it is Microvascular complication of DM.pptx

. Microvascular complications of diabetes are those long-term complications that affect small blood vessels. These typically include retinopathy, nephropathy, and neuropathy. Retinopathy is divided into two main categories: Nonproliferative retinopathy and proliferative retinopathy.

1. Moderator: prof . yeweyenehareg Feleke ( consultant internist & Endocriologist ) Presenter: Beza Guesh (R3) April 30, 2020 Micro vascular complication of DM

2. Outline Introduction Evidence on Micro vascular complication Path physiologic features of Micro vascular complication Diabetic Retinopathy Diabetic Nephropathy Diabetic Neuropathy Reference

3. I ntroduction Diabetes-related complications affect many organ systems and are responsible for the majority of morbidity and mortality associated with the disease. In US diabetes has been the leading cause of new blindness in adults, renal failure, and non traumatic lower extremity amputation. Recently emerged as a leading contributor to coronary heart disease (CHD).

4. Continued …. Diabetes mellitus accounts for 50% of all non trauma amputations in the United States. The risk of cardiovascular complications is increased by two fold to six fold in subjects with diabetes. Overall, life expectancy is about 7 to 10 years shorter than for people without diabetes mellitus because of increased mortality from diabetic complications.

5. Continued… Many of the diabetes-related complications can be prevented or delayed with a focus on diet, fitness, early detection, aggressive glycemic control, and efforts to minimize the risks of complications .

6. Continued… Diabetes-related complications can be divided: Vascular Microvascular : retinopathy, neuropathy, nephropathy Macro vascular : coronary heart disease [CHD], peripheral arterial disease [PAD], cerebro vascular disease) Nonvascular complications; Gastro paresis ,Infection ,Hearing loss …

7. Micro vascular complications are diabetes-specific, whereas Macro vascular complications have path physiologic features that are both shared with the general population and diabetes-specific.

8. Evidence regarding Micro vascular complications Large prospective clinical studies show a strong relationship between glycemia and Diabetic micro vascular complications in both type 1 diabetes mellitus (T1DM) and type 2 diabetes (T2DM).

9. UKPDS The United Kingdom Prospective Diabetes Study (UKPDS) studied the course of >5000 individuals with type 2 DM for >10 years.

10. Continued…. Individuals in the intensive treatment arm achieved an HbA1c of 7%, compared to a 7.9% HbA1c in the standard treatment group. The UKPDS demonstrated that each percentage point reduction in HbA1c was associated with a 35% reduction in micro vascular complications.

11. Continued…. The beneficial effects of blood pressure control were greater than the beneficial effects of Glycaemic control. Lowering blood pressure to moderate goals (144/82 mmHg) reduced the risk of DM-related death, stroke, micro vascular endpoints, retinopathy, and heart failure (risk reductions between 32 and 56%).

12. Pathophysiologic Features of Micro vascular Complications In the retina, glomerulus, and vasa nervorum, diabetes specific micro vascular disease is characterized by similar Pathophysiologic features. Chronic hyperglycemia is the important etiologic factor leading to complications of DM.

13. How does Hyperglycemia cause Complications? Microvascular complications occur in cells and tissues which are unable to limit glucose transport in the face of hyperglycemia (particularly the retina , the mesangium in the kidney and Schwann cells ) .

14. Four mechanism Increased intracellular glucose formation of A dvanced glycosylation end products , which bind to a cell surface receptor , via the non enzymatic glycosylation of intra- and extracellular proteins cross-linking of proteins, accelerated atherosclerosis, glomerular dysfunction, endothelial dysfunction, and altered extracellular matrix composition.

15. Advanced glycation end products can cause damage and ultimately complications of diabetes in two ways: cross-linkage of matrix proteins, such as collagen and laminin , leading to thickening and stiffening of blood vessels which can affect permeability and elasticity. AGE- modified circulating proteins bind to specific receptors ( RAGEs) on several types of cell, including monocyte/ macrophages , glomerular mesangial cells and endothelial cells .

