Updated Guidance for Homozygous Familial Hypercholesterolemia

Updated treatment and management guidance for patients with homozygous familial hypercholesterolemia.

The European Atherosclerosis Society (EAS) released a 2023 updated consensus on homozygous familial hypercholesterolemia (HOFH) which was published in the European Heart Journal.

Homozygous familial hypercholesterolemia is a rare disease that presents as elevated low-density lipoprotein cholesterol (LDL-C) from birth coupled with accelerated development of atherosclerotic cardiovascular disease (ASCVD). At the time of the previous HOFH statement by the EAS in 2014, there were few therapeutic options available for HOFH.

The 2023 statement provided updated diagnostic criteria, screening recommendations, treatment algorithms, and guidance about family planning as well as new insights into the genetics of the disease.

The updated criteria for HOFH diagnosis are an untreated LDL-C level of greater than 13 mmol/L or a level of greater than 8 mmol/L in patients receiving standard therapy. Additional criteria include cutaneous or tendon xanthomas before the age of 10 years or having both parents with LDL-C levels consistent with heterozygous familial hypercholesteremia. Physicians should rule out other conditions that could be responsible for elevated LDL-C.

The last decade has seen much progress, particularly with new highly efficacious LDL-C-lowering therapies which offer the prospect of LDL-C goal attainment, leading to improved survival and quality of life.

Even if they do not meet the LDL-C criteria, patients suspected of having HOFH should receive genetic evaluation, as there can be LDL-C variability in this genetically complex disease. The most common affected pathogenic variants that have been associated with HOFH include a loss-of-function variant in low-density lipoprotein receptor (LDLR), a receptor-binding defective variant in apolipoprotein B (APOB), and a gain-of-function variant in proprotein convertase subtilisin/kexin type 9 (PCSK9). However, patients with HOFH may be carriers of other variants. As such, the EAS recommended for patients with suspected HOFH to receive targeted next-generation sequencing to both confirm the diagnosis and to guide appropriate treatment.

Patients with HOFH should be referred to a specialist for treatment and reverse cascade screening. These patients likely require multidisciplinary care involving pediatricians and cardiologists.

At diagnosis, patients should be started on high-intensity statins and ezetimibe. PCSK9-directed therapy should be added within 8 weeks. After patients have received 1 or 2 doses of PCSK9-targeted therapy, this therapy may be discontinued if the patient has not had a greater than 15% reduction in LDL-C.

The recommended LDL-C treatment target for children is less than 3 mmol/L and for adults is less than 1.8 or 1.4 mmol/L for patients without or with ASCVD risk factors, respectively. For patients who do not meet treatment goals, lomitapide and/or angiopoietin-like protein 3 (ANGPTL3)-directed therapy with or without lipoprotein apheresis should be considered.

 “HOFH is still underdiagnosed and/or identified too late and remains undertreated despite its severe adverse impact on cardiovascular health,” the study authors wrote. “The last decade has seen much progress, particularly with new highly efficacious LDL-C-lowering therapies which offer the prospect of LDL-C goal attainment, leading to improved survival and quality of life.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

This article originally appeared on The Cardiology Advisor


Cuchel M, Raal FJ, Hegele RA, et al. 2023 Update on European Atherosclerosis Society Consensus Statement on homozygous familial hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J. Published online May 2, 2023. doi:10.1093/eurheartj/ehad197