RHABDOMYOLYSIS (MYOGLOBINURIA)

Rhabdomyolysis

Rhabdomyolysis (literally dissolution of striated muscle) is myonecrosis on a massive scale with leakage of myofiber contents, including myoglobin, CK, and other proteins into the circulation. Myonecrosis is caused by two basic mechanisms, mechanical physical injury and energy depletion. Failure of ATP-powered pumps allows influx of calcium into the myofiber. Calcium activates proteases and phospolipases, leading to disintegration of plasma membrane, contractile filaments, and other myofiber contents.
The causes of rhabdomyolysis are listed in the table below.

Trauma, crush
Excessive exertion, including status epilepticus, and alcohol withdrawal
Muscle ischemia, including compartment syndromes
Inherited metabolic disorders affecting energy metabolism. These include: a. Glycolytic defects (phosphorylase deficiency-Glycogenosis type V or McArdle disease, phosphofructokinase deficiency-Glycogenosis type VII or Tarui disease and other) b. Disorders of lipid metabolism ( carnitine palmitoyl transferase deficiency, medium-, long-, and very long-chain-acyl-CoA dehydrogenase deficiency and other c. Mitochondrial myopathies
Other genetic disorders: LPIN1 mutations. LPIN1 is expressed in muscle and adipose tissue and is important in triglyceride synthesis. Mutations of LPIN1 cause autosomal recessive acute recurrent myoglobinuria (ARARM). RYR1 mutations. The ryanodine receptor 1 (RYR1) is a calcium channel that releases calcium ions from the sarcoplasmic reticulum into the transverse tubular system(T-tubule). This stimulates muscle contraction. RYR1 mutations cause central core and multiminicore myopathy and malignant hyperthermia.
Muscle viral and bacterial infections, especially influenza and enteroviruses
Hyperthermia
Electrolyte imbalance and other severe metabolic derangements
Toxins (alcohol, heroin, cocaine)
Drugs, especially lipid-lowering agents

Clinically, rhabdomyolysis is characterized by weakness, myalgia, and muscle swelling, and biochemically by elevation of CK, which is proportionate to the extent of myonecrosis. Muscle regenerates rapidly following myonecrosis. The most important complication of severe rhabdomyolysis is renal failure. When plasma myoglobin exceeds 0.5-1.5 mg/dl, it leaks into the urine and when its urine concentration rises above 100 mg/dl, it gives urine a red-brown color (myoglobinuria) and precipitates in distal tubules in the form of casts. Myoglobinuria is used synonymously with rhabdomyolysis. A large proportion of acute renal failure cases and associated deaths are caused by rhabdomyolysis. Myoglobin causes intrarenal vasoconstriction, tubular injury, and tubular obstruction by casts.

The lipid lowering agents statins, which are the most frequently prescribed drugs today, cause a range of neuromuscular adverse effects, which include myalgia, elevated CK, rhabdomyolysis, immune-mediated myopathy, mitochondrial myopathy, and peripheral neuropathy. Furthermore, statins can unmask or precipitate symptoms of other myopathies. The muscle biopsy in statin-related neuromuscular disorders may show myonecrosis, inflammatory myopathy, mitochondrial abnormalities, or denervation atrophy.

While statins are the most frequent cause of drug-induced neuromuscular adverse effects, numerous other agents, partially listed in the table below, can cause muscle disease by a variety of mechanisms.

DRUG INDUCED MUSCLE DISEASES

DRUGS, AGENTS	MUSCLE DISEASE, PATHOLOGY
Alcohol, drugs of abuse, statins, emetine, hypokalemia, ε-aminocaproic acid	Myonecrosis
d-penicillamine, phenytoin, α-interferon, L-tryptophan	Inflammatory myopathy
AZT, cyclosporin, statins	Mitochondrial myopathy
IV corticosteroids and neuromuscular blockade agents	Myosin loss, critical illness myopathy
Corticosteroids	Type 2 fiber atrophy
Antimalarials, amiodarone, perhexilene	Vacuolar myopathy (lysosomal)
Cochicine, vinristine	Vacuolar myopathy (sarcoplasmic reticulum)

Chapter 13

MYOPATHOLOGY

RHABDOMYOLYSIS (MYOGLOBINURIA)

Further Reading