Homozygous Familial Hypercholesterolaemia: New Insights and Guidance for Clinicians to Improve Detection and Clinical Management

A Position Paper From the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society

Marina Cuchel; Eric Bruckert; Henry N. Ginsberg; Frederick J. Raal; Raul D. Santos; Robert A. Hegele; Jan Albert Kuivenhoven; Børge G. Nordestgaard; Olivier S. Descamps; Elisabeth Steinhagen-Thiessen; Anne Tybjærg-Hansen; Gerald F. Watts; Maurizio Averna; Catherine Boileau; Jan Borén; Alberico L. Catapano; Joep C. Defesche; G. Kees Hovingh; Steve E. Humphries; Petri T. Kovanen; Luis Masana; Päivi Pajukanta; Klaus G. Parhofer; Kausik K. Ray; Anton F. H. Stalenhoef; Erik Stroes; Marja-Riitta Taskinen; Albert Wiegman; Olov Wiklund; M. John Chapman


Eur Heart J. 2014;35(32):2146-2157. 

In This Article

Abstract and Introduction


Aims Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH.

Methods and results Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary.

Conclusion This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.


Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening disease originally characterized clinically by plasma cholesterol levels >13 mmol/L (>500 mg/dL), extensive xanthomas, and marked premature and progressive atherosclerotic cardiovascular disease (ACVD). Studies in cultured fibroblasts from these patients showed a severe defect in the ability to bind and internalize LDL particles, subsequently shown to be caused by mutations in both alleles of the gene encoding the LDL receptor (LDLR).[1] Recent genetic insights, however, indicate that mutations in alleles of other genes, including APOB, PCSK9, and LDLRAP1, may be present in some individuals with HoFH.

Untreated, most patients with markedly elevated LDL-C levels develop overt atherosclerosis before the age of 20 years, and generally do not survive past 30 years.[1] Thus, the primary goals of management are prevention of ACVD by early and comprehensive control of hypercholesterolaemia, and early detection of complications, with specific focus on ostial occlusion and aortic stenosis.[2] Unfortunately, HoFH is typically diagnosed when considerable coronary atherosclerosis has already developed, emphasizing the need for optimization of treatment in childhood.

Recent advances have highlighted the (i) prevalence and (ii) heterogeneity of the genetic defects underlying HoFH and its clinical phenotype, which are both more pronounced than originally believed. Therefore, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed current and emerging data with the aim of providing clinical guidance for the recognition and management of HoFH patients. These recommendations are directed not only to cardiologists and lipid specialists, but also to a wide spectrum of clinicians, including primary care physicians, paediatricians, dermatologists, and endocrinologists, who are often the first to see and hopefully refer these patients. These recommendations will also be a useful reference when decisions are made about provision of healthcare for HoFH.