A 52-year-old man with premature coronary artery disease presents with xanthomas on the Achilles tendon and corneal arcus. Lipid panel shows total cholesterol 480 mg/dL, LDL-C 420 mg/dL, HDL-C 35 mg/dL, triglycerides 150 mg/dL. Which single feature best distinguishes familial hypercholesterolaemia (FH) from familial combined hyperlipidaemia (FCH)?

Explanation

## Distinguishing FH from FCH ### Core Pathophysiology **Key Point:** FH is a monogenic disorder (LDL receptor deficiency/dysfunction) causing isolated severe LDL-C elevation, whereas FCH is a polygenic disorder with overproduction of VLDL and variable lipid phenotypes across family members. ### Comparison Table | Feature | Familial Hypercholesterolaemia (FH) | Familial Combined Hyperlipidaemia (FCH) | |---------|--------------------------------------|------------------------------------------| | **LDL-C level** | Markedly elevated (>300 mg/dL) | Moderately elevated (200–300 mg/dL) | | **Triglycerides** | Normal or near-normal (<150 mg/dL) | Often elevated (>200 mg/dL) | | **VLDL production** | Normal | Increased | | **Inheritance** | Monogenic (autosomal dominant) | Polygenic | | **Lipid phenotype in relatives** | Consistent (all have high LDL-C) | Variable (some high LDL, some high TG, some both) | | **Xanthomas** | Present in heterozygotes (>30% by age 40) | Rare unless severe hypertriglyceridaemia | | **Corneal arcus** | Common | Uncommon | ### Why Option 1 is Correct **High-Yield:** The **hallmark discriminator** is that FH causes **isolated, severe LDL-C elevation with normal triglycerides**, reflecting a primary defect in LDL receptor-mediated clearance. VLDL production is normal, so triglycerides remain in the normal range. In contrast, FCH stems from increased hepatic VLDL secretion, so triglycerides are often elevated alongside LDL-C, and the lipid phenotype varies within families. ### Clinical Pearl **Clinical Pearl:** Xanthomas and corneal arcus occur in both conditions but are **more common and earlier in FH** due to the severity and consistency of LDL-C elevation. However, their presence alone does not discriminate; the **lipid profile pattern does**. ### Mnemonic **Mnemonic: FH = "Fixed High LDL"** — LDL-C is consistently and severely elevated because the LDL receptor is defective. FCH = "Flexible, Combined" — lipid levels vary within the family and triglycerides are often elevated. ### Diagnostic Criterion The **Dutch Lipid Clinic Network Criteria** and **MEDPED criteria** for FH diagnosis emphasize: - LDL-C >190 mg/dL (untreated) in adults - **Normal triglycerides** (typically <150 mg/dL) - Monogenic inheritance pattern FCH diagnosis relies on finding: - Elevated apoB despite variable LDL-C and TG - **Discordant lipid phenotypes** in first-degree relatives