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  1. 1. Serum Lipid Abnormalities M Chadi Alraies, MD Chief Medical Resident Case Western Reserve University / St. Vincent Hospital Cleveland, Ohio Saturday, December 20, 2007
  2. 2. A quick look at the differential diagnosis of Heart Murmurs
  3. 3. Intervention HOCM Aortic Stenosis Mitral Regurgitation Valsalva Increased Decreased Standing Increased Increased Decreased or same Decreased Handgrip or squatting Decreased Decreased Increased Supine position with legs elevated Decreased Increased No change Exercise Increased Increased Decreased Amyl nitrite Markedly increased Markedly increased Increased Decreased Increased Decreased or IsoProterenol
  4. 4. Lipid abnormalities
  5. 5. Terminology Primary prevention Secondary prevention Lipoproteins. Apoproteins.
  6. 6. General consideration The two main lipids in blood are cholesterol and triglyceride. Why lipids are deposited into the walls of large and medium-sized arteries is not known. medium-
  7. 7. Lipoproteins Particles that have a hydrophobic core (TG/Cholesterol), Surrounded by a hydrophilic phospholipid outer layers which allows transport through the blood. LDL, VLDL, IDL, CHYLOMICRONS, HDL
  8. 8. Apoproteins Small proteins. Surrounding Lipoproteins. Helps lipoproteins: Binding to receptors. Activating enzymes.
  9. 9. LIPOPROTEINS ATHEROGENESIS The higher the LDL, the greater the risk of CHD. The higher the HDL, the lower the risk of (CHD). The mechanism of formation of atherosclerotic plaques is not known.
  10. 10. Lipid Fractions In fasting serum« Most triglyceride is found in VLDL particles, which contain five times as much triglyceride by weight as cholesterol.
  11. 11. Lipid Fractions the LDL should always be estimated as the mean of at least two determinations« Valid only if TG 400 mg/dl
  12. 12. Lipoproteins
  13. 13. Chylomicrons (I) Large globules. Apo (B48, CII, E) CII activates LPL (lipoprotein lipase). LPL removes TG from chylomicrons. Familial LPL deficiency Familial CII deficiency.
  14. 14. VLDL (IV) Apo (B100, CII, E) Smaller than chylomicrons Contain more cholesterol than chylomicrons. Metabolized by LPL by means of CII. Familial LPL deficiency Familial CII deficiency. FCHL
  15. 15. IDL (III) Apo B100, E VLDL remnant. ½ taken by liver. Strong affinity to B100 E ½ stays in plasma and convert to LDL. Familial betadyslipoproteinemia.
  16. 16. LDL (IIA) Apo B100«ONLY! Formed from IDL 2/3 binds to receptors 1/3 scavenged. Liver receptors have a weak affinity to B100. Familial hypercholesterolemia. FCHL
  17. 17. LDL receptors DownDown-regulated or decreased: High dietary cholesterol or saturated fat. Age Familial hypercholesterolemia. UpUp-regulated or increased: Low dietary cholesterol Estrogen Thyroxine Acute illness Meds: statins and bile acid resins.
  18. 18. HDL Apo (A1, A2, C) Protein and phospholipids. Very little cholesterol and TG Scavenges the unesterified cholesterol. Low HDL low apo C (including CII) increased VLDL and Chylomicrons.
  19. 19. Familial hyperlipidemia syndromes Type What is elevated? Defect Name I TG (chylomicrons) LPL deficiency CII deficiency Familial LPL deficiency Familial CII deficiency IIA Cholesterol (LDL) Decreased LDL receptors Apo B + VLDL overproduction Familial hypercholesterolemia FCHL IIB TG + Cholesterol (LDL VLDL) Apo B + VLDL overproduction FCHL III TG + Cholesterol (IDL) Abnormal apo E (E2/E2) Familial dysbetalipoproteinemia IV TG (VLDL) LPL deficiency CII deficiency Apo B + VLDL overproduction Familial hyper TG FCHL Familial CII deficiency V TG Chylomicrons VLDL LPL deficiency CII deficiency Apo B + VLDL overproduction Familial LPL deficiency FCHL Familial CII deficiency
  20. 20. I + IV = V have isolated hypertriglyceridemia IIa = cholesterol alone IIb and III = both cholesterol and TG.
