What are the causes of rhabdomyolysis?

Causes of Rhabdomyolysis

Rhabdomyolysis results from skeletal muscle breakdown triggered by trauma, medications (especially statins), excessive muscle activity, infections, metabolic disorders, toxins, temperature extremes, genetic defects, and prolonged immobilization. 1, 2

Medication and Toxin-Induced Causes

Statins are the most common drug cause of rhabdomyolysis, with an incidence of 1.6 per 100,000 patient-years, particularly when combined with other medications that affect their metabolism. 2 The risk increases dramatically when statins are combined with:

• Gemfibrozil (carries a 10-fold higher rhabdomyolysis risk compared to fenofibrate) 1
• Macrolide antibiotics (azithromycin, clarithromycin, erythromycin) 2
• Cyclosporine, antifungal drugs, and niacin 2

Red yeast rice supplements containing lovastatin can cause drug-induced rhabdomyolysis and should be discontinued. 1, 2 Other high-risk supplements include creatine monohydrate, wormwood oil, licorice, and Hydroxycut. 1

Recreational drugs including cocaine, methamphetamine, ecstasy (MDMA), ketamine, and heroin are important toxin-related causes. 1

Physical and Traumatic Causes

Trauma, especially crush injuries and severe limb trauma, is a major risk factor for rhabdomyolysis. 1 The pathophysiology involves direct injury to the sarcolemma, leading to increased intracellular calcium concentration and fiber necrosis. 3

Excessive muscle activity, particularly novel overexertion or unaccustomed exercise volume/intensity, commonly triggers rhabdomyolysis. 1, 2 The highest risk occurs during:

• The first 4 days of new training regimens or transition periods (e.g., returning after injury) 2
• Exercise in high-temperature environments (above 80°F/27°C) 2
• Unaccustomed resistance training, which can produce CK levels greater than 3,000 U/L 1

Prolonged muscle compression during surgery or immobilization can also precipitate rhabdomyolysis. 2, 4

Metabolic and Endocrine Disorders

Hypothyroidism is a critical risk factor that predisposes patients to both statin-induced and spontaneous rhabdomyolysis and must be screened when muscle symptoms develop. 1, 2

Vitamin D deficiency increases susceptibility to muscle symptoms and should be corrected. 2

Glycogen storage diseases, particularly type III, can predispose to rhabdomyolysis due to failure of energy production. 2, 3

Other metabolic causes include mitochondrial fatty acid β-oxidation defects, LPIN1 mutations, inborn errors of glycogenolysis and glycolysis, mitochondrial respiratory chain deficiency, purine defects, and peroxisomal α-methyl-acyl-CoA-racemase defect (AMACR). 3

Genetic and Hereditary Causes

Malignant hyperthermia susceptibility due to pathogenic variants in the RYR1 or CACNA1S genes can precipitate severe rhabdomyolysis when exposed to triggering anesthetic agents, particularly succinylcholine (suxamethonium). 2 This initiates a hypermetabolic crisis with uncontrolled calcium release and rapid muscle breakdown. 2

Sickle cell trait increases the risk of rhabdomyolysis during intense physical exertion. 2

Muscular dystrophies and structural myopathies increase baseline vulnerability to muscle breakdown. 2, 3

Infections and Inflammatory Conditions

Viral myositis and bacterial infections can trigger rhabdomyolysis, often precipitated by febrile illness. 1, 3 The elevated temperature and high circulating levels of pro-inflammatory mediators such as cytokines and chemokines contribute to metabolic decompensation. 3

Rheumatologic disorders, including polymyalgia rheumatica and autoimmune myopathies, require evaluation with ANA, ASMA, and ANCA markers. 1, 2

Temperature Extremes

Both hyperthermia and hypothermia can cause rhabdomyolysis. 5, 4 Heat-related rhabdomyolysis is particularly common in athletic settings with inadequate hydration. 2

Muscle Hypoxia and Ischemia

Prolonged ischemia from vascular compromise or compartment syndrome leads to muscle breakdown. 5, 6 Compartment syndrome can both cause and complicate rhabdomyolysis, with early signs including pain, tension, paresthesia, and paresis. 1

Patient-Specific Risk Factors

The following factors increase susceptibility to rhabdomyolysis:

• Advanced age (especially over 80 years) 2
• Female sex and small body frame 2
• Chronic renal insufficiency (increases susceptibility to medication-induced rhabdomyolysis and worsens outcomes) 2
• Hepatic dysfunction (impairs drug metabolism, particularly for statins metabolized via CYP3A4) 2
• Diabetes and cardiovascular disease 1
• Polypharmacy (use of multiple medications) 2
• Dehydration 2

Common Pitfalls

Do not overlook altered mental status as both a cause and consequence of rhabdomyolysis. AMS may be a precipitating cause (seizures, prolonged immobilization, drug intoxication), a consequence (electrolyte disturbances, uremia from acute kidney injury), or an unrelated complicating condition (neuroleptic malignant syndrome, serotonin syndrome). 1

Impact trauma can drastically increase CK levels without reflecting true muscle breakdown, and CK elevation from simple contusion may not carry the same risk of acute kidney injury as true rhabdomyolysis. 1 However, given clinical uncertainty, assume true muscle breakdown until proven otherwise. 1