From the Guidelines
The diagnosis of Homozygous Familial Hypercholesterolemia (FH) should be made based on clinical criteria and family history, with genetic testing being the most accurate method to identify pathogenic variants that impair LDL receptor function and cause hypercholesterolaemia 1. The diagnostic approach for Homozygous Familial Hypercholesterolemia (FH) involves a combination of the following:
- Clinical evaluation to identify characteristic physical findings such as tendon xanthomas, xanthelasmas, and premature arcus cornealis
- Lipid panel testing to measure LDL cholesterol levels, which are typically extremely elevated in patients with HoFH
- Genetic analysis to identify mutations in genes like LDLR, APOB, PCSK9, and LDLRAP1, which is essential for definitive diagnosis
- Family history assessment, as HoFH follows an autosomal recessive inheritance pattern Additional testing may include imaging studies like echocardiography or cardiac CT to assess for atherosclerotic cardiovascular disease, which often develops early in these patients 1. It is worth noting that while the 2016 ESC/EAS guidelines for the management of dyslipidaemias provide recommendations for the detection and treatment of patients with heterozygous familial hypercholesterolaemia, the most recent and highest quality study, the 2023 international atherosclerosis society guidance, prioritizes genetic testing and clinical criteria for the diagnosis of FH 1, 2. However, genetic testing is currently the most accurate method for diagnosing FH, and it should be used to identify pathogenic variants that impair LDL receptor function and cause hypercholesterolaemia 1.
From the FDA Drug Label
A diagnosis of HoFH was defined by the presence of at least one of the following clinical criteria: (1) documented functional mutation(s) in both LDL receptor alleles or alleles known to affect LDL receptor functionality, or (2) skin fibroblast LDL receptor activity <20% normal, or (3) untreated TC >500 mg/dL and TG <300 mg/dL and both parents with documented untreated TC >250 mg/dL.
The diagnostic tests for Homozygous Familial Hypercholesterolemia (FH) include:
- Genetic testing: to identify functional mutations in both LDL receptor alleles or alleles known to affect LDL receptor functionality 3
- Skin fibroblast LDL receptor activity: to measure LDL receptor activity, with a threshold of <20% normal 3
- Lipid profile: to measure untreated total cholesterol (TC) and triglyceride (TG) levels, with thresholds of TC >500 mg/dL and TG <300 mg/dL, and both parents with documented untreated TC >250 mg/dL 3
From the Research
Diagnostic Tests for Homozygous Familial Hypercholesterolemia (FH)
The diagnostic tests for Homozygous Familial Hypercholesterolemia (FH) include:
- Genetic testing to confirm the diagnosis, as stated in 4
- Measurement of low-density lipoprotein cholesterol (LDL-C) levels, which are typically markedly elevated in individuals with HoFH, as mentioned in 5, 4, 6, 7
- Physical examination for signs such as cutaneous or tendon xanthomas, as noted in 4
- Family history, including parents with elevated LDL-C levels consistent with heterozygous FH, as mentioned in 4
- Imaging studies, such as Doppler echocardiographic evaluation of the heart and aorta, stress testing, and computed tomography coronary angiography, to assess the extent of atherosclerotic cardiovascular disease (ASCVD), as recommended in 4
Clinical Features and Diagnostic Criteria
The clinical features and diagnostic criteria for HoFH include:
- Extremely high LDL-C levels, often above 500 mg/dL, as mentioned in 6, 7
- Premature ASCVD, including coronary artery disease and aortic stenosis, as noted in 4, 7
- Cutaneous or tendon xanthomas, as mentioned in 4, 6
- Family history of hypercholesterolemia or premature ASCVD, as noted in 4
Laboratory Tests
Laboratory tests used to diagnose and monitor HoFH include: