A 52-year-old man with familial hypercholesterolaemia is counselled about the molecular basis of his condition. All of the following are recognized mechanisms of familial hypercholesterolaemia EXCEPT:

Explanation

## Familial Hypercholesterolaemia — Molecular Mechanisms **Key Point:** Familial hypercholesterolaemia (FH) is caused by defects in **LDL clearance** (predominantly), NOT by increased synthesis. The primary mechanism is impaired hepatic uptake of LDL particles. ### Recognized Genetic Causes of FH | Mechanism | Gene | Effect | Frequency in FH | |-----------|------|--------|------------------| | **Loss of LDL receptor function** | LDLR | Reduced hepatic LDL uptake | ~85% of heterozygous FH | | **Gain of PCSK9 function** | PCSK9 | Enhanced LDL receptor degradation | ~3–5% of heterozygous FH | | **Loss of ApoB-100 function** | APOB | LDL particles not recognized by receptors | ~5–10% of heterozygous FH | | **Loss of LDLRAP1 function** | LDLRAP1 | Defective LDL receptor internalization | Rare (autosomal recessive) | **High-Yield:** The three main mechanisms all result in **impaired LDL clearance**, not increased synthesis. Plasma LDL cholesterol accumulates because the liver cannot remove it efficiently. ### Why Option 3 (HMG-CoA Reductase Overactivity) Is NOT a Cause of FH 1. **Cholesterol synthesis is NOT the primary defect in FH.** FH patients have normal or even slightly reduced hepatic cholesterol synthesis rates. 2. **SREBP regulation is intact in FH.** The SREBP pathway responds appropriately to intracellular cholesterol levels; the problem is that **extracellular LDL cannot be cleared**, so it never enters hepatocytes to suppress SREBP. 3. **HMG-CoA reductase mutations are not associated with FH.** Mutations that increase its activity would cause hypercholesterolaemia via overproduction, not the clearance defect seen in FH. 4. **The SREBP regulatory region is not mutated in FH.** FH is caused by defects in the **LDL receptor pathway**, not the synthesis pathway. ### Pathophysiology: Why LDL Accumulates in FH ```mermaid flowchart TD A[Defective LDL receptor<br/>or PCSK9 gain-of-function<br/>or ApoB-100 loss-of-function]:::urgent --> B[Impaired hepatic LDL uptake]:::outcome B --> C[Circulating LDL accumulates]:::outcome C --> D[Extracellular cholesterol cannot enter hepatocytes]:::outcome D --> E[Hepatic SREBP remains active]:::action E --> F[Continued HMG-CoA reductase expression]:::action F --> G[Cholesterol synthesis continues<br/>despite high plasma LDL]:::outcome G --> H[Severe hypercholesterolaemia]:::urgent ``` **Clinical Pearl:** In FH, the liver is "starved" of cholesterol because LDL cannot enter. The hepatocyte senses low intracellular cholesterol and keeps SREBP active, perpetuating synthesis. The problem is **uptake**, not production. **Mnemonic:** **FH = "Failed Hepatic uptake"** — not failed synthesis. The liver makes cholesterol fine; it just cannot remove LDL from the blood. ### Therapeutic Implications - **Statins** inhibit HMG-CoA reductase, reducing synthesis — but this is a **secondary benefit** in FH because the primary defect is clearance. - **PCSK9 inhibitors** (evolocumab, alirocumab) are highly effective in FH because they prevent PCSK9-mediated degradation of LDL receptors, restoring clearance capacity. - **LDL apheresis** is used in severe FH to mechanically remove LDL particles from circulation.