Familial hypercholesterolaemia (FH) is a hereditary dyslipidaemia characterised by a permanent and isolated elevation in circulating low-density lipoprotein (LDL) levels. Prevalence is estimated at 1 in 500 for the heterozygous dominantly inherited form of the disease but much less frequent forms of FH have been described. FH is often transmitted as a codominant trait and two clinical forms have been described. The heterozygous form is often clinically silent and may be diagnosed at any age following a complete lipid analysis (carried out after a period of fasting of over 12 hours) and diagnostic scores based on familial history (over three or more generations) or a personal history of coronary artery disease, extravascular deposits and isolated hypercholesterolaemia that does not respond to a lipid-controlled diet.
The severe homozygous form is very rare (1/1 million) with onset in the first two years of life and is characterised by extravascular cholesterol deposits (cutaneous or tendon xanthomas), LDL levels > 3.30 g/L and an arteriopathy (aortic stenosis, coronary artery disease) manifesting before 10 years of age. Recessively inherited hypercholesterolaemia (less than 20 cases reported so far) is characterised by xanthomas and/or atherosclerosis in children with severe hypercholesterolaemia born to parents with normal lipid levels. HF is caused by genetic mutations resulting in defective endocytosis of LDLs. For the dominant forms, mutations have been identified in the following genes: LDLR (responsible for between 2/3 and 3/4 of dominantly inherited cases), APOB encoding the LDL receptor ligand and PCSK9 a modulator of hepatic endocytosis. For the recessive forms, causative mutations have been identified in the LDLRAP1 and ABCG5/ABCG8 genes. The differential diagnosis should include familial combined hyperlipidaemia (total lipid count > 2g/L in multiple relatives) and polygenetic combined hyperlipidaemia (characterised by moderate and fluctuating LDL hyperlipidaemia that normalises in response to a lipid-controlled diet and no familial history of FH over three generations). Diagnostic scores allow clinical distinction of adults and children with heterozygous HF from those with combined hyperlipidaemia. The diagnosis can be confirmed by molecular analysis. Due to the high risk of cardiovascular disease, the diagnosis of HF in an individual should lead to investigation and management of the whole family. Management should be initiated as early as possible, preferably during the clinically silent phase of the disease when the arterial manifestations are reversible. Prenatal diagnosis should be offered to all families with at least one affected member with homozygous HF and in which the causative mutations carried by the parents have been identified.
Management of severe HF should be carried out within specialised centres for hereditary metabolic diseases. Heterozygous HF responds to a lipid-restricted diet and medical treatment (statin, an inhibitor of cholesterol/resin absorption) aimed at reducing LDL cholesterol by 50%. The prognosis depends on the age of the patient, the level of LDL cholesterol, and the degree of exposure of the artery to high levels of LDL since birth. In the absence of treatment, the risk of sudden death (initial manifestation of progressive arteriosclerosis located proximally to the coronary arteries) before 40 years of age is fifty times higher in individuals with FH than in the general population. However, the prognosis is excellent for patients given early, adapted treatment.