Dm complications

Anthony Edwards:'Be what you are.Don't change yourself for anything. God made you that way for a reason.'

Chronic Complications of DM Dr WaseemShafqat Associate Professor Medical Unit IV

Scenario A 45 years old diabetic patient presented to you with C/O Impaired vision , progressive over 2 years Paraesthesias in both lower limbs and mild numbness of hands Poly-uria worsening since 2 weeks Dizziness especially on rising up early in the morning On examination; pulse 106/min with no variation with respiration B.P 130/80 in supine and 90/60 on standing(after 3 minutes) pupils bilaterally white An ulcer in right heel What is your diagnosis???

COMPLICATIONS OF DIABETES Microvascular/neuropathic Retinopathy, cataract Impaired vision Nephropathy Renal failure Peripheral neuropathy Sensory loss ,Motor weakness Autonomic neuropathy Postural hypotension, Gastrointestinal problems (gastroparesis; altered bowel habit) Foot disease Ulceration , Arthropathy

Macrovascular Coronary circulation Myocardial ischemia/infarction Cerebral circulation Transient ischemic attack , Stroke Peripheral circulation Claudication , Ischemia

The development of a foot ulcer, renal impairment, sensory loss or retinopathy in a patient with long-standing diabetes would be recognized as a long-term complication of the disorder. It can also be a manifestations of a diabetic complication may be the presenting finding in a patient who is not known to have diabetes.

Diabetes may be first suspected when a patient visits an optometrist or podiatrist. Between 20% and 25% of patients with type 2 diabetes have evidence of established diabetic complications at the time of initial diagnosis. Diabetes may be detected for the first time when a patient presents with hypertension or a vascular event such as an acute myocardial infarction or stroke. Blood glucose should therefore be checked in all patients presenting with such pathology.

DIABETIC RETINOPATHY One of the most common causes of blindness in adults between 30 and 65 years of age in developed countries. Retinal photocoagulation is an effective treatment, particularly if it is given at a relatively early stage when the patient is usually symptomless. This means that regular examination of the fundi, with the pupils fully dilated, is mandatory in all diabetic patients.

Pathogenesis Hyperglycaemia increases retinal blood flow and metabolism and has direct effects on retinal endothelial cells and pericyte loss, which impairs vascular autoregulation. The resulting uncontrolled blood flow initially dilates capillaries but also increases production of vasoactive substances and endothelial cell proliferation, resulting in capillary closure. This causes chronic retinal hypoxia and stimulates production of growth factors, including vascular endothelial growth factor (VEGF), which stimulate endothelial cell growth (causing new vessel formation) and increase vascular permeability (causing retinal leakage and exudation).

CLINICAL FEATURES OF DIABETIC RETINOPATHY Microaneurysms Retinal haemorrhages Exudates Cotton wool spots Venous changes Neovascularisation Pre-retinal haemorrhage Vitreous haemorrhage Fibrosis

Microaneurysms ; In most cases these are the earliest clinical abnormality detected. They appear as tiny, discrete, circular, dark red spots near to, but apparently separate from, the retinal vessels. They look like tiny haemorrhages but photographs of injected preparations of retina show that they are in fact minute aneurysms arising mainly from the venous end of capillaries near areas of capillary closure.

Early fluorescein angiogram: microaneurysms and capillary telangiectasia in the parafoveal capillary bed for 360° around the macular center

Hemorrhages; These most characteristically occur in the deeper layers of the retina and hence are round and regular in shape and described as 'blot' hemorrhages. The smaller ones may be difficult to differentiate from microaneurysms and the two are often grouped together as 'dots and blots'. Superficial flame-shaped hemorrhages in the nerve fiber layer may also occur, particularly if the patient is hypertensive

IRMA Blot hemorrhage The black arrow points to IRMA (Intra-Retinal Microvascular Abnormalities) and the white arrows show blot hemorrhages.

Exudates ; These are characteristic of diabetic retinopathy. They vary in size from tiny specks to large confluent patches and tend to occur particularly in the perimacular area. They result from leakage of plasma from abnormal retinal capillaries and overlie areas of neuronal degeneration. The terms 'hard' exudates and 'soft' exudates (i.e. cotton wool spots) are no longer recommended.

