Complications of Diabetes Mellitus Path Slides PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Complications of Diabetes Dr. Najia Shamsi Complications of Diabetes Mellitus Class Year 2 Course Pathology/Medicine Lecturer Date  LEARNI...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Complications of Diabetes Dr. Najia Shamsi Complications of Diabetes Mellitus Class Year 2 Course Pathology/Medicine Lecturer Date  LEARNING OUTCOMES List the microvascular & macrovascular complications of diabetes Explain the pathophysiology of each complication Outline the risk factors for the development of the complications of diabetes Outline the common signs & symptoms of each complication Outline the overarching principles of investigation & management of complications of diabetes Analyze the impact of diabetic complications on quality of life, healthcare costs, & mortality rates HEALTH IMPACT OF THE DISEASE 5th leading Life expectancy cause of death 5 to 10 yr Renal failure* Cardiovascular Diabetes disease 2X to 4X Blindness* Amputation* Nerve damage in 60-70% of patients * Diabetes is the no. 1 cause of renal failure, new cases of blindness, and nontraumatic amputations HYPERGLYCEMIA IS STRONGLY CORRELATED WITH MICROVASCULAR DISEASE NEJM 1993 329:977-986  SUMMARY OF PATHOLOGICAL COMPLICATIONS OF DIABETES Coma - hypoglycaemia, ketoacidosis, hyperosmolar non-ketotic (don’t forget diabetics get all causes of coma that non diabetics get!) Cardiovascular complication: – Atheroma - cardiovascular disease, stroke, peripheral vascular disease (limb amputation) – Microangiopathy - cardiac failure, retinopathy, diabetic kidney disease, neuropathy Renal failure - diabetic kidney disease, pyelonephritis, renal papillary necrosis Sepsis and infections - tuberculosis, bronchopneumonia, Covid-19, skin infections (diabetic foot) and fungal infections Eye - retinopathy ,cataracts, macular oedema and glaucoma Pregnancy - gestational diabetes or pre-existing diabetes which leads to large infants, increase risk of developmental abnormalities and increase in obstetric complications for mother  HOW DIABETES DAMAGES TISSUES Glucose molecules Protein Glycosylated protein In diabetes the protein basement membrane becomes abnormally thickened. This reduces the blood flow causing ischaemia. They are also fragile causing haemorrhage.  PROTEINS THAT GET DAMAGED ARE BLOOD VESSEL WALLS AND CAPILLARY BASEMENT MEMBRANES Capillary basement membranes through the body become thicker These vessels do not function well, not enough blood to adjacent tissues , they are fragile and can bleed Vessels in kidney – diabetic glomerulosclerosis, renal papillary necrosis Vessels supplying nerves - neuropathy Vessels in eyes - diabetic retinopathy Vessels in skin – (particularly feet) - ulcers  DIABETIC NEPHROPATHY The best place to see the abnormal capillaries is in the kidney with a PAS stain. This image is an example of a kidney glomerulus with thickening of the capillary basement membranes and an increase in protein deposition in the mesangium. There will be more about this later in the lecture.  PROPOSED MECHANISMS OF HYPERGLYCEMIA-INDUCED TISSUE DAMAGE Genetic Factors Repeated acute changes in cellular metabolism Tissue Hyperglycemia Damage Cumulative long-term changes in stable macromolecules Independent accelerating factors: hypertension, hyperlipidemia, etc. Adapted from: Diabetes. 2005; 54: 1615  MOLECULAR PATHWAYS IMPLICATED IN THE PATHOGENESIS OF DIABETIC TISSUE DAMAGE Polyol pathway: – Aldose Reductase: Glucose ➔ Sorbitol – Decreased NADPH ➔ Decreased Glutathione: Oxidative stress Advanced glycosylation end-products (AGE): – Modification of intracellular and extracellular proteins – Increased inflammatory cytokines and growth factors Protein Kinase C activation: altered gene expression – Decreased endothelial nitric oxide synthase (eNOS) – Increased Endothelin-1, TGF-β, PAI-1, VEGF, NFκB – Net: Vasoconstriction, coagulation, angiogenesis, inflammation Hexosamine pathway: – Diversion from the glycolysis pathway (G—G6P—F6P…) – Increased N-acetyl glucosamine: Altered gene expression: TGF-β, PAI-1  MICROVASCULAR COMPLICATIONS OF DM Retinopathy Nephropathy Neuropathy  DIABETIC RETINOPATHY (DR) One of the most common cause of blindness in adults between 20-74 Many patients with DR have no symptoms until very late stages (by which time it's too late for effective treatment) Symptoms: Decreased visual acuity Prevalence increases progressively with increasing duration of disease Type 1 diabetes: – Onset 3-5 years after diagnosis – Nearly all patients are affected at 15-20 years Type 2 Diabetes: – Prevalence about 20% at the time of diabetes diagnosis – Onset averages 4-7 years before diagnosis – 50-80% incidence at 20 years RISK FACTORS FOR DIABETIC RETINOPATHY Duration of diabetes Level of glycemic control Hypertension Presence of other microvascular complications (e.g.