Journal of Atherosclerosis and Thrombosis · 11 authors, 12 centres
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These guidelines update the diagnosis and management of familial hypercholesterolemia (FH) in Japan, emphasizing early detection and aggressive LDL-C lowering. Key changes include revised Achilles tendon thickness cutoffs (≥8.0 mm in men, ≥7.5 mm in women on X-ray) and a prevalence estimate of ~1 in 300. Statins are first-line therapy, with ezetimibe and PCSK9 inhibitors as add-ons, and lipoprotein apheresis is recommended for homozygous FH and severe drug-resistant cases.
**Background:** Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated LDL cholesterol, premature coronary artery disease (CAD), and tendon xanthomas. It is an extremely high-risk condition requiring early diagnosis, aggressive treatment, and family cascade screening. These 2022 Japanese guidelines update diagnostic criteria and treatment recommendations based on recent evidence.
**Methods:** The guidelines were developed by the Japan Atherosclerosis Society working group, reviewing literature up to 2021. Evidence levels were classified for treatment (1+ to 4) and epidemiology (E-1a to E-3). Recommendations are graded A (strongly recommended) or B (weakly recommended). Key updates include revised Achilles tendon thickness cutoffs based on a 2021 study of 986 cases (485 genetically confirmed FH).
**Key Results:** - **Prevalence:** FH affects approximately 1 in 300 people in the general population, 1 in 30 with CAD, and 1 in 15 with premature CAD. In Japan, Mabuchi et al. reported 1 in 208 in the Hokuriku region. - **Prognosis:** Untreated heterozygous FH (HeFH) has a 10–20 times higher odds ratio for CAD vs. non-FH. Before statins, 73% of men and 64% of women with HeFH died of cardiac death; statin therapy increased mean age of death from 63 to 76 years in HeFH and from 28 to 59 years in homozygous FH (HoFH). - **Diagnostic criteria:** FH is diagnosed if ≥2 of: (1) untreated LDL-C ≥180 mg/dL, (2) tendon xanthomas (Achilles thickening on X-ray ≥8.0 mm men, ≥7.5 mm women; or ultrasound ≥6.0 mm men, ≥5.5 mm women) or cutaneous nodular xanthomas, (3) family history of FH or premature CAD (men <55, women <65 years). Genetic testing confirms diagnosis. - **Treatment targets:** Primary prevention LDL-C <100 mg/dL; secondary prevention <70 mg/dL. Statins are first-line (13 randomized trials in HeFH). Combination with ezetimibe and/or PCSK9 inhibitors is recommended if targets not met. In the FAME registry, only 12.3% of primary prevention and 1.8% of secondary prevention patients achieved targets. - **Lipoprotein apheresis:** Recommended for HoFH and severe HeFH with drug resistance. In HoFH, apheresis reduces LDL-C by 60–80% per session and improves xanthomas and atherosclerosis. Starting age is typically 4–6 years. - **Pregnancy:** Statins and most lipid-lowering drugs (except anion exchange resins) should be stopped ≥3 months before conception and during lactation. Lipoprotein apheresis can be safely continued during pregnancy.
**Clinical Implications:** These guidelines emphasize that FH is not rare (1 in 300) and is underdiagnosed in Japan. Early diagnosis through cascade screening and aggressive LDL-C lowering with statins, ezetimibe, and PCSK9 inhibitors can substantially reduce cardiovascular risk. Revised Achilles tendon cutoffs improve sensitivity while maintaining specificity. For HoFH, early initiation of lipoprotein apheresis and newer drugs (MTP inhibitors) are critical. The guidelines also provide specific recommendations for women of childbearing age and genetic counseling.