Cotton wool spots; These are similar to those seen in hypertension, and also occur particularly within five disc diameters of the optic disc. They represent arteriolar occlusions causing retinal ischemia and hence are a feature of pre-proliferative diabetic retinopathy; they are most often seen in rapidly advancing retinopathy or in association with uncontrolled hypertension

Intraretinal microvascular abnormalities Intraretinal microvascular abnormalities (IRMA); Dilated, tortuous capillaries which represent the remaining patent capillaries in an area where most have been occluded and are a feature of severe pre-proliferative retinopathy.

Neovascularisation ; This may arise from the venous circulation either on the optic disc or in the retina in response to an ischaemic retina. The earliest appearance is that of fine tufts of delicate vessels forming arcades on the surface of the retina. As they grow, they may extend forwards onto the posterior surface of the vitreous. They are fragile and leaky and are liable to rupture, causing haemorrhage which may be pre-retinal ('sub-hyaloid') or into the vitreous.

Serous products leaking from these new vessel systems stimulate a connective tissue reaction, called gliosis. This first appears as a white, cloudy haze among the network of new vessels. As it extends, the new vessels may be obliterated and the surrounding retina covered by a dense white sheet. At this stage, bleeding is less common but retinal detachment can occur due to contraction of adhesions between the vitreous and the retina.

A tangle of blood vessels on the retinal surface is a crude attempt at vascularizing ischemic tissue.

Venous changes; These include venous dilatation (an early feature probably representing increased blood flow), 'beading' (sausage-like changes in calibre) and increased tortuosity including 'oxbow lakes' or loops. These latter changes indicate widespread capillary non-perfusion and are a feature of advanced pre-proliferative retinopathy.

An oxbow lake is a U-shaped body of water formed when a wide meander from the main stem of a river is cut off to create a lake.

Rubeosisiridis ; The more severe types of retinopathy may be accompanied by the development of new vessels on the anterior surface of the iris: 'rubeosisiridis'. These vessels may obstruct the drainage angle of the eye and the outflow of aqueous fluid, causing secondary glaucoma.

Rubeosisiridis (neovascularisation of the iris) is a disease of the iris of the eye in which there is formation of a fibrovascular membrane on the anterior surface of the iris

Classification Microaneurysms, abnormalities of the veins, and small blot haemorrhages and exudates situated in the periphery will not interfere with vision unless they are associated with oedema and thickening in the macular area. Macular oedema cannot be detected by direct ophthalmoscopy but should be suspected if there is impairment of visual acuity in association with mild peripheral non-proliferative retinopathy and no other obvious pathology.

New vessels may be symptomless until sudden visual loss occurs from a pre-retinal or vitreous haemorrhage. Although these frequently resolve, the risk of recurrence is high, and the more frequent the haemorrhage, the slower and less complete the recovery. Fibrous tissue may seriously interfere with vision by obscuring the retina and/or causing further retinal haemorrhage or detachment.

Non-proliferative 'background' retinopathy without maculopathy Venous dilatation Peripheral Microaneurysms Blot haemorrhages Exudates

Prognosis and action required; No immediate threat to vision Maximise control of blood glucose, lipids and blood pressure Give advice to stop smoking and reduce intake of alcohol. Observe carefully, i.e. fundoscopy with dilated pupils every6-12 months.Refer for specialist opinion if rate of progression increases significantly

Maculopathy Macula Exudation Haemorrhage Ischaemia Macular oedema

The arrows outline the edema Macular edema; The arrows outline the edema

Prognosis and action required; Sight-threatening Refer for specialist opinion. Medical review of risk factors, glycaemic control, blood pressure and lipid levels

Pre-proliferative retinopathy Venous loops and beading Prognosis and action required; Sight-threatening Refer for specialist opinion.

Clusters/sheets of microaneurysms and small blot haemorrhages and/or large retinal haemorrhagesIntraretinal microvascular abnormalities Multiple cotton wool spots. Macular oedema with reduced visual acuity Perimacular exudates ± retinal haemorrhages of any size. Prognosis and action required; At this stage rapid lowering of the blood glucose may result in abrupt worsening of retinopathy with the appearance of cotton wool spots and an increased number of haemorrhages; it may be safer to lower the blood glucose gradually over a period of months

Proliferative retinopathy Pre-retinal haemorrhageNeovascularisationFibrosisExudativemaculopathy Prognosis and action required; Sight-threatening . Urgent treatment.

