Complications of diabetes melitue
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  • 1. COMPLICATIONS OF DIABETES MELLITUS
  • 2.  A metabolic disorder of various etiologies, characterized by chronic hyperglycemia due to insulin deficiency and/or insulin resistance as well as increased hepatic glucose output.
  • 3. Type 1 Type 2 Other causes (Genetic defect of β cell function, genetic defects of insulin action, disease of exocrine pancreas, endocrinopathies, drug/chemicalinduced, infections and uncommon forms)  Gestational DM   
  • 4. COMPLICATIONS OF DIABETES MELLITUS ACUTE • Diabetic Ketoacidosis • Hyperglycemic Hyperosmolar State • Hypoglycemia -Diabetic Foot Ulcer -Infections CHRONIC • Microvascular - Retinopathy - Nephropathy - Neuropathy • Macrovascular - Accelerated arteriosclerosis - Myocardial infarction - Stroke - Lower extremity gangrene
  • 5. CHRONIC COMPLICATIONS OF DIABETES MELLITUS
  • 6. HCO3- Hypertriglyceridemia Resembles Pancreatitis
  • 7. Reduced insulin:glucagon ratio ↓ ↑Lipolysis ↓ Fruity smell in ↑fatty acid the breath ↓ Excess acetyl CoA Ketonuria ↑Acetone Metabolic ↓ acidosis Ketonemia ↑ Ketogenesis ↓ Reduce HCO3↑Beta hydroxy butyrate (toxic to body) Kussmaul ↓ respiration (to Induce nausea/vomiting compensate)‘air hunger’
  • 8. Absolute insulin deficiency/Increase counter regulatory hormones ↓ ↑Catabolism of carbohydrate, fats and proteins ↓ Hyperglycemia ↓ Osmotic diuresis ↓ Polyuria and nocturia (loss of electrolytes + fluid) Nausea and ↓ Impairs vomiting Dehydration renal excretion of ↓ H+ and Thirst center ketone ↓ Polydipsia Affect pH dependent enzyme Aggravate acidosis
  • 9. Increased chylomicrons in the blood (>1000mg/L) ↓ Obstruct capillaries ↓ Local ischemia and acidemia ↓ Local damage expose TG to pancreatic lipases ↓ TG → Fatty acids ↓ Further local injury + ↑ inflammatory mediators and free radicals ↓ Resembles Pancreatitis
  • 10.         Tachycardia Dehydration/hypotension Tachypnea Abdominal tenderness (resembles pancreatitis/surgical abdomen) Lethargy/ Reduce alertness (obtundation) Cerebral edema Coma
  • 11.  severe ketoacidosis + histotoxic action of the ketone bodies + disturbances in water and electrolyte balance → reduced oxidative metabolism of the central nervous system → diabetic coma
  • 12.       Hyperglycemia: Test with dipstick, confirm with venous blood glucose level Ketonemia: test plasma with Ketostix. Finger prick sample for β-hydroxybutyrate Ketouria: measure urine ketone levels Acidosis: measure - pH of arterial blood - bicarbonate in venous blood Arterial blood gas Urinalysis
  • 13. Symptoms of hyperglycemia from history Pulse: >100bpm/ <60bpm Systolic BP <90 mmHg Glasgow Coma Score <12/abnormal ‘Alert, Voice,Pain, Unresponsive’ scale (AVPU)  O2 saturation <92% on air (If normal respiratory function)    
  • 14.       Replace fluid losses Replace electrolyte losses Restore acid-base balance Replace deficient insulin Monitor blood glucose closely Treat underlying cause
  • 15. • • • Usually occur in Type 2 DM Caused by relative insulin deficiency and inadequate fluid intake Involved mostly elderly patients Hyperglycemia Dehydration Ketosis Decreased consciousness
  • 16.    Dehydration Stupor/Coma Confusion ABSENCE OF KETOACIDOSIS No nausea, vomiting and Kussmaul respiration (delays the seeking of medical attention 
