What is Familial Hypercholesterolemia and how is it managed?

Familial Hypercholesterolemia: Understanding and Management

Familial hypercholesterolemia (FH) is an inherited genetic disorder causing severely elevated LDL cholesterol levels from birth, leading to premature cardiovascular disease if left untreated. This condition requires early diagnosis and aggressive treatment to prevent cardiovascular complications and death 1.

What is Familial Hypercholesterolemia?

FH is characterized by:

• Genetic basis: An autosomal dominant disorder primarily caused by mutations in:

  • LDL receptor gene (most common)
  • Apolipoprotein B-100 gene
  • PCSK9 gene 1, 2

• Prevalence: Affects approximately 1 in 311 people worldwide (about 35 million people) 1

• Clinical features:

  • Extremely elevated LDL cholesterol levels from birth
  • LDL cholesterol typically 2-3 times higher than normal levels
  • Possible physical signs like tendon xanthomas (fatty deposits in tendons)
  • Strong family history of premature cardiovascular disease 1

Health Consequences

Without treatment, FH significantly increases cardiovascular risk:

• By age 40, ischemic heart disease affects 1 in 6 men and 1 in 10 women with FH
• By age 50% of men and 25% of women with untreated FH will experience clinical cardiovascular disease
• Coronary artery disease occurs in 50% of men by age 50 and 30% of women by age 60 1

Diagnosis

FH can be diagnosed through:

1. Clinical assessment:

   • Elevated LDL cholesterol levels (≥190 mg/dL in adults or ≥160 mg/dL with family history)
   • Family history of premature cardiovascular disease
   • Physical examination for xanthomas 1

2. Genetic testing:

   • Provides definitive diagnosis by identifying pathogenic mutations
   • Particularly valuable for cascade screening of family members 1

Management Approach

For Adults with FH:

1. Lifestyle modifications:

   • Low saturated fat diet (limit to 7% of total calories)
   • Limit cholesterol intake to 200 mg/day
   • Regular physical activity
   • Maintain healthy weight 2

2. Pharmacological therapy:

   • Statins: First-line therapy at high intensity doses
   • Ezetimibe: Added when LDL goals not achieved with statins alone
   • PCSK9 inhibitors: For patients not reaching targets with maximum tolerated statin plus ezetimibe
   • Bile acid sequestrants: Additional option for combination therapy 1, 3

3. LDL-C targets:

   • <100 mg/dL (<2.6 mmol/L) for adults with FH
   • <70 mg/dL (<1.8 mmol/L) for adults with FH who also have CHD or diabetes 1

For Children with FH:

1. Screening:

   • Children with family history of FH or premature cardiovascular disease should be screened 1

2. Initial management:

   • Dietary and lifestyle interventions for all children with elevated LDL cholesterol 1

3. Pharmacological therapy:

   • Consider medication for children ≥10 years with:
     • LDL cholesterol ≥190 mg/dL despite dietary therapy, or
     • LDL cholesterol ≥160 mg/dL with family history of premature CVD or two other risk factors 1
   • Statins are approved for children ≥10 years with heterozygous FH (starting dose 10-20 mg daily) 3

Special Considerations

Homozygous FH:

• Much rarer and more severe form (approximately 1 in 300,000-1,000)
• Often requires combination therapy including statins, ezetimibe, PCSK9 inhibitors
• May need LDL apheresis (a dialysis-like procedure to remove LDL from blood)
• Dosing range for statins is 10-80 mg daily 3

Pregnancy:

• Statins are contraindicated during pregnancy
• Women with FH should discuss medication management before conception
• If pregnancy occurs while on statins, they should be discontinued immediately 3

Importance of Family Screening

Cascade screening (testing family members of diagnosed individuals) is crucial because:

• 50% of first-degree relatives will have the condition
• Early identification allows for earlier treatment and prevention of cardiovascular complications
• Many affected individuals remain undiagnosed (only about 10% worldwide are diagnosed) 1

Common Pitfalls to Avoid

1. Delayed diagnosis: Don't wait for cardiovascular symptoms to appear before testing
2. Undertreatment: Many patients don't reach LDL goals with standard therapy and need combination treatment
3. Overlooking family screening: All first-degree relatives of diagnosed patients should be tested
4. Inadequate monitoring: Regular lipid testing is needed to ensure treatment goals are met

Remember that FH is a lifelong condition requiring ongoing management, but with proper treatment, patients can significantly reduce their cardiovascular risk and live normal lifespans.