What are the distinctive types of Familial Hypercholesterolemia (FH)?

Distinctive Types of Familial Hypercholesterolemia

Familial hypercholesterolemia encompasses three distinct genetic forms based on the causative gene mutation: LDLR-mediated FH (the most common), APOB-mediated FH (familial defective apolipoprotein B-100), and PCSK9-mediated FH, with clinical severity further categorized by zygosity status (heterozygous vs. homozygous). 1

Primary Genetic Classification

1. LDLR-Mediated FH (Classic FH)

• Accounts for the majority of FH cases, with approximately 700 different mutations identified worldwide in the LDL receptor gene 1, 2
• Results from deficient or defective LDL receptors that impair hepatic clearance of LDL particles 3, 2
• Up to 5% of LDLR-FH patients have deletions or rearrangements detectable by multiplex ligation-dependent probe amplification (MLPA) 1
• Presents with the full spectrum of clinical severity depending on the specific mutation and zygosity 1, 4

2. APOB-Mediated FH (Familial Defective Apolipoprotein B-100)

• Represents approximately 3% of FH patients in the UK, North Europe, and USA 1, 2
• Caused by a specific mutation in the apolipoprotein B-100 gene, which is the ligand for the LDL receptor 1
• Produces a milder phenotype than LDLR-FH, though hypercholesterolemia still occurs in childhood and premature coronary heart disease develops in some affected individuals 1, 5
• The defective apoB-100 protein binds poorly to LDL receptors, impairing LDL clearance 2

3. PCSK9-Mediated FH

• Results from gain-of-function mutations in the protein convertase subtilisin/kexin type 9 gene 1, 4
• Causes increased degradation of LDL receptors, reducing the number of receptors on hepatocyte surfaces 1, 2
• Represents a smaller proportion of monogenic FH cases but is clinically significant for therapeutic targeting 1, 6

Clinical Severity Classification by Zygosity

Heterozygous FH (HeFH)

• Prevalence of approximately 1 in 200-500 individuals in the general population 1, 7
• Characterized by LDL-cholesterol typically 2-3 times normal levels (often 190-400 mg/dL untreated) 1, 8
• Angina, myocardial infarction, or death typically occurs in men between 30-50 years and women between 50-70 years if untreated 1
• Physical stigmata (tendon xanthomas, corneal arcus) may be present but are increasingly rare with early statin treatment 1

Homozygous FH (HoFH) and Compound Heterozygous FH (cHeFH)

• Extremely rare disorders (approximately 1 in 160,000-300,000) with both alleles affected 9
• LDL-cholesterol concentrations typically exceed 500 mg/dL (often >650 mg/dL) untreated 1, 9
• Presents much earlier with more pronounced clinical phenotype, often with xanthomas in childhood and cardiovascular disease in the first or second decade of life 1, 9
• Median age at clinical diagnosis is approximately 6 years (range 2.9-12.9 years) 9
• LDL-cholesterol levels can vary significantly in HoFH according to the type of genetic defect and cannot alone establish the diagnosis 1, 5

Important Differential: Polygenic Hypercholesterolemia

• Approximately 60% of patients with a clinical diagnosis of FH do not have an identifiable monogenic mutation 6
• These patients likely have polygenic hypercholesterolemia due to co-inheritance of multiple common LDL-cholesterol-raising variants 6, 7
• Distinguishing monogenic from polygenic hypercholesterolemia requires genetic testing, as phenotypic overlap exists 1, 7
• Polygenic scores are not yet fully standardized and should be used with caution 3

Critical Clinical Pitfalls

The most dangerous error is assuming "mild FH" exists based on lower LDL-cholesterol levels or absence of clinical stigmata. 5 All FH patients have lifetime exposure to elevated LDL-cholesterol from birth, creating cumulative atherosclerotic burden that conventional risk calculators underestimate 5, 3. A 15-year-old with heterozygous FH has the same atherosclerotic burden as a 20-35 year old with average lipids 3.

Genetically confirmed homozygous FH can occur with LDL-cholesterol levels below traditional thresholds, demonstrating that cholesterol levels alone cannot establish disease severity 5. All genetically or phenotypically diagnosed FH patients require aggressive cholesterol-lowering therapy regardless of baseline LDL-cholesterol levels 5.

The term "severe FH" should be reserved for phenotypic diagnosis in adults with markedly elevated LDL-cholesterol plus major cardiovascular risk factors or established disease, not to distinguish between genetic subtypes 5.