What is Familial Hypercholesterolemia?

Familial Hypercholesterolemia (FH) is a genetic disorder that causes severely elevated LDL ("bad") cholesterol from birth. Without treatment, it leads to early and aggressive cardiovascular disease, including heart attacks in young adulthood (30s-40s).

Types:

1. Heterozygous FH (HeFH):

• One abnormal gene (from one parent)
• More common: 1 in 250 people
• LDL cholesterol: 190-400 mg/dL (untreated)
• Heart attacks typically in 40s-50s (men), 50s-60s (women) if untreated

2. Homozygous FH (HoFH):

• Two abnormal genes (from both parents)
• Very rare: 1 in 160,000-300,000
• LDL cholesterol: >400-1000 mg/dL (untreated)
• Heart attacks can occur in childhood/adolescence if untreated
• Much more severe

Genetics:

• Mutations in genes affecting LDL receptor function (LDLR, APOB, PCSK9)
• LDL receptors don't work properly → body can't clear LDL from blood → extremely high levels
• Autosomal dominant inheritance (50% chance of passing to each child if one parent has FH)

Symptoms and Signs:

Often NO Symptoms Until Cardiovascular Event

Physical Signs (Visible in Some Patients):

• Tendon Xanthomas: Cholesterol deposits in tendons (especially Achilles, hands)—feel like hard lumps
• Xanthelasmas: Yellowish cholesterol deposits on eyelids
• Corneal Arcus: White/gray ring around cornea (in patients <45 years suggests FH)

Cardiovascular Symptoms (If Disease Has Progressed):

• Chest pain (angina)
• Heart attack, stroke
• Peripheral artery disease (leg pain with walking)

When to Suspect FH:

• LDL cholesterol ≥190 mg/dL (adults) or ≥160 mg/dL (children)
• Personal History: Early heart disease (<55 years in men, <65 years in women)
• Family History: Early heart attacks, high cholesterol, sudden cardiac death in family
• Physical Signs: Tendon xanthomas, xanthelasmas, corneal arcus (in young adults)

Diagnosis:

Lipid Panel:

• Markedly elevated LDL (typically >190 mg/dL in adults, >160 mg/dL in children)
• Other lipid levels usually normal (unless additional conditions present)

Clinical Diagnosis (Dutch Lipid Clinic Criteria or Simon Broome):

• Based on LDL level + family history + physical findings + genetic testing

Genetic Testing:

• Confirms diagnosis
• Identifies specific mutation (useful for family screening)
• Recommended for definitive diagnosis

Cascade Screening:

• Once FH diagnosed, test all first-degree relatives (parents, siblings, children)
• Early detection allows early treatment → prevents heart disease

Treatment:

Goal: Aggressive LDL Lowering from Childhood/Early Adulthood

LDL Targets:

• Heterozygous FH: <100 mg/dL (ideally <70 mg/dL)
• Homozygous FH: <100 mg/dL or ≥50% reduction from baseline

1. Lifestyle Modifications:

• Heart-healthy diet (low saturated fat, trans fat, cholesterol)
• Regular exercise
• Maintain healthy weight
• No smoking
• Note: Lifestyle alone is NOT sufficient—medications required

2. Medications:

High-Intensity Statins (First-Line):

• Start in childhood (age 8-10 for HeFH, earlier for HoFH)
• Atorvastatin 40-80 mg or Rosuvastatin 20-40 mg
• Lower LDL by 50-60%

Ezetimibe (Add-On):

• Blocks cholesterol absorption
• Additional 15-25% LDL reduction
• Usually combined with statin

PCSK9 Inhibitors (If Statin + Ezetimibe Insufficient):

• Evolocumab (Repatha®), Alirocumab (Praluent®)
• Subcutaneous injections every 2-4 weeks
• Lower LDL by additional 50-60%
• FDA-approved for FH; often covered by insurance for this indication

Bempedoic Acid (Nexletol®):

• Oral alternative if statin-intolerant
• Lowers LDL by 15-25%

Bile Acid Sequestrants:

• Cholestyramine, Colesevelam
• Lower LDL by 15-25%
• GI side effects limit use

3. For Homozygous FH (More Aggressive Therapies):

• Lomitapide (Juxtapid®): Oral medication; lowers LDL by 40-50%; significant GI side effects, liver toxicity
• Evinacumab (Evkeeza®): IV infusion monthly; lowers LDL by 50%; newest agent for HoFH
• LDL Apheresis: Dialysis-like procedure to physically remove LDL from blood; every 1-2 weeks; for refractory cases
• Liver Transplant: Curative (provides normal LDL receptors); reserved for severe, refractory HoFH

Monitoring:

• Lipid Panel: Every 3-6 months initially, then annually once stable
• Liver Enzymes, CK: Baseline and if symptoms develop
• Cardiovascular Risk Assessment: Stress test, coronary calcium score, carotid ultrasound (depending on age/risk)
• Screen Family Members

Prognosis:

• With Early, Aggressive Treatment: Life expectancy can approach normal
• Without Treatment: 50% of men with HeFH have heart attack by age 50; 30% of women by age 60
• Homozygous FH: Even with treatment, cardiovascular disease often occurs earlier than HeFH

Special Considerations:

• Pregnancy: Stop statins 1-3 months before conception; continue ezetimibe, PCSK9 inhibitors (some safe), bile acid sequestrants
• Children: Screen children of affected parents starting at age 2; start treatment by age 8-10