Commentary – Update to consensus statement on homozygous familial hypercholesterolaemia

In 2014, the European Atherosclerosis Society published a consensus statement specifically focused on homozygous familial hypercholesterolaemia (HoFH) (1), aiming to improve the care of individuals with this rare and difficult-to-treat condition. This statement subsequently catalysed initiatives to refine what is meant by ‘HoFH’ in terms of genetics, new therapeutic approaches, as well as a global registry on HoFH care to inform health policy. The Homozygous Familial Hypercholesterolaemia International Clinical Collaboration (HICC) registry, an international network of healthcare providers managing HoFH patients, provided important information on the burden of HoFH. With data from over 750 HoFH patients across 38 countries (2), the HICC  registry showed that patients were diagnosed too late (median age of 12 years), when one in 10 had already experienced a coronary event. Treatment disparity between high and non-high-income countries was also evident, impacting patient outcome, with a first cardiovascular event occurring about a decade earlier among those in less affluent versus high income countries (2).

The 2023 update to this HoFH consensus statement has addressed several areas of persistent concern (Box 1) (3). A key strength is provision of updated diagnostic criteria for HoFH, with the recommendation to prioritise phenotypic features over genotype. Importantly, an untreated low-density lipoprotein cholesterol >10 mmol/L (>~400 mg/dL) is suggestive of HoFH and should prompt further evaluation.

Box 1. What is new in the 2023 EAS Consensus Statement on Homozygous Familial Hypercholesterolaemia?

– Updated diagnostic criteria, prioritising phenotype over genotype
– Updated genetic terminology
– Updated recommendations for screening strategies to improve early identification of HoFH
– Updated recommendations for HoFH management, including cardiovascular work-up and review, and family planning
– Updated treatment algorithm, including novel treatments and alternatives where these are not available or affordable

The consensus statement acknowledged that the term ‘HoFH’ is somewhat inaccurate, given that FH is now recognised as an autosomal semi-dominant condition (4). Thus, patients with ‘HoFH’ have two different pathogenic variants either in the same or two different causative genes, i.e., LDLR (loss-of-function), APOB (receptor binding-impaired), PCSK9 (gain-of-function) or LDLRAP1 (loss-of-function) genes. Only those variants reported as ‘pathogenic/likely pathogenic’ according to recognised criteria provide confirmation of a genetic diagnosis of HoFH (5,6). In the absence of a genetic diagnosis, the consensus statement recommends the use of the term ‘phenotypic HoFH’ as a practical clinical shorthand (3).

Another strength of the consensus statement is an updated treatment algorithm which recognises limitations in access to novel treatments such as PCSK9 inhibitors, evinacumab and lomitapide in many regions of the world. Where such treatments are not available or affordable, the statement recommends lipoprotein apheresis, or if not available plasma exchange, as pragmatic effective therapeutic options.

As HoFH care improves and individuals survive well into adulthood, family planning discussions become a priority for both men and women. Pregnancy in HoFH women is associated with an increased cardiovascular risk and is potentially life-threatening; after counselling, those contemplating pregnancy should receive integrated care from a multidisciplinary team. As lipid lowering therapy is a challenge given restrictions on the use of most treatments, weekly or fortnightly lipoprotein apheresis is recommended (7-9). Statin therapy (alone or in combination with other lipid lowering therapy) could be restarted from the second trimester, with evidence that this appears to be safe (9), and supported by recent FDA recommended changes to statin contraindications for high-risk pregnant women (10) (although European agencies have so far not responded).

There is still much to do to improve the care of patients with HoFH, in whom delayed diagnosis and undertreatment are the norm in most countries (2). This 2023 update has thrown down the gauntlet, providing pragmatic clinical guidance to drive better care and improve outcome and quality of life for HoFH patients globally. The challenge will be delivery, with new thinking needed on how best to implement best HoFH care for patients.


1.           Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. 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. Eur Heart J. 2014;35(32):2146-57.

2.           Tromp TR, Hartgers ML, Hovingh GK, Vallejo-Vaz AJ, Ray KK, Soran H, et al. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet. 2022;399(10326):719-28.

3.           Cuchel M, Raal FJ, Hegele RA, Al-Rasadi K, Arca M, Averna M, et al. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J. 2023.

4.           Berberich AJ, Hegele RA. The complex molecular genetics of familial hypercholesterolaemia. Nat Rev Cardiol. 2019;16(1):9-20.

5.           Chora JR, Iacocca MA, Tichy L, Wand H, Kurtz CL, Zimmermann H, et al. The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. Genet Med. 2022;24(2):293-306.

6.           Lazarte J, Hegele RA. Editorial comment: hazards of interpreting genetic reports. Curr Opin Lipidol. 2021;32(2):81-2.

7.           Ogura M, Makino H, Kamiya C, Yoshimatsu J, Soran H, Eatough R, et al. Lipoprotein apheresis is essential for managing pregnancies in patients with homozygous familial hypercholesterolemia: Seven case series and discussion. Atherosclerosis. 2016;254:179-83.

8.           Russi G. Severe dyslipidemia in pregnancy: The role of therapeutic apheresis. Transfus Apher Sci. 2015;53(3):283-7.

9.           Graham DF, Raal FJ. Management of familial hypercholesterolemia in pregnancy. Curr Opin Lipidol. 2021;32(6):370-7.

10.        US Food And Drugs Administration. Drug Safety Communication 7-20-2021. FDA requests removal of strongest warning against using cholesterol-lowering statins during pregnancy; still advises most pregnant patients should stop taking statins. 2021 [Available from:,not%20generally%20necessary%20during%20pregnancy.