Prevention of diabetic Retinopathy Glycaemic and blood pressure control; Good glycaemic control, particularly in the early years following the development of diabetes, reduces the risk of developing retinopathy. Early diagnosis followed by effective treatment is particularly important for those with type 2 diabetes, 25% of whom present with established retinopathy.

Hyperglycemia promotes retinal hyperperfusion, so a rapid reduction in blood glucose may cause an initial deterioration of retinopathy by causing relative ischemia. Blood pressure lowering is of proven benefit in hypertensive patients. Elevated plasma cholesterol is a risk factor for diabetic retinopathy, but evidence for the beneficial use of a statin is awaited.

Screening; Regular screening for retinopathy is essential in all diabetic patients but is particularly important in those with risk factors. These include early onset, long duration of diabetes, hypertension, poor glycaemic control, pregnancy, use of the oral contraceptive pill, smoking, excessive alcohol consumption and evidence of microangiopathy elsewhere, particularly neuropathy and proteinuria. The preferred screening option is a digital imaging photographic system, with reference if necessary to an ophthalmologist examination by slit lamp biomicroscopy.

Management Severe non-proliferative and proliferative retinopathy is treated with retinal photocoagulation, which has been shown to reduce severe visual loss by 85% (50% in patients with maculopathy). Photocoagulation is used: To destroy areas of retinal ischaemia (since it is thought that this plays a major role in the development of neovascularisation) To seal leaking microaneurysms and reduce macular oedema To gliose new vessels directly on the retinal surface (but not on the optic disc)

Argon laser photocoagulation is the usual form of laser used for pan-retinal photocoagulation and for treatment of macular oedema with topical anaesthesia and in skilled hands carries little risk; it can be very effective. Vision being maintained in up to 90% of patients. Extensive bilateral photocoagulation can cause significant visual field loss, which may interfere with driving ability and reduce night vision.

Vitrectomy may be used in selected cases with advanced diabetic eye disease where visual loss is due to recurrent vitreous haemorrhage which has failed to clear, or retinal detachment resulting from retinitis proliferans. Rubeosisiridis is managed by early pan-retinal photocoagulation.

OTHER CAUSES OF VISUAL LOSS IN PEOPLE WITH DIABETES; Around 50% of visual loss in people with type 2 diabetes is due to causes other than diabetic retinopathy. These include; Cataract Age-related macular degeneration Retinal vein occlusion Retinal arterial occlusion Non-arteriticischaemic optic neuropathy Glaucoma. Some of these conditions are to be expected in this group.

DIABETIC NEPHROPATHY Diabetic nephropathy is an important cause of morbidity and mortality, and is now among the most common causes of end-stage renal failure (ESRF) in developed countries. Management is frequently difficult and the benefits of prevention are substantial. About 30% of patients with type 1 diabetes have developed diabetic nephropathy after 20 years, but the risk after this time falls to less than 1% per year, and from the outset the risk is not equal in all patients. Overall incidence is declining as standards of glycaemic and blood pressure control have improved.

Pathology; The first changes (seen at the time of microalbuminuria) are thickening of the glomerular basement membrane and accumulation of matrix material in the mesangium. Subsequently, nodular deposits (Kimmelstiel-Wilson nodule ) are characteristic, and glomerulosclerosis worsens (heavy proteinuria develops) until glomeruli are progressively lost and renal function deteriorates.

Normal Glomerulous Diabetic Nephropathy

Microalbuminuria is an important indicator of risk of developing overt diabetic nephropathy, although it is also found in other conditions. It is therefore most reliable as an indicator of diabetic nephropathy within the first 10 years of type 1 diabetes (the majority will progress to overt nephropathy within a further 10 years), and less reliable in older patients with type 2 diabetes, in whom it may be accounted for by other diseases. In particular, the presence of microalbuminuria in patients with type 2 diabetes is associated with an increased risk of macrovascular disease. Progressively increasing albuminuria, or albuminuria accompanied by hypertension, is much more likely to be due to early diabetic nephropathy.

