A 52-year-old man from Delhi presents with recurrent premature coronary artery disease (CAD) diagnosed 6 months ago. His lipid panel shows: Total cholesterol 320 mg/dL, LDL-C 240 mg/dL, HDL-C 32 mg/dL, Triglycerides 180 mg/dL. Physical examination reveals tendon xanthomas on the Achilles tendon and dorsum of hands, and corneal arcus. His father died of MI at age 48. Genetic testing confirms a heterozygous mutation in the LDL receptor gene. Which of the following best explains the severe hypercholesterolemia and premature CAD in this patient?

Explanation

## Pathophysiology of Familial Hypercholesterolemia (FH) ### LDL Receptor Defect **Key Point:** Heterozygous familial hypercholesterolemia (FH) is caused by mutations in the LDL receptor gene, resulting in reduced number or function of LDL receptors on hepatocytes. ### Mechanism of Elevated LDL-C The LDL receptor is the primary mechanism for hepatic clearance of LDL particles from circulation. When receptor number or function is reduced: 1. **Impaired LDL clearance** → LDL particles remain in circulation longer 2. **Increased LDL-C concentration** → severe hypercholesterolemia (typically 2–3× normal) 3. **Compensatory hepatic synthesis** → increased VLDL production (secondary effect) 4. **Peripheral uptake via scavenger receptors** → xanthoma formation and atherosclerosis ### Clinical Features in This Case | Feature | Explanation | |---------|-------------| | **Tendon xanthomas** | Cholesterol deposits in tendons due to prolonged LDL elevation | | **Corneal arcus** | Lipid deposition in cornea; suggests severe, long-standing hypercholesterolemia | | **Premature CAD** | Heterozygous FH affects ~1 in 500; CAD typically develops in 4th–5th decade in males | | **Family history** | Autosomal dominant inheritance; father's early MI is typical | | **LDL-C 240 mg/dL** | Diagnostic for heterozygous FH (usually 150–500 mg/dL) | **High-Yield:** Heterozygous FH is the most common monogenic dyslipidemia (~1:500 prevalence) and is a major cause of premature CAD in young patients without traditional risk factors. ### Genetic Testing Result The LDL receptor gene mutation confirms loss-of-function in the receptor, not in apoB or other apolipoproteins. **Clinical Pearl:** Patients with heterozygous FH require aggressive lipid-lowering therapy (statins, ezetimibe, PCSK9 inhibitors, or apheresis) to reduce cardiovascular risk. ### Why This Is Distinct from Other Dyslipidemias ```mermaid flowchart TD A[Severe Hypercholesterolemia + Xanthomas + Early CAD]:::outcome --> B{Genetic defect?}:::decision B -->|LDL receptor| C[Familial Hypercholesterolemia]:::action B -->|ApoB-100| D[Familial Defective ApoB-100]:::action B -->|Lipoprotein lipase| E[Type I Hyperlipoproteinemia]:::action C --> F[Reduced LDL clearance]:::outcome D --> G[Impaired LDL receptor binding]:::outcome E --> H[Chylomicron accumulation]:::outcome ``` [cite:Harrison 21e Ch 397]