Familial Hypercholesterolemia

Introduction

Familial Hypercholesterolemia (FH) is a genetic disorder of lipid metabolism characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) from birth. While FH is widely studied in adults due to its strong association with premature coronary artery disease (CAD) and myocardial infarction, its manifestation in children is increasingly recognized as a serious, early-onset health risk. The condition challenges conventional perspectives on cardiovascular disease, traditionally considered an ailment of middle or older age, by underscoring how genetic and metabolic disturbances can initiate pathophysiological changes in arteries from the earliest years of life.

Children with FH inherit defective genes, typically involving the LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9), leading to impaired clearance of LDL-C from circulation. As a result, cholesterol accumulates in blood vessels, predisposing affected individuals to accelerated atherosclerosis, even before adolescence. Early recognition and management are therefore critical for preventing long-term cardiovascular morbidity and mortality.

This article explores the pathophysiology, clinical presentation, early-onset risks, diagnostic strategies, and management approaches for familial hypercholesterolemia in children, with an emphasis on prevention and comprehensive care strategies.

Pathophysiology of FH in Children

The fundamental abnormality in FH is a genetic defect in LDL metabolism, leading to reduced or absent clearance of LDL particles from circulation.

LDLR Mutations
- Represent ~85–90% of cases.
- Mutations impair receptor binding or recycling, resulting in prolonged LDL-C half-life and elevated plasma cholesterol.
APOB Mutations
- Account for ~5–10% of cases.
- ApoB is the ligand for LDLR. Mutations reduce binding affinity, limiting receptor-mediated uptake of LDL.
PCSK9 Gain-of-Function Mutations
- Cause degradation of LDL receptors.
- Lead to extreme hypercholesterolemia due to decreased receptor availability.
Homozygous vs. Heterozygous FH
- Heterozygous FH (HeFH): Occurs in 1 in ~200–250 children. LDL-C levels are 2–3× normal.
- Homozygous FH (HoFH): Occurs in 1 in ~160,000–300,000 children. LDL-C levels are >4–6× normal, leading to severe atherosclerosis in early childhood.

The cumulative burden of high LDL-C is referred to as the “cholesterol-years effect.” The earlier LDL-C is elevated, the earlier atherosclerosis begins, which is why FH in children is uniquely concerning.

Early-Onset Risks

1. Accelerated Atherosclerosis

Fatty streaks in arteries appear in childhood.
In FH children, these streaks can rapidly evolve into fibrous plaques.
Arterial stiffness and endothelial dysfunction occur decades earlier compared to non-FH peers.

2. Premature Coronary Artery Disease (CAD)

Children with FH are at risk of myocardial infarction as early as their teens or twenties (especially HoFH).
In untreated HeFH, CAD can occur 20–30 years earlier than in the general population.

3. Aortic Valve Disease

FH can also lead to aortic stenosis, especially in HoFH, due to cholesterol deposition in the aortic root.

4. Xanthomas and Physical Manifestations

Tendon xanthomas, xanthelasmas, and corneal arcus may be observed in severe cases, though these signs are less common in younger children.

5. Psychological Burden

Living with a genetic, lifelong disease can impose significant psychological stress, impacting self-esteem, social functioning, and quality of life.

Clinical Presentation in Children

While FH is often clinically silent in children, several manifestations can provide diagnostic clues:

Markedly Elevated LDL-C: Total cholesterol >190 mg/dL (or >160 mg/dL with family history).
Family History: Premature cardiovascular disease (CVD) in first-degree relatives (<55 years in men, <65 years in women).
Cutaneous or Tendon Xanthomas: Seen more commonly in HoFH, often in Achilles tendon, elbows, or hands.
Corneal Arcus: Rare in children but may appear in adolescence with severe FH.

Because most children do not present with overt symptoms, screening programs and family history evaluation are critical for early detection.

Diagnosis

1. Clinical Criteria

Dutch Lipid Clinic Network Criteria (modified for children).
Simon Broome Criteria (UK).