16. binding of AGE to receptors leads to: G eneration of reactive oxygen species Activation of secondary messengers such as: protein kinase C (PKC ) release of transcription factor NFκB and stimulation of cytokine and growth factor production, result in inflammatory cell adhesion (via increased VCAM-1, procoagulant protein expression and increased vascular permeability (via VEGF)

17. Hyperglycemia increases glucose metabolism via the sorbitol pathway related to the enzyme aldose reductase . Aldose reductase is a ubiquitous enzyme found in many tissues but specifically nerve cells, retinal cells, the glomerulus and kidney tubule, and blood vessel walls. Sorbitol does not diffuse easily across cell membranes and damage may occur because of osmotic stress .

18. ( 3 ) Hyperglycemia increases the formation of diacylglycerol , leading to activation of protein kinase C , which alters the transcription of genes for fibronectin, type IV collagen , contractile proteins, and extracellular matrix proteins in endothelial cells and neurons.

19. (4 ) Hyperglycemia increases the flux through the hexosamine pathway, which generates fructose-6-phosphate, a substrate for O-linked glycosylation and proteoglycan production, leading to altered function by glycosylation of proteins such as endothelial nitric oxide synthase by changes in gene expression of transforming growth factor β ( TGF- β ) - profibrogenic cytokine or plasminogen activator inhibitor-1 which promotes thrombosis

20. Genetic Determinants of Susceptibility to Micro vascular Complications Clinicians have long observed that different patients with similar duration and degree of hyperglycemia differ markedly in their susceptibility to micro vascular complication. A role for a genetic determinant of susceptibility to diabetic nephropathy is most strongly supported by familial clustering, with an estimated heritability of at least 40%.

21. Numerous associations have been made between various genetic polymorphisms and the risk of diabetic complications. Examples include the 5′ insulin gene polymorphism, the G2m23+ immunoglobulin allotype , angiotensin -converting enzyme (ACE) insertion/deletion polymorphisms, HLA-DQB10201/0302 alleles, polymorphisms of the aldose reductase gene….

22. Diabetic eye disease Diabetic retinopathy Iris – Rubeosis iridis Lens –snow storm cataract

23. Diabetic Retinopathy Diabetic eye disease primarily affects the retinal vasculature . Most people with diabetes will show signs of retinopathy after 25 years duration but only a minority progress to the severest form . D iabetic retinopathy can be classified as non proliferative and proliferative.

24. Non proliferative retinopathy The earliest pathological features are thickening of the retinal capillary basement membrane, loss of tight junctions in the retinal endothelium, and loss of pericytes which are the contractile cells enveloping the capillaries and which control vessel calibre and thus perfusion.

25. Non proliferative Retinopathy is marked by Retinal vascular microaneurysms Blot hemorrhages and cotton-wool spots in case of more extensive disease, changes in venous vessel caliber, intraretinal microvascular abnormalities( IrMa )

26. Capillary closure is a feature of advancing retinopathy and the resultant ischaemia is a driver for subsequent proliferation . Capillary closure causes microinfarcts in the nerve fibre layer and these appear as indistinct white patches and are termed cotton wool spots. More advanced ischaemia results with the development of intraretinal microvascular abnormalities(IRMA ) which are clumps of small irregularly branching vessels within the retina, and venous dilatation beading.

27. Proliferative Retinopathy The appearance of neovascularization in response to retinal hypoxemia. These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment.

28. Classification of retinopathy

29. Treatment of Retinopathy Glycaemic control Is best method for the primary prevention of new retinopathy, and secondary prevention of progression of existing retinopathy.(DCCT&UKPDS) R apid improvement in glycaemia can result in an early worsening of retinopathy . ADA 2020 ; Optimize glycemic control to reduce the risk or slow the progression of diabetic retinopathy. A

30. Blood pressure control UKPDS: 34 % risk reduction in progression of retinopathy , and 35% risk reduction in the need for laser photocoagulation when BP <150/85 Post hoc analysis suggested every 10mmHg reduction in blood pressure there is a 13% decrease in the aggregate microvascular endpoint . ADA 2020:Optimize blood pressure and serum lipid control to reduce the risk or slow the progression of diabetic retinopathy. A

31. Laser photocoagulation Pan retinal laser photocoagulation (PRP ) reduces the risk of blindness in eyes with proliferative retinopathy by 61% , and this has now become the cornerstone of treatment of advanced disease . Focal laser photocoagulation can be effective for more discrete neovascularisation or ischaemia . There is no evidence that PRP confers benefit until sight-threatening proliferative retinopathy is present.