  • 17. marked increase in plasma osmolarity (reaches 340mOsm/L (280-295mOsm/L) ↓ Profound cellular dehydration ↓ severe loss of intracellular fluid in the brain cells ↓ Coma Plasma osmolality = (2(Na+ + K+) + glucose + urea) all in mmol/L
  • 18.   Due to insulin treatment for both Type 1 and Type 2 DM Due to improper dosing with exogenous insulin or by induction of endogenous insulin Exercise, fasting, low glucose intake ↓ Hypoglycemia ↓ Low insulin, High Counter regulatory hormone ↓ Insulin treatment X Restore blood glucose level ↓ Hypoglycemia Release of glucagon
  • 19.          sweating Confusion Irritability Headaches Abnormal behaviour Motor incoordination Coma Weakness Convulsion
  • 20.   Rapid oral/IV glucose IM glucagon
  • 21. 1.Coronary heart disease 2.Peripheral arterial disease 3.Cerebrovascular disease
  • 22.    Also called ischemic heart disease. Caused by a hardening or thickening of the walls of the blood vessels that go to the heart. Blood supplies oxygen and other materials to the heart for normal functioning. If the blood vessels to the heart become narrowed or blocked by fatty deposits, the blood supply is reduced or cut off, resulting in a heart attack.
  • 23. Pathogenesis : Diabetes mellitus – metabolic disorder Increase production of advanced glycation end products (AGEs) Endothelial injury Make the platelets ‘sticker’ Increase permeability and adhesion of molecules ; monocyte,leukocyte,platelet, lipids (LDL) Increase coagulation potential Abnormal clot formation (thrombosis) Oxidized LDL attracts macrophages and monocytes to the site Smooth muscle emigration from media to intima Lipids engulf by cells  foam cells, smooth muscle cells proliferate Collagen and other ECM deposition Accumulation of lipid intracellularly & extracellularly Atheroslerotic plaque Coronary heart disease
  • 24. Pathophysiology : Reduction of blood flow Decreased blood supply to the myocardium, decreased oxygen supply Anaerobic metabolism Acidosis Chest pain Decreased myocardial contractility  low cardiac output Myocardial ischemia  myocardial necrosis Inflammatory response Hyperthermia/fever Decreased systemic circulation Sympathetic stimulation Tachycardia Redirection of blood from skin  major organs Decreased perfusion of oxygenated blood to other organs Dyspnea, fatigue and body weakness Pallor
  • 25. Signs and symptoms :  Chest pain – usually a feeling of squeezing/pressure. If the patient has autonomic diabetic neuropathy, he may not has the chest pain  Decreased tolerance for physical activity  Chronic fatigue  Shortness of breath  Swelling of the legs and ankles  Palpitation
  • 26.     refers to a group of conditions that affect the circulation of blood to the brain, causing limited or no blood flow to affected areas of the brain Atherosclerosis is one of the conditions that can cause cerebrovascular disease. During this process, high cholesterol levels coupled with inflammation in areas of the arteries in the brain can cause the cholesterol to build up in the vessel in the form of a thick, waxy plaque. This plaque can limit, or completely obstruct, blood flow to the brain, causing a stroke, transient ischemic attacks, or dementia, which may lead to a variety of other health complications.
