Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is a semi-dominant, autosomal, monogenic lipoprotein disorder characterized by severe elevations in low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). The most common form, heterozygous FH, has an estimated prevalence of approximately 1 per 311 individuals, making it one of the most common hereditary disorders in medicine. FH is caused by pathogenic variants in the LDL receptor (LDLR) gene, or in genes encoding proteins involved in receptor-mediated LDL particle uptake, including apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9). Other genes account for a minority of cases.

Diagnosis is based on LDL-C levels, a family history of elevated LDL-C or premature ASCVD, supportive physical findings such as tendinous xanthomas, and, when available, molecular confirmation of a pathogenic FH-causing variant. Prompt recognition and treatment with statins, often combined with ezetimibe, modifies the natural course of the disease. Sex differences in FH diagnosis and treatment are widely reported, with women diagnosed later and treated less intensively than men. PCSK9 inhibitors are often required in patients with FH who meet criteria for treatment intensification. In statin-intolerant patients, bempedoic acid may provide additional therapeutic options. The most severe form, homozygous FH (HoFH), has an estimated prevalence of ~1 in 367,000 individuals and is associated with ASCVD in youth, calcific aortic stenosis, and a markedly reduced life expectancy. Patients with HoFH require specialized care and may need LDL apheresis and specific orphan drugs such as lomitapide or evinacumab.