1. DYSLIPIDEMIA

2. Objectives At the end of this lecture you will be able to: Define different types of lipoprotein and recognize their functions. State the pathophysiology of atherosclerosis. Identify the primary and secondary causes of hyperlipidemia. Classify hyperlipoproteinemia. Determine when to check lipids and their goals. Outline the treatment lines of hyperlipidemia. List the main antihyperlipidemic agents.

3. A 24- year old male patient is found to have a cholesterol of 290 mg/dL. He notes that his mother and grandmother had problems with high cholesterol. He is thought to have familial hypercholesterolemia. What will do next ?

4. Introduction

5. Definitions Lipids circulate in plasma as lipoproteins. Chylomicrons transport fats from the intestinal mucosa to the liver. In the liver, the chylomicrons release triglycerides and some cholesterol and become low-density lipoproteins (LDL). LDL then carries fat and cholesterol to the body’s cells. High-density lipoproteins (HDL) carry fat and cholesterol back to the liver for excretion.

9. HDL metabolism and reverse cholesterol transport

11. Pathophysiology of Atherosclerosis When oxidized LDL cholesterol gets high, it provokes inflammatory response, so monocytes recruited & transformed into macrophages resulting in cholesterol laden foam cell accumulation, which are beginning of arterial fatty streaks, then atheroma formation occurs, which causes atherosclerosis. HDL cholesterol is able to go and remove cholesterol from the atheroma. Atherogenic cholesterol → LDL, VLDL, IDL. VLDL= TG/5

12. Arterial Wall Endothelium Atherogenesis: an inflammatory response to injury

13. Damage SmokingHypertension Infection?? LDL R Turbulent flow

14. oxLDL R ROS Monocytes/ macrophages Damages ROS: reactive oxygen species Damages

15. Foam cells – cholesterol rich

17. Hyperlipidemia Hyperlipoproteinemia: abnormally increased plasma lipoproteins- one of the risk factor for atherosclerosis. Hyperlipemia: increased level of TG.

18. Hyperlipoproteinemia Fredrickson Classification Lipoprotein Elevation SynonymsType Chylomicrons''Primary hyperlipoproteinemia'', or ''Familial hyperchylomicronemia'' I (rare) LDL''Polygenic or Familial hypercholesterolemia'‘ IIa LDL+VLDL''Combined hyperlipidemia''IIb Chylomicrons+ IDL ''Familial dysbetalipoproteinemia'' III (rare) VLDL''Familial hyperlipemia''IV VLDL+ Chylomicrons ''Endogenous hypertriglyceridemia'' V (rare)

19. Hereditary Causes of Hyperlipidemia Caused by Known Single Gene Mutations Familial Hypercholesterolemia: Occurs in 1 in 500 individuals/ AD. Mutation in LDL receptor, resulting in elevated levels of LDL at birth and throughout life. High risk for atherosclerosis, tendon xanthomas and xanthelasmas of eyes, CHD Familial Combined Hyperlipidemia: Autosomal dominant. Increased secretions of LDL& VLDLs. High risk for atherosclerosis, no xanthomas. Dysbetalipoproteinemia: Affects 1 in 10,000 A binding-defective form of apoE (which usually plays important role in catabolism of chylomicron and VLDL). Increased risk for atherosclerosis, palmar xanthomas, CHD, PVD.

21. During a routine physical examination, flesh-colored papules were noted on a 36-year-old man’s elbows, and knees. They had been present for a long time, were nonpruritic, and had remained the same color and size. He had no significant medical or surgical history and no medication allergy. He smoked 1 pack of cigarettes per day, drank alcohol socially. What is the name of his lesion?

22. Secondary Causes of Lipoprotein Abnormalities Hypercholesterolemia Hypothyroidism; Cholestasis; Nephrotic syndrome; Drugs: progestogen, cyclosporine, thiazides, steroids. Hypertriglyceridemia Obesity, DM, Pregnancy, CRF, Alcohol, Stress, Sepsis, Acute hepatitis, SLE, Drugs: (estrogen, β- blockers, steroids, interferon, thiazides), MM, Lymphoma, Acromegaly Low HDL Type-2 DM, Rheumatoid arthritis, Malnutrition, Obesity, Cigarette smoking, Beta blockers.

23. What is the low density lipoprotein goal for a patient with ischemic heart disease?

24. Checking lipids Nonfasting lipid panel Measures HDL and total cholesterol. Fasting lipid panel Measures HDL, total cholesterol and TG. LDL cholesterol is calculated: LDL = total cholesterol – (HDL + TG/5)

25. When to check lipid panel? – 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 CV risk factors, DM, or family history of either elevated cholesterol levels or premature CVD.

26. Goals for Lipids LDL – < 100 →Optimal – 100-129 → Near optimal – 130-159 → Borderline – 160-189→ High – ≥ 190 → Very High Total Cholesterol – < 200 → Desirable – 200-239 → Borderline – ≥240 → High HDL – < 40 → Low – ≥ 60 → High Serum TG – < 150 → normal – 150-199 → Borderline – 200-499 → High – ≥ 500 → Very High

27. Determining Cholesterol Goal (LDL!) Cigarette smoking Hypertension (BP ≥140/90 or on treatment) Low HDL cholesterol (< 40 mg/dL) Family History of premature coronary heart disease (CHD) (CHD in first-degree male relative <55 or CHD in first-degree female relative < 65) Age (men ≥ 45, women ≥ 55)

28. LDL Goals 0-1 Risk Factors: LDL goal is 160 If LDL ≥ 160: Initiate TLC (therapeutic lifestyle changes). If LDL ≥ 190: Initiate pharmaceutical treatment. 2 + Risk Factors: LDL goal is 130 If LDL ≥ 130: Initiate TLC If LDL ≥ 160: Initiate pharmaceutical treatment CHD or CHD Risk Equivalent LDL goal is 100 (or 70) If LDL ≥ 100: Initiate TLC and pharmaceutical treatment

29. Treatment of Hyperlipidemia Therapeutic Lifestyle Changes (TLC): – Restricted total fat, saturated fats, cholesterol intake. – Moderate increase in polyunsaturated fat. – Increase soluble fiber intake. – Exercise: moderate intensity 30min/ day most days. – Weight reduction ( initial goal of 10%) if needed. – Smoking cessation. – Treat HTN.