- diabetic nephropathy & neuropathy) Dyslipidemia Pregnancy, which transiently increases risk & progression  PATHOPHYSIOLOGY OF DIABETIC RETINOPATHY Hyperglycemia – Dysregulated retinal blood flow – Oxidative stress and inflammation – Increased vascular permeability (edema) – Microthrombosis: ischemia – Growth factors (IGF-1, PDGF, VEGF): proliferation Genetic factors – Increased incidence in first-degree relatives – Association with nephropathy (in T1DM) Hypertension Dyslipidemia (+/-)  CLASSIFICATION OF RETINOPATHY Two major categories – Non-proliferative retinopathy (NPDR) Mild/Moderate/Severe – Proliferative retinopathy (PDR) Early/High-Risk/Severe Macular edema – Can occur at any stage of retinopathy – “Clinically significant” (CSME) Size of area affected, proximity to macula  EYE FINDINGS IN RETINOPATHY Mild: – Microaneurysms – Dot Hemorrhages – Hard exudates: Lipid leakage within macrophages Moderate/Severe (above findings plus): – Soft exudates (cotton wool spots): – Venous beading – Intraretinal microvascular abnormalities (IRMA) Occluded vessels, dilated and tortuous capillaries  MILD NPDR Normal Fundus Nonproliferative Retinopathy Microaneurysms and Lipid exudates dot hemorrhages 5% annual progression to PDR NEJM 1993:329:977-86  SEVERE NPDR 50-75% annual progression to PDR  PDR Neovascularization of Neovascularization Elsewhere the Optic Disc (NVD) on Retina (NVE) PREVENTION OF RETINOPATHY Cornerstones of therapy: Glycemic control DCCT, UKPDS Trials Antihypertensive therapy Weaker evidence: Lipid lowering therapy Antiplatelet agents Carbonic anhydrase inhibitors TREATMENT OF RETINOPATHY NPDR with CSME: Focal laser photocoagulation High-risk and severe PDR: – Panretinal photocoagulation (PRP) 600-1600 laser burns, grid pattern – Medical therapy Intravitreal glucocorticoids VEGF inhibitors Vitrectomy indications: Non-clearing vitreous hemorrhage Traction retinal detachment involving the fovea Retina with PRP laser burns Severe PDR not responsive to PRP  NEPHROPATHY Leading cause of kidney disease Onset 5-20 years after diabetes – Annual incidence 2.5% (Lifetime 25-35%) – Less than 1% per year after 20-25 years (T1DM) – Present at diagnosis in T2DM in about 3% Most common cause of kidney failure – Accounts for 40% of patients on dialysis – Incidence 4 - 20% at 20 years Independent risk factor for both cardiovascular & overall mortality  RISK FACTORS FOR NEPHROPATHY Poor glycemic control Hypertension Age Genetic factors Race – Black or African-American, Pima Indian, Mexican- American Obesity Tobacco use Other microvascular disease: retinopathy  PATHOLOGIC CHANGES Glomerular disease – Mesangial expansion – Glomerular basement membrane thickening – Glomerular sclerosis Albuminuria – Microalbuminuria (high albuminuria) 30-300 mg/g Creatinine – Proteinuria (macro- or very-high albuminuria) > 300 mg/g Creatinine  PATHOLOGIC CHANGES IN NEPHROPATHY Normal Glomerulus Diabetic Nephropathy Mesangial Expansion Basement membrane thickening. Glomerular sclerosis  DIABETIC NEPHROPATHY H&E showing glomerulus with diffuse and nodular glomerulosclerosis. Kimmelstiel-Wilson nodules characteristic of nodular glomerulosclerosis (marked as ‘N’). Compare with normal glomerulus  NATURAL HISTORY Glomerular hyperfiltration – Increased kidney size on ultrasound Microalbuminuria (high albuminuria) Regression to normoalbuminuria – 15-65%, associated with risk-factor management Progression to macroalbuminuria Decreased GFR – May precede or follow development of albuminuria Progression to end-stage kidney failure (ESKD) and dialysis DIABETIC NEPHROPATHY Eli A. Friedman  PREVENTION OF NEPHROPATHY Glycemic control Blood pressure control Treatment of dyslipidemia Measurement of spot urine microalbumin to creatinine ratio (i.e.