## Distinguishing Features of FH vs Polygenic Hypercholesterolemia ### Key Pathophysiologic Difference **Key Point:** Familial hypercholesterolemia (FH) results from mutations in the LDL receptor gene (or apoB or PCSK9 genes), causing severe deficiency in LDL receptor-mediated clearance. Polygenic hypercholesterolemia arises from multiple common genetic variants affecting cholesterol metabolism and is not associated with a single gene defect. ### Clinical Discriminators | Feature | FH | Polygenic Hypercholesterolemia | |---------|----|---------------------------------| | **Tendon xanthomas** | Present (pathognomonic) | Absent | | **Corneal arcus** | Early onset, common | Rare, late if present | | **LDL-C level** | Markedly elevated (>300 mg/dL in heterozygotes) | Moderately elevated (150–250 mg/dL) | | **Inheritance** | Autosomal *dominant* | Polygenic (multifactorial) | | **CAD onset** | Very premature (men <45, women <55) | Premature but later than FH | | **Family history** | Strong (vertical transmission) | Weak or multifactorial | ### Why Tendon Xanthomas Are the Best Discriminator **High-Yield:** Tendon xanthomas (especially Achilles tendon and extensor tendons of the hand) are **pathognomonic for FH**. They develop due to chronic, severe LDL elevation and cholesterol deposition in connective tissue. They are virtually absent in polygenic hypercholesterolemia because LDL levels, though elevated, rarely reach the threshold needed for xanthoma formation. **Clinical Pearl:** Corneal arcus (lipid deposition in the cornea) can also occur in FH but is less specific and may be seen in normal aging. Tendon xanthomas, by contrast, are age-independent and highly specific for FH. ### Mnemonic for FH Diagnosis **DUTCH** — Defective LDL receptor, Unique xanthomas (tendon), Tendon xanthomas, Corneal arcus, High LDL, Hypercholesterolemia. [cite:KD Tripathi 8e Ch 28]
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