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Yasar Kucukardali Professor Yeditepe University Department of Internel Medicine Objectives To learn correct management of hyperlipidemia Review NCEP ATP III Guidelines Discuss laboratory monitoring Relation between plasma cholesterol concentration and six-year coronary heart disease risk in 361,662 men (ages 35 to 57) screened during the MRFIT study. There is a continuous, positive, graded correlation between the plasma cholesterol concentration and coronary risk. Data from Stamler, J, Wentworth, D, Neaton, JD, JAMA 1986; 256:2823. Cholesterol Essential component of the cell membrane Precursor molecule from which steroid hormones, bile salts, and vitamin D are synthesized Derived from the diet synthesized within the body,mainly in the liver. Dietary sources of Cholesterol Type of Fat Main Source Effect on Cholesterol levels Monounsaturated Olives, olive oil, canola oil, peanut oil, cashews, almonds, peanuts and most other nuts; avocados Lowers LDL, Raises HDL Polyunsaturated Corn, soybean, safflower and cottonseed oil; fish Lowers LDL, Raises HDL Saturated Whole milk, butter, cheese, and ice cream; red meat; chocolate; coconuts, coconut milk, coconut oil , egg yolks, chicken skin Raises both LDL and HDL Trans Most margarines; vegetable shortening; partially hydrogenated vegetable oil; deep-fried chips; many fast foods; most commercial baked goods Raises LDL Çoklu doymamış YAğlar: Mısır, ayçiçek, soya, susam, fındık, keten tohumu Tekli doymamış yağlar: zeytinyağı Doymuş yağlar: Tereyağ, sade yağ, krema, kaymak, süt, peynir ve etlerin bileşiminde bulunan yağlar Cholesterol circulates as a component of lipoproteins The principal plasma lipoproteins chylomicrons (CMs) very low density lipoproteins (VLDL) low-density lipoproteins (LDL) high-density lipoproteins (HDL) The principal fat in the diet is the triglycerides (TG), which are absorbed in the intestine The lipoproteins are transported in combination with apoproteins (apo), like apo-A, apo-B, and apo-C Clasification Hyperlipidemias are classified as primary or secondary Primary hyperlipidemia have been classified into 5 major groups according to plasma lipoprotein patterns Causes of Sec. Hyperlipidemia Diet Hypothyroidism Nephrotic syndrome Anorexia nervosa Obstructive liver disease Obesity Diabetes mellitus Pregnancy Acute hepatitis AIDS (protease inhibitors) Pancreatitis Hematopoietic diseases (myeloma, Waldenstrom's macroglobulinemia, cryoglobulinemia, hemochromatosis Systemic lupus erythematousus drugs like estrogens, corticosteroids, and retinoids Genetic primary hyperlipidemias Symptoms of Hyperlipidemia Hyperlipidemia usually has no noticeable symptoms and tends to be discovered during routine examination or evaluation for atherosclerotic cardiovascular disease. Deposits of cholesterol (known as xanthomas) may form under the skin Individuals with hypertriglyceridemia may develop numerous pimple-like lesions across their body. ** Extremely high levels of triglycerides may also result in pancreatitis, a severe inflammation of the pancreas that may be life-threatening. Dermatologic Markers of Lipid Derangement Abnormalities of lipid metabolism may favor lipid deposition in the skin and present as xanthomas Xanthelasma palpebrarum is the commonest type of cutaneous xanthoma The major lipid stored in xanthomas is esterified cholesterol However, only about half of the patients with xanthelasma are hyperlipidemic The most frequent hyperlipidemia associated with xanthelasma is type IIa Isolated xanthelasmata are often treated with destructive modalities, like trichloroacetic acid, electrocautery, surgical excision, carbon dioxide laser, pulsed dye laser, and erbium:YAG laser Disorders of lipid storage Individuals with hypertriglyceridemia may develop numerous pimple-like lesions across their body NCEP Guidelines The NCEP Adult Treatment Panel (ATP) first published guidelines for managing hypercholesterolemia in 1988 (ATP I) Revised them in 1993 (ATP 2) The latest NCEP report (ATP III) has been published in 2001. managing hypercholesterolemia The first step is to determine lipoprotein levels after a 9- to 12-hour fast Next, coronary heart disease (CHD) risk equivalents and major risk factors should be established. CHD risk equivalents include clinical CHD symptomatic carotid artery disease peripheral arterial disease abdominal aortic aneurysm diabetes Major risk factors (exclusive of LDL cholesterol) cigarette smoking hypertension low HDL cholesterol (<40 mg/dL) family history of premature CHD age (men >45 years; women >55 years) CHD risk equivalents and risk factors are then used to determine the risk category of the patient Coronary Equivalents Risk Factors Abdominal Aortic Aneurysm Hypertension Peripheral Artery Disease HDL <40 mg/dl (>60 mg/dl “negative” risk factor) Renal Artery Stenosis Carotid Artery Stenosis Cerebral Vascular Disease Diabetes Mellitus Family history of premature CAD (male <55 female <65) Male >45, Women >55 Cigarette Smoking Checking lipids Nonfasting lipid panel measures HDL and total cholesterol Fasting lipid panel Measures HDL, total cholesterol and triglycerides LDL cholesterol is calculated: LDL cholesterol = total cholesterol – (HDL + triglycerides/5) When to check lipid panel Two different Recommendations Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP) Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile consisting of total cholesterol, LDL, HDL and triglycerides Repeat testing every 5 years for acceptable values United States Preventative Services Task Force Women aged 45 years and older, and men ages 35 years and older undergo screening with a total