What is the recommended approach for testing and managing familial hypercholesterolemia (high levels of low-density lipoprotein cholesterol)?

Testing and Management of Familial Hypercholesterolemia

The diagnosis of familial hypercholesterolemia (FH) should be made using both phenotypic criteria and genetic testing when available, with screening recommended for children at risk of heterozygous FH (HeFH) by age 5 or as early as age 2 with strong family history of premature atherosclerotic cardiovascular disease. 1, 2

Diagnostic Approach

Initial Screening and Detection

• Use validated clinical criteria such as the Dutch Lipid Clinic Network or Simon Broome criteria for phenotypic diagnosis 2
• Digital technologies should be used to search electronic health records to enable systematic detection of potential cases 1
• Laboratory reports of standard lipid profiles should include alerts and interpretive comments to enable case detection 1
• Opportunistic detection should be performed by:
  • Dermatologists (before starting isotretinoin)
  • Rheumatologists and orthopedic surgeons (for patients with Achilles xanthomas)
  • Ophthalmologists (for premature arcus cornealis or xanthelasma)
  • Occupational physicians and pharmacists 1

Diagnostic Testing

1. Lipid Profile Measurement

   • Non-fasting samples may be considered when screening for FH 1
   • For patients with hypertriglyceridemia >4.5 mmol/l (>400 mg/dl) and suspected FH, re-screen with a 12-hour fasting sample and direct LDL-C assay 1
   • Account for effects of cholesterol-lowering medications by adjusting LDL-C values:
     • Multiply on-treatment values by correction factors based on specific medication and dose 2
   • Repeat lipid measurements after recovery from acute illness 1

2. Genetic Testing

   • Gold standard for diagnosis - identifies pathogenic variants in LDLR, APOB, or PCSK9 genes 2
   • Should be used to confirm diagnosis in index cases when feasible 1
   • A negative genetic test does not rule out FH if clinical presentation strongly suggests the condition 2

Diagnostic Criteria

• Adults: Elevated LDL-C (>3.5 mmol/L or >135 mg/dL), positive family history of premature coronary artery disease, and high LDL-C in at least one parent 2
• Children: LDL-C level ≥3.5 mmol/L (≥135 mg/dL) predicts FH with 0.98 posttest probability 2

Cascade Screening

• Should be offered to all first-degree relatives of an index case with definite FH 2
• Children at risk of HeFH should be screened at age 5 years or older, or as early as 2 years with strong family history of premature ASCVD 1, 2
• Children with suspected homozygous FH (HoFH) or at risk of FH (both parents known to have FH) should be tested as early as possible (newborn stage or by 2 years) 1
• All healthcare professionals involved in screening should be adequately trained in local guidance on data protection 1

Management Approach

Treatment Goals

LDL-C targets based on risk stratification 2:

• 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)

Treatment Algorithm for Adults

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

   • Atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily 2, 3
   • Statins have been shown to effectively reduce LDL-C levels and cardiovascular disease incidence in FH patients 2

2. Second-line therapy: Add ezetimibe if LDL-C targets not achieved 2

3. Third-line therapy: Add PCSK9 inhibitors if LDL-C targets still not achieved

   • Alirocumab options 4:
     • 75 mg every 2 weeks or 300 mg every 4 weeks subcutaneously
     • Can increase to 150 mg every 2 weeks if response inadequate
   • For HeFH undergoing LDL apheresis or HoFH: 150 mg every 2 weeks 4

4. Additional options for HoFH:

   • Evolocumab 420 mg monthly (reduces LDL-C by 31%) 2
   • Consider lipoprotein apheresis for treatment-resistant cases 2

Treatment Algorithm for Children

1. For children aged 8 years and older with HeFH 4:

   • Body weight <50 kg: Alirocumab 150 mg once every 4 weeks subcutaneously
     • May adjust to 75 mg every 2 weeks if response inadequate
   • Body weight ≥50 kg: Alirocumab 300 mg once every 4 weeks subcutaneously
     • May adjust to 150 mg every 2 weeks if response inadequate

2. Pediatric diagnosis should ideally be made by a pediatrician with training in lipidology 2

Clinical Pearls and Pitfalls

Important Considerations

• High lipoprotein(a) concentrations may affect the phenotypic diagnosis of FH 2
• Underdiagnosis and undertreatment are major issues despite effective treatments being available 2
• Failure to adjust LDL-C values for patients already on lipid-lowering therapy can lead to missed diagnoses 2
• Early diagnosis and treatment are crucial as atherosclerotic burden depends on degree and duration of exposure to high LDL-C levels 5

Prognosis

• By age 50,25% of women and 50% of men with untreated FH will develop clinical cardiovascular disease 2
• Premature atherosclerotic cardiovascular disease is the major complication of FH 2
• FH patients have different rates of CVD events, even among those with the same genetic mutations and comparable LDL-C levels, suggesting additional risk factors beyond LDL-C 6

By following this structured approach to testing and management, clinicians can effectively diagnose FH and implement appropriate treatment strategies to reduce cardiovascular risk in affected individuals.