RISK FACTORS FOR DEVELOPING DIABETIC NEPHROPATHY Poor control of blood glucose Long duration of diabetes Presence of other microvascular complications Ethnicity (e.g. Asian races, Pima Indians) Pre-existing hypertension Family history of diabetic nephropathy Family history of hypertension

SCREENING FOR MICROALBUMINURIA; Identifies nephropathy in type 1 and type 2 diabetes; independent predictor of macrovascular disease in type 2 diabetes Risk factors include increased blood pressure, poor glycaemic control, smoking Random urine sample can estimate urinary albumin:creatinine ratio (3-30 mg/mmol (27-270 μg/mg)) (abnormal values: male > 2.5, female > 3.5) If possible confirm with an albumin excretion rate (AER) of 20-200 μg/min (30-300 mg/24 hrs); requires timed collection of urine (overnight or 24 hrs)

Who to screen Patients with type 1 diabetes annually from 5 years after diagnosis Patients with type 2 diabetes from time of diagnosis annually Abnormal tests Exclude recent (24 hrs) vigorous exercise, fever, heart failure, urine infection, prostatitis, menstruation Confirm observation twice within 3-6 months Look for blood pressure above target levels

Management If there is evidence of incipient nephropathy, vigorous efforts should be made to reduce the risk of progression by: improved control of blood glucose Aggressive reduction of blood pressure

Institution of angiotensin-converting enzyme inhibitor (ACE-I) therapy ('In patients with type 1 diabetes and microalbuminuria, ACE inhibitor treatment reduced the progression to established proteinuria by 69%, regardless of whether blood pressure was elevated or not.‘) Aggressive cardiovascular risk factor reduction ('In type 2 patients with microalbuminuria, intensive treatment (including control of glycaemia and hypertension, with use of ACE inhibitors, statins and aspirin) reduced the risk of cardiovascular disease by 53%, of nephropathy by 61%, and of retinopathy by 58% compared with conventional treatment.‘)

ACE inhibitors have been shown to provide greater benefit than equal blood pressure reduction achieved with other drugs. 'In type 2 patients with microalbuminuria, angiotensin receptor blockers reduced the development of persistent proteinuria from 15% to 5%. ACE inhibitors have similar benefits.' There may be particular problems with the use of either in diabetic nephropathy because of hyperkalaemia and renal artery stenosis.

Non-dihydropyridine calcium antagonists (diltiazem, verapamil) may be suitable alternatives in these circumstances. Diabetic control becomes difficult as renal impairment progresses. Treatment with metformin should be abandoned when creatinine is higher than 150 μmol/l (1.7 mg/dl) as the risk of lactic acidosis is increased. Long-acting sulphonylureasshould be replaced by short-acting agents that are metabolised rather than excreted.

Renal replacement therapy may benefit diabetic patients at an earlier stage than other patients with ESRF, although it may carry additional difficulties. Renal transplantation can dramatically improve the life of many, although macrovascular disease causing cardiac failure and peripheral vascular disease, and microvascular disease causing neuropathy and retinopathy show continued progression.

The progression of recurrent diabetic nephropathy in the allograft is usually too slow to be a serious problem. Coronary heart disease is the major cause of death. Pancreatic transplantation (generally carried out at the same time as renal transplantation) can produce insulin independence and can slow or reverse microvascular disease, but the supply of organs is very limited and this is available to few.

DIABETIC NEUROPATHY This is a relatively early and common complication Symptomless in the majority Prevalence is related to the duration of diabetes and the degree of metabolic control. The central nervous system is affected in long-term diabetes, the clinical impact of diabetes is mainly manifest in the peripheral nervous system. They can occur in motor, sensory and autonomic nerves.

HISTOPATHOLOGY Axonal degeneration of both myelinated and unmyelinatedfibres Early: axon shrinkage Later: axonal fragmentation; regeneration Thickening of Schwann cell basal lamina Patchy, segmental demyelination Thickening of basement membrane and microthrombi in intraneural capillaries

Regions of axonal loss were identified by zones of complete loss of recognizable fiber cylinders and replacement by homogeneous eosinophilic matrix (asterisk).

