A 52-year-old Indian man presents to the outpatient clinic with recurrent premature coronary artery disease (CAD). His father died of MI at age 48. On examination, he has xanthomas on his Achilles tendons and corneal arcus. Lipid profile: Total cholesterol 520 mg/dL, LDL-C 450 mg/dL, HDL-C 35 mg/dL, Triglycerides 150 mg/dL. Genetic testing confirms homozygous familial hypercholesterolaemia (FH). Which of the following mechanisms best explains the markedly elevated LDL-C in this patient?

Explanation

## Pathophysiology of Familial Hypercholesterolaemia ### LDL Receptor Defect **Key Point:** Homozygous familial hypercholesterolaemia (HoFH) results from mutations in the LDLR gene, leading to complete or near-complete absence of functional LDL receptors on hepatocytes. ### Mechanism of Elevated LDL-C The LDL receptor is the primary mechanism by which the liver clears LDL particles from circulation. When receptors are absent or non-functional: 1. LDL particles cannot bind to hepatocyte surface receptors 2. Normal hepatic uptake and catabolism of LDL is blocked 3. LDL accumulates in blood, reaching levels 6–10 times normal 4. Prolonged LDL circulation time increases oxidation and atherogenicity ### Clinical Features Explained - **Xanthomas** (tendon and skin): Result from LDL deposition in connective tissue - **Corneal arcus**: Lipid deposition in cornea, visible before age 40 in HoFH - **Premature CAD**: Markedly elevated LDL-C and prolonged circulation time accelerate atherosclerosis ### Diagnostic Criteria | Feature | Heterozygous FH | Homozygous FH | |---------|-----------------|---------------| | LDL-C (mg/dL) | 350–550 | >500 | | LDL Receptor Function | ~50% | <10% | | Xanthomas | Age >30 | Age <20 | | CAD onset | Age 40–60 | Age <20 | **High-Yield:** Homozygous FH is a medical emergency requiring aggressive lipid-lowering therapy (statins, ezetimibe, PCSK9 inhibitors, and sometimes apheresis) to prevent premature death from MI. **Clinical Pearl:** The presence of xanthomas and corneal arcus in a young patient with very high LDL-C is virtually diagnostic of homozygous FH and warrants immediate genetic testing and family screening.