- Screening for DM nephropathy) – Annually after 5 years in T1DM – Begin at diagnosis in T2DM  TREATMENT OF NEPHROPATHY ACE Inhibitor or Angiotensin II Receptor Blocker – Improves or normalizes albuminuria – Does not prevent onset of microalbuminuria – ACE-I: Perindopril, Enalapril, Lisinopril… – ARB: Losartan, Valsartan, Irbesartan… Dietary restriction: Sodium Weight loss REDUCING MICROALBUMINURIA WITH ACE INHIBITION OR ARB Decreased urinary protein Efferent arteriole is dilated to reduce glomerular pressure  DIABETIC NEUROPATHY Most common microvascular complication Diabetic polyneuropathy: Most common form of neuropathy in developed countries 50-70% lifetime incidence of at least one form of neuropathy  RISK FACTORS FOR DIABETIC NEUROPATHY Age Duration of diabetes Poor glucose control Blood vessel damage Mechanical injury to nerves Genetic susceptibility Hypertension Dyslipidemia: hypertriglyceridemia Tobacco use Excessive alcohol use  TYPES OF DM NEUROPATHY Motor neuropathy Sensory neuropathy Mixed sensori-motor neuropathy Compression neuropathies Cranial nerve palsies Mononeuritis multiplex Autonomic neuropathy PERIPHERAL NEUROPATHY Most common type of diabetic neuropathy Distal, symmetric polyneuropathy – Axonal neuropathy – “Stocking-glove” distribution – Sensory > Motor Symptoms: – Decreased sensation – Paresthesia: Tingling, Burning, Electric shock – Hyperesthesia – Worse at night  TREATMENT OF PAINFUL NEUROPATHY Anticonvulsants: – Pregabalin, Valproic Acid, Gabapentin Tricyclic Antidepressants (TCA) – Amitryptiline, Desipramine Serotonin Norepinephrine Reuptake Inhibitors (SNRI) – Duloxetine (Cymbalta), Venlafaxine (Effexor) Topical agents: Caspaicin cream Opioids: Dextromethorphan, Mo norphine, Oxycodone Antioxidants: Alpha-Lipoic Acid (ALA) TENS (Electric Nerve Stimulation)  PREVENTION OF NEUROPATHY Glucose control Blood pressure control Treatment of dyslipidemia Smoking cessation Decreased alcohol intake DIABETIC NEUROPATHY & FOOT PATHOLOGY Pressure Ulcer DIABETIC NEUROPATHY & FOOT PATHOLOGY Charcot arthropathy  PREVENTION OF FOOT ULCERS Avoid walking barefoot Proper fitting shoes Trimmed toenails: avoid sharp edges Daily foot inspection – Use a mirror, examination by another person Daily foot washing Moisturizing cream or lotion Follow up with a podiatrist  SUMMARY: MICROVASCULAR Retinopathy – NPDR without CSME: risk factor management – PDR or CSME: Photocoagulation Nephropathy: – Microalbuminuria – Renin-angiotensin inhibition Neuropathy: – Polyneuropathy MACROVASCULAR COMPLICATIONS OF DIABETES MELLITUS  MACROVASCULAR COMPLICATIONS Coronary artery disease Cerebrovascular disease Peripheral vascular disease  CARDIOVASCULAR DISEASE (CVD) & DM Number one cause of death Accounts for 2/3 of all deaths in people with DM Risk of CVD is increased approximately 2-fold in men & 3-4-fold in women  DIABETES INCREASES CORONARY MORTALITY Haffner, SM, Lehto, S, Ronnemaa, T, et al, NEJM 1998; 339:229.  MACROVASCULAR COMPLICATIONS Heart 3-5X risk of MI More deaths and complications in hospital and following tx. May be presenting feature of type 2 diabetes Often silent ischaemia Dx of type 2 diabetes implies same risk and management of MI prevention as if someone has had an MI already Stroke 2-3X risk (thrombo-embolic/ischaemic stroke) Peripheral vascular disease (atheroma in lower limb arterial supply) Multiple, diffuse lesions, often more distal than in non-DM 40X risk amputation Neuropathy/infection contribute to risk Gangrene - isolated toe or heel typical (pressure points)  RISK FACTORS FOR CARDIOVASCULAR DISEASE Age Duration of diabetes Poor glucose control Hypertension Dyslipidemia Albuminuria and kidney disease Gender (W>M) Obesity Smoking Sedentary lifestyle  PREVENTION OF MACROVASCULAR DISEASE Glucose control Blood pressure control Lipid control Reduction of microalbuminuria Weight loss and exercise Smoking cessation +/- Aspirin For those with ASCVD, treatment with GLP-1 agonists & SGLT-2 inhibitor (more on this in pharmacology lecture)  COSTS AND EFFECTS ON QOL Total costs of diagnosed diabetes $327 billion in 2017 (data from ADA) 30% of total cost for hospital inpatient care Prescription medications to treat complications of diabetes (30%) Anti-diabetic agents and diabetes supplies (15%) Physician office visits (13%) People with diagnosed diabetes incur average medical expenditures of $16,752 per year (~2.3 times higher than what expenditures would be in the absence of diabetes)  SUMMARY: MACROVASCULAR Glucose control: early intervention Risk factor management: – Blood pressure – Dyslipidemia – Microalbuminuria – Weight loss and exercise – Smoking cessation – Aspirin (Secondary prevention or high-risk)