What are the diagnostic criteria and treatment options for Familial Hypercholesterolemia (FH)?

Diagnostic Criteria and Treatment Options for Familial Hypercholesterolemia (FH)

The diagnosis of Familial Hypercholesterolemia should be made using both clinical criteria (Dutch Lipid Clinic Network or Simon Broome criteria) and genetic testing when available, with treatment starting with high-intensity statins and progressing to combination therapy with ezetimibe and PCSK9 inhibitors as needed to achieve LDL-C targets. 1, 2

Diagnostic Criteria

Clinical Diagnosis

• Dutch Lipid Clinic Network and Simon Broome criteria are the most widely used clinical diagnostic methods 1
• Key clinical elements include:
  • Elevated LDL-C levels (≥4.9 mmol/L or ≥190 mg/dL in adults)
  • Family history of premature cardiovascular disease
  • Physical findings such as tendon xanthomas, xanthelasma, or premature arcus cornealis
  • Personal history of premature ASCVD 1, 2

Laboratory Testing

• LDL-C measurement should be performed:
  • Fasting (preferred) or non-fasting
  • On at least two separate occasions
  • With adjustment for patients already on lipid-lowering therapy 1, 2
• Threshold LDL-C values for suspecting FH:
  • Adults: ≥4.9 mmol/L (≥190 mg/dL)
  • Children: LDL-C above the 95th percentile for age and sex 2

Genetic Testing

• Genetic testing is the most accurate way to diagnose FH but is not universally available 1
• Should target:
  • LDLR (most common)
  • APOB
  • PCSK9
  • LDLRAP1 (for recessive forms) 2
• A negative genetic test does not rule out FH if clinical presentation strongly suggests the condition 2

Treatment Options

Treatment Goals

• LDL-C targets based on risk stratification:
  • Adults with FH without ASCVD: <2.6 mmol/L (100 mg/dL)
  • Adults with FH and ASCVD or diabetes: <1.8 mmol/L (70 mg/dL)
  • Children with FH: <3.5 mmol/L (135 mg/dL) 1, 3
• When targets cannot be achieved, a reduction of ≥50% in LDL-C levels is an acceptable alternative 4

Treatment Algorithm

1. First-line therapy: High-intensity statins (maximum tolerated dose)

   • Atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily 1, 3

2. Second-line therapy: Add ezetimibe 10 mg daily if LDL-C targets not achieved 1, 3

3. Third-line therapy: Add PCSK9 inhibitors if LDL-C remains above target

   • Evolocumab 140 mg every 2 weeks or 420 mg monthly (shown to reduce LDL-C by 61% in HeFH patients) 5
   • For HeFH patients with LDL-C >3.6 mmol/L (140 mg/dL) despite maximum tolerated statin plus ezetimibe 1

4. For Homozygous FH (HoFH):

   • Evolocumab 420 mg monthly (reduces LDL-C by 31%) 5
   • Consider lipoprotein apheresis for treatment-resistant cases 4
   • Note: Patients with two LDL-receptor negative alleles may not respond to PCSK9 inhibitors 5

Special Considerations

Pediatric Patients

• Screening recommended:
  • At age 5 years or older for children at risk of HeFH
  • As early as 2 years with strong family history of premature ASCVD
  • At newborn stage or by 2 years for suspected HoFH 2
• Treatment in pediatric patients with HeFH:
  • Evolocumab 420 mg monthly reduced LDL-C by 38% compared to placebo in patients aged 10-17 years 5

Cascade Screening

• Should be offered to all first-degree relatives of an index case with definite FH
• Use both phenotypic criteria and genetic testing when available 1, 2
• Digital technologies and electronic health record searches can help identify potential cases 1

Common Pitfalls in FH Management

• Underdiagnosis and undertreatment are major issues despite effective treatments being available 6, 4
• Failure to adjust LDL-C values for patients already on lipid-lowering therapy can lead to missed diagnoses 1, 2
• Relying solely on calculated LDL-C in patients with hypertriglyceridemia >4.5 mmol/L (400 mg/dL) can be inaccurate 2
• Delaying treatment while waiting for genetic test results is inappropriate; therapy should be initiated based on clinical presentation 2
• Overlooking FH in patients with early treatment who may not develop physical stigmata like tendon xanthomas 1

FH remains underdiagnosed despite being one of the most common genetic disorders. Early identification and aggressive treatment are essential to reduce the risk of premature cardiovascular disease in these high-risk patients 6, 7.