Causes of Rhabdomyolysis
Rhabdomyolysis results from skeletal muscle breakdown triggered by medications (particularly statins), physical trauma, excessive exercise, metabolic disorders, infections, toxins, temperature extremes, genetic muscle diseases, and prolonged immobilization—all of which lead to muscle cell death and release of toxic intracellular contents into circulation. 1
Medication and Drug-Induced Causes
Statins represent the most common drug cause of rhabdomyolysis, with an incidence of 1.6 per 100,000 patient-years, and risk escalates dramatically when combined with other medications that affect their metabolism. 1, 2
- Macrolide antibiotics (azithromycin, clarithromycin, erythromycin) combined with statins significantly increase rhabdomyolysis risk through metabolic drug interactions. 1
- Gemfibrozil carries a 10-fold higher rhabdomyolysis risk compared to fenofibrate when used with any statin and should be avoided. 2
- Other high-risk medications include cyclosporine, antifungal drugs, and niacin, particularly when combined with statins. 1
- Red yeast rice supplements containing lovastatin can cause drug-induced rhabdomyolysis and should be discontinued before elective surgery. 1, 2
- Dietary supplements associated with rhabdomyolysis include creatine monohydrate, wormwood oil, licorice, and Hydroxycut. 2
- Recreational drugs including cocaine, methamphetamine, ecstasy (MDMA), ketamine, and heroin are important causes. 2
Physical and Traumatic Causes
Excessive muscle activity, particularly novel overexertion or unaccustomed exercise volume/intensity, commonly triggers rhabdomyolysis, especially during the first 4 days of new training regimens. 1
- Crush injuries and severe limb trauma cause direct muscle damage leading to rhabdomyolysis. 2
- Prolonged muscle compression during surgery or immobilization can precipitate muscle breakdown. 1
- High-temperature environments (above 80°F/27°C) increase rhabdomyolysis risk during exercise. 1
- Impact trauma from falls can drastically increase CK levels, though simple contusion may not carry the same acute kidney injury risk as true rhabdomyolysis. 2
Metabolic and Endocrine Disorders
Hypothyroidism is a critical risk factor that must be screened when muscle symptoms develop, as it predisposes patients to both statin-induced and spontaneous rhabdomyolysis. 1
- Vitamin D deficiency increases susceptibility to muscle symptoms and should be corrected. 1
- Glycogen storage diseases, particularly type III, predispose to rhabdomyolysis. 1
- Metabolic myopathies including CPT2, PYGM, ACADM, AMPD1, and VLCAD gene defects cause recurrent rhabdomyolysis. 2
- Hereditary muscle enzyme defects represent an important category of inherited causes. 3
Genetic and Hereditary Causes
Malignant hyperthermia susceptibility, caused by RYR1 and CACNA1S gene mutations, can trigger rhabdomyolysis when susceptible individuals are exposed to certain anesthetic agents, particularly suxamethonium. 4, 1
- Suxamethonium produces rhabdomyolysis in MH-susceptible patients and those with other myopathies. 4
- Muscular dystrophies increase baseline vulnerability to muscle breakdown. 1
- SLCO1B1 gene mutations increase the risk of statin-induced rhabdomyolysis. 2
- Sickle cell trait, particularly during intense physical exertion, increases rhabdomyolysis risk. 1
Infections and Inflammatory Conditions
Viral myositis and febrile illnesses frequently precipitate rhabdomyolysis episodes, particularly in patients with underlying metabolic disorders. 5
- Rheumatologic disorders, including polymyalgia rheumatica and autoimmune myopathies, require evaluation with ANA, ASMA, and ANCA markers. 1
- Pro-inflammatory cytokines released during infections may directly lead to metabolic decompensation and rhabdomyolysis. 5
Temperature-Related Causes
Both hyperthermia and hypothermia can trigger rhabdomyolysis through direct thermal injury to muscle cells. 3
- Malignant hyperthermia represents a specific genetic predisposition where triggering anesthetics cause hypermetabolic crisis with severe muscle breakdown. 4
- Elevated temperature during febrile illness or exercise creates conditions that precipitate rhabdomyolysis in susceptible individuals. 5
Organ Dysfunction as Contributing Factors
- Reduced renal function increases susceptibility to medication-induced rhabdomyolysis and worsens outcomes. 1
- Hepatic dysfunction impairs drug metabolism, particularly for statins metabolized via CYP3A4. 1
Common Pathophysiological Pathway
Regardless of the initiating cause, rhabdomyolysis follows a common pathway involving increased intracellular calcium concentration, which activates proteolytic enzymes, intensifies muscle contractility, induces mitochondrial dysfunction, and produces reactive oxygen species, ultimately resulting in muscle cell death. 6, 7
- Direct injury to the sarcolemma or failure of energy production leads to increased cellular permeability to sodium ions, followed by calcium accumulation. 7
- Calcium activates proteolytic enzymes that injure the cell membrane, allowing efflux of myoglobin, creatine kinase, and potassium into circulation. 7