Chronic Complications of Diabetes Mellitus PDF

Chronic Complications of Diabetes Mellitus ILOs At the end of this session, the student will be able to: ▪ Classify chronic diabetic complications into macrovascular, microvascular complications, and others. ▪ Recognize the risk factors for the development of different diabe...

Chronic Complications of Diabetes Mellitus ILOs At the end of this session, the student will be able to: ▪ Classify chronic diabetic complications into macrovascular, microvascular complications, and others. ▪ Recognize the risk factors for the development of different diabetic complications. ▪ Understand the pathogenesis of chronic diabetic complications. ▪ Identify the clinical presentations of chroniccomplications of diabetes. ▪ Discuss the lines of treatment of chronic diabetic complications. Chronic Complications of Diabetes A number of pathologic changes that involve small and large blood vessels, cranial and peripheral nerves, the skin, and the lens of the eye. These lesions lead to hypertension, end-stage chronic kidney disease, blindness, autonomic and peripheral neuropathy, amputations of the lower extremities, myocardial infarction, and cerebrovascular accidents. These late manifestations correlate with the duration of diabetes. In type 1 diabetes, end-stage chronic kidney disease develops in up to 40% of patients, compared with less than 20% of patients with type 2 diabetes. Proliferative retinopathy ultimately develops in both types of diabetes but has a slightly higher prevalence in type 1 patients (25% after 15 years duration). In patients with type 1 diabetes, complications from end-stage chronic kidney disease are a major cause of death. Whereas patients with type 2 diabetes are more likely to have macrovascular diseases leading to myocardial infarction and stroke as the main causes of death. Cigarette use adds significantly to the risk of both microvascular and macrovascular complications in diabetic patients. Ocular Complications: 1.Diabetic cataracts: Premature cataracts occur in diabetic patients and correlates with both duration and severity of chronic hyperglycemia. Nonenzymatic glycosylation of lens protein is twice as high in diabetic patients as in age-matched nondiabetic persons. 2. Diabetic retinopathy: Non-proliferative and proliferative. 3. Glaucoma: occurs in approximately 6% of persons with diabetes. It is responsive to the usual therapy for open-angle disease. Neovascularization of the iris can predispose to closed-angle glaucoma. Diabetic Retinopathy: Diabetic retinopathy is present in about one-third of patients in whom diabetes has been diagnosed, and about one-third of those have sight- threatening disease. It is the leading cause of blindness among adults aged 20-65 years. Retinopathy increases in prevalence and severity with increasing duration and poorer control of diabetes.  In type 1 diabetes, retinopathy is not detectable for the first 5 years after diagnosis. In type 2 diabetes, about 20% of patients have retinopathy at diagnosis likely because they had diabetes for an extensive period of time before diagnosis. Macular involvement is the most common cause of blindness. There are two main categories of diabetic retinopathy: non-proliferative and proliferative. Diabetic macular edema can occur at any stage. Non-proliferative retinopathy is subclassified as mild, moderate, or severe; Proliferative retinopathy is less common but causes more severe visual loss. Nonproliferative ("background") retinopathy represents the earliest stage of retinal involvement by diabetes. During this stage, the retinal capillaries leak proteins, lipids, or red cells into the retina. When this process occurs in the macula (macular edema), there is interference with visual acuity; this is the most common cause of visual impairment. Proliferative retinopathy involves the growth of new capillaries and fibrous tissue on the surface of the retina, extending into the vitreous chamber. It is a consequence of small vessel occlusion, which causes retinal hypoxia; this, in turn, stimulates new vessel growth. Clinical Findings: Clinical assessment comprises visual acuity testing, examination of the retina, retinal imaging with optical coherence tomography, and sometimes fluorescein angiography. Non-proliferative retinopathy manifests as microaneurysms, retinal hemorrhages, venous beading, retinal edema, and hard exudates. In mild non-proliferative diabetic retinopathy, there are mild retinal abnormalities without visual loss. Reduction of vision is most commonly due to diabetic macular edema, which may be focal or diffuse, but it can also be due to macular ischemia. Proliferative retinopathy is characterized by neovascularization, arising from either the optic disk or the major vascular arcades. Prior to proliferation of new capillaries, a pre-proliferative phase often occurs in which