L37 Hyperlipidaemia PDF

Hyperlipidemia  Learning outcomes By the end of the session, students should be able to: ❑ Describe different types of dyslipidemia ❑Determine the types and causes of hyperlipidemia ❑Describe the pathophysiology of hyperlipidemia. ❑Outline strategy for controlling hyperlipid...

Hyperlipidemia  Learning outcomes By the end of the session, students should be able to: ❑ Describe different types of dyslipidemia ❑Determine the types and causes of hyperlipidemia ❑Describe the pathophysiology of hyperlipidemia. ❑Outline strategy for controlling hyperlipidemia Case study A 55 years old woman presents with crushing substernal chest pain and shortness of breath. A coronary artery is occluded due to an atherosclerotic plaque, and myocardial infarction is diagnosed. 1. What is the biochemical base of the disease? 2. Enumerate different drugs suggested for hyperlipidemia Dyslipidemia  Dyslipidemia: Is an abnormal amount of lipids in the blood Types: A. Hyperlipidemia is defined as abnormally elevated levels of any or all lipids and/or lipoproteins in the blood. B. Hypolipidemia: defined as abnormally lowered levels of any or all lipids and/or lipoproteins in the blood. There are 3 major lipids in blood 1. Cholesterol 2. Triglycerides 3. Phospholipids  Hyperlipidemia Defined as abnormally elevated levels of any or all lipids and/or lipoproteins in the blood Key lipids involved in hyperlipidemia are: Low-Density Lipoprotein (LDL) Cholesterol: Often called "bad cholesterol" because it contributes to plaque buildup in the arteries. High-Density Lipoprotein (HDL) Cholesterol: "Good cholesterol" that helps remove excess cholesterol from the bloodstream.  Sources and functions of plasma lipoproteins Type Source Function Chylomicron Intestine Transport of exogenous TAG (mainly), cholesterol & cholesterol esters from the intestine to the tissues. VLDL Liver Transport of endogenous TAG from the liver to the peripheral tissues LDL VLDL Transport of cholesterol from the liver to the peripheral tissues HDL Liver Transport of cholesterol from peripheral tissues to the liver for & intestine elimination (reverse= retrograde cholesterol transport) Overview Chylomicrons transport TGs from the intestinal mucosa to the liver From the liver, the VLDL release TGs and some cholesterol and become LDL LDL then carries cholesterol to the cells of the body HDL carry cholesterol back to the liver for metabolism &excretion  Hyperlipidemia and Its Role in Atherosclerosis Excess Cholesterol: When there is too much LDL cholesterol, it tends to accumulate in the artery walls, especially if the levels of HDL (which clears LDL) are low. Plaque Formation: LDL particles that build up in the arterial walls are oxidized and trigger an inflammatory response. White blood cells, particularly macrophages, try to digest the cholesterol but become "foam cells" and accumulate, leading to plaque formation.  Hyperlipidemia and Its Role in Atherosclerosis Plaque Growth: Over time, these plaques harden, narrow the arteries, and reduce blood flow Hyperlipidemia can significantly increase the risk of developing cardiovascular disease, including disease of blood vessels supplying the heart (coronary artery disease), brain (cerebrovascular disease), and limbs (peripheral artery disease). Classification of hyperlipidemia They are classified into two main categories A. Primary (Familial hyperlipidemia): ❑It is caused by specific genetic defects in lipid or lipoprotein metabolism. ❑ It is classified according to Fredrickson classification B. Secondary Hyperlipidemia: It results from an alternate underlying etiology A. Primary (Familial hyperlipidemia): Fredrickson classification Type I: Familial Hyperchylomicronemia Elevated Lipoproteins: Chylomicrons Plasma level abnormality: Very high Chylomicrons Cause: Often due to genetic mutations affecting enzymes like LPL or apoC-II (a necessary cofactor for lipase). Risk: Low for atherosclerosis, but high for pancreatitis. Prevalence: Very rare.  