cell membranes into cells C. The control of blood glucose levels operates by a negative feedback mechanism D. The exocrine pancreas produces digestive enzymes References Robbins and Cotran, Pathologic Basis of Disease Harrison’s , Principles of Internal Medicine Rosai and Ackerman’s Surgical Pathology Kidney Health Australia www.kidney.org.au