arteriolar ischemia is manifested as cotton-wool spots (small infarcted areas of retina). Vision is usually normal until macular edema, vitreous hemorrhage, or retinal detachment occurs. Proliferation into the vitreous of blood vessels, with associated fibrosis, may lead to vitreous hemorrhage (common) and tractional retinal detachment. Diabetic retinopathy may worsen after bariatric surgery or in patients with long-standing hyperglycemia that is rapidly brought under tight control, such as after initiating insulin therapy. Macular edema may be associated with thiazolidinedione (e.g. pioglitazone). Screening: Visual symptoms and visual acuity are poor guides to the presence of diabetic retinopathy. Adult and adolescent patients with diabetes should undergo regular screening by fundus photography. Patients with type 1 diabetes mellitus should be screened 5 years after the diabetes is diagnosed. Patients with type 2 diabetes mellitus should be screened at or shortly after diagnosis of diabetes.  More frequent monitoring is required in women with type 1 or 2 diabetes during pregnancy and in those planning pregnancy. Treatment: Optimizing blood glucose, blood pressure, and serum lipids. Glycemic control is the most important modifiable factor in treating patients with diabetic retinopathy, but intensive blood pressure control and avoiding tobacco use also slow retinopathy progression. Macular edema and exudates, but not macular ischemia, may respond to laser photocoagulation; to intravitreal administration of a VEGF inhibitor (ranibizumab, bevacizumab) or corticosteroid; or to vitrectomy. VEGF inhibitor therapy improves diabetic retinopathy severity in eyes at all levels of non-proliferative diabetic retinopathy and is the mainstay of treatment for diabetic macular edema. In patients with severe non-proliferative retinopathy, fluorescein angiography can help determine whether pan-retinal laser photocoagulation should be undertaken prophylactically by determining the extent of retinal ischemia. Vitrectomy is necessary for removal of persistent vitreous hemorrhage, to improve vision, for treatment of tractional retinal detachment involving the macula, and for management of rapidly progressive proliferative disease. Proliferative retinopathy is usually treated by intravitreal injection of a VEGF inhibitor or pan-retinal laser photocoagulation, preferably before vitreous hemorrhage or tractional detachment has occurred. When to Refer: All diabetic patients with sudden loss of vision or retinal detachment should be referred emergently to an ophthalmologist. Proliferative retinopathy or macular involvement requires urgent referral to an ophthalmologist. Severe non-proliferative retinopathy or unexplained reduction of visual acuity requires early referral to an ophthalmologist. Diabetic nephropathy is initially manifested by albuminuria; subsequently, as kidney function declines, urea and creatinine accumulate in the blood. An albumin-creatinine ratio in an early morning spot urine collected upon awakening is the preferred method to assess albumin excretion. In the early morning spot urine, a ratio of albumin (mcg/L) to creatinine (mg/L) of less than 30 mcg/mg creatinine is normal, and a ratio of 30-300 mcg/mg creatinine means microalbuminuria.  At least two early morning spot urine collections over a 3–6-month period should be abnormal before a diagnosis of microalbuminuria is justified. Short-term hyperglycemia, exercise, urinary tract infections, heart failure, and acute febrile illness can cause transient albuminuria and so testing for microalbuminuria should be postponed until resolution of these problems. Subsequent end-stage chronic kidney disease can be predicted by persistent urinary albumin excretion rates exceeding 30 mcg/mg creatinine. Diabetic Nephropathy: Glycemic control as well as a protein diet of ~0.8 g/kg/day may reduce both the hyperfiltration and the elevated microalbuminuria in patients in the early stages of diabetes and those with incipient diabetic nephropathy. Antihypertensive therapy also decreases microalbuminuria. ACE inhibitors can reduce intraglomerular pressure in addition to their lowering of systemic hypertension. An ACE inhibitor in normotensive diabetic patients impedes progression to proteinuria and prevents the increase in albumin excretion rate. SGLT2 therapy should be instituted in patients with type 2 diabetes who have kidney disease, together with optimal anti-hypertensive therapy, which includes an ACE inhibitor or angiotensin receptor blocker. Diabetic nephropathy is the most common cause of ESRD. The incidence is approximately 30% in both type 1 and type 2 diabetes mellitus. ESRD is much more likely to develop in persons with type 1 diabetes mellitus. With the current epidemic of obesity and type 2 diabetes mellitus, rates of diabetic nephropathy will continue to increase. Mortality rates are higher for diabetics with kidney disease compared to those without CKD. Clinical Findings: Develops about 10 years after the onset of diabetes. It may be present at the time type 2 diabetes mellitus is diagnosed. The first stage of diabetic nephropathy is hyperfiltration with an increase in GFR, followed by the development of microalbuminuria (30-300 mg/day). With progression, albuminuria increases > 300 mg/day and can be detected on a urine dipstick (overt proteinuria); GFR subsequently declines over time.  