CLASSIFICATION OF DIABETIC NEUROPATHY Somatic Polyneuropathy Symmetrical, mainly sensory and distal Asymmetrical, mainly motor and proximal (including amyotrophy) Mononeuropathy (including mononeuritis multiplex)

Visceral (autonomic) Cardiovascular Gastrointestinal Genitourinary Sudomotor Vasomotor Pupillary

Symmetrical sensory polyneuropathy Frequently asymptomatic. Diminished perception of vibration sensation distally, 'glove-and-stocking' impairment of all other modalities of sensation, and loss of tendon reflexes in the lower limbs.

Symptoms include paraesthesiae in the feet and, rarely, in the hands, pain in the lower limbs (dull, aching and/or lancinating, worse at night, and mainly felt on the anterior aspect of the legs), burning sensations in the soles of the feet, cutaneoushyperaesthesia and an abnormal gait (commonly wide-based), often associated with a sense of numbness in the feet. Muscle weakness and wasting develop only in advanced cases, but subclinical motor nerve dysfunction is common.

The toes may be clawed with wasting of the interosseous muscles, which results in increased pressure on the plantar aspects of the metatarsal heads with the development of callus skin at these and other pressure points. A diffuse small-fibre neuropathy causes altered perception of pain and temperature and is associated with symptomatic autonomic neuropathy; characteristic features include foot ulcers and Charcot neuroarthropathy.

Charcot Foot 3 years later Normal Foot 3 years before

Asymmetrical motor diabetic neuropathy Sometimes called diabetic amyotrophy, this presents as severe and progressive weakness and wasting of the proximal muscles of the lower (and occasionally the upper) limbs. It is commonly accompanied by severe pain, mainly felt on the anterior aspect of the leg, and hyperaesthesia and paraesthesiae. Sometimes there may also be marked loss of weight ('neuropathic cachexia'). The patient may look extremely ill and be unable to get out of bed. Tendon reflexes may be absent on the affected side(s).

Sometimes there are extensor plantar responses and the cerebrospinal fluid protein is often raised. This condition is thought to involve acute infarction of the lower motor neurons of the lumbosacral plexus. Other lesions involving this plexus, such as neoplasms and lumbar disc disease, must be excluded. Although recovery usually occurs within 12 months, some deficits become permanent. Management is mainly supportive.

Mononeuropathy Either motor or sensory function can be affected within a single peripheral or cranial nerve. Unlike the gradual progression of distal symmetrical and autonomic neuropathies, mononeuropathies are severe and of rapid onset; they eventually recover. The nerves most commonly affected are the 3rd and 6th cranial nerves, resulting in diplopia, and the femoral and sciatic nerves.

Rarely, involvement of other single nerves results in paresis and paraesthesiae in the thorax and trunk (truncalradiculopathies). Nerve compression palsies commonly affect the median nerve, giving the clinical picture of carpal tunnel syndrome, and less commonly the ulnar nerve. Lateral popliteal nerve compression occasionally causes foot drop.

AUTONOMIC NEUROPATHY Cardiovascular (recall the scenario) Postural hypotension Resting tachycardia Fixed heart rate Gastrointestinal Dysphagia, due to oesophagealatony Abdominal fullness, nausea and vomiting, unstable glycaemia, due to delayed gastric emptying ('gastroparesis') Nocturnal diarrhoea ± faecal incontinence Constipation, due to colonic atony

Genitourinary Difficulty in micturition Urinary incontinence Recurrent infection, due to atonic bladder Erectile dysfunction and retrograde ejaculation Sudomotor Gustatory sweating Nocturnal sweats without hypoglycaemia Anhidrosis; fissures in the feet

Vasomotor Feet feel cold, due to loss of skin vasomotor responses Dependent oedema, due to loss of vasomotor tone and increased vascular permeability Bullous formation Pupillary Decreased pupil size Resistance to mydriatics Delayed or absent reflexes to light

TESTS OF CARDIOVASCULAR AUTONOMIC FUNCTION Simple cardiovascular reflex tests Heart rate variation during deep breathing Heart rate response to standing Heart rate changes during the Valsalvamanoeuvre Blood pressure response to standing Blood pressure response to sustained hand grip Other tests Baroreflex sensitivity using power spectral analysis of heart rate Time-domain analysis of heart rate and blood pressure variations MIBG (meta-iodobenzylguanidine) scan of the heart