  • 27. Hyperglycemia ↓ Non-enzymatic glycosylation of collagen and others protein in interstitial tissue and blood vessel wall ↓ Formation of irreversible advanced glycosylation end products (AGES) ↓ Cause cross link between polypeptides + interstitial proteins, including low-density lipoprotein (LDL)
  • 28. ↓ Promote the deposition of the cholesterol in the blood vessel intima ↓ Accelerates atherogenesis ↓ Atherosclerosis ↓ Compromised the blood supply to the tissue ↓ To brains vessels ↓ Coma and stroke
  • 29. Atherosclerosis compromised the blood supply Coronary artery lower extremities vessel brain vessel MI, angina, IHD coma, stroke coagulative necrosis + infections gangrene
  • 30.    In the walls of the large blood vessels, AGEmodified collagen accumulates, thickening the vessel wall and narrowing the lumen. AGE-modified arterial collagen immobilizes circulating LDL, contributing to atheroma formation. The cumulative effect of these changes is a progressive narrowing of the vessel lumen and decreased perfusion of affected tissues. The binding of AGEs to specific cellular receptors that have been identified on the surface of smooth-muscle cells, endothelial cells, neurons, monocytes, and macrophages results in increased vascular permeability and thrombus formation, proliferation of smooth muscle in vessel walls, and phenotypic alteration in monocytes and macrophages
  • 31. This last result causes hyperresponsiveness of monocytes and macrophages upon stimulation, with resultant increases in the production of proinflammatory cytokines and certain growth factors.  These cytokines and growth factors contribute to the chronic inflammatory process in the formation of atherosclerotic lesions. 
  • 32. Another condition related to heart disease and common in people with diabetes.  The blood vessels in the legs are narrowed or blocked by fatty deposits, decreasing blood flow to the legs and feet.  Increases the chances of a heart attack or stroke occurring. Poor circulation in the legs and feet also raises the risk of amputation. 
  • 33.         Intermittent claudication - pain, weakness, numbness, or cramping in muscles due to decreased blood flow Rest pain - occurs when the artery occlusion is so critical that there is not enough blood and oxygen supply to the lower extremities even at rest and represents a more serious form of the condition. Numbness of the extremities Weakness and atrophy (diminished size and strength) of the calf muscle A feeling of coldness in the legs or feet Changes in color of the feet; feet turn pale when they are elevated, and turn dusky red in dependent position Hair loss over the dorsum of the feet and thickening of the toenails on affected limbs and digits Painful ulcers and/or gangrene in tissue where there is critical ischemia; typically in the toes ( heals slowly or not all )
  • 34. In normal endothelial cells, biologically active substances are synthesized and released to maintain vascular homeostasis, ensuring adequate blood flow and nutrient delivery while preventing thrombosis and leukocyte diapedesis. ( Diapedesis - The movement or passage of blood cells, especially white blood cells, through intact capillary walls into surrounding body tissue) Among the important molecules synthesized by the endothelial cell is nitric oxide (NO), which is constitutively produced by endothelial NO synthase (eNOS) through a 5-electron oxidation of the guanidine-nitrogen terminal of L-arginine. The bioavailability of NO represents a key marker in vascular health. NO causes vasodilation by activating guanylyl cyclase on subjacent vascular smooth muscle cells. In addition, NO protects the blood vessel from endogenous injury—ie, atherosclerosis—by mediating molecular signals that prevent platelet and leukocyte interaction with the vascular wall and inhibit vascular smooth muscle cell proliferation and migration.
  • 35. Conversely, the loss of endothelium-derived NO permits increased activity of the proinflammatory transcription factor nuclear factor kappa B (NF-κΒ), resulting in expression of leukocyte adhesion molecules and production of chemokines and cytokines. These actions promote monocyte and vascular smooth muscle cell migration into the intima and formation of macrophage foam cells, characterizing the initial morphological changes of atherosclerosis. Thus, decreased levels of NO in diabetes may underlie its atherogenic predisposition. The bioavailability of NO reflects a balance between its production via NOS and its degradation, particularly by oxygen-derived free radicals. Many of the metabolic derangements known to occur in diabetes, including hyperglycemia, excess free fatty acid liberation, and insulin resistance, mediate abnormalities in endothelial cell function by affecting the synthesis or degradation of NO.