Yearly screening for microalbuminuria is recommended for all diabetic patients to detect disease at its earliest stage. The most common lesion in diabetic nephropathy is diffuse glomerulosclerosis, but nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) is pathognomonic. The kidneys are usually enlarged. Kidney biopsy is not required in most patients unless atypical findings are present, e.g., sudden onset of proteinuria, nephritic features, massive proteinuria (>10 g/day), urinary cellular casts, or rapid decline in GFR. Patients with diabetes are prone to other renal diseases. These include papillary necrosis, chronic interstitial nephritis, and type 4 renal tubular acidosis. Patients are more susceptible to AKI from many insults, including intravenous contrast material and concomitant use of NSAID. Treatment: With the onset of microalbuminuria, aggressive treatment is necessary. Strict glycemic control should be emphasized early in diabetic nephropathy. Recommended blood pressure goal for those with diabetic nephropathy should be 130/80 mm Hg or less. ACE inhibitors or ARBS in those with albuminuria lower the rate of progression to ESRD by reducing intraglomerular pressure and via antifibrotic effects. Diabetic patients are at high risk for hyperkalemia with inhibition of the RAS, so monitoring for hyperkalemia or a decline in GFR >30% with initiation or up titration of RAS inhibitors, requires dose reduction or discontinuation. Combination ARB and ACE inhibitor therapy is not recommended due to lack of efficacy and increased adverse events of hyperkalemia. In addition to their cardioprotective effects, the SGLT2 inhibitors slow progression of diabetic nephropathy; their use is limited to those with eGFR greater than 20 mL/min/1.73 m². Use of these agents may require reduction in diuretic dosing in those patients requiring natriuresis. Treatment of other cardiovascular risk factors and obesity is crucial. Many with diabetes have multiple comorbid conditions; therefore, in patients with ESRD who progress to dialysis, mortality over the first 5 years is high. Diabetic Neuropathy: Diabetic neuropathies are the most common complications of diabetes, affecting up to 50% of patients with diabetes. Peripheral Neuropathy: A. Distal symmetric polyneuropathy: This is the most common form of diabetic peripheral neuropathy where loss of function appears in a stocking-glove pattern and is due to an axonal neuropathic process. Longer nerves are especially vulnerable, hence the impact on the foot. Both motor and sensory nerve conduction is delayed in the peripheral nerves, and ankle jerks may be absent. Sensory involvement usually occurs first and is generally bilateral, symmetric, and associated with diminished perception of vibration, pain, and temperature. The pain can range from mild discomfort to severe incapacitating symptoms. The sensory deficit may eventually be of sufficient protective threshold should be instructed to inspect their feet daily for abrasions, or lacerations. Occasionally severe "burning" pain, particularly at night, can become physically and emotionally disabling. Nortriptyline or desipramine in doses of 25-150 mg/day orally may provide relief for pain from diabetic neuropathy. Patients often attribute the benefit to having a full night's sleep. Mild to moderate morning drowsiness is a side effect that generally improves with time or can be lessened by giving the medication before bedtime. Amitriptyline, 25-75 mg orally at bedtime, can also be used but has more anticholinergic side effects. Gabapentin (900-1800 mg orally daily in 3 divided doses) has also been shown to be effective in the treatment of painful diabetic neuropathy. Pregabalin, has been shown to be more effective. However, because of its abuse potential, it has been categorized as a controlled substance. Duloxetine (60-120 mg), a serotonin and norepinephrine reuptake inhibitor, is approved for the treatment of painful diabetic neuropathy. Capsaicin, a topical irritant, is effective in reducing local nerve pain; it is dispensed as a cream to be rubbed into the skin over the painful region two to four times daily.  