32. Anti-Vascular Endothelial Growth Factor(anti-VEGF) The FDA approved ranibizumab for the treatment of diabetic retinopathy in 2017. Resulted in visual acuity outcomes that were not inferior to those observed in patients treated with pan retinal laser at 2 years of follow up.

33. Other medical treatment Renin angiotensin system (RAS) blockade Lisinopril : no statistically significant benefit candesartan : significantly associated with less retinopathy progression Lipid - lowering agents The Fenofi brate Intervention and Event Lowering in Diabetes (FIELD ) study found a significant reduction in the need for laser therapy (5.2% versus 3.6%: p = 0.0003) in 9795 patients with type 2 diabetes treated for 5 years .

34. Growth hormone inhibitors Octreotide (a somatostatin analogue that blocks growth hormone release) has been shown to decrease progression of severe non -proliferative or early proliferative retinopathy but had serious GI side effects. Intravitreal steroids Both triamcinolone (by injection) and fluocinolone ( by implant ) have been shown to reduce macular oedema and improve visual acuity but with the serious side effects of glaucoma and cataract formation

35. Surveillance and screening Adults with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes. Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist at the time of the diabetes diagnosis .

36. Continued… If there is no evidence of retinopathy for one or more annual eye exams and glycemia is well controlled ,then screening every 1–2 years may be considered. If any level of diabetic retinopathy is present, subsequent dilated retinal examinations should be repeated at least annually by an ophthalmologist or optometrist.

37. Continued… Eye examinations should occur before pregnancy or in the first trimester in patients with preexisting type 1 or type 2 diabetes, and then patients should be monitored every trimester and for 1 year postpartum as indicated by the degree of retinopathy. B

38. Diabetic Nephropathy Diabetic kidney disease is usually a clinical diagnosis made based on the presence of Albuminuria and/or reduced eGFR in the absence of signs or symptoms of other primary causes of kidney damage. is the leading cause of chronic kidney disease (CKD), ESRD, and CKD requiring renal replacement therapy.

39. Only 20–40% of patients with diabetes develop diabetic nephropathy. Albuminuria in individuals with DM is associated with an increased risk of cardiovascular disease. Individuals with diabetic nephropathy commonly have diabetic retinopathy.

40. Risk factors for nephropathy

41. Clinical presentation The typical presentation of diabetic kidney disease is considered to include a long-standing duration of diabetes, retinopathy, Albuminuria without gross hematuria, and gradually progressive loss of eGFR. Diabetic kidney disease typically develops after diabetes duration of 10 years in type 1 diabetes , but may be present at diagnosis of type 2 diabetes.

42. pathophysiology The earliest pathological feature is thickening of the glomerular capillary basement membrane due to an accumulation of matrix material. Increasing proteinuria is preceded and accompanied by further accumulations of matrix material (mostly type IV collagen and laminin ) in the mesangium ( called diffuse glomerulosclerosis ), due to both overproduction and reduced breakdown and clearance . Ultimately this process obliterates the capillary and reduces filtration , leading to renal failure .

43. Surveillance Albuminuria and e GFR should be monitored regularly: To enable timely diagnosis of CKD Monitor progression of CKD Detect superimposed kidney diseases including AKI Assess risk of CKD complications Dose drugs appropriately ,and determine whether nephrology referral is needed.

44. At least once a year, assess urinary albumin (e.g., spot urinary albumin-to creatinine ratio) and estimated glomerular filtration rate (eGFR) in patients with type1 diabetes with duration of >5years and in all patients with type2 diabetes regardless of treatment . B Patients with urinary albumin >30 mg/g creatinine and/or an eGFR<60mL/min/1.73m2 should be monitored twice annually to guide therapy. C

45. Management Glycaemic control G ood glycaemic control can prevent the development of microalbuminuria and this benefit was apparent for at least 8–10 years (as it is shown in DCCT/EDIC and UKPDS) But it can’t prevent or delay the progress of nephropathy once it is established because after nephropathy has been initiated (by largely glucose-dependent mechanisms ), it is continued by pathways that are no longer sensitive to changes in glycaemia.

