Familial hypercholesterolemia: state-of-the-art

Résumé fourni par la source

Familial hypercholesterolemia (FH) affects about 20 million people worldwide and remains markedly underdiagnosed and undertreated. Contemporary studies estimate the prevalence of heterozygous FH (HeFH) at 1 in 192 to 1 in 310, and the prevalence of homozygous FH (HoFH) at about 1 in 300,000. The 2016 United States National Health and Nutrition Examination Survey estimated FH prevalence at 1 in 250 adults. Untreated HeFH causes fatal coronary events before age 55 in about 50% of men and before age 60 in about 15% of women. Pathogenic variants in the low-density lipoprotein receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 (PCSK9) cause most FH cases. Polygenic burden and genetic modifiers influence phenotype and treatment response. Clinical diagnosis relies on the Dutch Lipid Clinic Network (DLCN), the Simon Broome criteria, or the Make Early Diagnosis to Prevent Early Death criteria. Next-generation sequencing (NGS) increases diagnostic certainty and enables cascade screening. In severe hypercholesterolemia, NGS detects mutations in 57% of cases overall and in 92% when low-density lipoprotein cholesterol (LDL-C) exceeds 310 mg/dL. In contrast, population screening using LDL-C >190 mg/dL identifies pathogenic variants in fewer than 5% of cases. Cascade screening yields range from 0.4 to 0.7 per index case in some United Kingdom series, about 2 in several Australian and Brazilian programs, and up to 8 in optimized Dutch programs. In primary care, the Familial Hypercholesterolemia Case Ascertainment Tool discriminated FH better than other criteria in 1,030,183 patients, with an area under the curve (AUC) of 0.844, compared with 0.730 for Simon Broome, 0.766 for DLCN, and 0.579 for LDL-C above the 99th percentile. Management begins with high-intensity statins and ezetimibe. Treatment aims for at least a 50% reduction in LDL-C and LDL-C <70 mg/dL for primary prevention or <55 mg/dL for very-high-risk patients. In children older than 10 years, the LDL-C target is <135 mg/dL. PCSK9-directed therapies further lower LDL-C. Evolocumab reduces LDL-C by 59% to 61% in RUTHERFORD-2 and by 31% in TESLA Part B; alirocumab reduces LDL-C by 51% to 58% in ODYSSEY FH I/II; inclisiran reduces LDL-C by 48% in ORION-9; and evinacumab reduces LDL-C by about 49% in HoFH. Lipoprotein apheresis acutely reduces LDL-C by about 50% to 75% per session. Earlier detection, cascade screening, and equitable access to combination therapy remain central to reducing premature atherosclerotic cardiovascular disease in FH.

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