A 48-year-old woman is found to have markedly elevated LDL cholesterol (220 mg/dL) and total cholesterol (320 mg/dL) on routine screening. Her triglycerides are 95 mg/dL and HDL-C is 52 mg/dL. She has no personal history of cardiovascular disease but her father died of myocardial infarction at age 55. Physical examination reveals tendon xanthomas on the Achilles tendons and corneal arcus. What is the most appropriate next step?

Explanation

## Clinical Diagnosis: Familial Hypercholesterolemia (FH) **Key Point:** This patient has the classic triad of FH: 1. **Markedly elevated LDL-C** (>190 mg/dL in adults, >150 mg/dL in children) 2. **Tendon xanthomas** — pathognomonic for FH, especially on Achilles tendon 3. **Premature family history of coronary artery disease** — father with MI at age 55 4. **Corneal arcus** — lipid deposition in cornea ## Pathophysiology Familial hypercholesterolemia is caused by loss-of-function mutations in: - **LDLR gene** (85% of cases) — defective LDL receptor → impaired LDL clearance - **APOB gene** (10% of cases) — defective apolipoprotein B → poor LDL receptor binding - **PCSK9 gene** (5% of cases) — gain-of-function → increased LDLR degradation Result: Severely elevated LDL-C from childhood, accelerated atherosclerosis, and early coronary events. ## Diagnostic Approach **High-Yield:** Before initiating therapy, genetic testing is indicated to: - Confirm the diagnosis of FH - Identify the specific mutation for family screening - Guide intensity of therapy (homozygous FH requires more aggressive treatment) - Determine eligibility for newer therapies (e.g., PCSK9 inhibitors, inclisiran) **Mnemonic: FH Diagnosis = DUTCH** - **D**utch Lipid Clinic Network criteria (or similar scoring systems) - **U**nderstanding the mutation type - **T**endon xanthomas (clinical hallmark) - **C**oronal arcus - **H**ypercholesterolemia (LDL >190 mg/dL) + family history ## Management Sequence 1. **Genetic testing** (next step) — confirm FH, identify mutation 2. **Intensive statin therapy** — atorvastatin 40–80 mg or rosuvastatin 20–40 mg 3. **Add ezetimibe** — additional 15–20% LDL-C reduction 4. **Consider PCSK9 inhibitor** (if PCSK9 mutation) or inclisiran 5. **Screen first-degree relatives** — cascade screening **Clinical Pearl:** Patients with heterozygous FH have a 20-fold increased risk of premature MI compared to the general population. Homozygous FH (1 in 160,000–1,000,000) presents in childhood with severe hypercholesterolemia and requires aggressive intervention. ## Why Genetic Testing Is the Next Step Genetic testing confirms the diagnosis, identifies the specific mutation, and guides treatment intensity and family screening. It also determines eligibility for mutation-specific therapies (e.g., PCSK9 inhibitors for PCSK9 mutations, antisense oligonucleotides for APOB mutations). [cite:Harrison 21e Ch 417; Robbins 10e Ch 9]