Disease of Lipoprotein Metabolism and Lipidemia, Obesity

By… Krairat Komdee, MD.

Department of Internal Medicine, Phayao Hospital

Dietary cholesterol ~ 300-700mg/day

Biliary cholesterol ~ 1000mg/day

Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082-1150.

Physiologic role of cholesterolNormal biologic function

Component of cell membranes

Precursor of other steroids

Cortisol, progesterone, estrogen, testosterone, bile acids

Excess cholesterol

CHD

XanthomasAdapted from Saladin KS. Anatomy and Physiology. 2nd ed. Boston: McGraw-Hill, 2001; Jones PH et al. In Hurst’ s The Heart. Arteries and Veins. 9th ed. New York: McGraw-Hill, 1998:1553-1581; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149.

Fredrickson Classification of Dyslipidemias

PhenotypeLipoprotein

elevated

SerumCholesterol

Level

SerumTriglyceride

LevelAtherogenicity

I Chylomicrons Normal to None seen

IIa LDL Normal +++

IIb LDL and VLDL +++

III IDL +++

IV VLDL Normal to +

V VLDL and chylomicrons

Notmal to +

Types of Dyslipidemia1. Hypertriglyceridemia

2. Hypercholesterolemia

3. Hyperalphalipoproteinemia

4. Hypoalphalipoproteinemia

5. Hypobetalipoproteinemia

Common genetic dyslipidemiaFamilial hypercholesterolemia

Polygenic hypercholesterolemia

Familial defective apolipoprotein B100

Familial hypertriglyceridemia

Familial combined hyperlipidemia

LDL-Cholesterol defectsDisoder Lipid levels Confirmatory

studiesPhysical findings

Familial hypercholesterolemia

High TC TG usually normal

LDL receptor defect by cell studies or DNA mapping

Tendon xanthomata in patient or one 1st or 2nd degree relative

Familial combined hyperlipidemia

High TC TG usually normal

LDL-chol/apo B < 1.2 Xanthelasma ; corneal arcus, tendon xanthomas

Familial hyperapobetalipoproteinemia

TC and/or TG> 90th percentile in pt and 1st or 2nd degree relatives c similar profile

LDL-chol/apo B <1.2 Xanthelasma

Polygenic hypercholesterolemia

TC > 90th percentile TG < 90th percentile

Exclusion : tendon xanthomata in patient or family members

Secondary cause of hyperlipidemiaLDL HDL VLDL Chylomicron

Elevated Reduced Elevated Reduced Elevated Elevated

• Hypothyroidism • Nephrotic

syndrome • Cholestasis • Acute

intermittent porphyria

• Anorexia nervosa

• Hepatoma • Drugs: thiazides,

cyclosporine, tegretol

• Severe liver disease

• Malabsorption • Malnutrition • Gaucher disease • Chronic

infectious disease

• Hyperthyroidism • Drugs: niacin

toxicity

• Alcohol • Exercise • Drugs: estrogen

• Smoking • DM2 • Obesity • Malnutrition • Gaucher disease • Drugs: anabolic

steroids, betablocker

• Obesity • DM2 • Glycogenstorage

disease • Alcoholic

hepatitis • Renal failure • Cushing

syndrome • Pregnancy • Acromegaly • Lipodystrophy • Drugs: estrogen,

betablocker, furosemide, glucocorticoids, PIs, retinoic acid

• Autoimmune disease

• Drug: Isotretinoin

CHD risk based on risk factors other than LDL level

Positive risk factors

Male more than 45 years

Female more than 55 years or postmenopausal without estrogen replacement therapy

FH of premature CHD (definite MI or sudden death before age 55 in father or other male first-degree relative or before age 65 in mother or other female first-degree relative)

Current cigarette smoking

HT

HDL cholesterol level less than 35mg/dL

Diabetes mellitus

Negative risk factor

High HDL cholesterol level more than 60mg/dL

Screening for risk group1. Hx of CAD, CVA, PAD

2. Whom has CHD risk

1. Age; male ≥ 45, female ≥ 55

2. FH; male ≤ 55, female ≤ 65

3. DM2

4. HT

5. Smooking

3. Positive finding on PE; corneal arcus, tendon xanthoma, xanthelasma,palmar xanthoma,eruptive xanthoma

Lipoprotein measurement

• Total cholesterol, Triglyceride, HDL-C • Calculate LDL-C by Friedewald equation :

LDL-C = TC - (TG/5 + HDL-C) • TG-C must be less than 400 for calculate

Prepare before ExamNPO 9-12hrs

Regular diet more than 3 weeks

12 wks after pregnancy, surgery, critical care, infection

12th hrs or after 6 weeks after acute MI

48th hrs or after 12 weeks after CVA

NCEP guidellines : LDL-C Treament Cutpoints and target for therapy

Category LDL-C target Diet Drug

No CHD, <2RF <160 ≥160 ≥190

No CHD, ≥2RF <130 ≥130 ≥160

with CHD or other aterosclerotic disease

≤100 >100 ≥130

Management of dyslipidemia

Lifestyle modification

exercise and weight reduction

Medical Treatment

Bile acid sequestrant resins : Cholestyramine

HMG Co A reductase inhibitors; statin

Fibric acid and derivatives

Nicotinic acid and derivatives

Selective cholesterol absorption inhibitor; ezetimibe

!

Bile acid sequestrant resins

bind bile acid in intestine and promote excretion in stool; interrupt enterohepatic bile acid circulation

used in hypercholesterolemia

low side effects ; bloating, constipation

drugs of choice in children, pregnancy, lactation

HMG CoA reductase inhibitorsInhibits HMG-CoA reductase

Interpatient variability in response to statin

most common side effect; myopathy, hepatotoxicity

Nicotinic acid and derivatives

inhibits lipoprotein secretion

used in hypercholesterolemia

side effects; flushing, itching, hepatitis, oesophageal reflux

increase HDL-C at high dose

Selective cholesterol absorption inhibitor

improve LDL-C, TC, HDL, TG

cholesterol absorption inhibitors

target cholesterol absorption in intestine

mechanism of action complementary of statin

achieves lipid reductions greater than statin alone

may be use as mono therapy for patients intolerant to statin