30. Dietary sources of Cholesterol Type of FatMain SourceEffect on Cholesterol levels MonounsaturatedOlives, olive oil, canola oil, peanut oil, cashews, almonds, peanuts and most other nuts; avocados Lowers LDL, Raises HDL PolyunsaturatedCorn, soybean, cottonseed oil; fishLowers LDL, Raises HDL SaturatedWhole milk, butter, cheese, and ice cream; red meat; chocolate; coconuts, coconut milk, coconut oil, egg yolks, chicken skin Raises both LDL and HDL TransMost margarines; partially hydrogenated vegetable oil; deep- fried chips; many fast foods; most commercial baked goods Raises LDL

31. Most patients should receive 3 m TLC trial before starting drugs unless very high risk. If unable to reach goals with TLC alone choose lipid- lowering drugs based on lipoprotein disorder. Combination therapy may be necessary.

32. Medications for Hyperlipidemia Drug ClassAgentsEffects (% of change) Side Effects HMG CoA reductase inhibitors Lovastatin 20-80mg Pravastatin 40- 80mg Atrovastatin 10-80mg  LDL,  TG,  HDL Myopathy, increased liver enzymes, rhabdomyolysis Cholesterol absorption inhibitor Ezetimibe 10 mg/d  LDL,  HDL  Triglyceride Headache, GI distress Nicotinic Acid Niacin 100- 1000mgtid (  LDL&VLDL synthesis)  LDL,  HDL  Triglyceride Flushing, Hyperglycemia, Hyperuricemia, GI distress, hepatotoxicity Fibric Acids (  VLDL synthesis) Gemfibrozil 600mg bid Fenofibrate 145mg qd Clofibrate  LDL,  HDL  Triglyceride Dyspepsia, gallstones, myopathy Bile Acid sequestrant Cholestyramine 4-30 g /d Colestipol 5-40 g/d  LDL,  VLDL, GI distress, constipation, decreased absorption of fat soluble vit. and other drugs( digoxin,thyroxin, warfarin)

33. Summary of Drug choice Lipid abnormality typeFirst choiceAdditionalRemarks ↑ LDLStatinEzetimibeMyopathy ↑ ↑ TGFibrateNiacin↓ CHO intake ↓ HDLNiacinFibrateExercise ↑ LDL + ↑ TGStatin + FibrateNiacinMyo risk ↑ ↑ ↑ LDL + ↓ HDLStatin + NiacinFibrateExercise ↑ TG + ↓ HDLFibrate + NiacinStatinExercise ↑ LDL + ↑ TG + ↓ HDLStatin + FibrateNiacin, Eze.Myo risk ↑ ↑ ↑

35. Back to the case of xanthomas Total cholesterol level was 746 mg/dL; triglyceride level, 1730 mg/dL; and HDL level, 38 mg/dL. Low-density cholesterol was not calculable. The remainder of the laboratory results were normal. What is the treatment?

36. Omega 3 Fatty Acids Diet rich in omega 3 FA (oil fish) decrease TC, TG, increase HDL & decrease CV events. FDA approved as dietary adjunct for very high TG levels ( > 500 mg/ dl). < 3g daily is safe. Adverse effects: thrombocytopenia, abnormal LFT, worsening glycemic control, GI disturbance.

37. Hypertriglyceridemia Associated with lipoprotein types I, III, IV, V. Exclude primary disorders. TLC: - achieve desirable body weight. - diet low in saturated fat, cholesterol. - regular exercise. - smoking cessation. - alcohol restriction.

38. Borderline- high TG+ CHD risk factors: - FH of premature CHD. - concomitant LDL elevation or low HDL. - genetic forms associated with CHD (familial dysbetalipoproteinemia and familial combined hyperlipidemia - consider initiation of niacin. Alternative therapies: - gemfibrozil, statins, fish oil, fibrates.

39. Very high TG (> 500 mg/ dL) associated with pancreatitis. Genetic form often coexist with other causes like DM. Medications: - Gemfibrozil: preferred in diabetics. - Niacin. - Higher potency statins. - Fenofibrate.

40. Low level of HDL cholesterol is a risk factor for coronary heart disease, true or false?

41. Low HDL- C Strong CHD risk predictor. Causes: - DM type 2. - physical inactivity. - insulin resistance. - cigarette smoking. - very high carbohydrate intake. Treatment: TLC, drugs ( fibric acid derivatives, niacin)

42. Summery Dyslipidemia is elevation of plasma cholesterol, TG, or both, or a low HDL level that contributes to the development of atherosclerosis. Causes may be primary (genetic) or secondary. Diagnosis is by measuring plasma levels of total cholesterol, TG, and individual LP. Treatment is dietary changes, exercise, and lipid lowering drugs. References: Davidson’s Principles& Practice of Medicine Harrison’s Principles of Internal Medicine