Microvascular complication (m)(t)

Microvascular complication (M.V.C)

• When we talk about (M.V.C) we usually talk we are talking about: (Nephropathy, Retinopathy and Neuropathy).

• We will deal with Retinopathy .

Agenda :

• Eye anatomy.• Types of retinopathy.• What is retina ?• Disease of retinopathy. • Factor affecting retina arterioles.• Treatment• Conclusion and prevention

eye anatomy

Retinopathy

• Types of retinopathy

3) Retinopathy

of hypertensive

2) Retinopathy of diabetics

mellitus

1) Retinopathy

of Prematurity

Retina • the innermost of the three tunics of the EYE

, surrounding the vitreous body and continuous posteriorly with the optic nerve. The retina is composed of light-sensitive neurons arranged in three layers; the first layer is made up of rods and cones and the other two transmit impulses from the rods and cones to the OPTIC NERVE. The rods are sensitive in dim light, and the cones are sensitive in bright light and are responsible for color vision.

• The retina is a specialized layer of neural tissue that coats the back of the eye. It is an outgrowth of the brain and therefore can be classified as a member of the central nervous system. Although, the retina can easily be compared to the film inside a camera, that analogy is misleading because the retina is very complex. It has many blood vessels that supply nutrients and oxygen to the retinal cells.

• The retina is composed of many specialized neural cells. The first layer of the retina to receive visual information is the specialized photoreceptor layer, which is composed of rods (cells responsible for night vision) and cones (the cells responsible for color vision). When excited, the photoreceptors pass their signals along to neighboring neurons in the retina that help to begin processing the visual information and in turn pass their signals on to the brain through the optic nerve.

Factor affecting retina

• Diameter of retina is very important in regulation of retinal blood flow.

• Retinal vascular system have no autonomic nervous supply.

• Since that the diameter of retinal arterioles is management through local factors from vascular lumen , vascular wall and perivascular retinal tissues.

• This regulation divided into:•

Pressure auto regulation Metabolic regulation

Change in diameter of retinal arterioles that ensure constant perfusion the capillary blood flow when blood pressure change

Adjustment balance between supply of nutrient and drain of metabolite waste products.

1) Retinopathy of Prematurity (ROP)

• Def. : Retinopathy of prematurity (ROP) is a vascular vitreoretinopathy that affects infants with short gestational age and low birth-weight.

• The condition is a multifactorial disease and is clinically similar to familial exudative vitreoretinopathy (FEVR), which is a bilateral hereditary eye disorder affecting full-term infants. Both of them are characterized by the abnormal vessel growth in the vitreous that can lead to vitreoretinal traction, retinal detachment and other.

• complications resulting in blindness. Despite the recent advances in diagnosis and treatment, ROP remains a major cause of childhood blindness in developed countries. The etiology of pathogenesis of advanced ROP is currently unknown. In the past, many causative factors such as length of time exposed to supplemental oxygen, excessive

• Vitreoretinopathy : Any of various eye diseases affecting the retina and vitreous humor.• ambient light exposure and hypoxia have been suggested but evidence for these as independent risk factors in• recent years is not compelling. It is not clear why ROP in a subset of infants with low birth-weight progresses to a• severe stage (retinal detachment) despite timely intervention whereas in other infants with similar clinical characteristics

ROP regresses spontaneously. Recent research with candidate gene approach, higher concordance rate in• monozygotic twins and other clinical and experimental animal studies, suggest a strong genetic predisposition to• ROP besides environmental factors such as prematurity. Three genes, which are involved in the Wnt signaling pathway,

are mutated in both FEVR (Familial Exudative Vitreoretinopathy, Autosomal Dominant)• and in a small percentage of ROP disorder. However, none of the genetic factors• identified thus far in ROP, account for a substantial number of patient population. Future studies involving• genomics, bioinformatics and proteomics may provide a better understanding of the pathophysiology and• management of ROP

