Familial hypercholesterolaemia

FH is characterised by markedly elevated LDL-C from birth, with progressive atherosclerotic plaque deposition in the coronary and other arterial beds. Heterozygous FH (HeFH) typically manifests with premature coronary artery disease in adulthood (men before 55 years, women before 65 years), with variable physical findings including tendinous xanthomas (most often Achilles and extensor tendons of the hands), xanthelasmas, and corneal arcus; tendon xanthomas were historically reported in 30-50% of affected individuals, with lower prevalence in the setting of widespread statin use. Homozygous or biallelic FH (HoFH) manifests in childhood with LDL-C above 500 mg/dL (>13 mmol/L), interdigital and tendon xanthomas, severe coronary artery disease by the mid-20s, and frequent aortic valve stenosis. In pre-statin natural history cohorts, untreated men carried a 50% risk of a fatal or non-fatal coronary event by age 50 years and untreated women a 30% risk by age 60 years.

The estimated prevalence of heterozygous FH is 1/250. Estimates derive principally from European, North American, East Asian, and Australian cohorts; prevalence remains unknown in approximately 90% of the world’s countries.

FH is caused by germline pathogenic variants in LDLR (>50% of cases), APOB (~5-10%), PCSK9 (<1%), or, in a recessive form, biallelic variants in LDLRAP1 (<1%). LDLR encodes the low-density lipoprotein receptor, which mediates hepatic endocytosis of LDL particles; loss-of-function variants reduce receptor number or LDL-C binding capacity. APOB encodes apolipoprotein B-100, the LDLR ligand on LDL particles; pathogenic variants impair LDL-receptor binding. Gain-of-function variants in PCSK9 accelerate LDLR degradation and reduce LDL-C clearance. Biallelic loss-of-function variants in LDLRAP1 disrupt LDLR internalisation in hepatocytes, producing a recessive phenocopy of severe LDLR-related FH.

FH is inherited in an autosomal dominant manner for LDLR-, APOB-, and PCSK9-related forms; LDLRAP1-related FH is autosomal recessive. Each child of an individual with autosomal dominant FH has a 50% chance of inheriting the familial pathogenic variant. De novo variants appear to be very rare. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The clinical diagnosis rests on established consensus criteria, most prominently the endorsed in the 2013 consensus statement, with the and the as further validated frameworks. Meeting the criteria establishes the clinical diagnosis of FH. Supportive biochemical findings include untreated LDL-C above 190 mg/dL (>4.9 mmol/L) in adults, above 160 mg/dL in children with a first-degree relative carrying hyperlipidaemia or premature coronary artery disease, and total cholesterol above 310 mg/dL (>8 mmol/L). LDL-C above 500 mg/dL (>13 mmol/L) is characteristic of homozygous or biallelic FH.

Main differential diagnoses include:

• : childhood xanthomas and early-onset coronary artery disease with haematologic abnormalities (haemolytic anaemia, thrombocytopenia, stomatocytes) and characteristically poor statin response; ABCG5, ABCG8
• Familial dysbetalipoproteinemia (hyperlipoproteinemia type III): cutaneous and tuberous xanthomas with elevated triglycerides alongside elevated cholesterol; APOE
• Lysosomal acid lipase deficiency (cholesterol-ester storage disease / Wolman disease): elevated LDL-C with hepatosplenomegaly, raised liver enzymes, and elevated triglycerides; infantile Wolman disease additionally with malnutrition, liver disease, and adrenal cortical insufficiency; LIPA

• Establishing the diagnosis at the molecular level confirms the clinical suspicion and clarifies the causal gene.
• Identifying the underlying pathogenic variant supports specific and individualised surveillance and clinical management decisions, which remain the responsibility of the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, predictive testing of at-risk relatives is technically possible and supports family-based cascade screening.

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