Hypercholesterolemia

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).