the Wnt signaling pathway• Wnt proteins are a large family of secreted glycoproteins. Wnt proteins bind to the Frizzled receptors• and LRP5/6 co-receptors, and through stabilizing the critical mediator β-catenin, initiate a complex signaling• cascade that plays an important role in regulating cell proliferation and differentiation. Deregulation of the• canonical Wnt/β-catenin signaling pathway, mostly by inactivating mutations of the APC tumor suppressor, or• oncogenic mutations of β-catenin, has been implicated in colorectal tumorigenesis. Although oncogenic• mutations of β-catenin have only been discovered in a small fraction of non-colon cancers, elevated levels of β-

catenin protein, a hallmark of activated canonical Wnt pathway, have been observed in most common forms of• human malignancies, indicating that activation of this pathway may play an important role in tumor• development. Over the past 15 years, our understanding of this signaling pathway has significantly improved• with the identification of key regulatory proteins and the important downstream targets of β-catenin/Tcf• transactivation complex. Given the fact that Wnt/β-catenin signaling is tightly regulated at multiple cellular• levels, the pathway itself offers ample targeting nodal points for cancer drug development. In this review, we• discuss some of the strategies that are being used or can be explored to target key components of the Wnt/β-

catenin signaling pathway in rational cancer drug discovery.

The C terminal cytoplasmic Lys Thr X X X Trp motif in frizzled receptors ‐ ‐ ‐ ‐ ‐ ‐mediates Wnt/β catenin signaling‐

• Frizzled receptors are components of the Wnt signaling pathway, but how they activate the canonical Wnt/β catenin pathway is not clear. Here we use three ‐distinct vertebrate frizzled receptors (Xfz3, Xfz4 and Xfz7) and describe whether and how their C terminal cytoplasmic regions transduce the Wnt/β catenin signal. We ‐ ‐show that Xfz3 activates this pathway in the absence of exogenous ligands, while Xfz4 and Xfz7 interact with Xwnt5A to activate this pathway. Analysis using chimeric receptors reveals that their C terminal cytoplasmic regions are functionally ‐equivalent in Wnt/β catenin signaling. Furthermore, a conserved motif (Lys Thr X‐ ‐ ‐ ‐X X Trp) located two amino acids after the seventh transmembrane domain is ‐ ‐required for activation of the Wnt/β catenin pathway and for membrane ‐relocalization and phosphorylation of Disheveled. Frizzled receptors with point mutations affecting either of the three conserved residues are defective in Wnt/β‐catenin signaling. These findings provide functional evidence supporting a role of this conserved motif in the modulation of Wnt signaling. They are consistent with the genetic features exhibited by Drosophila Dfz3 and Caenorhabditis elegans mom‐5 in which the tryptophan is substituted by a tyrosine.

Pathology of Retinopathy of Prematurity

• Pathogenesis The International Classification of ROP divides the development of the disorder into 5 stages. In the early stages, ROP is characterized by an incomplete vascularization of the retina (Fig. 1 panel A), with a sharply demarcated boundary between vascularized and a vascularized retina (stage 1). This can progress to an elevated ridge (Fig. 1 panel B) that consists of mesenchymal tissue (stage 2). In more advanced stages of the disease , extra-retinal fibro-vascular proliferation occurs (Fig. 1panel C) on the posterior border

Immature retina

Stage 1: Demarcation Line

Stage 2: Ridge

Stage 3: Ridge + Epiretinal Fibro vascular Proliferation

Treatment:

• A)Surgically treatment1)Cryotherapy ( mostly outdated) s. US Cryotherapy2)Laser treatment (gold standard)3)Anti-VEGF (adjuvant) before laser and surgery4)Surgery• B)Non surgically: 1)Oxygen2)Light3)Vitamins4)DHEA (dehydroepiandrosterone)5)Other Supplements

Treatment:• Cryotherapytreatments available to the publicWhole Body Cryotherapy (WBC) is exposure to subzero temperatures. Extreme cold stimulates skin sensors, activating a Central Nervous System (CNS) response. This causes the release of endorphins, the body's natural pain inhibitors and mood elevators, while the enhanced circulation activity (blood movement into and out of the core) decreases inflammation by clearing toxins and metabolic waste with a supply of oxygen and nutrient enriched blood to stimulate cellular regeneration (faster healing). Treatments have been adopted by elite athletes and pro teams for muscle and injury recovery. WBC is becoming nationally well documented as being used for the daily management of pain, inflammation, energy, and stress related conditions. US Cryotherapy is the national leader as the most complete center model concept for safe, effective, and affordable