Autonomic Neuropathy This is not necessarily associated with peripheral somatic neuropathy. Either parasympathetic or Sympathetic nerves may be predominantly affected in one or more visceral system. The development of autonomic neuropathy is less clearly related to poor metabolic control than somatic neuropathy, and improved control rarely results in amelioration of symptoms. Within 10 years of developing overt symptoms of autonomic neuropathy, 30-50% of patients are dead- manyfrom sudden cardiorespiratory arrest, the cause of which is unknown. Patients with postural hypotension (a drop in systolic pressure of ≥ 20 mmHg on standing from the supine position) have the highest subsequent mortality.

Erectile dysfunction; Erectile failure (impotence) affects 30% of diabetic males and is often multifactorial. Although neuropathy and vascular causes are common, psychological factors, including depression, anxiety and reduced libido, may be partly responsible. Alcohol and antihypertensive drugs such as thiazide diuretics and β-adrenoceptor antagonists (β-blockers) may cause sexual dysfunction and, rarely, patients may have an endocrine cause such as testosterone deficiency or hyperprolactinaemia.

Management Pain and paraesthesiae from peripheral somatic neuropathies; Intensive insulin therapy (strict glycaemic control) Tricyclic antidepressants (amitriptyline, imipramine) Anticonvulsants (gabapentin, carbamazepine, phenytoin, pregabalin) Substance P depleter capsaicin-topical Opiates (tramadol, oxycodone) Membrane stabilisers (mexiletine, intravenous lidocaine) Antioxidant (α-lipoic acid)

Postural hypotension Support stockings Fludrocortisoneα-adrenoceptor agonist (midodrine) Non-steroidal anti-inflammatory drugs (NSAIDs) Gastroparesis Dopamine antagonists (metoclopramide, domperidone) Erythromycin Diarrhoea Loperamide Broad-spectrum antibiotics Clonidine Octreotide

Constipation Stimulant laxatives (senna) Atonic bladder Intermittent self-catheterisation Excessive sweating Anticholinergic drugs (propantheline, poldine) Clonidine Topical antimuscarinic agent (glycopyrrolate cream)

Erectile dysfunction (impotence); Oral Phosphodiesterase type 5 inhibitors (sildenafil, vardenafil, tadalafil) Sublingual Dopamine agonist (apomorphine) Prostaglandin E1 (alprostadil) either Injected into corpus cavernosum, or intra-urethral administration of pellets (MUSE) Vacuum tumescence devices Implanted penile prosthesis Psychological counselling; psychosexual therapy

THE DIABETIC FOOT The foot is a frequent site for complications in patients with diabetes and for this reason foot care is particularly important. Tissue necrosis in the feet is a common reason for hospital admission in diabetic patients and may end with amputation.

Aetiology Foot ulceration occurs as a result of trauma (often trivial) in the presence of neuropathy and/or peripheral vascular disease with infection occurring as a secondary phenomenon following disruption of the protective epidermis. In most cases all three components are involved but sometimes neuropathy or ischaemia may predominate. Ischaemia alone accounts for a minority of foot ulcers in diabetic patients, with most being either neuropathic or neuro-ischaemic in type. The most common cause of ulceration is a plaque of callus skin beneath which tissue necrosis occurs. This eventually breaks through to the surface.

CLINICAL FEATURES OF THE DIABETIC FOOT

MANAGEMENT OF DIABETIC FOOT ULCERS Remove callus skin Treat infection Avoid weight-bearing Ensure good glycaemic control Control oedema Undertake angiogram to assess feasibility of vascular reconstruction where indicated….(Before amputation)

DIABETIC FOOT: PRACTICE POINTS Prevention is the most effective way of dealing with the problem of tissue necrosis in the diabetic foot. A podiatrist is an integral part of the diabetes team to ensure regular and effective podiatry and to educate patients in care of the feet Specially manufactured and fitted orthotic footware is required to prevent recurrence of ulceration and protect the feet of patients with Charcot neuroarthropathy.

Acute complications? Hypoglycemia Diabetic ketoacidosis (DKA) Non-ketotichyperosmolar coma/Hyperglycemic Hyper-osmolar state (HHS)

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