  • 36.  To reduce the risk of progression and of cardiovascular disease by  Improved control of blood glucose ▪ Reduced intake of blood glucose ▪ Control diet!!!  Aggressive reduction of blood pressure ▪ For DM 1, ACE inhibitor provide greater benefit ▪ For DM 2, angiotensin 2 receptor blocker has better effect  Aggressive cardiovascular risk factor reduction ▪ Eg; reduced in cholesterol intake
  • 37. Treatment  Antihypertensive (ACEi, ARB)  To prevent hypertension  Statin  To prevent lipid abnormalities  ACE inhibitor / ARB  To prevent cardiovascular risk  Low-dose aspirin (antiplatelet)  To reduce arteriolar thrombosis & macrovascular risk
  • 38.    DIABETIC RETINOPATHY DIABETIC NEUROPATHY DIABETIC NEPHROPATHY
  • 39.      Diabetic retinopathy is a complication of diabetes and a leading cause of blindness. Is the result of damage to the tiny blood vessels that nourish the retina They leak blood and other fluids that cause swelling of retinal tissue and clouding of vision Usually affects both eyes The longer the person has diabetes, the more likely they will develop diabetic retinopathy
  • 40.      Hyperglycemia will increase retinal blood flow and metabolism and has direct effects on retinal endothelial cells and pericyte loss which will impair vascular autoregulation The uncontrolled blood flow will dilates capillaries and increase production of vasoactive substances and endothelial proliferation, resulting in capillary closure This causes chronic retinal hypoxia and stimulates growth factors (VEGF) production VEGF – will stimulate changes of endothelial cell growth (new vessel formation) and increase vascular permeability (causing retinal leakage and exudation)
  • 41.  1. There are 4 types of diabetic retinopathy Non-proliferative without maculopathy   2. Maculopathy   3. No immediate threat to vision It includes venous dilatation, peripheral (microaneurysms, exudates and blot haemorrhages) Is a sight threatening Presence of exudation, haemorrhage, ischemia and oedema Pre-proliferative   Is a sight threatening Presence of venous loops and beading, microaneurysms, haemorrhages, intra-retinal microvascular abnormalities, multiple cotton wool spots, macular oedema with reduced visual acuity and exudation
  • 42.  Proliferative  Is a sight threatening  Involves pre-retinal haemorrhage, neovascularisation, fibrosis and exudative maculopathy
  • 43. • Microaneurysms tiny, discrete, circular, dark red spots near the retinal vessels. most cases, this is the earliest clinical abnormalities. • Retinal haemorrhages occur in deeper layer of retina round, regular in shape- `blot’ haemorrhage. • Exudates characteristics of dibetic retinopathy occur in perimacular area. • Cotton wool spots features of pre-proliferative diabetic retinopathy. • Venous changes • Neovascularisation • Pre-retinal haemorrhage • Vitreous haemorrhage • Fibrosis
  • 44. microaneurysm (soft exudates)
  • 45. Increase intracellular glucose Activation of polyol pathway Reduce in Na/K ATPase activity Osmotic effect (intracellular overhydration) Non enzymatic glycosylation of terminal end amino groups
  • 46. Intermediate glycosylated compund Advanced glycosylation end products. ( AGEs) Changes in cellular function Imbedded lens Swelling and opacity Blurring of vision (retinopathy)
  • 47.  Prevention  Rapid reduction in blood glucose  Blood pressure lowering  Annual screening for retinopathy (in those with risk factor)  Retinal photocoagulation (laser treatment)  Focal laser to treat leaking microaneurysm, retinal thickening, reduced macular edema  To destroys area of retinal ischemia, thus reduce the intraocular levels of VEGF (important for neovascularisation)  Reduced risk of recurrent haemorrhage (by inducing fibrosis of the new vessel)
  • 48. Opacification of the lens Due to sorbitol infiltration Senile cataract develops 10-15 years earlier in diabetic patients  Clinical features     Gradual painless deterioration of vision  Reduced visual acuity  Treatment  Cataract extraction  Insertion of an intraocular lens
