A 28-year-old woman from Delhi presents with acute-onset severe myalgia, dark urine, and elevated serum creatinine (2.1 mg/dL) after starting a statin for hypercholesterolemia. Serum CK is 8,500 U/L. Urine myoglobin is positive. She also reports a history of recurrent exercise-induced muscle pain and fatigue since childhood, which improved with rest and carbohydrate intake. Genetic testing reveals a heterozygous mutation in the *CPT II* gene. Which metabolic consequence of CPT II deficiency best explains her acute presentation?

Explanation

## Clinical Context: CPT II Deficiency & Statin-Induced Crisis This patient has **CPT II deficiency** (confirmed by genetic testing) with a precipitating factor: statin therapy. The acute presentation of rhabdomyolysis with myoglobinuria is triggered by increased energy demand during statin-induced muscle stress. ## Pathophysiology of CPT II Deficiency **Key Point:** CPT II catalyzes the final step of the carnitine shuttle — it removes the carnitine moiety from long-chain acylcarnitine on the inner mitochondrial membrane, regenerating long-chain acyl-CoA for β-oxidation. **High-Yield:** In CPT II deficiency, long-chain fatty acyl-CoA **cannot enter the mitochondrial matrix** for oxidation. During periods of high energy demand (exercise, illness, statin-induced myopathy), muscles cannot access their primary fuel source, leading to: 1. **Energy crisis** → ATP depletion → muscle cell death 2. **Accumulation of long-chain acyl-CoA** → lipid droplet formation in muscle 3. **Rhabdomyolysis** → myoglobinuria → acute kidney injury ## Why Statins Precipitate Crisis? ```mermaid flowchart TD A[Statin therapy]:::action --> B[Inhibits HMG-CoA reductase]:::outcome B --> C[Reduced cholesterol synthesis]:::outcome C --> D[Increased energy demand to compensate]:::action D --> E[Muscle relies on fatty acid oxidation]:::action E --> F{CPT II functional?}:::decision F -->|Yes| G[β-oxidation proceeds normally]:::outcome F -->|No| H[Acyl-CoA accumulates]:::urgent H --> I[Lipotoxicity + oxidative stress]:::urgent I --> J[Rhabdomyolysis]:::urgent ``` ## Metabolic Mechanism | Step | Normal | CPT II Deficiency | |------|--------|-------------------| | **Fatty acid activation** | Acyl-CoA synthetase → long-chain acyl-CoA | ✓ Normal | | **Carnitine conjugation** | CPT I → long-chain acylcarnitine | ✓ Normal | | **Transport across inner membrane** | Carnitine-acylcarnitine translocase | ✓ Normal | | **Carnitine removal** | **CPT II** → long-chain acyl-CoA in matrix | **✗ BLOCKED** | | **β-oxidation** | Acyl-CoA dehydrogenase → acetyl-CoA | ✗ Cannot proceed | **Clinical Pearl:** Heterozygous CPT II deficiency is often **asymptomatic at rest** but manifests during metabolic stress (fasting, exercise, infection, drugs). Homozygous forms cause neonatal presentation with hypoketotic hypoglycemia and hepatomegaly. **Mnemonic: "CPT II = CARnitine Transporter Exit — if it's blocked, fatty acyl-CoA is TRAPPED in the matrix"** ## Management **Warning:** Avoid: - Prolonged fasting - Strenuous exercise - Statins (or use with extreme caution) - Fibrates (increase β-oxidation demand) **Recommended:** - High-carbohydrate diet - Frequent meals - Avoid triggers [cite:Harrison 21e Ch 297; KD Tripathi 8e Ch 12]