## Familial Hypercholesterolaemia and LDL Receptor Deficiency ### Genetic Basis **Key Point:** Familial hypercholesterolaemia (FH) is an autosomal dominant disorder caused by loss-of-function mutations in the *LDLR* gene, which encodes the LDL receptor. ### Pathophysiology of LDL Receptor Deficiency ```mermaid flowchart TD A[LDL Receptor Gene Mutation]:::outcome --> B[Defective or Absent LDL Receptors]:::outcome B --> C[Impaired LDL Uptake by Hepatocytes]:::action C --> D[Elevated Plasma LDL-C]:::urgent D --> E[Increased Cholesterol Synthesis]:::action E --> F[Accelerated Atherosclerosis]:::urgent D --> G[Xanthomas, Corneal Arcus]:::outcome ``` ### Molecular Mechanism 1. **Normal pathway:** LDL binds to LDL receptor → receptor-mediated endocytosis → hepatic clearance 2. **In FH:** Absent or dysfunctional LDL receptors → impaired hepatic uptake → accumulation in blood 3. **Compensatory response:** Increased HMG-CoA reductase activity (feedback dysregulation) → increased cholesterol synthesis ### Phenotypic Severity | Genotype | Receptor Function | LDL-C Level | Clinical Features | | --- | --- | --- | --- | | **Heterozygous (FH)** | ~50% normal | 350–550 mg/dL | Xanthomas, early CAD (age 30–50) | | **Homozygous (FH)** | <10% normal | >600 mg/dL | Severe xanthomas, CAD in childhood | ### Clinical Features **High-Yield:** Heterozygous FH affects ~1 in 500 people; homozygous FH is rare (~1 in 1 million). Key clinical signs include: - Tendon xanthomas (especially Achilles tendon, extensor tendons of hand) - Corneal arcus (lipid deposition in cornea) - Xanthelasmas (eyelid xanthomas) - Premature coronary artery disease **Clinical Pearl:** Familial hypercholesterolaemia is one of the most common genetic causes of premature CAD and is a major indication for statin therapy and LDL apheresis in severe cases. **Mnemonic:** FH = **F**aulty **H**epatic LDL receptor → **F**ailure to clear **H**igh cholesterol.
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