  • 49.     Increased intraocular pressure damaging optic nerve and results in visual field defects Leaky new vessel formation  reduced outflow of aqueous humour through trabecular meshwork  increased intraocular pressure  glaucoma Diagnosis is made after IOP is measured Treatment  Beta-blocker  Prostaglandin analogue  Carbonic anhydrase inhibitors
  • 50. Diabetic Neuropathy •Neurological disorder associated with diabetes mellitus •Affects all peripheral nerves including pain fibers, motor neurons and autonomic nervous system •Symptoms vary according to the nerves affected •Common symptoms includes: •Numbness & tingling of extremities (‘Gloves & stockings distribution’) •Dysesthesia (abnormal sensation to a body part) •Dizziness •Urinary incontinence •Muscle weakness •Difficulty swallowing
  • 51. Pathogenesis The pathogenesis is not clearly understood but these 4 factors are thought to be involved: 1. Microvascular disease a. Diabetes causes narrowing of blood vessels, abnormal vasoconstriction, capillary membrane thickening and endothelial hyperplasia which contributes to tissue (nerve) hypoxia b. Nerve hypoxia can lead to neuronal ischemia which impairs nerve functions 2. Advanced glycated end products (AGE) a. Elevated intracellular levels of glucose can cause a nonenzymatic covalent bonding with proteins which alters their structure and inhibit their function. b. Seen in cells that unable to reduce glucose intake due to hyperglycemia (e.g. endothelial cells). c. A complex pathway involving oxidative stress or reactive oxygen species.
  • 52. 3. Protein Kinase C (PKC) a. Increased levels of glucose cause an increase in intracellular diacylglycerol which activates PKC b. PKC inhibitors will be activated to compensate the abnormal activation of PKC c. PKC inhibitors increase nerve conduction velocity by increasing neuronal blood flow, causing abnormal sensation. 4. Polyol pathway a. Aka sorbitol/aldose reductase pathway. b. Increase glucose level will activate this alternative biochemical pathway. c. This pathway decreases glutathione and increase reactive oxygen species & is dependent on enzyme aldose reductase. d. Cells of retina, kidney & nervous tissues are not insulin dependent. e. Any glucose not used will enter the polyol pathway and be converted to sorbitol
  • 53. 4. Polyol pathway f. Under normal condition, this interchange will cause no problem as aldose reductase has low affinity for glucose at normal concentration. g. In hyperglycemic state, sorbitol accumulates. h. Sorbitol can’t cross cell membrane, when it accumulates, it produces osmotic stress by drawing water into cell. i. Fructose which is also made further on in this chemical pathway has the same effect. j. The deposition of sorbitol and fructose can damage the Schwann cell membrane and causes abnormalities or decrease nerve conductions.
  • 54. hyperglycemia Activation of sorbitol/aldose pathway Accumulation of sorbitol and fructose in the cell and also depletion of NADPH needed for GSH production Osmotic stress of Schwan cell and also production ROS
  • 55. Abnormality or delayed nerve conduction Diabetic neuropathy
  • 56. DEFINITION : Any deleterious effect on kidney structure and/or function caused by diabetes mellitus.  Chacterized by albuminuria, hypertension, and progressive renal insufficiency  Approx. 20-30% of patients with diabetes (type 1 and type 2) develop nephropathy  The earliest clinical manifestation is the presence of small but abnormal levels of albumin in the urine (microalbuminuria) generally preceds overt proteinuria by 5-10 years.
  • 57.      Once proteinuria is detected, renal function gradually deteriorates over 10-15 years Diabetic nephropathy may result in end-stage renal disease (ESRD) requiring dialysis or kidney transplantation. Considerably fewer people with type 2 diabetes progress to ESRD Microalbuminuria is a risk factor for premature coronary artery disease in diabetics Coexisting hypertension accelerates the development of renal failure.
  • 58. Diabetic Kidney The kidney may be damaged by diabetes in three main ways : 1) Glomerular damage diabetic nephropathy 2) Ischaemia resulting from hypertrophy and hyalinization of afferent and efferent arterioles  ischaemic damage to kidneys. 3) Ascending infection  UTI due to bladder stasis resulting from autonomic neuropathy and infections.
