What other conditions can cause rhabdomyolysis besides statin therapy?

Causes of Rhabdomyolysis Beyond Statins

Rhabdomyolysis has numerous causes beyond statin therapy, including trauma, excessive exercise, other medications, infections, metabolic disorders, toxins, prolonged immobilization, and genetic muscle diseases—all of which must be systematically evaluated when muscle injury occurs. 1

Medication and Substance-Related Causes

High-Risk Medications

• Fibrates (especially gemfibrozil) significantly increase rhabdomyolysis risk, particularly when combined with statins, with gemfibrozil-statin combinations showing 15 times higher rhabdomyolysis reports compared to fenofibrate combinations 2
• Macrolide antibiotics (clarithromycin, erythromycin, azithromycin) increase risk through CYP3A4 enzyme inhibition 2, 1
• Cyclosporine (immunosuppressant) substantially elevates rhabdomyolysis risk 2, 1
• Azole antifungals (itraconazole, ketoconazole, fluconazole) increase risk via CYP3A4 inhibition 2
• HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir) are associated with increased risk 2
• Niacin can contribute to rhabdomyolysis, especially in combination with other lipid-lowering agents 2

Recreational Drugs and Supplements

• Cocaine, methamphetamine, ecstasy (MDMA), ketamine, and heroin are important recreational drug causes that should be specifically asked about 3
• Red yeast rice supplements containing lovastatin can cause drug-induced rhabdomyolysis 1
• Creatine monohydrate, wormwood oil, licorice, and Hydroxycut should be discontinued as they may contribute to rhabdomyolysis 3

Physical and Traumatic Causes

Exercise-Induced Rhabdomyolysis

• Novel overexertion or unaccustomed exercise volume/intensity is a common cause, particularly during the first 4 days of new training regimens 1
• Eccentric exercise against high resistance is one of the main physical causes 4
• High-temperature environments (above 80°F/27°C) during exercise increase risk 1
• Sickle cell trait during intense physical exertion significantly elevates rhabdomyolysis risk 1

Trauma and Compression

• Crush injuries and severe limb trauma are major risk factors for rhabdomyolysis 3
• Prolonged immobilization (such as after falls, intoxication, or altered mental status) can cause muscle compression and breakdown 5, 1
• Compartment syndrome can both cause and complicate rhabdomyolysis, with early signs including pain, tension, paresthesia, and paresis 3

Metabolic and Endocrine Disorders

Critical Metabolic Causes

• Hypothyroidism is a critical risk factor that predisposes patients to both statin-induced and spontaneous rhabdomyolysis and must be screened when muscle symptoms develop 6, 1
• Vitamin D deficiency increases susceptibility to muscle symptoms and should be corrected 1
• Glycogen storage diseases (particularly type III) can predispose to rhabdomyolysis 1
• Electrolyte disturbances, especially disturbances in intracellular calcium balance, contribute to muscle cell breakdown 4

Energy Metabolism Disorders

• Lack of available ATP and metabolic dysfunction can trigger rhabdomyolysis through cellular energy depletion 4, 7
• Genetic testing for CPT2, PYGM, ACADM, AMPD1, and VLCAD genes should be considered in patients with recurrent rhabdomyolysis 3

Infectious and Inflammatory Causes

Infections

• Viral myositis should be considered with appropriate viral studies if clinically indicated 3
• Various infections can trigger rhabdomyolysis through direct muscle injury or systemic inflammatory responses 5, 8

Rheumatologic Disorders

• Polymyalgia rheumatica and other rheumatologic disorders must be evaluated when muscle symptoms develop 6, 1
• Autoimmune myopathies require evaluation with ANA, ASMA, and ANCA markers 3, 1

Organ Dysfunction

Renal and Hepatic Impairment

• Reduced renal function increases susceptibility to medication-induced rhabdomyolysis and worsens outcomes 1
• Hepatic dysfunction impairs drug metabolism, particularly for medications metabolized via CYP3A4 1

Genetic and Hereditary Causes

Malignant Hyperthermia Susceptibility

• RYR1 and CACNA1S gene mutations should be tested in patients with exertional rhabdomyolysis or heat illness, as these indicate malignant hyperthermia susceptibility 3, 1
• Muscular dystrophies increase baseline vulnerability to muscle breakdown 1

Temperature Extremes

• Malignant hyperthermia can occur in genetically predisposed individuals exposed to certain anesthetics 1
• Heat stroke and extreme environmental temperatures can trigger rhabdomyolysis 1

Common Clinical Pitfalls

The most critical pitfall is failing to evaluate for underlying metabolic disorders or genetic myopathies when rhabdomyolysis occurs, as this can lead to recurrent episodes and preventable complications 1. The ACC/AHA guidelines specifically mandate evaluation for hypothyroidism, renal/hepatic dysfunction, rheumatologic disorders, vitamin D deficiency, and primary muscle diseases when muscle symptoms develop 6, 1.

Impact trauma from falls can drastically elevate CK levels without reflecting true muscle breakdown, but given clinical context, assume true rhabdomyolysis until proven otherwise 3. Remember that CK levels peak 24-120 hours after the inciting event, so initial levels may not represent the peak 3.