Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is the most common genetic cause of premature atherosclerotic cardiovascular diseases (ASCVD), with estimated prevalence of 1 in 270 for heterozygous FH and 1 in 300,000 for homozygous cases.

FH is generally asymptomatic until the development of ASCVD, so screening to prevent complications is the best strategy.

FH should be suspected if a patient presents with:

• elevated total cholesterol (greater than 7.5 millimoles per litre (mmol/L) and low-density lipoprotein cholesterol (LDL) (greater than 4.9 mmol/L);
• early ASCVD in the form of acute coronary syndrome or, less frequently, stroke, transient ischemic attack or peripheral arterial disease before age 60 in heterozygous FH;
• peripheral stigmata of hyperlipidaemia (tendon xanthoma, xanthelasma or corneal arcus below age 45);
• family history of early ASCVD (below age 50 in second-degree relatives or below age 60 in first-degree relatives); or
• family history of documented raised cholesterol levels greater than 7.5mmol/L in adult first-degree or second-degree relatives; and
• all inherited in an autosomal dominant pattern.

Rarer forms of FH include:

• homozygous FH, clinical features of which include:
  • total cholesterol greater than 13mmol/L and LDL cholesterol greater than 11mmol/L;
  • extremely premature cardiovascular disease (onset before age 30);
  • supravalvular aortic stenosis; and
  • prevalence of 1 in 300,000 (more common in South African Afrikaaners and French Québécois).
• Autosomal recessive FH:
  • combination of severe hypercholesterolaemia and premature ASCVD in an index case without a clear family history of ASCVD or hypercholesterolaemia;
  • consistent with autosomal recessive inheritance; and
  • prevalence of 1 in 1,000,000 (more common in Sardinia).

FH is caused by pathogenic changes (variants) in three main genes involved in the metabolic pathway of clearing LDL cholesterol:

• the LDL cholesterol receptor (LDLR) gene, which is the most common (accounting for 93% of cases);
• the apolipoprotein B (APOB) gene (5%); and
• the proprotein convertase subtilisin/kexin type-9 (PCSK9) gene (3%).

On rare occasions, other genes are responsible. In autosomal recessive FH, for example, apolipoprotein E (p.Leu 167 del) (autosomal dominant) and the LDL adaptor protein 1 (LDLRAP1) gene can be causative.

Other genetic lipid conditions that may present with any of the physical signs, premature ASCVD and/or hypercholesterolaemia that characterise FH include sitosterolaemia (ABCG5 and ABCG8) and lysosomal acid lipase deficiency (LIPA).

The vast majority of FH cases are inherited in an autosomal dominant pattern, whereby a variant in the LDLR, APOB, PCSK9 or APOE genes is transmitted to offspring from one affected parent. The chance of a first-degree relative being affected is 50%. Penetrance of pathogenic variants for traits such as hypercholesterolaemia is usually high.

Variants in LDLRAP1, ABCG5, ABCG8 and LIPA are inherited in an autosomal recessive pattern, whereby both parents are carriers with a 25% chance of having an affected child.

Heterozygous FH cases are managed with a combination of healthy lifestyle and lipid-lowering therapy. Statins and ezetimibe are effective in reducing the incidence of ASCVD in primary and secondary prevention. New injectable lipid-lowering therapies targeting PCSK9 (monoclonal antibodies such as alirocumab and evolocumab) or siRNA (inclisiran) may be added as third-line agents.

In homozygous FH, standard therapies are used but options also include therapies targeting angiopoietin-like protein 3 (ANGPTL3) (evinacumab) or microsomal transfer protein (MTP) (lomitapide). Some patients need to undergo lipoprotein apheresis regularly to remove excess LDL cholesterol.

For clinicians

• Heart UK: A focus on familial hypercholesterolaemia
• NHS England: National Genomic Test Directory
• NICE: Familial hypercholesterolaemia: Identification and management
• UCL Partners Proactive Care Framework: Lipid management including familial hypercholesterolaemia (PDF, 29 pages)

References:

• Moorjani S, Roy M, Gagné C and others. ‘Homozygous familial hypercholesterolemia among French Canadians in Québec province’. Arteriosclerosis, Thrombosis, and Vascular Biology 1989: volume 9, pages 211–216. DOI: 10.1161/01.ATV.9.2.211
• Filigheddu F, Quagliarini F, Campagna F and others. ‘Prevalence and clinical features of heterozygous carriers of autosomal recessive hypercholesterolemia in Sardinia‘. Atherosclerosis 2009: volume 207, issue 1, pages 162–167. DOI: 10.1016/j.atherosclerosis.2009.04.027

For patients

• British Heart Foundation: Familial hypercholesterolaemia
• Heart UK: Familial hypercholesterolaemia (PDF, 13 pages)
• Heart UK: Genetic testing