  • 59. STAGE CHARACTERISTICS STAGE 1 Hypertrophy and hyperfunction - Increase in size of kidney - Higher blood flow and rate of filtration Thickening of basal membrane Onset of Nephropathy Microalbuminuria - Microalbuminuria testing: - Rise in blood pressure Clinical nephropathy Normal range : -Macroalbuminuria <20mg/l -High blood pressure Microalbuminuria: 20 – 200mg/l Macroalbuminuria : >200mg/l STAGE 2 STAGE 3 STAGE 4
  • 60. PATHOPHYSIOLOGY => Renal hypertrophy and increase in glomerular filtration rate High levels of blood sugar Kidney filter too much blood stress on basal membranes More vasolidation of afferent arteriole than efferent glomerular arteriole Increases intraglomerular filtration pressure further damage glomerular capillary
  • 61. intraglomerular filtration pressure Local shearing forces (mesangial cell hypertrophy) and secretion of extracellular mesangial matrix material Further damage glomerular capillary Glomerular sclerosis Thickening of BM Disruptions of protein cross lingkages that makes an effective filter Progressive leak of large molecules(proteins) into urine
  • 62. Small amount of protein appears in urine; microalbuminuria 30-300mg/day  Overt nephropathy with macroalbuminemia >300mg/day + HPT  May develop end stage renal failure  Requiring dialysis or renal transplant 
  • 63.  Screening for microalbuminuria 30-300mg/day  Microalbuminuria is the earliest evidence of the diabetic nephropathy  The amount is so small to be detected.  Have to be tested by using special dipstick or radioimmunoassay
  • 64. Impairs immune system minor trauma DM ↓ Defective insulin action ↓ Hyperglycaemia ↓ good medium for bacterial growth ↓ prone to get infection glycosylation of polymorphnuclear cells ↓ impaired effectiveness & function bacterial invasion & proliferation ↓ INFLAMMATION ↓ Capillary dilatation, fluid exudation, neutrophils exudation ↓ Liquefactive tissue necrosis Gangrene ↓ ULCER AMPUTATION (red, warm, swollen, tender skin lesion) tissue injury
  • 65. ischaemia neuropathy symptoms Claudication Rest pain Usually painless Sometimes painful neuropathy inspection Dependent rubor Trophic changes High arch Clawing of toes No trophic changes palpation Cold pulseless Warm Bounding pulses ulceration Painful Heels and toes painless Plantar (pressure point)
  • 66.   Dorsum of 2nd toe shows ischaemic lesion. Whitish color on the tip d/t ischaemia
  • 67.     Ulcer on the 1st metatarsal head. Health granulation tissue on its bed. Callus formation on its surrounding ulcer lesion.
  • 68.   Death of tissue Generally d/t loss of vascular supply& followed by bacterial infection
  • 69.  Laboratory test FBC – presence & severity of infection blood sugar – hyperglycemia  X-ray sign of damage to bones or arthritis gas in soft tissue-indicate gangrene  Ultrasound doppler ultrasound-blood flow through the arteries & veins in lower extremities
  • 70. Resolve infection -antibiotics  Wound care - surgical debridement - improvement of circulation - special dressing - maggot therapy  Follow up -compliance to antibiotic -sign of improvement-less pain, swelling, redness, shrinkage 
  • 71.  Poorly controlled diabetes entails increased susceptibility of infections  Skin infection  GIT infection  Urinary tract infection  Pyelonephritis  Pneumonia  Pulmonary tuberculosis  Pathophysiology  Hyperglycemia  impaired neutrophil superoxide generation  chemotaxis & phagocytosis of neutrophil are impaired  infections Infection also leads to loss of glycemic control and ketoacidosis  Increase insulin dose for DM patient complicated with 