  21. 21. Clinical findings
  22. 22. Tendinous xanthomas: Achilles xanthomas
  23. 23. Tendinous xanthomas: elbow xanthomas
  24. 24. Tendinous xanthomas: knuckle xanthomas
  25. 25. Lipemia retinalis
  26. 26. CLINICAL PRESENTATIONS No specific symptoms or signs. Triglyceride level (1000 mg/dL) High LDL concentrations eruptive xanthomas Tendinous xanthomas on tendons of (Achilles, patella, back of the hand). Triglyceride levels (above 2000 mg/dL): Lipemia retinalis.
  28. 28. Cause Associated Lipid Abnormality Obesity Increased triglycerides, decreased HDL cholesterol Sedentary lifestyle Decreased HDL cholesterol Diabetes mellitus Increased triglycerides, increased total cholesterol Alcohol use Increased triglycerides, increased HDL cholesterol Hypothyroidism Increased total cholesterol Hyperthyroidism Decreased total cholesterol Nephrotic syndrome Increased total cholesterol Chronic renal insufficiency Increased total cholesterol, increased triglycerides Hepatic disease (cirrhosis) Decreased total cholesterol Obstructive liver disease Increased total cholesterol Malignancy Decreased total cholesterol Cushing's disease (or corticosteroid use) Increased total cholesterol Oral contraceptives Increased triglycerides, increased total cholesterol Diuretics Increased total cholesterol, increased triglycerides Beta Blockers Increased total cholesterol, decreased HDL
  29. 29. Therapeutic Effects of Lowering Cholesterol Primary prevention is statistically significant and showed clinically important reductions in: Rates of myocardial infarctions, New cases of angina, Need for coronary artery bypass procedures. In general, decrease in morbidity. morbidity.
  30. 30. Primary prevention Pravastatin: West of Scotland Study. Lovastatin: AFCAPS/TexCAPS study. Atorvastatin: (ASCOT) study.
  31. 31. Secondary prevention 1. 2. 3. Regression of atherosclerotic plaques. Reduces the progression of atherosclerosis in saphenous vein grafts. Slow or reverse carotid artery atherosclerosis.
  32. 32. SECONDARY CONDITIONS THAT AFFECT LIPID METABOLISM These are important for two reasons: Abnormal lipid levels may be the presenting sign of some of these conditions. correction of the underlying condition may obviate the need to treat an apparent lipid disorder.
  34. 34. Who should be screened for high lipids? CHD CHD risk equivalents: 1. 2. 3. 4. 5. Peripheral artery disease. AAA Symptomatic carotid artery disease Diabetes mellitus Multiple risk factors that confer a greater than 20% 10-year risk for developing CHD! 10-
  35. 35. National Cholesterol Education Program (NCEP): Screen all adults aged 20 years or older. USPSTF: Screen every 35 years in men and age 45 years in women unless there are other risk factors for CHD.
  36. 36. Risk factors of coronary artery disease Age and gender Men aged 45 years or older. Women aged 55 years or older A family history of premature CHD: 1. MI or sudden cardiac death 1. 2. 2. 3. 4. 55 years in a 1st degree male relative. 65 years in a 1st degree female relative. Hypertension (whether treated or not.) Current cigarette smoking (10 or more cigarettes per day). HDL cholesterol ( 40 mg/dL).
  37. 37. 10-year risk of developing CHD using 10Framingham projections of 10-year risk 10 Because risk factors alone are an imprecise measure of CHD risk, estimating the 10-year 10risk using Framingham data is likely to be helpful even in patients with one or no risk factors.
  38. 38. Screening in Women Low HDL is more important risk factor than a high LDL cholesterol in women. Using estimates of 10-year CHD risk may be 10particularly helpful in women. Women are less likely to benefit from therapy unless their LDL cholesterol is extremely high (greater than 190 mg/dL).
  39. 39. Screening in Older Patients Patients age 75 years or older: + CHD: LDL-lowering therapy can be continued. LDL No CHD: recommend screening and treatment. Decisions to discontinue therapy: Overall functional status. Life expectancy. Comorbidities. Patient preference.
  40. 40. Treatment
  41. 41. Goal of treatment
  42. 42. Risk Category LDL Goal (mg/dL) LDL Level at Which to Initiate Lifestyle Changes (mg/dL) LDL Level at Which to Consider Drug Therapy (mg/dL) High risk: CHD or CHD risk equivalents (10-year risk 20%) 100 100 100 Moderately high risk: 2+ risk factors (10-year risk 10% to 20%) 130 130 130 Moderate risk: 2+ risk factors (10-year risk 10%) 130 130 160 Low risk: 0±1 risk factors 160 160 190
  43. 43. Treatment of High LDL Cholesterol General measures: Quitting smoking: increase HDL lower LDL. Exercise (and weight loss) reduce the LDL increase the HDL. Modest alcohol use (1²2 ounces a day): raises HDL (1²
  44. 44. Diet
  45. 45. Diet Therapy 5²10% decrease in LDL cholesterol. Should be assessed 4 weeks after initiation. Reduce« Total daily fat to 25²30% 25² Saturated fat to less than 7% of daily calories. Dietary cholesterol less than 200 mg/d. Polyunsaturated fats decrease LDL and HDL Monounsaturated fats: Decrease LDL Increase HDL« GOOD!
