What laboratory tests are recommended for diagnosing familial hypercholesterolemia (high cholesterol due to genetic disorder)?

Laboratory Tests for Diagnosing Familial Hypercholesterolemia

LDL-cholesterol measurement is the primary laboratory test for diagnosing familial hypercholesterolemia (FH), with genetic testing strongly recommended to confirm the diagnosis in patients with clinical features suggestive of FH. 1

Initial Laboratory Evaluation

• Lipid Profile:

  • LDL-cholesterol (primary screening test)
  • Total cholesterol
  • HDL-cholesterol
  • Triglycerides
  • Apolipoprotein B (Apo B)
  • Non-HDL cholesterol

• Diagnostic Thresholds:

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

Testing Considerations

Fasting vs. Non-fasting Samples

• Non-fasting samples may be considered for initial screening 1
• However, the Friedewald equation (commonly used to calculate LDL-C) should be used with caution due to potential inaccuracies with hypertriglyceridemia 1
• For patients with hypertriglyceridemia >4.5 mmol/L (>400 mg/dL) where FH is strongly suspected:
  • Re-screen with a 12-hour fasting sample
  • Use direct LDL-C measurement assay 1

Adjustments for Medications and Illness

• Account for cholesterol-lowering medications when interpreting results
• Adjust LDL-C values for patients on statins, ezetimibe, PCSK9 inhibitors, or other lipid-lowering therapies 1
• If pretreatment values are unavailable, estimated corrections should be applied
• Repeat LDL-C measurement after recovery from acute illness if diagnosis is uncertain 1

Genetic Testing

When to Perform Genetic Testing

• Strongly recommended for:

  • Patients with phenotypic HoFH (homozygous FH)
  • Definite or highly probable phenotypic HeFH (heterozygous FH) based on clinical criteria 1
  • Children with suspected HoFH or at risk of FH (both parents known to have FH) 1

• Consider for:

  • Patients with probable phenotypic diagnosis of HeFH 1
  • Patients with possible HeFH, especially when genetic results would affect clinical management 1

Genetic Testing Methodology

• Should be performed in an accredited laboratory using targeted next-generation sequencing of:
  • All exons and exon-intron boundaries of LDLR, APOB, PCSK9, and LDLRAP1 genes
  • Exons in APOB that encode the LDLR ligand-binding region
  • Analysis for deletions and duplications in LDLR 1

Cascade Testing

• After identifying an index case with definite FH, cascade testing should be offered to all close relatives 1
• Cascade testing should use both phenotypic (LDL-C) and genetic methods when available 1
• If genetic testing is not feasible, use age-specific, sex-specific LDL-C thresholds for relatives 1
• "Reverse" cascade testing (from child to parents) should be offered when a child is identified as having FH 1

Clinical Diagnostic Criteria

While laboratory tests are essential, clinical diagnostic criteria are used alongside them:

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

These incorporate laboratory values with clinical findings and family history to establish the diagnosis.

Common Pitfalls to Avoid

1. Failing to adjust LDL-C values for patients already on lipid-lowering therapy
2. Relying on calculated LDL-C in patients with hypertriglyceridemia >4.5 mmol/L (>400 mg/dL)
3. Excluding FH when genetic testing doesn't identify a pathogenic variant (some cases result from undetected genetic variants) 1
4. Using diagnostic tools for probands (like Dutch Lipid Clinic Network criteria) when evaluating relatives during cascade screening 1
5. Measuring lipids during acute illness, which can affect results

By following this comprehensive laboratory approach, clinicians can effectively diagnose FH and initiate appropriate treatment to reduce the risk of premature cardiovascular disease.