What is the diagnostic approach for familial hypercholesterolemia (high cholesterol due to genetic disorder)?

Diagnostic Approach for Familial Hypercholesterolemia

The diagnosis of familial hypercholesterolemia (FH) requires a combination of LDL-cholesterol measurement, clinical evaluation, and genetic testing when available, with opportunistic screening recommended for adults with LDL-C ≥4.9 mmol/L (≥190 mg/dL). 1, 2

Initial Screening and Detection

• Primary screening method: Measure LDL-cholesterol concentration (fasting or non-fasting)

  • Adults: LDL-C ≥4.9 mmol/L (≥190 mg/dL) should trigger FH screening 1, 2
  • Children/adolescents: Use age-specific and sex-specific LDL-C concentrations above the 95th percentile 1, 2

• Screening strategies:

  • Selective screening: Target individuals with premature ASCVD and/or family history of premature ASCVD/hypercholesterolemia 1
  • Opportunistic screening: When elevated LDL-C is found incidentally 1
  • Universal screening: Consider for children and adolescents 1

Diagnostic Criteria

Multiple clinical diagnostic tools can be used to establish the diagnosis:

1. Dutch Lipid Clinic Network criteria:

   • Combines family history, clinical signs, and LDL-C levels
   • Point system: >8 points = definite FH; 6-8 points = probable FH; 3-5 points = possible FH 2

2. Simon Broome criteria:

   • Combines cholesterol levels, clinical findings, and family history 2

3. US MED-PED criteria:

   • Uses age-specific LDL-C thresholds 2

Physical Examination

Look for characteristic physical signs:

• Tendon xanthomas (particularly Achilles tendons and extensor tendons of hands)
• Xanthelasma (yellowish deposits around eyelids)
• Corneal arcus before age 45 3

These physical signs significantly increase the likelihood of FH diagnosis and should prompt immediate lipid testing 3.

Laboratory Testing Considerations

• Non-fasting samples may be used for initial screening, but use the Friedewald equation with caution 1, 2
• For hypertriglyceridemia >4.5 mmol/L (>400 mg/dL): Re-screen with 12-hour fasting sample and use direct LDL-C measurement 1, 2
• Adjust LDL-C values for patients already on lipid-lowering medications 2
• Avoid testing during acute illness as it may affect results 2

Genetic Testing

Genetic testing is strongly recommended for:

• Patients with phenotypic homozygous FH (HoFH)
• Definite or highly probable heterozygous FH (HeFH) based on clinical criteria
• Children with suspected HoFH or at risk of FH (both parents with FH) 2

Testing should include:

• Targeted next-generation sequencing of LDLR, APOB, PCSK9, and LDLRAP1 genes
• Analysis for deletions and duplications in LDLR 2

Cascade Testing

After identifying an index case with definite FH:

1. Offer cascade testing to all close relatives using both phenotypic and genetic methods when available
2. If genetic testing is unavailable, use age-specific and sex-specific LDL-C thresholds for relatives
3. Consider "reverse" cascade testing (from child to parents) when a child is identified with FH 1, 2

Common Pitfalls to Avoid

• Failing to adjust LDL-C values for patients already on lipid-lowering therapy
• Relying on calculated LDL-C in patients with hypertriglyceridemia >4.5 mmol/L
• Excluding FH when genetic testing is negative, as some cases result from undetected variants
• Using diagnostic tools for probands when evaluating relatives during cascade screening
• Measuring lipids during acute illness 2

Following this systematic approach will help identify individuals with FH early, allowing for appropriate intervention to reduce the risk of premature cardiovascular disease.