Etiology

Rhabdomyolysis is a consequence of different disease entities that cause muscle fiber destruction. These processes may be classified as traumatic or medically induced.

Trauma, including overexertional states, results in direct muscle injury. Patients with vascular injuries or muscle ischemia with subsequent reperfusion are at higher risk for rhabdomyolysis.[2]

There are various medical causes. Rare, inherited muscle enzyme defect disorders, as well as seizures, infections, metabolic abnormalities, hypoxic conditions, temperature-related entities, and certain immunologic diseases, may result in rhabdomyolysis.

In essence, any condition that causes intrinsic or extrinsic damage to myocytes results in release of intracellular contents into the vascular compartment and the ensuing complications. A small proportion of rhabdomyolysis cases are classified as idiopathic. These, however, are thought to be from as yet unrecognized hereditary defects or earlier undiagnosed metabolic causes.[1]

Drug-induced rhabdomyolysis

Prescribed drugs, illicit drugs, and dietary supplements may lead to rhabdomyolysis:[5][6][7][8][9][10][11][12][13][14]

  • Cocaine, amphetamines, and phencyclidine may cause hyperdynamic muscular states.

  • Narcotics and other central nervous system depressants (barbiturates, sedative-hypnotics) may cause tissue hypoperfusion and prolonged immobilization and limb compression.

  • Salicylate toxicity uncouples oxidative phosphorylation, which inhibits adenosine triphosphate (ATP) formation.

  • Diuretics may lead to potassium depletion severe enough to result in rhabdomyolysis.

  • Statin therapy for cholesterol control has a significant unwanted effect of rhabdomyolysis.[8][9] Statins currently licensed worldwide include, but are not limited to, rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, and lovastatin. Another statin, cerivastatin, was taken off the market by its manufacturer in 2001 after it was found to have been associated with approximately 100 rhabdomyolysis-related deaths.[15] The mechanism is not clearly defined. Statins and other medications (e.g., daptomycin) may have a synergistic effect on muscle breakdown.[16]

  • Antipsychotic use is a risk factor for rhabdomyolysis. It has been reported in the presence or absence of neuroleptic malignant syndrome.[13][14]

  • Certain antidepressants (venlafaxine, escitalopram, sertraline) when used in combination with other medications, including antiretrovirals (tenofovir) or antibiotics (daptomycin), or with alcohol, can have a synergistic effect on muscle breakdown and cause rhabdomyolysis.

  • Dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g., sitagliptin) can cause myopathy and rhabdomyolysis when used in association with statins.

  • Certain weight loss or performance enhancing dietary supplements can cause rhabdomyolysis, possibly as a result of metabolic stress.

With increasing polypharmacy, due diligence should be given to drug-to-drug interactions. For example, fibrates prescribed alongside statins increase the risk of rhabdomyolysis.[17][18] Similarly, medications that precipitate rhabdomyolysis when used in cases of undiagnosed endocrine (e.g., hypothyroidism) and metabolic abnormalities (e.g., hypokalemia, hypophosphatemia) can cause rhabdomyolysis. 

Toxins and envenomation

Toxins, such as cyanide, mercury, copper, carbon monoxide, and toluene, disrupt ATP use or production at the cellular level, and subsequently cause muscle damage.[5][6]

Toxin-induced rhabdomyolysis has been documented following envenomation (bee stings, centipede bites, and snakebites).[5][6]

Pathophysiology

Muscle cells have a cell membrane called the sarcolemma and contain myofibrils in a matrix called the sarcoplasm. Despite the multiple causes of rhabdomyolysis, the final pathway is disruption of the sarcolemma with resultant release of intracellular contents (including myoglobin, creatine kinase, potassium, magnesium, phosphorus, and uric acid). Cellular integrity and function is dependent on the strict maintenance of low intracellular sodium and calcium ion concentrations regulated by adenosine triphosphatase-dependent cation exchange mechanisms.[1][5] Direct physical injury such as trauma or toxic injury allows disruption of ionic homeostasis across the sarcolemma and cellular swelling with subsequent lysis. Because homeostasis is also adenosine triphosphate (ATP)-dependent, any process impairing its production by skeletal muscle causes myocyte destruction, and any state where skeletal muscle energy requirements exceed the available ATP may also lead to rhabdomyolysis.[2][5]

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