A 48-year-old woman on atorvastatin 40 mg daily for hypercholesterolaemia reports muscle pain and weakness. Her serum creatine kinase (CK) is 2200 U/L (normal <200 U/L). Which investigation is most appropriate to determine whether statin-induced muscle toxicity is due to myopathy versus rhabdomyolysis?

## Statin-Induced Muscle Toxicity: Differential Diagnosis **Key Point:** Serum and urine myoglobin are the most appropriate investigations to differentiate statin-induced myopathy (elevated CK without myoglobinuria) from statin-induced rhabdomyolysis (elevated CK with myoglobinuria and risk of acute kidney injury). ### Pathophysiology of Statin-Induced Muscle Injury Statins inhibit HMG-CoA reductase, reducing cholesterol synthesis and depleting intracellular CoQ~10~ and other isoprenoid intermediates critical for mitochondrial function and muscle energy metabolism. This leads to: 1. **Myopathy** — muscle pain and weakness with elevated CK (<10× upper limit of normal) but no myoglobin release 2. **Rhabdomyolysis** — severe muscle breakdown with CK >10× normal, myoglobinuria, and risk of acute tubular necrosis ### Diagnostic Algorithm ```mermaid flowchart TD A[Statin user with muscle pain + elevated CK]:::outcome --> B{CK level and clinical severity?}:::decision B -->|Mild elevation, no dark urine| C[Check serum and urine myoglobin]:::action B -->|Severe elevation, dark urine| C C --> D{Myoglobin present?}:::decision D -->|Absent| E[Statin-induced myopathy]:::outcome D -->|Present| F[Statin-induced rhabdomyolysis]:::urgent E --> G[Discontinue statin, supportive care]:::action F --> H[Discontinue statin, aggressive IV hydration, monitor renal function]:::action ``` ### Comparison of Investigations | Investigation | Myopathy | Rhabdomyolysis | Clinical Utility | |---|---|---|---| | **Serum myoglobin** | Normal or mildly elevated | Markedly elevated (>500 ng/mL) | Distinguishes severity; indicates muscle breakdown | | **Urine myoglobin** | Absent | Present (dark/cola-coloured urine) | Gold standard for rhabdomyolysis diagnosis | | **CK level** | Mildly elevated (<1000 U/L) | Markedly elevated (>5000 U/L) | Non-specific; both conditions elevate CK | | **Serum creatinine** | Normal | Elevated (acute kidney injury risk) | Prognostic marker in rhabdomyolysis | | **EMG/muscle biopsy** | Shows myopathic pattern or mitochondrial changes | Non-specific; invasive | Not first-line for acute differentiation | | **Transaminases (AST/ALT)** | May be mildly elevated | Often elevated due to hepatic involvement | Non-specific; reflects overall muscle and liver injury | **High-Yield:** Myoglobinuria (dark urine with positive dipstick for blood but no RBCs on microscopy) is pathognomonic for rhabdomyolysis and indicates a medical emergency requiring immediate statin discontinuation and aggressive fluid resuscitation to prevent acute kidney injury. **Clinical Pearl:** In this patient, CK of 2200 U/L is moderately elevated. The presence or absence of myoglobinuria on urinalysis and serum myoglobin level will determine whether she has myopathy (which may resolve on statin discontinuation) or rhabdomyolysis (which requires intensive management and may progress to renal failure). **Warning:** Do not rely on CK level alone to differentiate myopathy from rhabdomyolysis — myoglobin is the critical marker. Some patients with myopathy may have CK >1000 U/L without myoglobinuria.