HYPERCHOLESTEROLEMIA
Definition and Importance
- Cholesterol: Essential for cell membrane function; precursor of steroid hormones.
- Hypercholesterolemia: Elevated levels of low-density lipoprotein (LDL) cholesterol.
- Increases risk for atherosclerosis → can lead to coronary heart disease (CHD), cerebrovascular disease, and peripheral vascular disease.
NCEP Guidelines for LDL Cholesterol
- National Heart, Lung, and Blood Institute issued three guidelines (1988, 1993, 2002).
- Third Report (ATP III) of the National Cholesterol Education Program (NCEP) sets cutoffs:
- LDL <100 mg/dL = optimal.
- Higher LDL → higher CHD risk.
- Risk factors (e.g., smoking, hypertension, low high-density lipoprotein [HDL], family history of premature CHD, age ≥45 [men] or ≥55 [women]) modify LDL goal.
- CHD or risk equivalent (e.g., diabetes) → LDL goal <100 mg/dL.
- ≥2 risk factors → LDL goal <130 mg/dL.
- 0–1 risk factor → LDL goal <160 mg/dL.
- Updated guidelines (NCEP ATP IV) expected in fall 2011 may modify these targets.
Etiology of High LDL Cholesterol
- Dietary factors: Diets high in saturated fats and cholesterol ↑ blood cholesterol.
- LDL receptor pathway is primary regulator of serum cholesterol:
- LDL receptors on cell surfaces bind apolipoproteins (apo) B100 and E → clearance of LDL, chylomicron remnants, very low-density lipoproteins (VLDL), etc.
Familial Hypercholesterolemia (FH)
- Autosomal dominant disorder.
- Mutations in LDL receptor gene → decreased or defective LDL receptors.
- → ↑ plasma LDL cholesterol (3–6× reference range).
- Clinical findings:
- Premature CHD.
- Tendon xanthomas, xanthelasma.
- Homozygotes more severely affected than heterozygotes.
Familial Defective apo B100
- Mutations in apo B100 gene → defective LDL binding to LDL receptor.
- Phenotype mirrors FH (↑ LDL cholesterol, premature CHD, tendon xanthomas).
Familial Hyperapobetalipoproteinemia and Familial Combined Hyperlipidemia
- Autosomal dominant inheritance with yet unknown genetic defects.
- Characterized by:
- ↑ plasma LDL cholesterol and/or ↑ triglycerides.
- Possibly low HDL.
- Associated with obesity, hyperuricemia, fasting hyperglycemia.
- No xanthomas typically.
- Increased risk of premature CHD.
Hypercholesterolemic Xanthomatosis
Cutaneous and Tendinous Xanthomas
- Occur when LDL cholesterol is markedly elevated.
- Macrophages take up LDL in nonsaturable manner → become foam cells.
- Xanthelasma: Usually on eyelids, accompanied by arcus corneae in persons <40.
- Tuberous xanthomas: Elbows, knees, buttocks (often irritated by clothing).
- Tendinous xanthomas: Found in tendon tissue (extensor tendons of hands, Achilles, patellar).
Atherosclerosis
- High LDL → formation of foam cells, fatty streaks, atheromatous plaques in arteries.
- Leads to early-onset CHD if untreated.
Specific Monogenic Causes
Familial Hypercholesterolemia (FH)
- Defect: Mutations in LDL receptor gene.
- Types of molecular mutations:
- ↓ LDL receptor synthesis.
- ↓ transport of receptor to membrane.
- Defective LDL-receptor binding.
- Defect in receptor internalization.
- Heterozygous FH (1 in 500 persons):
- Plasma total cholesterol >300 mg/dL, LDL >250 mg/dL.
- Tendon xanthomas in ~75% of patients.
- Premature CHD, often before 45 years.
- Homozygous FH:
- Plasma total cholesterol 600–1000 mg/dL, LDL ~550–950 mg/dL.
- Tuberous xanthomas in early childhood (<6 years).
- Aortic valve involvement in ~50%.
- Extremely high risk of myocardial infarction before age 20 if untreated.
Treatment of FH
- Heterozygous FH: Low-cholesterol diet + pharmacotherapy (statins, bile acid sequestrants, cholesterol-absorption inhibitors).
- Homozygous FH: More resistant to standard therapies; often require LDL apheresis every 1–3 weeks to remove LDL from circulation.
Familial Defective apo B100
- Mutation: Single point mutation in apo B100 gene → poor LDL receptor binding.
- Presentation mimics heterozygous FH:
- ↑ LDL, tendon xanthomas, premature CHD.
- Usually less severe than FH, but clinically indistinguishable.
- Treatment: Similar to heterozygous FH.
Other Causes of Tendon Xanthomas with Elevated or Normal LDL
Sitosterolemia
- Autosomal recessive; defective adenosine triphosphate–binding cassette (G5, G8).
- Excess absorption of dietary plant sterols → elevated plant sterols in plasma/tissues.
- Tendon xanthomas, premature CHD.
- LDL also elevated.
Cerebrotendinous Xanthomatosis (CTX)
- Autosomal recessive; deficiency of 27-hydroxylase (CYP27A1 mutation).
- Abnormal bile acid synthesis → cholesterol/cholestanol accumulation in tissues.
- Normal plasma lipids.
- Tendon xanthomas + neurologic manifestations (cerebellar ataxia, pyramidal tract signs).