• Vitamins1)Vitamin E therapy in retinopathy of prematurity: Vitamin E is a fat soluble antioxidant and as a result it is able to scavenge free radicals derived from oxygen. The premature infant and the retina are likely to be particularly vulnerable to the deleterious effects of these oxygen derived free radicals, and as a result prophylactic vitamin E has been suggested for the management of retinopathy of prematurity (ROP). However, despite numerous trials, prophylactic supplementation with vitamin E remains controversial. This paper will critically review the use of vitamin E in ROP and consider the risk/benefit relationship of such treatment in premature infants.2)Vitamin A supplementation improves retinal function in infants at risk of retinopathy of prematurity:• Hyperoxia: occurs when tissues and organs are

exposed to an excess supply of oxygen (O2) or higher than normal partial pressure of oxygen. In medicine, it refers to excess oxygen in the lungs or other body tissues, which can be caused by breathing air or oxygen at pressures greater than normal atmospheric pressure.

Incident:

• The overall incidence of ROP is 16-17% for all premature infants.

• In infants with birth weight below 1251 grams, the incidence is 66%

• Major risk factors include: decreased gestational age, decreased birth weight, and supplemental oxygen therapy. Associated risk factors include acidosis, apnea, patent Ductus arteriosus, septicemia, blood transfusions, and intraventricular hemorrhage

2) Retinopathy of diabetics mellitus

• Diabetes• Definition• Risk factors• Pathogenesis• Classification : proliferative / non-proliferative• Sign & symptoms • Treatment & follow up• Screening for DR• Apply with case study

Diabetes mellitus

• Group of common metabolic disorders

• Caused by a complex interaction of genetics and environmental factors

• Lack of insulin hyperglycemia

• Diagnostic criteria : Fasting plasma glucose > 126 mg/dl

• Type 1 DM – Insulin-dependent diabetes (IDDM)

– Results from pancreatic beta-cell destruction, usually leading to absolute or near total

insulin deficiency

• Type 2 DM - Non-insulin-dependent diabetes (NIDDM)

– Variable degrees of insulin resistance and impaired insulin secretion, resulting in

hyperglycemia and other metabolic derangements due to insufficient insulin action.

Diabetes mellitus

• Long-standing hyperglycemia leads to multiple organ damage

– Macro vascular complications

• Stroke

• Heart disease and hypertension

• Peripheral vascular disease

• Foot problems

– Micro vascular complications

• Diabetic eye disease : retinopathy and cataracts

• Renal disease

• Neuropathy

• Foot problems

Diabetic retinopathy(D.E)• Prolonged hyperglycemia is the major etiologic agent in all of

the microvascular complications of diabetes, including diabetic retinopathy

• The most severe of ocular complications of diabetes• Caused by damage to blood vessels of the retina, leads to

retinal damage• Microvascular complication of longstanding diabetes mellitus

[1]

• Most prevalence cause of legal blindness between the ages of 20 and 65 years

• Common in DM type 1 > type 2

Risk factors• Duration of diabetes

– Most important– Pt diagnosed before age 30 yr

• 50% DR after 10 yrs• 90% DR after 30 yrs

• Poor metabolic control– Less important, but relevant to development and progression of DR– HbA1c ass. with risk

• Pregnancy– Ass with rapid progression of DR– Predicating factors : poor pre-pregnancy control of DM, too rapid

control during the early stages of pregnancy

Types of Diabetic retinopathy

• Microvascular leakage • Microvascular occlusion

Microvascular leakage

Degeneration and loss of pericytes

Plasma leakage

Intraregional hemorrhageHard exudate(Circinate pattern)

