What tests should be ordered to diagnose Familial Hypercholesterolemia (FH)?

Diagnostic Tests for Familial Hypercholesterolemia (FH)

The diagnosis of Familial Hypercholesterolemia should be made using both LDL-cholesterol measurement and genetic testing, with LDL-C as the primary screening test followed by genetic confirmation in suspected cases. 1, 2

Primary Screening Tests

LDL-Cholesterol Measurement

• Initial screening: Measure LDL-cholesterol concentration (fasting or non-fasting) 1, 2
  • Adults: LDL-C ≥4.9 mmol/L (≥190 mg/dL) should trigger FH evaluation
  • Children: Age-specific and sex-specific LDL-C concentrations above the 95th percentile
• Special considerations for LDL-C testing:
  • Non-fasting samples may be used for initial screening 1
  • For patients with hypertriglyceridemia >4.5 mmol/L (>400 mg/dL), re-screen with a 12-hour fasting sample and direct LDL-C measurement 1
  • Account for cholesterol-lowering medications when interpreting results; adjust LDL-C values for patients on statins, ezetimibe, PCSK9 inhibitors 1, 2
  • Repeat LDL-C measurement after recovery from acute illness if diagnosis is in doubt 1

Clinical Assessment

• Evaluate for physical stigmata of FH:
  • Tendon xanthomas (especially Achilles)
  • Xanthelasma palpebrarum
  • Premature arcus cornealis (before age 45)
  • Planar xanthomas 1
• Detailed family history of:
  • Premature atherosclerotic cardiovascular disease (ASCVD)
  • Hypercholesterolemia 1, 2

Confirmatory Testing

Genetic Testing

• Strongly recommended for:
  • Patients with phenotypic HoFH (homozygous FH)
  • Definite or highly probable phenotypic HeFH based on clinical criteria
  • Children with suspected HoFH or at risk of FH (both parents known to have FH) 2
• Testing methodology:
  • Should be performed in an accredited laboratory
  • Use targeted next-generation sequencing of all exons and exon-intron boundaries of:
    • LDLR (LDL receptor gene)
    • APOB (apolipoprotein B gene)
    • PCSK9 (proprotein convertase subtilisin/kexin 9 gene)
    • LDLRAP1 (LDL receptor adaptor protein 1 gene)
  • Include analysis for deletions and duplications in LDLR 2

Diagnostic Criteria Systems

Apply one of these validated clinical diagnostic tools:

• Dutch Lipid Clinic Network criteria
• Simon Broome criteria
• US MED-PED criteria 2

These incorporate:

• LDL-C levels
• Physical findings
• Family history
• Genetic test results

Screening Strategies

Selective Screening

• Target individuals with:
  • Premature ASCVD
  • Family history of premature ASCVD or hypercholesterolemia 1, 2

Cascade Testing

• Offer to all close relatives of an index case with definite FH
• Use both phenotypic and genetic methods when available
• If genetic testing unavailable, use age-specific and sex-specific LDL-C thresholds 1, 2
• Consider "reverse" cascade testing (from child to parents) when a child is identified with FH 2

Special Considerations for Children

• Screen children at risk of HeFH using LDL-C at or after age 5, or as early as 2 years with strong family history of premature ASCVD 1
• Test children with suspected HoFH as early as possible (newborn stage or by 2 years) 1

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 (>400 mg/dL)
• Excluding FH when genetic testing doesn't identify a pathogenic variant
• Using diagnostic tools for probands when evaluating relatives during cascade screening
• Measuring lipids during acute illness 2

Early diagnosis and treatment of FH is crucial to prevent premature cardiovascular disease and mortality, making appropriate diagnostic testing essential for improved patient outcomes 3, 4.