46. Blood pressure control Blood pressure levels,140/90mmHg are generally recommended to reduce CVD mortality and slow CKD progression among all people with diabetes . ADA 2020 Lower blood pressure targets <130/80 is recommended in Patients with CKD are at increased risk of CKD progression (particularly those with Albuminuria >300mg/day) and CVD.

47. ACE inhibitors or ARBs are the preferred first -line agent for blood pressure treatment among patients with diabetes, hypertension, eGFR ,60 mL /min/ 1.73 m2, and UACR >300 mg/g Cr because of their proven benefits for prevention of CKD progression. An ACE inhibitor or ARB is not recommended for the primary prevention of CKD inpatients with diabetes who have normal blood pressure, normal urinary albumin to-creatinine ratio(,30mg/g creatinine),and normal e GFR. A

48. Diabetic Neuropathy Diabetic neuropathy occurs in ~50% of individuals with longstanding type 1 and type 2 DM. Diabetic neuropathy should not be diagnosed solely on the basis of one symptom , physical sign or test; it is recommended that a minimum of two abnormalities be detected (symptoms, signs or test abnormalities – nerve conduction, quantitative sensory testing or quantitative autonomic testing)

49. Continued… Diabetic neuropathy is a diagnosis of exclusion. Non diabetic neuropathies may be present in patients with diabetes and may be treatable .

50. Risk factor of Diabetic neuropathy Duration of diabetes Glycaemic control. Body mass index (BMI) (the greater the BMI, the greater the risk of neuropathy) Smoking

51. Clinical manifestation Positive symptoms of neuropathy are distressing, often occur at night, are disabling and difficult to treat. sensory loss and pain, up to 50% of patients do not have symptoms of neuropathy. Symptoms may include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads proximally.

52. clinical tests used to assess small and large-fiber function and protective sensation : 1. Small-fiber function: pinprick and temperature sensation 2. Large-fiber function: vibration perception and 10-g monofilament 3. Protective sensation: 10-g monofilament when there is Loss of protective function(LOPS) there is distal sensorimotor polyneuropathy risk factor for foot ulceration

53. Monofilament test In identifying feet at risk of ulceration, the 10g monofilament has a sensitivity of 86–100 %. The monofilament should be applied to the sole of each foot in four places (over the hallux and metatarsal heads 1, 3, 5)

54. Chronic sensorimotor neuropathy Chronic sensorimotor neuropathy is the most common form of diabetic neuropathy . results from the distal dying back of axons that begins in the longest nerves. Sensory loss is most evident; autonomic involvement is usual. Neuro exam- loss of reflex

55. Compression neuropathies Pressure palsies comprise focal lesions of peripheral nerves that occur at sites of entrapment or compression. Diabetic nerve are sensitive for mechanical injury. E.g carpal tunnel syndrome – medial nerve compression MX : surgical decompression

56. Focal neuropathy In mononeuropathies , single nerves or their roots are affected. these conditions are of rapid onset and reversible, which suggests an acute, possibly vasculitic or inflammatory origin rather than chronic metabolic disturbance . The most well known is femoral neuropathy or diabetic amyotrophy

57. Autonomic neuropathy Long standing diabetes Can affect organs that receive an autonomic innervation. Common manifestations : postural hypotension (systolic blood pressure fall >30mmHg on standing ) blunting of physiological heart rate variations, diarrhoea and impotence . Gastroparesis (delayed gastric emptying and vomiting ) and bladder dysfunction are rare

58. Complication of diabetic neuropathy • Foot ulceration • Neuropathic edema, caused by increased blood flow in the foot, which has reduced sympathetic innervation • Charcot arthropathy , with chronic destruction, deformity and inflammation of the joints and bones of the mid- foot.

59. Screening All patients should be assessed for diabetic peripheral neuropathy starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter. B

60. Treatment of diabetic neuropathy

61. Summary of diabetes-related complications ( 1) Duration and degree of hyperglycemia correlate with complications. ( 2) Intensive glycemic control is beneficial in all forms of DM . (3) Blood pressure control is critical, especially in type 2 DM. ( 4) Survival in patients with type 1 DM is improving, and diabetes-related complications are declining. ( 5) Not all individuals with diabetes develop diabetes-related complications: genetic sensentivity

62. Reference Harrison 20 th Edition Williams text book of Endocriology 12 th edition Handbook of diabetes 4 th edition ADA guideline 2020 Internet Up todate 2019

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