What are the causes of rhabdomyolysis beyond intense physical exertion in patients with a history of medical conditions such as hypothyroidism, hyperthyroidism, or muscular dystrophy?

Causes of Rhabdomyolysis Beyond Physical Exertion

Rhabdomyolysis has multiple etiologies beyond intense exercise, including medications (particularly statins), metabolic/endocrine disorders (hypothyroidism, hyperthyroidism), infections, toxins, temperature extremes, genetic muscle disorders, prolonged immobilization, and trauma—all of which must be systematically evaluated when muscle injury occurs. 1, 2, 3

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. 2 The ACC/AHA guidelines specifically identify several high-risk drug combinations:

• Statin + macrolide antibiotics (azithromycin, clarithromycin, erythromycin) significantly increase rhabdomyolysis risk 2
• Statin + gemfibrozil carries a 10-fold higher risk compared to fenofibrate and should be avoided entirely 2
• Statin + cyclosporine, antifungal drugs, or niacin can precipitate muscle breakdown, especially in susceptible patients 2
• Red yeast rice supplements containing lovastatin cause drug-induced rhabdomyolysis and should be discontinued before elective surgery 2, 4

Other causative agents include recreational drugs (cocaine, methamphetamine, ecstasy/MDMA, ketamine, heroin), alcohol abuse, and supplements like creatine monohydrate, wormwood oil, licorice, and Hydroxycut. 2, 4

Metabolic and Endocrine Disorders

The ACC/AHA guidelines mandate evaluation for metabolic conditions that predispose to muscle injury:

• Hypothyroidism is a critical risk factor that must be screened when muscle symptoms develop, as it predisposes patients to statin-induced and spontaneous rhabdomyolysis 1, 4
• Hyperthyroidism can similarly trigger muscle breakdown through hypermetabolic states 3
• Electrolyte abnormalities including disturbances in calcium, phosphorus, and potassium homeostasis contribute to muscle injury 3, 5
• Vitamin D deficiency increases susceptibility to muscle symptoms and should be corrected 1

Genetic and Hereditary Muscle Disorders

Primary muscle diseases and hereditary enzyme defects represent important causes, particularly in patients with recurrent episodes:

• Glycogen storage diseases (particularly type III) predispose to rhabdomyolysis 2
• Muscular dystrophies increase baseline vulnerability to muscle breakdown 1
• Metabolic myopathies including CPT2, PYGM, ACADM, AMPD1, and VLCAD gene mutations cause recurrent rhabdomyolysis 4
• Malignant hyperthermia susceptibility (RYR1 and CACNA1S gene mutations) can trigger severe episodes with anesthetic exposure or exertion 4
• Sickle cell trait increases risk during intense physical exertion 2

Infections and Inflammatory Conditions

Multiple infectious etiologies can precipitate rhabdomyolysis:

• Viral myositis should be considered with appropriate viral studies when clinically indicated 4, 3, 5
• Severe bacterial infections can trigger muscle breakdown through sepsis-related mechanisms 3, 6
• Rheumatologic disorders including polymyalgia rheumatica and autoimmune myopathies require evaluation with ANA, ASMA, and ANCA markers 1, 4

Temperature-Related Causes

• Hyperthermia from environmental heat exposure or malignant hyperthermia increases rhabdomyolysis risk 2, 3, 5
• Hypothermia can similarly cause muscle injury through metabolic derangements 3, 5

Trauma and Immobilization

• Crush injuries and severe limb trauma directly damage muscle tissue 4, 3, 5
• Prolonged immobilization during surgery or unconsciousness causes compression-related muscle necrosis 2, 6
• Compartment syndrome both causes and complicates rhabdomyolysis, requiring urgent fasciotomy when compartment pressure exceeds 30 mmHg 4

Organ Dysfunction

• Reduced renal function increases susceptibility to medication-induced rhabdomyolysis and worsens outcomes 1, 2
• Hepatic dysfunction impairs drug metabolism, particularly for statins metabolized via CYP3A4 1

Critical Risk Factors for Severe Disease

The ACC/AHA identifies specific patient characteristics that amplify rhabdomyolysis risk:

• Advanced age (especially >80 years) 2
• Female sex and small body frame 2
• Polypharmacy with multiple interacting medications 2
• Chronic renal insufficiency 2
• Diabetes mellitus 2
• Cardiovascular disease 2

Common Pitfall to Avoid

Do not attribute all muscle symptoms to the most obvious cause (e.g., recent exercise or statin use) without systematically excluding other etiologies. The ACC/AHA specifically mandates evaluation for hypothyroidism, renal/hepatic dysfunction, rheumatologic disorders, vitamin D deficiency, and primary muscle diseases when muscle symptoms develop. 1 Missing an underlying metabolic disorder or genetic myopathy can lead to recurrent episodes and preventable complications including acute kidney injury, life-threatening hyperkalemia, and compartment syndrome. 4, 3, 5, 6