The clinical presentation of HoFH is variable and important to diagnose early

Both children and adults can present with a combination of the following signs according to the severity of the phenotype

ASCVD=atherosclerotic cardiovascular disease. CVD=cardiovascular disease. MI=myocardial infarction.

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2023 ESC/EAS diagnostic criteria

• HoFH can be diagnosed using clinical and/or genotypic criteria recommended by the EAS Guidelines³
• HoFH should be suspected if untreated LDL-C levels are >10 mmol/L (> 400 mg/dL), requiring further evaluation including a detailed medical and family history and/or genetic testing³

Clinical diagnostic criteria		Genotypic diagnostic criteria
LDL-C >10 mmol/L*	Cutaneous or tendon xanthomas before ​age 10 years​ and/or Untreated elevated LDL-C levels consistent with HeFH in both parents†	Confirmation of two pathogenic variants in the LDLR, ​APOB, PCSK9, or LDLRAP1 genes or ≥2 such variants at different loci†

LDLRAP=low-density lipoprotein receptor adapter protein 1. EAS=European Atherosclerosis Society. ESC=European Society of Cardiology.
LDLR=low-density lipoprotein receptor. APOB=apolipoprotein B. PCSK9=proprotein convertase subtilisin/kexin type 9.

* Lower LDL-C levels, especially in children or in treated patients, can be seen in genetically confirmed HoFH.

† In digenic form, one parent may have normal LDL-C levels and the other may have LDL-C levels consistent with HoFH.

‡ Bi-allelic pathogenic/likely pathogenic variants on different chromosomes at the LDLR, APOB, PCSK9, or LDLRAP1 genes or >2 such variants at different loci.

While genetic testing may aid diagnosis, HoFH may be present in patients without known FH-related mutations.⁷

Genetic testing is useful for risk stratification and, in the case of LDLR-deficient patients, may predict poor response to drug treatment.¹

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Importance of early and accurate diagnosis

HoFH is underdiagnosed and undertreated in the general population^8,9

• There is a lack of awareness of HoFH among physicians¹⁰
• Many cases are not diagnosed in childhood, when atherosclerosis may be preventable¹¹
• A significant proportion of patients are misdiagnosed following initial presentation, with HoFH often mistaken for HeFH^3,12

The extent and duration of elevated total cholesterol, 90% of which is LDL-C in patients with HoFH, is generally proportional to the severity of atherosclerosis and all-cause and cardiovascular mortality, highlighting the need for prompt diagnosis and treatment initiation.¹³

Increasing risk of all-cause mortality with higher cholesterol level (on treatment)¹³

Adapted from Thompson, G R et al., 2018

TC=total cholesterol.

*Retrospective survey of lipid levels and clinical outcomes of 133 HoFH patients treated with a combination of lipid-lowering measures between 1990 and 2014 in South Africa and the UK