  46. 46. Diet Therapy Mediterranean diet´, monounsaturated fat such as that found in canola oil and in olives, peanuts, avocados, and their oils. Soluble fiber, reduce LDL cholesterol by 5² 5² 10%. Garlic, soy protein, vitamin C, pecans, and plant sterols. Antioxidants, found primarily in fruits and vegetables.
  47. 47. Pharmacologic treatment
  48. 48. General measures Aspirin prophylaxis at a dose of 81 mg/d. The therapeutic goal is: Approached slowly Watching for side effects. Encouraging adherence to nonpharmacologic Rx. Achieve a 30²40% reduction in LDL. 30² Combinations of drugs may be necessary. Monitor periodically (every 6²8 weeks) after 6² starting therapy.
  49. 49. NIACIN (NICOTINIC ACID) Decrease the production of VLDL. FullFull-dose niacin therapy, 3²4.5 g/d 3² 15²25% reduction in LDL cholesterol. 15² 25²35% increase in HDL cholesterol. 25² Reduce triglycerides by half. Side effects: Flushing and pruritus. Less with aspirin 325 mg. Increase blood sugar. Exacerbate gout and peptic ulcer disease.
  50. 50. BILE ACID-BINDING RESINS ACID Cholestyramine and Colestipol. Decrease plasma LDL levels 15²25%. 15² Increase Triglyceride level. Don·t affects HDL. Side effects: constipation and gas Nausea and vomiting. Absorption of fat-soluble vitamins. fat
  51. 51. (HMG(HMG-COA) REDUCTASE INHIBITORS (STATINS) atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Reduce MI and total mortality in secondary prevention. Significant reduction in risk of stroke. Decrease LDL level by up to 35%. Increases HDL levels Decreases triglyceride levels. Myositis and hepatitis. Monitor LFT·s Q 2-3 months then 2x/year if stable. 2-
  52. 52. Fibric Acid Derivatives Gemfibrozil, Fenofibrate and Clofibrate. Increase the activity of LPL on VLDL. Reduce triglyceride levels by about 40% Reduce LDL levels by about 10²15%. 10² Raise HDL levels by about 15²20%. 15² Side effects (mainly Clofibrate): cholelithiasis, hepatitis and hepatic cancer and myositis.
  53. 53. EZETIMIBE Inhibits the intestinal absorption of dietary and biliary cholesterol. Reduces LDL 15% - 20% when used as monotherapy. The usual dose of ezetimibe is 10 mg/d orally.
  54. 54. HDL
  55. 55. What increase HDL?
  56. 56. HDL increases Nicotinic acid Statins. Moderate alcohol intake Gemfibrozil Exercise Stopping smoking Losing weight.
  57. 57. HDL decreases in « Beta blockers (except Labetalol). Smoking High polyunsaturated diet.
  58. 58. High Blood Triglycerides Risk for pancreatitis. Treat fasting levels above 500 mg/dL.
  59. 59. High Blood Triglycerides The primary therapy is dietary: Avoiding alcohol Avoiding simple sugars Avoiding refined starches Avoiding saturated trans fatty acids. Restricting total calories. Medications: niacin, a fibric acid derivative, or an HMGHMG-CoA reductase inhibitor. Elevated TG increase CHD risk in men by 14% and in women by 37%.
  60. 60. Metabolic syndrome 25% of Americans 3 or more of the following: 1. 2. 3. 4. 5. Waist circumference 102 cm in men or 88 cm in women Serum triglyceride level of at least 150 mg/dL HDL level of 40 mg/dL in men or 50 mg/dL in women. Blood pressure of at least 130/85 mm Hg Serum glucose level of at least 110 mg/dL.
  61. 61. NCEP ATP III 1. 2. TG (150²199 mg/dL): calorie restriction and (150² exercise. TG ( 200 mg/dL): Diet and medications to make non-HDL cholesterol 30 mg/dL higher nonthan the LDL goal. Should be used for high risk patients.
  62. 62. References CMDT 2007. Harrison·s principles of internal medicine. MedStudy 2007/2008. Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486²97. 16;285(19):2486²
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