Application of a 5% lidocaine patch over an area of maximal pain has been reported to be of benefit. B. Isolated Peripheral Neuropathy Involvement of the distribution of only one nerve ("mono-neuropathy") or of several nerves ("mono-neuropathy multiplex"). Characterized by sudden onset with subsequent recovery of all or most of the function. This neuropathology has been attributed to vascular ischemia. Cranial or femoral nerves are commonly involved, and motor abnormalities predominate. The patient with cranial nerve involvement usually has diplopia and single third, fourth, or sixth nerve weakness on examination. A full recovery of function occurs in 6-12 weeks. Diabetic amyotrophy: presents with onset of severe pain in the front of the thigh. Within a few days or weeks of the onset of pain, weakness and wasting of the quadriceps develops. As the weakness appears, the pain tends to improve. Management includes analgesia and improved diabetes control. The symptoms improve over 6-18 months. Autonomic neuropathy: Neuropathy of the autonomic system occurs principally in patients with diabetes of long duration. It affects many diverse visceral functions including blood pressure and pulse, gastrointestinal activity, bladder function, and erectile dysfunction. Treatment is directed specifically at each abnormality. A. Gastrointestinal System: Manifested by nausea, vomiting, postprandial fullness, reflux or dysphagia, constipation or diarrhea (or both). Gastroparesis should be considered in diabetic patients in whom unexpected fluctuations and variability in their blood glucose develops after meals. Metoclopramide can help in treating diabetic gastroparesis, in a dose of 10 mg orally, 30 minutes before every meal. Drowsiness, fatigue are common adverse effects. Tardive dyskinesia and extrapyramidal effects can occur. Erythromycin appears to bind to motilin receptors in the stomach and has been found to improve gastric emptying.  In selected patients, injections of botulinum toxin into the pylorus can reduce pylorus sphincter resistance and enhance gastric emptying. Gastric electrical stimulation has been reported to improve symptoms in patients with gastroparesis refractory to pharmacologic therapy. Diarrhea associated with autonomic neuropathy may respond to broad- spectrum antibiotic therapy (such as rifaximin, metronidazole, amoxicillin/clavulanate, ciprofloxacin, or doxycycline). Refractory diabetic diarrhea is often associated with impaired sphincter control and fecal incontinence. Therapy with loperamide, or diphenoxylate with atropine, may provide relief. In more severe cases, codeine may be required to reduce the frequency of diarrhea and improve the consistency of the stools. Clonidine may help with diabetic diarrhea; however, its usefulness is limited by its tendency to lower BP, resulting in worsening of orthostatic hypotension. Constipation usually responds to stimulant laxatives such as senna. B. Genitourinary System: Incomplete emptying of the bladder can sometimes occur. Bethanechol may improve emptying of the atonic urinary bladder. Catheter decompression of the distended bladder may be needed. Erectile dysfunction can result from neurologic, psychological, or vascular causes, or a combination of these causes. The phosphodiesterase type 5 (PDE5) inhibitors sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) are useful to improve erection. The PDE5 inhibitors potentiate the hypotensive effects of nitrates, and their use is contraindicated in patients on nitrates therapy. Intracorporeal injection of vasoactive medications (e.g., prostaglandin E1) causes penile engorgement and erection. C. Orthostatic Hypotension: Use of fitted stockings, tilting the head of the bed, and arising slowly from the supine position can be helpful in treating symptoms of orthostatic hypotension. When such measures are inadequate, treatment with fludrocortisone orally can be considered. However, it can result in supine hypertension. The alpha-agonist midodrine can also be used. Cardiovascular Complications: A. Heart disease: Microvascular complications may occur in the and this may explain the development of diabetic cardiomyopathy. More commonly, however, heart disease in patients with diabetes is due to coronary atherosclerosis (macrovascular complication). Myocardial infarction is 3-5 times more common in diabetic patients and is the leading cause of death in patients with type 2 diabetes. Cardiovascular disease risk is increased in patients with type 1 diabetes as well, although the absolute risk is lower than type 2 diabetes. Premenopausal women who normally have lower rates of coronary artery disease lose this protection once diabetes develops. The increased risk in patients with type 2 diabetes reflects the combination of hyperglycemia, dyslipidemia, abnormalities of platelet adhesiveness, coagulation factors, and hypertension. Reducing these risk factors would have a protective effect. Lowering LDL cholesterol reduces first events in patients without known coronary disease and secondary events in patients with known