Familial hypercholesterolemia
Familial hypercholesterolemia is an inherited defect of LDL clearance, most often an LDL-receptor mutation, that produces lifelong severe LDL cholesterol elevation and premature atherosclerotic cardiovascular disease. The clinical diagnosis rests on an LDL cholesterol of 190 mg/dL or higher plus a qualifying family history, and treatment is age-independent high-intensity statin therapy, escalated with ezetimibe and PCSK9-pathway agents.
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What this article covers
- Overview
Definition: familial hypercholesterolemia (FH) is an inherited disorder of low-density lipoprotein (LDL) clearance, most often an LDL receptor (LDLR) mutation, that raises LDL cholesterol (LDL-C)…
- Epidemiology
Heterozygous FH: affects about 1 in 500 people, inherited as an autosomal codominant trait, one of the most common inherited metabolic disorders.
- Risk factors
First-degree relative with FH: an affected parent transmits the mutant allele with 50% probability, so relatives of an index case carry the highest pretest probability.
- Pathophysiology
LDL receptor defect: most cases carry an LDLR mutation; the receptor normally binds circulating LDL for hepatic clearance, so a nonfunctional or reduced-number receptor leaves LDL in circulation far longer than normal.
- Clinical features
AHA clinical diagnostic criteria: diagnosis is made when the LDL-C is 190 mg/dL or higher plus either a first-degree relative with an LDL-C of 190 mg/dL or higher, or a first-degree relative with…
- Differential diagnosis
Familial combined hyperlipidemia: far more common, about 1 in 50 to 1 in 100, polygenic; LDL elevation is less extreme, triglycerides are often raised too, and tendon xanthomas are absent, unlike FH.
- Diagnosis
What establishes the diagnosis: the American Heart Association (AHA) clinical criteria confirm FH when the LDL-C is 190 mg/dL or higher plus either a first-degree relative with an LDL-C of 190 mg/dL…
- Management
First action: in patients 20 to 75 years old with FH, start high-intensity statin therapy, atorvastatin 40-80 mg PO once daily or rosuvastatin 20-40 mg PO once daily, regardless of calculated 10-year ASCVD risk.
- Complications
Premature coronary heart disease: myocardial infarction and the need for revascularization occur decades earlier than in the general population when FH is untreated.
- Prognosis
Untreated heterozygous FH: carries markedly increased lifetime risk of CHD, with events presenting substantially earlier than in the general population.
- Prevention
Population screening: the US Preventive Services Task Force recommends dyslipidemia screening beginning at age 35 in men and age 45 in women, with risk-factor assessment every 4 to 6 years from ages…
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