Capillary wall weakening

micro aneurysm

Retinal edema

Pericytes role • Blood vessels are composed of two interacting cell types. Endothelial cells form

the inner lining of the vessel wall, and perivascular cells—referred to as pericytes, vascular smooth muscle cells or mural cells—envelop the surface of the vascular tube. Over the last decades, studies of blood vessels have concentrated mainly on the endothelial cell component, especially when the first angiogenic factors were discovered, while the interest in pericytes has lagged behind. Pericytes are, however, functionally significant; when vessels lose pericytes, they become hemorrhagic and hyper dilated, which leads to conditions such as edema, diabetic retinopathy, and even embryonic lethality. Recently, pericytes have gained new attention as functional and critical contributors to tumor angiogenesis and therefore as potential new targets for antiangiogenic therapies. Pericytes are complex. Their ontogeny is not completely understood, and they perform various functions throughout the body. This review article describes the current knowledge about the nature of pericytes and their functions during vessel growth, vessel maintenance, and pathological angiogenesis.

Microvascular occlusion

Neovascularizationand fibro vascular proliferation

VEGF

Increased plasma viscosityDeformation of RBCIncreased platelets stickiness

Decreased capillary blood flowand perfusion

Endothelial cell damage and proliferation

Capillary basement membrane thickening

Retinal hypoxia

A-V shuntIRMA*

*intraretinal micro vascular abnormalities

Proliferative retinopathy

Rubeus's iridis

Classification

Non-proliferative diabetic retinopathy (NPDR)

Proliferative diabetic retinopathy (PDR)

1)Mild NPDR2)Moderate NPDR3)Severe NPDR

Non-proliferative retinopathy

Macular edema Proliferative retinopathy

In non-proliferative retinopathy, the most common form of retinopathy, capillaries in the back of the eye balloon and form pouches. Non-proliferative retinopathy can move through three stages (mild, moderate, and severe), as more and more blood vessels become blocked.

Although retinopathy does not usually cause vision loss at this stage, the capillary walls may lose their ability to control the passage of substances between the blood and the retina. Fluid can leak into the part of the eye where focusing occurs, the macula. When the macula swells with fluid, a condition called macula edema, vision blurs and can be lost entirely. Although non-proliferative retinopathy usually does not require treatment, macular edema must be treated, but fortunately treatment is usually effective at stopping and sometimes reversing vision loss

In some people, retinopathy progresses after several years to a more serious form called proliferative retinopathy. In this form, the blood vessels are so damaged they close off. In response, new blood vessels start growing in the retina. These new vessels are weak and can leak blood, blocking vision, which is a condition called vitreous hemorrhage. The new blood vessels can also cause scar tissue to grow. After the scar tissue shrinks, it can distort the retina or pull it out of place, a condition called retinal detachment.

Medical therapy• Prevention• Pregnancy makes DR worsen • The Fundamental Aim is - Glycemic

Control

HbA1C < 7.0%Pre-prandial PG 90 – 130 mg/dlPostprandial PG < 180 mg/dlBlood Pressure < 130/80 mmHgLipids-LDL < 100 mg/dlTriglycerides < 150

mg/dlHDL > 40 mg/dl

• Laser• Photocoagulation

• Diet and Exercise to achieve Euglycemia.

If Euglycemia not achieved; Follow Step 2.

• Step 2: Monotherapy with:– Sulfonylurea– Bigunide– Glitazones– Meglitinides (Repaglinides)– Alpha-glucosidase

• Step 3: Addition of second oral agent or Insulin.

Consider Insulin therapy in Type I DM always

Mechanisms causing diabetic complications-1

Accumulation of SorbitolPolyol (Polyhydroxy alcohols) Pathway

Sorbitol is formed from glucose catalyzed by aldose reductase

This pathway is activated in hyperglycemia Sorbitol does not cross cell membranes, accumulates

intracellularly and produces osmotic stress. Sorbitol normally helps in osmoregul

Consequences of high Sorbitol concentration

• Osmotic damage to cells: caused by impermeable Sorbitol intracellularly

• Reduction in nerve myoinositol: causes decrease activity of Na/K ATP Pump- causes decreased nerve conduction velocity

• Inhibition of nitric oxide (NO) production: results in vasoconstriction and hypertension

• Increased production of free radicals: which cause oxidative damage to tissue

Mechanisms causing diabetic complications-2

Glycation of Proteins Sugars in the blood and inside cells form chemical bonds to proteins and

to DNA by glycation or no enzymatic glycosylation. Over time, the glycated proteins are chemically modified to become

molecular structures called Advanced Glycation End products (AGEs).

