How does familial hypercholesterolemia (FH) present?

Clinical Presentation of Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) presents with markedly elevated LDL cholesterol levels, tendon xanthomas, xanthelasma, premature arcus cornealis, and a family history of premature cardiovascular disease. 1

Key Clinical Features

Laboratory Findings

• Elevated LDL-C levels:
  • Adults: ≥4.9 mmol/L (≥190 mg/dL) 1
  • Children: LDL-C concentrations above the 95th percentile for age and sex 1
  • In heterozygous FH (HeFH): LDL-C typically 2-3 times normal levels 2
  • In homozygous FH (HoFH): LDL-C typically >13 mmol/L (>500 mg/dL), though can occur with LDL-C <10 mmol/L (<400 mg/dL) 2

Physical Examination Findings

• Tendon xanthomas: Pathognomonic finding, especially in Achilles tendons and extensor tendons of hands 2, 3
• Xanthelasma: Yellowish cholesterol deposits around eyelids 1
• Premature arcus cornealis: Gray-white opacification of the peripheral cornea before age 45 1
• Cutaneous nodular eruptions: Particularly over extensor aspects of limbs 3

Family History

• Autosomal dominant inheritance pattern 2
• First-degree relatives with elevated cholesterol levels 2
• Family history of premature atherosclerotic cardiovascular disease (ASCVD) 1
  • Men: <55 years
  • Women: <60 years

Diagnostic Approaches

Clinical Diagnostic Criteria

• Dutch Lipid Clinic Network criteria: Point-based system incorporating LDL-C levels, physical findings, family history, and genetic testing 1
• Simon Broome criteria: Combines cholesterol levels, physical findings, family history, and genetic testing 1
• US MED-PED criteria: Based primarily on age-specific LDL-C levels and family history 1

Genetic Testing

• Gold standard for diagnosis is genetic testing identifying pathogenic variants in:
  • LDLR (LDL receptor gene) - most common cause 2
  • APOB (apolipoprotein B gene) - approximately 3% of FH cases 2
  • PCSK9 (protein convertase subtilisin/kexin type 9) 2
  • LDLRAP1 (for autosomal recessive form) 1

Clinical Variants

Heterozygous FH (HeFH)

• More common (prevalence ~1/500) 2
• Presents with:
  • LDL-C typically 2-3 times normal levels
  • Premature CHD (men: 30-50 years, women: 50-70 years) 2
  • Physical findings may develop in adulthood

Homozygous FH (HoFH)

• Rare but severe form
• Presents with:
  • Markedly elevated LDL-C (typically >13 mmol/L or >500 mg/dL) 2
  • Earlier and more pronounced clinical phenotype 2
  • Cutaneous and tendinous xanthomas appearing in childhood 2
  • Very early onset cardiovascular disease (often in childhood or adolescence)

Complications and Prognosis

• Premature atherosclerotic cardiovascular disease is the major complication 4
• Aortic valve stenosis may develop due to cholesterol deposition
• Without treatment:
  • 50% of men with HeFH will develop coronary heart disease by age 50
  • 30% of women will develop it by age 60 2

Diagnostic Pitfalls

• Underdiagnosis: FH is frequently underdiagnosed despite its relatively high prevalence 1
• Missed diagnosis in treated patients: Those receiving early lipid-lowering therapy may not develop characteristic physical findings like tendon xanthomas 1
• Failure to adjust LDL-C values: Not accounting for patients already on lipid-lowering therapy can lead to missed diagnoses 1
• Genetic testing limitations: A negative genetic test does not rule out FH if clinical presentation strongly suggests the condition 1
• Phenotypic variability: Some individuals with confirmed genetic mutations may have less severe LDL-C elevations 2

Early identification of FH is crucial as prompt treatment significantly reduces cardiovascular morbidity and mortality. Cascade screening of family members should be initiated once an index case is identified to enable early intervention in affected relatives.