Which feature best distinguishes familial hypercholesterolaemia (FH) heterozygotes from patients with polygenic hypercholesterolaemia?

Explanation

## Distinguishing FH Heterozygotes from Polygenic Hypercholesterolaemia ### Key Clinical Discriminator **Key Point:** Tendon xanthomas (especially Achilles tendon and extensor tendons of hands) and corneal arcus appearing in childhood or early adulthood are pathognomonic for FH heterozygotes and virtually absent in polygenic hypercholesterolaemia. ### Comparison Table | Feature | FH Heterozygotes | Polygenic Hypercholesterolaemia | | --- | --- | --- | | **Tendon xanthomas** | Present (50–75% by age 30) | Absent | | **Corneal arcus** | Common in childhood/young adults | Rare; if present, only in older age | | **LDL cholesterol** | Very high (400–600 mg/dL) | Moderately elevated (200–350 mg/dL) | | **Age of MI** | <50 years (often <40 in males) | >50 years | | **Family history** | Autosomal dominant (50% of first-degree relatives) | Multifactorial; less striking | | **Genetic basis** | Single gene (LDLR, APOB, PCSK9) | Multiple genes + environment | | **Xanthomas (eruptive/tuberous)** | Rare | Absent | ### Pathophysiology **High-Yield:** FH heterozygotes have ~50% reduction in functional LDL receptors on hepatocytes. This causes: 1. Severely impaired hepatic LDL uptake 2. Markedly elevated plasma LDL (2–3× normal) 3. Chronic lipid deposition in tendons → xanthomas 4. Lipid infiltration of cornea → arcus Polygenic hypercholesterolaemia results from multiple common variants affecting cholesterol synthesis, absorption, and clearance—LDL elevation is modest and xanthomas do not form. ### Clinical Pearl **Clinical Pearl:** A 35-year-old Indian patient with LDL >400 mg/dL, Achilles tendon xanthoma, and family history of early MI in parent = FH heterozygote until proven otherwise. Genetic testing (LDLR, APOB, PCSK9) confirms diagnosis. Polygenic cases rarely present with xanthomas even at similar LDL levels. ### Why Xanthomas Discriminate Xanthomas form because: - Chronic, severe LDL elevation → lipid deposition in extracellular matrix - Macrophages take up oxidized LDL → foam cells → visible nodules - Requires sustained LDL >300 mg/dL for years - Polygenic patients rarely reach such levels; FH heterozygotes almost always do **Warning:** Do not confuse FH heterozygotes (1 in 500, treatable) with homozygotes (1 in 1,000,000, severe, often fatal by age 20).