Homozygous Familial Hypercholesterolaemia - New Treatments and Clinical Guidance
Summary of Recommendations
Diagnosis of homozygous familial hypercholesterolaemia
- Consider only variants reported as ‘pathogenic/likely pathogenic’ according to recognized criteria as a confirmed genetic diagnosis of HoFH.
Updated criteria for the diagnosis of homozygous familial hypercholesterolaemia
- Clinical criteria
- LDL-C criteria: Untreated LDL-C >10 mmol/L (>∼400 mg/dL) is suggestive of HoFH requiring further investigation to confirm the diagnosis.
- Additional criteria: Cutaneous or tendon xanthomas before age of 10 years and/or untreated elevated LDL-C levels consistent with heterozygous FH in both parents* *In digenic form, one parent may have normal LDL-C levels and the other may have LDL-C levels consistent with HoFH.
- Genetic criteria
- Genetic confirmation of bi-allelic pathogenic/likely pathogenic variants on different chromosomes at the LDLR, APOB, PCSK9, or LDLRAP1 genes or ≥2 such variants at different loci (Box 3); for abbreviations for genetic nomenclature see below. ABCG5, ABCG8: Genes encoding ATP-binding cassette subfamily G members 5 and 8
- APOB: Gene encoding apolipoprotein B LDLR: Gene encoding the low-density lipoprotein receptor LDLRAP1: Gene encoding low-density lipoprotein receptor adaptor protein 1 LIPA: Gene encoding lysosomal acid lipase PCSK9: Gene encoding proprotein convertase subtilisin/kexin type 9 protein (PCSK9)
Screening
- Paediatric guidelines should include newborn lipid screening when both parents are known to have HeFH or simply hypercholesterolaemia.
- The panel advocates for paediatric universal FH screening that will also improve the detection of HoFH.
- Education programmes are needed to increase awareness among all healthcare providers.
Managing HoFH
- Lipid-lowering treatment should start at diagnosis using multiple treatments and/or LA to reach LDL-C goal.
- A fast-track path for approval of novel treatments in children is needed to ensure their use from a young age, decreasing cumulative LDL-C exposure and improving outcomes.
- Gene therapy and CRISPR-based gene editing are promising approaches, but clinical trials are needed to evaluate efficacy and safety.
- Multidisciplinary management in specialist centres integrating imaging, treatment, and comprehensive support of these patients is needed.
Treatment pathway for homozygous familial hypercholesterolaemia in childhood
- Initiate lifestyle changes, statins, and ezetimibe from diagnosis
- If LDL-C >8 mmol/L (300 mg/dL), consider lipoprotein apheresis (LA)
- If LDL-C >3 mmol/L (115 mg/dL), consider novel therapies if available and affordable
- If LA or novel therapies are not available, consider liver transplantation
Cardiovascular imaging in HoFH management
- Polyvascular subclinical atherosclerosis may be present in coronary, femoral, and carotid vascular territories in HoFH. Where available and easily accessible, imaging is an important tool in HoFH management.
- Carotid plaque rather than increased carotid intima-medial thickness is a marker of early stage atherosclerosis. Quantitative carotid plaque measurement by three-dimensional ultrasound is a reliable measure of disease progression and response to therapy. High-resolution magnetic resonance imaging (MRI) has been shown to detect thrombosis and lipid-rich carotid plaques.
- Patients with HoFH should receive echocardiographic evaluation of the heart and aorta at baseline and annually thereafter. CT angiography should be performed at least once after age 3 as it also allows for differentiation of coronary ostial stenosis (which may be asymptomatic) and aortic stenosis. A stress electrocardiogram should only be performed after exclusion of coronary ostial or tight aortic stenosis.
- Follow-up CT angiography should be performed as clinically indicated. The follow-up interval in children depends on baseline disease, extent of LDL-C lowering, radiation risk, and cost. Radiation may be less of an issue with newer CT devices and imaging protocols. Early imaging can help to identify soft plaque to target for intervention and asymptomatic atherosclerosis.
- Coronary calcium scoring is less predictive in young patients since extensive calcification may not yet have developed in the plaques.
- Invasive coronary angiography is indicated in patients with symptoms and/or signs suggestive of ischaemia or valve malfunction.
- The atherosclerotic burden of the aorta can also be evaluated by MRI or transoesophageal echocardiography.
- Careful electrocardiographic or nuclear stress testing may be used to determine the presence of ischaemia. Coronary flow velocity reserve determined noninvasively with echocardiography has also been used to determine risk.
Family planning and pregnancy
- HoFH women should receive integrated care from a multidisciplinary team, including cardiovascular assessment, before, during, and after pregnancy.
- To minimize LDL-C exposure, LA should be offered during pregnancy, and statin plus other lipid-lowering therapy restarted from the second trimester.
Global perspectives
- Creation of national screening programmes tailored to the healthcare system and culture of individual countries. These underpin the universal recommendation for early identification of HoFH via universal screening or systematic cascade screening. The panel advocates genetic testing to facilitate cascade screening; where not yet possible or privacy concerns limit implementation, screening based on LDL-C cut-offs are equally acceptable.
- Creation of education programmes to improve awareness, both among clinicians, starting from medical school, and patients.
- Creation at the local (institutional), regional, and government level of management guidelines that take account of resources, including access to specialist centres and effective lipid-lowering treatments. These should address costs associated with treatment and access to care.
Recommendation Grading
Abbreviations
- HoFH:
homozygous Familial Hypercholesterolemia
Disclaimer
Overview
Title
Homozygous Familial Hypercholesterolaemia - New Treatments and Clinical Guidance
Authoring Organization
Publication Month/Year
May 3, 2023
Last Updated Month/Year
October 15, 2024
Supplemental Implementation Tools
Document Type
Consensus
Country of Publication
European
Document Objectives
This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy—both pharmacologic intervention and lipoprotein apheresis (LA)—is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.
Inclusion Criteria
Male, Female, Adolescent, Adult, Child, Older adult
Health Care Settings
Ambulatory
Intended Users
Nurse, nurse practitioner, physician, physician assistant
Scope
Diagnosis, Assessment and screening, Treatment, Management
Diseases/Conditions (MeSH)
D000090542 - Homozygous Familial Hypercholesterolemia
Keywords
Homozygous Familial Hypercholesterolaemia, Homozygous Familial Hypercholesterolemia, HoFH
Source Citation
Cuchel M, Raal FJ, Hegele RA, Al-Rasadi K, Arca M, Averna M, Bruckert E, Freiberger T, Gaudet D, Harada-Shiba M, Hudgins LC, Kayikcioglu M, Masana L, Parhofer KG, Roeters van Lennep JE, Santos RD, Stroes ESG, Watts GF, Wiegman A, Stock JK, Tokgözoğlu LS, Catapano AL, Ray KK. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J. 2023 Jul 1;44(25):2277-2291. doi: 10.1093/eurheartj/ehad197. PMID: 37130090; PMCID: PMC10314327.