Simon Broome Diagnostic Criteria for Familial Hypercholesterolemia (FH)

If definite or possible FH is diagnosed:

• Obtain a fasting lipid panel if not already done; repeat to confirm the diagnosis (two measurements are recommended in children).
• Assess for secondary causes, including: 
  
  • TSH.
  • Urinalysis for proteinuria.
  • Liver function tests.
  • Dietary assessment.
• Obtain a detailed family history, including a three-generation pedigree documenting cholesterol levels and premature cardiovascular events in relatives.
• Perform a physical examination, including inspection for tendinous xanthomas (e.g., Achilles tendons, extensor tendons of hands), corneal arcus, and xanthelasma.
• Consider genetic testing to confirm the diagnosis, especially when available and cost-effective, as it enables more accurate cascade screening and provides a definitive diagnosis.
• Assess for subclinical atherosclerosis in adults; consider carotid intima-media thickness or coronary artery calcium scoring, which may increase genetic testing yield.
• Initiate cascade screening:
  
  • Screen first-degree relatives (parents, siblings, children) with lipid panels.
  • Use LDL-C thresholds validated for cascade screening rather than Simon Broome Criteria for relatives.

Once FH is diagnosed, manage patients according to the most recent AHA/ESC/EAS guidelines; LDL-C target goals should be considered within individual clinical contexts.

Treatment goals:

• LDL-C <70 mg/dL (1.8 mmol/L) for heterozygous FH without ASCVD.
• LDL-C <55 mg/dL (1.4 mmol/L) for heterozygous FH with established ASCVD.

Therapeutic approach:

• First-line:
  
  • High-intensity statin: Rosuvastatin 40 mg or atorvastatin 80 mg daily (reduces LDL-C by 50%–60%).
  • Lifestyle modification: 
    
    • Saturated fat <7% of calories.
    • ≥150 minutes/week of moderate-intensity aerobic activity.
    • Weight management.
  • Consider combination therapy: Statin + ezetimibe 10 mg as first-line, given the difficulty of reaching targets with monotherapy (only 1.3% reach an LDL-C <70 mg/dL with single-drug therapy).
• Second-line (if target not achieved):
  
  • Ezetimibe 10 mg daily: Adds 15%–25% LDL-C reduction to statin therapy.
  • Bempedoic acid 180 mg daily: 
    
    • Adds 15%–20% LDL-C reduction.
    • May be an alternative before PCSK9 inhibitors in some health systems.
    • Has demonstrated ASCVD risk reduction in statin-intolerant patients.
• Third-line:
  
  • PCSK9 inhibitors: 
    
    • Evolocumab 140 mg or alirocumab 75 mg subcutaneously every 2 weeks (reduces LDL-C by 50%–60% when added to statin ± ezetimibe).
    • Has demonstrated cardiovascular event reduction.
  • Inclisiran 284 mg: 
    
    • Subcutaneous twice-yearly maintenance dosing after initial loading.
    • Similar LDL-C reductions to PCSK9 monoclonal antibodies.

Special populations:

• Children: 
  
  • Initiate statin therapy between ages 8-18 years.
  • Treatment reduces ASCVD events and carotid atherosclerosis progression.
• Pregnancy: 
  
  • Bile acid sequestrants are first-line.
  • Discontinue statins.

• Genetic testing remains the gold standard for FH diagnosis when available, as it provides definitive confirmation and enables more accurate cascade screening.
• Initiate high-intensity statin therapy promptly in confirmed or suspected FH, as delay increases cumulative LDL-C exposure and lifetime ASCVD risk.
• Do not withhold treatment while awaiting genetic testing results; clinical diagnosis is sufficient to initiate therapy.