Introduction
Familial Hypercholesterolemia (FH) is an inherited disorder characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C), commonly known as “bad cholesterol,” in the blood. It significantly increases the risk of early-onset cardiovascular diseases such as heart attack and stroke. FH is one of the most common genetic lipid disorders and can be passed from one generation to another in an autosomal dominant manner.
Molecular Basis of Familial Hypercholesterolemia
FH is primarily caused by mutations in genes responsible for the metabolism of LDL cholesterol. The most commonly affected genes include:
1. LDLR (Low-Density Lipoprotein Receptor) Gene
- Accounts for about 80–90% of FH cases.
- The LDLR gene provides instructions for making a receptor that removes LDL cholesterol from the blood.
- Mutations reduce the number or function of these receptors, leading to LDL buildup in the bloodstream.
2. APOB Gene
- Responsible for producing apolipoprotein B, which binds to the LDL receptor.
- Mutations impair binding, preventing LDL from being cleared efficiently.
3. PCSK9 Gene
- This gene controls degradation of LDL receptors.
- Mutations lead to increased breakdown of LDL receptors, further reducing LDL clearance.
Inheritance Pattern
- FH is typically inherited in an autosomal dominant fashion.
- Individuals with one mutated copy (heterozygous FH) have LDL-C levels about twice normal.
- Homozygous FH (mutations from both parents) leads to extremely high LDL-C and severe symptoms at a young age.
Symptoms of Familial Hypercholesterolemia
Symptoms depend on the severity of LDL cholesterol elevation and age of onset.
Common Symptoms:
- High LDL cholesterol levels: Usually >190 mg/dL in adults with heterozygous FH.
- Xanthomas: Yellowish fatty deposits in the skin or tendons, especially around elbows, knees, and Achilles tendons.
- Xanthelasma: Cholesterol deposits around the eyelids.
- Arcus corneae: Grayish-white ring around the cornea in the eye.
Severe Complications:
- Early-onset atherosclerosis
- Coronary artery disease (CAD)
- Heart attack (even in childhood for homozygous FH)
Diagnosis
- Lipid profile: Elevated LDL cholesterol with normal triglyceride levels
- Family history: Early heart disease or sudden death
- Genetic testing: To identify mutations in LDLR, APOB, or PCSK9
- Physical signs: Presence of xanthomas or corneal arcus
Treatments for Familial Hypercholesterolemia
The primary goal of treatment is to lower LDL cholesterol and reduce the risk of heart disease. Treatment varies depending on whether the individual has heterozygous or homozygous FH.
1. Lifestyle Modifications
- Low-fat, heart-healthy diet
- Regular physical activity
- Weight management
- Avoid smoking and excessive alcohol
2. Medications
- Statins: First-line drugs to lower LDL cholesterol.
- Ezetimibe: Reduces cholesterol absorption in the intestine.
- PCSK9 inhibitors: Newer injectable drugs (e.g., alirocumab, evolocumab) that significantly reduce LDL levels.
- Bile acid sequestrants: Bind bile acids and lower LDL indirectly.
3. Advanced Treatments for Homozygous FH
- Lomitapide: Reduces the production of lipoproteins.
- LDL Apheresis: A dialysis-like procedure to remove LDL from the blood.
- Liver transplant: In extreme cases, to provide functional LDL receptors.
Conclusion
Familial Hypercholesterolemia is a serious inherited condition that requires early detection and aggressive management. Understanding its molecular basis helps in personalized treatment. With proper medication, lifestyle changes, and monitoring, individuals with FH can significantly reduce their risk of cardiovascular complications and lead healthier lives.