Fredrickson classification A. Primary (Familial hyperlipidemia): Type II: Familial Hypercholesterolemia Subtypes: Type IIa: Elevated Lipoproteins: LDL. Primary Lipid Abnormality: High LDL cholesterol. Cause: Often due to LDL receptor deficiency or dysfunction Risk: High for atherosclerosis and cardiovascular disease. Symptoms: xanthomas (Cholesterol deposits in the skin) Type IIb (Familial Combined Hyperlipidemia): Elevated Lipoproteins: LDL and VLDL. Primary Lipid Abnormality: High LDL cholesterol and triglycerides. Cause: Genetic factors, often combined with lifestyle factors like diet and obesity and over production of VLDL by liver Risk: High for atherosclerosis and cardiovascular disease A. Primary (Familial hyperlipidemia): Fredrickson classification Type III: Familial Dysbetalipoproteinemia (Remnant Hyperlipidemia) Elevated Lipoproteins: IDL (Intermediate-Density Lipoproteins), also known as remnant lipoproteins. Primary Lipid Abnormality: High cholesterol and triglycerides. Cause: Mutation in Apo E Risk: High for atherosclerosis, particularly peripheral artery disease and premature coronary artery disease. A. Primary (Familial hyperlipidemia): Fredrickson classification Type IV: Familial Hypertriglyceridemia Elevated Lipoproteins: VLDL. Primary Lipid Abnormality: High triglycerides, with normal or slightly elevated cholesterol. Cause: Genetic and often associated with obesity, type 2 diabetes, or high- carbohydrate diets. Risk: Moderate for atherosclerosis A. Primary (Familial hyperlipidemia): Fredrickson classification Type V: Mixed Hyperlipidemia (Combined Hyperlipoproteinemia) Elevated Lipoproteins: VLDL and chylomicrons. Primary Lipid Abnormality: Very high triglycerides and elevated cholesterol. Cause: Overproduction or decreased clearance of CMs, VLDL Risk: Moderate for atherosclerosis; high risk for pancreatitis.  Primary (Familial hyperlipidemia) Fredrickson classification of hyperlipidemia Type Primary hyperlipidemia Plasma elevation Etiology Main complication I Familial Chylomicrons Deficiency of LPL or apoCII Pancreatitis hyperchylomicronemia IIa Familial LDL Decrease Or defect LDL Atherosclerosis hypercholesterolemia receptor IIb Familial combined LDL, VLDL Overproduction of VLDL by Atherosclerosis hypercholesterolemia liver III Familial IDL Abnormal apoE Atherosclerosis dysbetalipoproteinemia IV Simple hypertriglyceridemia VLDL Overproduction or impaired Atherosclerosis catabolism of VLDL V Familial mixed CMs, VLDL Overproduction or clearance Pancreatitis hypertriglyceridemia of CMs, VLDL Secondary Hyperlipidemia Secondary hyperlipidemia is the disorder of lipid metabolism induced by certain diseases, hormonal changes, and medication Ex : ❑ Obesity ❑ Diabetes mellitus ❑ Hypothyroidism ❑ Drugs (steroids, estrogens as contained in contraceptive medications) Management of hyperlipidemia The management of hyperlipidemia aims to reduce lipid levels in the blood to prevent complications such as atherosclerosis, heart attacks, and strokes. Treatment typically involves a combination of lifestyle changes and, if necessary, medication Non-pharmacological therapy (lifestyle modification) Diet low in cholesterol Exercise Quit smoking Eat: ✓ Omega 3 FA ✓ Olive oil ✓ Garlic ✓ Onion Don’t eat: ✓ Fried food ✓ Trans fat ✓ Too much Coffee or alcohol  Medications HMG CoA reductase Decrease synthesis of Cholesterol & inhibitor (statins) increase synthesis of LDL receptors Cholesterol absorption inhibit absorption of cholesterol by small inhibitors intestine Bile acid sequestrants prevent reabsorption of bile acids to as cholestyramine blood→ increase elimination of bile acids and cholesterol in the stool. Fibrates increase activity of lipoprotein lipase (LPL) and reduce levels of VLDL.→ decrease TGs  Hypolipidemia Abnormally lowered levels of any or all lipids and/or lipoproteins in the blood Disorders of Hypolipidemia Primary causes: Genetetic A. Tangier disease B. Familial LCAT Deficiency Secondary causes: Hyperthyroidism Malnutrition and Starvation Malabsorption Drug-Induced: Medications such as statins, fibrates, and niacin  1-Tangier [severe form of hypolipoproteinemia] Cause: Mutation in the ABCA1 gene which is a transporter protein that transports free cholesterol from extrahepatic tissues to apoA-1, to form the nascent HDL particle” This leads to defect in mobilization of cholesterol from the peripheral tissues → accumulation in various tissues, including the spleen, nerves, skin, and lymphoid tissue Patients have very low serum HDL The clinical features: yellowish-orange discoloration of the tonsils, tonsillar enlargement, hepatosplenomegaly, and peripheral neuropathy  2-Familial LCAT Deficiency Familial LCAT (lecithin cholesterol acyl transferase) deficiency is due to mutations in the LCAT gene, which results in reduced esterification of free cholesterol into cholesterol esters interfering with the function of HDL The clinical features: classically present with extensive corneal opacification that is often referred to as “fish-eye disease”  LCAT lecithin + free cholesterol Cholesterol ester + lysolecithin