coronary disease. Guidelines have designated diabetes as a coronary risk equivalent. Patients with diabetes should have an LDL cholesterol goal of < 100 mg/dl. Lowering LDL cholesterol to 70 mg/dl is a recommended target for diabetic patients who have multiple risk factors for cardiovascular disease. Aspirin at a dose of 75-162 mg daily is effective in reducing cardiovascular morbidity and mortality in patients who have a history of myocardial infarction or stroke (secondary prevention). For primary prevention, the use of aspirin should only be considered for patients with high cardiovascular risk and low bleeding risk. B. Hypertension: The systolic target of 130 mm Hg or less and diastolic target of 80 mm Hg or less are recommended for people with diabetes. Patients with cardiovascular disease or microalbuminuria should be considered for treatment with an ACE inhibitor or an Angiotensin receptor blocker (ARB). C. Peripheral Vascular Disease: Atherosclerosis is markedly accelerated in the larger arteries. It is often diffuse, with localized enhancement in certain areas of turbulent blood flow, such as at the bifurcation of the aorta or other large vessels. Clinical manifestations of peripheral vascular disease include ischemia of the lower extremities, and erectile dysfunction. The incidence of gangrene of the feet in patients with diabetes is 30 times that in age-matched controls. Factors responsible for development of gangrene, in addition to peripheral vascular disease, are peripheral neuropathy (loss of sensation), and secondary infection. In patients with ischemic gangrene, pedal pulses are not palpable. In patients with palpable pulses, reduced blood flow can still be demonstrated by Doppler ultrasound examination. Prevention of foot injury is essential. Agents that reduce peripheral blood flow such as tobacco should be avoided. Control of other risk factors such as hypertension is essential. Beta-blockers are relatively contraindicated because of their negative peripheral hemodynamic consequences. Cholesterol-lowering agents (statins) are useful as adjunctive therapy when early ischemic signs are detected and when dyslipidemia is present. Patients should be advised to seek urgently immediate medical care if a diabetic foot ulcer develops. Improvement in peripheral blood flow surgically with angioplasty and bypass operations is possible in certain patients. Skin and Mucous Membrane Complications: Bacterial infections of the skin may occur, especially in poorly controlled diabetic patients. Candidal infection can produce erythema and edema of intertriginous areas below the breasts, in the axillas, and between the toes. It causes vulvovaginitis in women with uncontrolled diabetes who have persistent glucosuria and is a frequent cause of pruritus. While antifungal creams containing miconazole or clotrimazole can relieve vulvovaginitis, recurrence is frequent unless glucosuria is reduced. In patients with poor glycemic control, severe hypertriglyceridemia may develop, which can present as eruptive xanthomas and pancreatitis.  The skin lesions appear as yellow morbilliform eruptions 2-5 mm in diameter. On extensor surfaces (elbows, knees, buttocks), disappear after TGs is reduced. Necrobiosis lipoidica diabeticorum is usually located over the anterior surfaces of the legs. They are oval or irregularly shaped plaques with demarcated borders and a glistening yellow surface. The condition is associated with type 1 diabetes, although it can occur in patients with type 2 diabetes. "Shin spots" (diabetic dermopathy) are common in adults with diabetes. They are brownish, rounded, painless macular lesions of the skin in the pretibial area. They are associated with microvascular complications of diabetes. Bone and Joint Complications: Long-standing diabetes can cause progressive contracture and tightening of skin over the joints (diabetic cheiroarthropathy), frozen shoulder (adhesive capsulitis), and carpal tunnel syndrome. These complications are believed to be due to glycosylation of collagen and perhaps other proteins in connective tissue. There may also be an inflammatory component. Patients with diabetes do appear to be at increased risk for bone fractures, when compared with those without diabetes. Duration of diabetes, and diabetes complications, such as neuropathy and kidney disease, likely affect the bone mineral density and fracture risk. Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by ossification of the anterior longitudinal ligaments of the spine and various extraspinal ligaments. It causes stiffness and decreased range of spinal motion. The peripheral joints most commonly affected are the metacarpophalangeal joints, elbows, and shoulders. Diabetes, obesity, hypertension, and dyslipidemia are risk factors for this condition. Hyperuricemia and acute and tophaceous gout are more common in type 2 diabetes.