Causes of Rhabdomyolysis
Rhabdomyolysis results from skeletal muscle breakdown with multiple etiologic categories: medications (particularly statins, fibrates, and their combinations), direct trauma/crush injury, excessive muscular activity, infections, toxins (especially illicit drugs and alcohol), metabolic/endocrine disorders, muscle ischemia, temperature extremes, and hereditary enzyme defects. 1, 2, 3, 4, 5
Medication-Induced Causes
Statins and Lipid-Lowering Agents
- Statin monotherapy carries a small but definite risk of severe myopathy (0.08-0.09% incidence), which can progress to rhabdomyolysis if not discontinued promptly 6, 7
- High-risk statin combinations dramatically increase rhabdomyolysis risk, particularly when combined with:
- Fibrates alone also carry myopathy risk, with fenofibrate being preferred over gemfibrozil when combination therapy is necessary 8
- Drug-drug interactions involving cytochrome P-450 3A4 isozyme significantly increase risk 6, 7
Other Medications
- Antipsychotics (including neuroleptic malignant syndrome) 4
- Fluoroquinolones can trigger rhabdomyolysis, particularly in patients with latent myopathic disorders or susceptibility to malignant hyperthermia 9
- Zidovudine, colchicine, selective serotonin reuptake inhibitors, and lithium 4
Trauma and Physical Causes
Direct Muscle Injury
- Crush injury from prolonged immobilization, entrapment, or compression 10, 1, 2
- Compartment syndrome with risk factors including crush injury, hemorrhagic injury, reperfusion of ischemic lesions, and hypotension 10
- Muscle ischemia from vascular compromise 2, 5
Excessive Muscular Activity
- Exertional rhabdomyolysis occurs primarily after strength training (78% of cases), with median age 28 years 11
- Strenuous exercise beyond physiologic capacity, particularly in unconditioned individuals 1, 2, 3
- Seizures causing prolonged muscle contractions 2, 5
Toxins and Substance Abuse
Exogenous toxins represent the most common cause overall (46% of cases), with multiple factors present in 60% of all rhabdomyolysis cases 4
- Illicit drugs (cocaine, amphetamines, MDMA) 4
- Alcohol abuse 4
- Prescribed drug polytherapy creates cumulative risk 4
Metabolic and Endocrine Disorders
- Electrolyte abnormalities (hypokalemia, hypophosphatemia, hypocalcemia) 2, 5
- Endocrinopathies (hypothyroidism, diabetic ketoacidosis) 2, 5
- Hereditary muscle enzyme defects (glycogen storage diseases, lipid metabolism disorders, mitochondrial myopathies) account for 10% of cases with high recurrence rates 4, 5
Infections and Temperature Extremes
- Viral, bacterial, and fungal infections can precipitate muscle breakdown 2, 5
- Hyperthermia (heat stroke, malignant hyperthermia) 2, 5
- Hypothermia 5
High-Risk Patient Populations
Patients at increased risk include those with:
- Complex medical problems and polypharmacy 6, 7
- Elderly age 8
- Multiple comorbidities (diabetes, hypertension, organ transplants) 8
- Low body mass index 12
- Asian ancestry 12
- HIV infection 12
- Renal or liver disease 12
- Pre-existing myopathy 12
Clinical Recognition Patterns
Multiple etiologic factors are present in 60% of cases, and rhabdomyolysis is recurrent in 11% of all cases 4
- In 7% of cases, no cause is identified despite thorough evaluation 4
- Underlying myopathy or metabolic defects show high recurrence rates, typically only one etiologic factor, and lower incidence of acute kidney injury 4
- Patients with intoxication, prolonged immobilization, and/or altered mentation require high clinical suspicion 1