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FH is a monogenic disease caused by loss-of-function mutations in the LDLR or apoB genes, or a gain-of-function mutation in the PCSK9 gene; around 95% of FH cases are caused by mutations in LDLR. More than 1000 different mutations that cause FH have been identified in LDLR. The different mutations cause reduced function or complete loss-of-function, the latter being associated with more severe hypercholesterolaemia and CVD. The diagnosis of FH is usually based on clinical presentation. The commonly used criteria from the Dutch Lipid Clinic Network are shown in Table 12. Other criteria are the Simon Broome register or the WHO criteria.364,365 The diagnosis can be verified by showing causative mutations in the pathogenic genes. However, in most studies, the frequency of detectable mutations in patients with a clinically definite or probable HeFH is between 6080%. This suggests that a considerable proportion of patients with FH have either a polygenic cause of the disease or that other genes, yet to be identified, are involved. Genetic testing and cascade screening. Probands (index cases) should be identified according to the following criteria: • TC >_8 mmol/L (>_310 mg/dL) without treatment in an adult or adult family member (or >95th percentile by age and gender for country); • Premature CHD in the patient or a family member; • Tendon xanthomas in the patient or a family member; or • Sudden premature cardiac death in a family member. Cascade screening of family members of a known index case allows for the efficient identification of new cases. Cascade screening is best performed by a lipid clinic. In most families, the cases may be identified with TC or LDL-C analysis; however, genetic testing is recommended when the causative mutation is known. Cholesterol-lowering treatment should be initiated as soon as possible after a diagnosis has been made. To improve risk assessment, the use of imaging techniques to detect asymptomatic atherosclerosis is recommended. The concept of cumulative cholesterol burden illustrates the importance of early treatment (for children, see below). Treatment should be initiated with high-intensity statin therapy, in most cases in combination with ezetimibe. In FH patients at very-high risk of ASCVD due to a prior history of ASCVD or another major risk factor, LDL-C goals are a >_50% reduction of LDL-C from baseline and an LDL-C <1.4 mmol/L (<55 mg/dL). In the absence of ASCVD or another major risk factor, patients with FH are categorized as high-risk, and LDL-C goals are a >_50% reduction of LDL-C from baseline and an LDL-C <1.8 mmol/L (<70 mg/dL). PCSK9 inhibitors lower LDL-C levels by up to 60% on top of statins. Two RCTs have reported a beneficial effect on clinical endpoints in ASCVD patients without FH.119,120 PCSK9 inhibitors are recommended in very-high-risk patients with FH if the treatment goal is not achieved on maximal tolerated statin plus ezetimibe. PCSK9 inhibitors are also recommended in FH patients who cannot tolerate statins.366,367 Recommendations for the detection and treatment of patients with HeFH are shown below. Recommendations for the detection and treatment of

patients with heterozygous familial hypercholesterolaemia

Recommendations Classa Levelb

It is recommended that a diagnosis of FH is considered in patients with CHD aged <55 years for men and <60 years for women, in people with relatives with premature fatal or non-fatal CVD, in people with relatives who have tendon xanthomas, in people with severely elevated LDL-C [in adults >5 mmol/L (>190 mg/dL), in children >4 mmol/L (>150 mg/dL)], and in first-degree relatives of FH patients. I C It is recommended that FH should be diagnosed using clinical criteria and confirmed, when possible, via DNA analysis. I C Once the index case is diagnosed, family cascade screening is recommended. I C It is recommended that FH patients with ASCVD or who have another major risk factor are treated as very-high-risk, and that those with no prior ASCVD or other risk factors are treated as high-risk. I C For FH patients with ASCVD who are at veryhigh risk, treatment to achieve a >_50% reduction from baseline and an LDL-C <1.4 mmol/L (<55 mg/dL) is recommended. If goals cannot be achieved, a drug combination is recommended. I C In primary prevention, for individuals with FH at very-high risk, an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) should be considered. IIa C Treatment with a PCSK9 inhibitor is recommended in very-high-risk FH patients if the treatment goal is not achieved on maximal tolerated statin plus ezetimibe. I C In children, testing for FH is recommended from the age of 5 years, or earlier if HoFH is suspected. I C Children with FH should be educated to adopt a proper diet and treated with a statin from 810 years of age. Goals for treatment should be LDL-C <3.5 mmol/L (<135 mg/dL) at >10 years of age. IIa C

ASCVD = atherosclerotic cardiovascular disease; CHD = coronary heart disease; CVD = cardiovascular disease; FH = familial hypercholesterolaemia; HoFH = homozygous FH; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9. aClass of recommendation. bLevel of evidence. Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026