1. DYSLIPIDEMIA

2. Objectives At the end of this lecture you must 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. Introduction

4. 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.

8. HDL metabolism and reverse cholesterol transport

9. 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

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

11. Hyperlipoproteinemia
Fredrickson Classification
Lipoprotein Elevation
Synonyms
Type
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)

12. 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.

13. Secondary Causes of Hyperlipidemia
Hypothyroidism (high LDL)
NS (high LDL)
Cholestasis (high LDL)
Obesity (high TG)
DM type 2 (high TG & chylomicrons)
Pregnancy (high TG)
Sepsis (high TG)
Stress
Reduced HDL: smoking, DM2, obesity, malnutrition, B- blockers
Acute hepatitis (high TG)
Drugs (thiazide, steroids, B- blockers, cyclosporine, protease inhibitors).
MM, lymphoma (high TG)
Glycogen storage disease (high TG).
Alcohol, interferon, estrogen, thiazide, steroid (high TG).
Acromegaly, renal failure (high TG).

14. 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)

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

16. Goals for Lipids LDL < 100 →Optimal 100-129 → Near optimal
→ Borderline
→ High
≥ 190 → Very High
Total Cholesterol
< 200 → Desirable
→ Borderline
≥240 → High
HDL
< 40 → Low
≥ 60 → High
Serum TG
< 150 → normal
→ Borderline
→ High
≥ 500 → Very High

17. Determining Cholesterol Goal (LDL!)
Look at JNC 7 Risk Factors.
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)

18. 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

19. 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.

20. 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, cottonseed oil; fish
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; partially hydrogenated vegetable oil; deep-fried chips; many fast foods; most commercial baked goods
Raises LDL

21. 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.

22. Medications for Hyperlipidemia
Drug Class
Agents
Effects (% 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 mgtid
( LDL&VLDL synthesis)
 Triglyceride
Flushing, Hyperglycemia,
Hyperuricemia, GI distress, hepatotoxicity
Fibric Acids
( VLDL synthesis)
Gemfibrozil 600mg bid
Fenofibrate 145mg qd
Clofibrate
LDL, HDL
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)

24. 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.

25. 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.

26. 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.

27. 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.

28. 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)

29. a. What is the goal LDL in this woman?
A 55-year-old woman without symptoms of CAD seeks assessment for routine health maintenance. Her BP is 135/85 mm Hg. She does not smoke or have diabetes and has been postmenopausal for 3 years.
Her BMI is 24. The patient has no FH of premature CAD. Lipoprotein analysis shows:
Total cholesterol = 240 mg/dL
HDL = 55 mg/dL
TG = 85 mg/dL
LDL = 180 mg/dL.
a. What is the goal LDL in this woman?
b. What would you do if exercise/diet change do not improve cholesterol after 3 months?