Familial Hypercholesterolemia

Introduction

Cardiovascular diseases remain the leading cause of morbidity and mortality across the globe, with elevated cholesterol being a well-established risk factor. While diet, lifestyle, and environmental influences play major roles in hypercholesterolemia, genetics can also profoundly shape lipid metabolism. Familial Hypercholesterolemia (FH) is one such example—a hereditary disorder that leads to extremely high levels of low-density lipoprotein cholesterol (LDL-C), often termed the “bad cholesterol.”

Unlike acquired hyperlipidemia, which develops gradually due to poor lifestyle habits, FH manifests from birth and dramatically increases the risk of premature atherosclerosis, myocardial infarction, and stroke. Despite being one of the most common genetic disorders, FH remains underdiagnosed and undertreated, making awareness crucial.

This article provides a detailed overview of FH, covering its genetic basis, clinical presentation, pathophysiology, diagnosis, management, and emerging therapeutic directions.

Historical Background

The first descriptions of FH date back to the 1930s, when Dutch physician Carl Müller observed a familial clustering of hypercholesterolemia and premature heart disease.
In the 1970s, the Nobel Prize–winning work of Michael Brown and Joseph Goldstein revealed the critical role of LDL receptors in cholesterol regulation, uncovering how mutations could lead to FH.
Since then, advances in molecular genetics and population studies have expanded our understanding of the disease, highlighting its global prevalence.

Epidemiology and Global Burden

FH affects approximately 1 in 200–300 individuals worldwide in its heterozygous form (HeFH).
The more severe homozygous FH (HoFH) is rare, occurring in about 1 in 160,000 to 1 in 300,000 individuals.
Despite this high prevalence, it is estimated that over 90% of FH cases remain undiagnosed globally.
FH accounts for a disproportionately high number of cases of premature coronary artery disease (CAD), often before age 50 in men and 60 in women.

Genetic Basis of FH

FH is primarily caused by mutations in genes that regulate LDL metabolism:

LDLR Gene (Low-Density Lipoprotein Receptor)
- Accounts for 60–80% of FH cases.
- Mutations impair the ability of LDL receptors to bind, internalize, or recycle LDL particles.
APOB Gene (Apolipoprotein B-100)
- ApoB-100 is the main protein component of LDL particles, necessary for LDLR binding.
- Mutations reduce LDL binding affinity, leading to accumulation in plasma.
PCSK9 Gene (Proprotein Convertase Subtilisin/Kexin Type 9)
- PCSK9 promotes degradation of LDL receptors.
- Gain-of-function mutations increase LDLR destruction, raising LDL-C levels.
Other Rare Genes
- Mutations in LDLRAP1 cause autosomal recessive FH.
- Novel variants in genes affecting cholesterol trafficking and metabolism continue to be discovered.

FH is thus most commonly autosomal dominant, meaning a child has a 50% chance of inheriting the disorder if one parent is affected.

Pathophysiology

The underlying pathology in FH centers on defective clearance of LDL-C from circulation:

In healthy individuals, LDL particles bind to LDL receptors on hepatocytes and are internalized for cholesterol metabolism.
In FH, mutations disrupt this pathway, leading to 2–6 times higher plasma LDL-C levels.
Elevated LDL-C promotes endothelial dysfunction, foam cell formation, and atherosclerotic plaque development.
The disease thus accelerates vascular aging and dramatically increases cardiovascular risk, even in young individuals.

Clinical Presentation

Heterozygous FH (HeFH)

LDL-C levels: typically 190–400 mg/dL.
Symptoms: often silent until early adulthood; premature CAD in 30s–40s.
Physical signs (not always present):
- Xanthomas: cholesterol-rich deposits in tendons (Achilles, hands).
- Xanthelasmas: yellowish eyelid plaques.
- Corneal arcus: whitish ring around the cornea in young patients.

Homozygous FH (HoFH)

LDL-C levels: often >500 mg/dL.
Severe, early-onset symptoms:
- Atherosclerosis in childhood.
- Angina or myocardial infarction before age 20.
- Cutaneous and tendon xanthomas appearing in early childhood.
Untreated HoFH is often fatal before age 30.

Diagnosis

Clinical Criteria

Dutch Lipid Clinic Network (DLCN) Score
- Uses family history, personal history of CAD, physical signs, and LDL-C levels.
- Classifies FH as “definite,” “probable,” or “possible.”
Simon Broome Criteria (UK)
- Combines cholesterol levels with family history and genetic testing.
US MEDPED Criteria
- Uses age- and family-specific LDL thresholds.

Genetic Testing

Identifies mutations in LDLR, APOB, or PCSK9 genes.
Confirms diagnosis and helps with cascade screening of relatives.

Cascade Screening

Screening first-degree relatives (siblings, children) is essential.
Early detection allows intervention before irreversible damage occurs.

Management of Familial Hypercholesterolemia

1. Lifestyle Modifications

Diet: low saturated fat, high fiber, inclusion of plant sterols/stanols.
Exercise: improves lipid profile and cardiovascular health.
Smoking cessation: essential to reduce CAD risk.

2. Pharmacological Therapies

Statins (HMG-CoA Reductase Inhibitors)
- First-line therapy; lower LDL-C by 30–50%.
- May be insufficient alone in FH due to defective receptors.
Ezetimibe
- Inhibits intestinal cholesterol absorption.
- Add-on therapy for statin-resistant cases.
PCSK9 Inhibitors (Alirocumab, Evolocumab)
- Monoclonal antibodies that block PCSK9-mediated LDLR degradation.
- Can reduce LDL-C by an additional 50–60%.
Bile Acid Sequestrants
- Bind bile acids, promoting cholesterol excretion.
Lomitapide and Mipomersen (for HoFH)
- Target ApoB synthesis and lipoprotein production.
- Reserved for severe, refractory cases.

3. Apheresis

LDL apheresis mechanically removes LDL from the blood.
Used in severe HoFH or refractory HeFH.

4. Gene Therapy (Emerging)

Strategies include CRISPR-based correction and viral vector–mediated gene delivery.
Still experimental but promising.

Psychosocial and Public Health Aspects

FH often runs silently in families, leading to sudden cardiac deaths in young adults.
Psychological impacts include anxiety, guilt (especially among parents who transmit the mutation), and lifestyle burden.
Public health strategies emphasize:
- Awareness campaigns for early screening.
- National FH registries to monitor cases.
- School-based cholesterol screening in high-prevalence regions.