Pathological Consequencesof Glycation of Proteins in Diabetics

Crosslinking reduces the flexibility, elasticity and functionality of the proteins.

The chemical modifications of glycation and crosslinking can initiate harmful inflammatory and autoimmune responses.

Glycation has been found in connective tissue collagen, arterial collagen, kidney glomerular basement membrane, eye lens crystalline, nerve myelin proteins and in the circulating low-density lipoprotein (LDL) of the blood.

Retinopathy of hypertensive• swelling of the optic nerve• Hypertensive retinopathy occurs in people who have high blood pressure. High

blood pressure causes blood vessel abnormalities. Abnormalities may include thickening of the small arteries, blockages of retinal blood vessels and bleeding from them. Sudden, severe high blood pressure may cause

• People with this disease frequently have no symptoms in the early stages. It may be discovered during a routine eye exam.

• Central serous retinopathy. Central serous retinopathy begins for reasons that are not well understood. In this condition, fluid accumulates in the membrane behind the retina. The fluid seeps in between layers of the retina and causes them to separate. This results in blurred vision or poor night vision

Treatment

• Prevention is the best cure until new treatment appear.

• Maintain blood and glucose level with the acceptable range.

Conclusion • Retinopathy means that disease has damaged the retina. The retina is the part

inside the eye that senses light. Different diseases can cause retinopathy. There can be partial or complete loss of vision. Retinopathy can develop slowly or suddenly, can get better on its own or lead to permanent damage.

Conclusion • retinopathy.

• The retina contains many blood vessels. Abnormalities in these vessels are a major cause of retinopathy.

• There are several types of retinopathy, including:• Retinopathy of prematurity (ROP). ROP occurs in some infants who are born prematurely or at a

low birth weight. When a child is born too early, retinal blood vessels do not have time to finish growing properly. In the early stages of ROP, there are only subtle changes and no obvious symptoms. In more advanced stages, the retina can become detached, causing blindness.

• Diabetic retinopathy. Diabetic retinopathy develops in people with type 1 or type 2 diabetes. It takes years to develop. Two kinds of diabetic retinopathy have the potential to diminish vision:

– In non proliferative retinopathy, blood vessels in the retina deteriorate. Deteriorating blood vessels can become blocked or deformed. Fluids, fats and proteins leak out of the abnormal blood vessels. Fluid can collect in the retina. This swelling impairs sharp vision.

– In proliferative retinopathy, new, structurally unstable blood vessels grow on the surface of the retina. These unstable blood vessels cause frequent minor bleeding. The bleeding causes local irritation and scarring.

Proliferative retinopathy can cause retinal detachment. This is a separation of the layers of the retina. It is one of the most serious consequences of proliferative retinopathy

Conclusion • The vitreous is the clear gel between the lens and the retina. Sudden bleeding into

the vitreous can obscure vision, often quite suddenly.

Conclusion • Hypertensive retinopathy. Hypertensive retinopathy occurs in people who have

high blood pressure. High blood pressure causes blood vessel abnormalities. Abnormalities may include thickening of the small arteries, blockages of retinal blood vessels and bleeding from them. Sudden, severe high blood pressure may cause swelling of the optic nerve.

People with this disease frequently have no symptoms in the early stages. It may be discovered during a routine eye exam.

• Central serous retinopathy. Central serous retinopathy begins for reasons that are not well understood. In this condition, fluid accumulates in the membrane behind the retina. The fluid seeps in between layers of the retina and causes them to separate. This results in blurred vision or poor night vision.

• Note : Hypertensive retinopathy and Diabetic retinopathy may be associated with glaucoma .