How do you diagnose familial hypercholesterolemia?

Diagnosing Familial Hypercholesterolemia

The diagnosis of familial hypercholesterolemia (FH) should be made using a combination of lipid profile testing, clinical evaluation for physical stigmata, family history assessment, and genetic testing when available. 1

Initial Screening and Detection

Lipid Profile Assessment

• Measure LDL-cholesterol (LDL-C) levels as the primary screening parameter:
  • Adults: LDL-C ≥190 mg/dL (4.9 mmol/L) suggests possible FH 1
  • Children: LDL-C ≥160 mg/dL (4.0 mmol/L) warrants further evaluation 1
  • Non-fasting samples may be used for initial screening, but fasting samples are preferred 1

Clinical Evaluation

• Examine for physical stigmata of FH:
  • Tendon xanthomas (especially Achilles tendon and extensor tendons of hands)
  • Cutaneous xanthomas
  • Xanthelasma (yellowish deposits around eyelids)
  • Arcus cornealis (corneal arcus) before age 45 1, 2

Family History Assessment

• Document:
  • Family history of premature coronary artery disease (males ≤55 years, females ≤65 years)
  • Family history of elevated cholesterol levels
  • Family history of tendon xanthomas 1

Formal Diagnostic Criteria

For Adult Index Cases

Use established diagnostic criteria such as:

1. Dutch Lipid Clinic Network Criteria (most widely used):

   • Family history of premature cardiovascular disease or elevated LDL-C
   • Personal history of premature cardiovascular disease
   • Physical examination findings (tendon xanthomas, arcus cornealis)
   • LDL-C levels (higher points for higher levels)
   • Genetic testing results 1

2. Simon Broome Criteria:

   • Combines cholesterol levels, physical findings, family history, and genetic testing 1

For Children and Adolescents

• Do not use adult criteria (like Dutch Lipid Clinic Network) for children 1
• Consider FH highly probable when:
  • Untreated LDL-C >4.9 mmol/L (>190 mg/dL) on at least two occasions
  • Plus parental history of high LDL-C, premature ASCVD, or positive genetic test 1

Genetic Testing

When to Perform Genetic Testing

Genetic testing should be offered to:

1. Children with persistent LDL-C ≥160 mg/dL or adults with persistent LDL-C ≥190 mg/dL with at least one similarly affected first-degree relative 1
2. Children with persistent LDL-C ≥190 mg/dL or adults with persistent LDL-C ≥250 mg/dL, even without family history 1
3. Individuals with strong clinical suspicion based on physical stigmata and family history 1

Genetic Testing Process

• Test for mutations in:
  • LDLR (LDL receptor gene) - most common cause
  • APOB (apolipoprotein B gene)
  • PCSK9 (proprotein convertase subtilisin/kexin type 9)
  • LDLRAP1 (for recessive forms) 1
• Use targeted next-generation sequencing of all exons and exon-intron boundaries 1
• Include analysis for deletions and duplications in LDLR 1

Special Considerations

Homozygous FH (HoFH)

• Suspect when:
  • Untreated LDL-C >10 mmol/L (>400 mg/dL)
  • Physical stigmata before age 10
  • Both parents have FH 1

Secondary Causes to Exclude

Always rule out secondary causes of hypercholesterolemia:

• Hypothyroidism
• Diabetes mellitus
• Renal disease
• Nephrotic syndrome
• Liver disease
• Medications that raise LDL-C 1

Cascade Testing

Once an index case is identified:

1. Offer genetic testing to all first-degree relatives if a pathogenic variant is found 1
2. If genetic testing is unavailable, use age-specific and sex-specific LDL-C thresholds 1
3. Extend testing to second-degree and third-degree relatives as needed 1
4. Consider "reverse cascade testing" from child to parents when a child is identified as having FH 1

Common Pitfalls to Avoid

1. Relying solely on LDL-C levels - Some FH patients may have lower LDL-C levels due to concurrent conditions or medications
2. Failing to adjust LDL-C for medication use - Account for cholesterol-lowering medications when interpreting results 1
3. Missing the diagnosis in hypertriglyceridemic patients - In patients with triglycerides >4.5 mmol/L (>400 mg/dL), use direct LDL-C measurement or reassess after triglyceride lowering 1
4. Excluding FH when genetic testing is negative - Up to 20% of clinically diagnosed FH patients may not have detectable mutations using current methods 1
5. Using adult criteria for children - This leads to underdiagnosis; use age-specific criteria 1

By following this systematic approach to diagnosis, FH can be identified early, allowing for timely intervention to reduce the risk of premature cardiovascular disease and mortality.