A 52-year-old male shopkeeper from Delhi presents with chest pain on exertion for 3 months. He has a family history of premature coronary artery disease (father died of MI at age 55). Physical examination reveals xanthomas over the knuckles and Achilles tendons. Serum total cholesterol is 580 mg/dL, LDL-C 520 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 severely elevated LDL cholesterol in this patient?

Explanation

## Pathophysiology of Homozygous Familial Hypercholesterolaemia **Key Point:** Homozygous FH results from biallelic loss-of-function mutations in the LDLR (LDL receptor) gene, causing severe impairment of hepatic LDL uptake and resulting in total cholesterol levels typically >500 mg/dL. ### Mechanism of LDL Elevation The LDL receptor is the primary mechanism for clearing LDL particles from circulation. In homozygous FH: 1. **Absent or severely dysfunctional LDL receptors** on hepatocytes 2. **Impaired hepatic uptake** of LDL-apoB100 particles 3. **Prolonged circulation time** of LDL particles 4. **Increased atherogenicity** due to prolonged oxidation exposure ### Clinical Features Explained | Finding | Mechanism | |---------|----------| | Xanthomas (knuckles, Achilles) | Lipid deposition in tendons and skin due to persistently elevated LDL | | Premature CAD (age <40 in homozygotes) | Accelerated atherosclerosis from chronic severe LDL elevation | | Total cholesterol >500 mg/dL | Loss of ~90% LDL clearance capacity | | Normal/low HDL | Secondary to severe dyslipidaemia | **High-Yield:** Homozygous FH presents in childhood/adolescence with tendon xanthomas and early CAD; heterozygous FH (1 in 500) presents in adulthood with premature CAD. ### Regulation of Cholesterol Synthesis Normally, elevated LDL-C suppresses HMG-CoA reductase via SREBP-2 feedback. In homozygous FH, hepatic cholesterol uptake is blocked, so SREBP-2 remains active and HMG-CoA reductase continues unchecked — but this is a *secondary* consequence, not the primary defect. **Clinical Pearl:** Statins (HMG-CoA reductase inhibitors) have limited efficacy in homozygous FH because the primary problem is absent LDL receptors, not excessive synthesis. PCSK9 inhibitors (which degrade LDL receptors) are contraindicated; instead, ezetimibe, bempedoic acid, inclisiran (PCSK9 antisense), or lipoprotein apheresis are used. [cite:Harrison 21e Ch 397]