2. Lipid Profile

LDL-C >130 mg/dL in children (or >160 mg/dL with family history) raises suspicion.
LDL-C >500 mg/dL suggests homozygous FH.

3. Genetic Testing

Confirms diagnosis by detecting mutations in LDLR, APOB, or PCSK9.
Helpful for cascade screening of family members.

4. Cascade Screening

Systematic testing of first-degree relatives is highly recommended.
Early detection in siblings can significantly reduce future CVD burden.

Management Strategies

Early intervention in FH is crucial because lifetime exposure to LDL-C determines cardiovascular risk. The goal is to lower LDL-C levels aggressively and as early as possible.

1. Lifestyle Interventions

Lifestyle modifications should begin at diagnosis, even in young children.

Dietary Modifications
- Limit saturated fats and trans fats.
- Emphasize fruits, vegetables, whole grains, lean proteins, and omega-3 fatty acids.
- Plant sterols and stanols may reduce LDL-C by up to 10%.
Physical Activity
- Encourage at least 60 minutes of moderate to vigorous activity daily.
- Reduces overall cardiovascular risk and improves endothelial function.
Weight Management
- Avoid obesity, which compounds lipid abnormalities.

Lifestyle changes alone, however, are insufficient in FH because of the genetic basis of the condition.

2. Pharmacological Therapy

a) Statins (First-line therapy)

Safe and effective in children as young as 8–10 years.
Mechanism: Inhibit HMG-CoA reductase, upregulate LDLR expression, lower LDL-C by 20–50%.
Examples: Pravastatin, Atorvastatin, Rosuvastatin.
Proven to slow progression of atherosclerosis in FH children.

b) Ezetimibe

Inhibits intestinal absorption of cholesterol.
Often used in combination with statins if LDL-C targets are not achieved.

c) PCSK9 Inhibitors (Alirocumab, Evolocumab)

Approved for adolescents ≥12 years with HoFH or severe HeFH.
Dramatically lower LDL-C by 50–60%.
Injectable, may pose compliance challenges.

d) Bempedoic Acid (emerging therapy)

May offer additional benefit in older adolescents with statin intolerance.

e) Lipoprotein Apheresis

Standard of care for children with HoFH or severe statin-resistant hypercholesterolemia.
Performed weekly or biweekly; can reduce LDL-C by 50–75%.
Invasive and time-consuming but life-saving.

3. Surgical and Advanced Therapies

Liver Transplantation
- Rarely performed, mainly in HoFH.
- Provides a functional source of LDL receptors.
Gene Therapy
- An evolving field; experimental trials aim to restore LDLR function.

4. Psychological and Family Support

Counseling to address anxiety, stigma, and adherence issues.
Family-based approaches enhance compliance with diet and medications.
Education programs ensure better disease awareness and management.

Challenges in Pediatric FH Management

Asymptomatic Nature
- Children often feel healthy, reducing urgency for treatment.
Adherence Issues
- Long-term therapy with medications can be burdensome.
Access to Care
- Many countries lack pediatric lipid clinics or screening programs.
Ethical Considerations in Screening
- Debates continue about universal vs. targeted screening.
Transition to Adult Care
- Adolescents may lose follow-up during transition, risking treatment discontinuity.

Long-Term Outlook

Studies consistently show that early statin therapy in FH children reduces the risk of premature CAD in adulthood. By lowering LDL-C levels early, it is possible to normalize life expectancy close to that of the general population.

For example, a landmark Dutch study demonstrated that children with FH treated with statins had dramatically reduced risk of cardiovascular events in later decades compared to untreated historical cohorts.

Future Directions

Wider Use of Genetic Testing
- Affordable sequencing technologies could enhance early diagnosis.
New Lipid-Lowering Agents
- Inclisiran (siRNA targeting PCSK9) may offer less frequent dosing, improving adherence.
Universal Pediatric Screening
- Countries like Slovenia have pioneered national FH screening programs with remarkable success.
Gene Editing (CRISPR-Cas9)
- Holds promise for permanent correction of LDLR mutations in the future.