and HDL cholesterol every 5 years. If total cholesterol > 200 or HDL <40, then a fasting panel should be obtained Cholesterol screening should begin at 20 years in patients with a history of multiple cardiovascular risk factors, diabetes, or family history of either elevated cholesteral levels or premature cardiovascular disease. Screening may be appropriate in older people who have never been screened, although screening a second or third time is less important in older people because lipid levels are less likely to increase after age 65. NCEP/ATP III Identify if patient has CAD or equivalent (PAD, DM, AAA, Carotid) Risk factor assessment (HTN, FHx, Tob, Age & Sex, HDL<40 or >60) If 2 or more risk factors; do Framingham 10-yr risk assessment. NCEP/ATP III Therapeutic lifestyle changes (TLC) TLC are considered first-line therapy in the management of high cholesterol A 3-month trial of TLC should precede the use of drug therapy The essential features of TLC (a) reduced intake of saturated fats [less than 7% of total calories] and cholesterol [less than 200 mg/d] (b) therapeutic options for enhancing LDL lowering - such as plant stanols/sterols [2 g/d] and increased soluble fiber [10-25 g/d; (c) weight reduction (d) increased physical activity According to ATP III, the most cost-effective approach to prevention of CHD diet modification exercise weight control cessation of smoking Cigarette smoking, leads to elevated triglycerides and low HDL levels Smoking cessation should receive prime emphasis in the clinical strategy to reduce CHD risk. While moderate intakes of alcohol in middleaged and older adults may reduce risk for CHD, high intakes of alcohol produce multiple adverse effects. Persons who do not drink should not be encouraged to initiate regular alcohol consumption. Physical activity as a component of TLC includes enough moderate exercise to expend at least 200 kcal per day. The NCEP recommends The use of statins as first-line therapy BASA's LDL-lowering effects may be enhanced in combination with other cholesterol-lowering medications, particularly statins. Nicotinic acid is recommended for high-risk patients with low levels of LDL cholesterol, high triglycerides, and low HDL cholesterol - a triad known as atherogenic dyslipidemia. Fibrates are primarily used for persons with very high triglycerides to reduce risk for acute pancreatitis and for those with dysbetalipoproteinemia. Drug treatment/ Statins The statins are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme Inhibition of HMG-CoA reductase leads to a decrease in intrahepatic cholesterol concentration ,leading to an increase in receptor-mediated LDL catabolism. The statins also decrease the activity of CETP Thus the overall effect is a small increment in HDL Statins decrease serum triglycerides. Statin-induced increased LDL-receptor activity also leads to the enhanced removal of the TG-rich lipoproteins VLDL and IDL. Similarly, increased activity of LDL receptor leads to enhanced uptake of CM remnants, thereby increasing postprandial TG clearance. Drug treatment/ Bile-acid sequestrating agents (BASA) BASA are anion exchange resins, BASA bind the bile acids, thus impeding their reabsorption and significantly increasing their fecal excretion. This leads to the depletion of intrahepatic cholesterol, which causes increased expression of LDL receptors. BASA promote apo-A1 synthesis by an unknown mechanism and tend to raise HDL levels. BASA nonspecifically bind anions and interfere with absorption of a number of drugs which are anionic at intestinal pH (statins, fenofibrate, corticosteroids, diuretics, tricyclic antidepressants, nonsteroidal antiinflammatory drugs, thyroxine, and digoxin). Drug treatment/ Nicotinic acid (NA) Plasma FFA are immediate precursors of hepatic and subsequently plasma triglycerides transported in VLDL. NA is immediately taken up by adipose tissue via a specific high-affinity G-protein-coupled receptor. It then inhibits lipolysis in adipose tissue, resulting in a decrease in plasma FFA NA, in a dose-dependent way, lowers triglyceride-rich VLDL and cholesterol-rich LDL. NA is the most potent HDL-raising drug. But the unpleasant side effect of flushing precludes many patients from taking this drug. Drug treatment Fibric acid derivatives (fibrates) Fibrates reduce triglycerides through PPARa-mediated reduced expression of apo-CIII, which serves as an inhibitor of lipolytic processing and receptor-mediated clearance. This leads to increased LPL synthesis and enhanced clearance of triglyceriderich lipoproteins. Fibrate-mediated increases in HDL are due to PPARa stimulation of apo-AI and apo-AII expression. Three fibric acid derivatives are currently available Fibrates are primarily used for lowering elevated triglycerides because the LDL cholesterol-lowering effects of fibrates are generally only 10% or less in persons with hypercholesterolemia. Other therapeutic targets in lipid metabolism Ezetimibe blocks uptake of cholesterol into jejunal enterocytes, hence selectively blocking dietary and biliary cholesterol absorption from the gut. It acts by decreasing the intestinal cholesterol supply to the liver, lowering hepatic cholesterol levels and thus inducing LDL receptor expression. Unlike the bile-acid sequestrants, it does not interfere with absorption of fat-soluble drugs. Moreover, ezetimibe does not increase serum TG. Lipid-lowering agents NCEP/ATP III Treat elevated TG (>150mg/dl) First lower LDL; if TG still >200 consider adding/increasing drug therapy But, if TG >500mg/dl, first lower triglycerides to prevent pancreatitis. When they are <500 then return to LDL lowering Treat HDL <40 after lowering LDL.