Rhabdomyolysis & Toxic/Metabolic Myopathies

How muscle breaks down

Final common pathway. Whatever the trigger, the injured myocyte runs out of ATP. The Na⁺/K⁺-ATPase and the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) fail, cytosolic calcium climbs, and calcium overload drives sustained contraction and activates proteases and phospholipases that digest the sarcolemma. Ruptured fibers release myoglobin, creatine kinase (CK), potassium, phosphate, purines (→ uric acid) and organic acids, while swollen muscle traps extracellular fluid.

Physical and toxic triggers. Crush injury and prolonged immobilization (hours on the floor after a fall or an overdose) cause pressure ischemia. Extreme or unaccustomed exertion strikes military recruits and marathon runners, especially in heat and with sickle cell trait. Heat stroke and status epilepticus also qualify. Cocaine and amphetamines act through vasoconstriction, agitation, seizures and hyperthermia; alcohol is directly myotoxic and adds immobilization and electrolyte loss.

Electrolyte triggers. Working muscle normally releases potassium that dilates its own arterioles; severe hypokalemia (typically <2.5 mEq/L) removes this signal and makes exercising muscle ischemic. Hypophosphatemia depletes ATP, classically in refeeding syndrome (insulin drives phosphate into cells), alcohol withdrawal and treated DKA. Lysis then releases potassium and phosphate, so the triggering deficit may be hidden by the time labs are drawn.

Statins. Toxicity ranges from myalgia with a normal CK to myositis to rare rhabdomyolysis. Risk rises with high doses, hypothyroidism, CKD, gemfibrozil and CYP3A4 inhibitors (clarithromycin, erythromycin, azole antifungals, HIV protease inhibitors, cyclosporine, grapefruit juice) that raise simvastatin, lovastatin and atorvastatin levels. Azithromycin barely inhibits CYP3A4 and rifampin induces it. Pravastatin and rosuvastatin are not CYP3A4 substrates, and fenofibrate interacts far less than gemfibrozil.

Malignant hyperthermia. An autosomal dominant RYR1 variant (rarely CACNA1S, the dihydropyridine receptor) lets volatile anesthetics or succinylcholine open the sarcoplasmic reticulum calcium channel unchecked. Masseter rigidity and a rising end-tidal CO₂ (often the first sign) precede tachycardia, rigidity, hyperkalemia, acidosis, rhabdomyolysis and, often later, hyperthermia. Stop the trigger and give dantrolene, which blocks RyR1.

McArdle disease. Glycogen storage disease type V (autosomal recessive, PYGM) lacks muscle glycogen phosphorylase. Intense exercise brings early fatigue, cramps and myoglobinuria; continuing at a lower pace brings a "second wind" after about 10 minutes as blood glucose and fatty acids replace glycogen. Venous lactate fails to rise on forearm exercise testing while ammonia still rises, and blood glucose is normal. Carnitine palmitoyltransferase II deficiency instead causes attacks after prolonged exercise or fasting, without a second wind.

Laboratory findings and complications

Creatine kinase. CK is often >10,000 U/L; it rises within hours, peaks at 24–72 hours and falls over days once injury stops. Myoglobin's half-life is only a few hours, so a normal serum level does not exclude the diagnosis.

Urine. Urine turns tea- or cola-colored. The dipstick blood pad detects the peroxidase activity of heme and cannot tell myoglobin from hemoglobin, so the dipstick is heme-positive while microscopy shows few or no red cells.

Pigment nephropathy. Myoglobin causes acute tubular necrosis in three ways: renal vasoconstriction (free heme scavenges nitric oxide, and fluid trapped in muscle lowers effective volume), tubular obstruction (myoglobin precipitates with Tamm-Horsfall protein into pigmented casts, favored by acidic urine) and oxidant injury from heme iron.

Electrolytes. Hyperkalemia appears within hours and is the main early threat to life; oliguric AKI worsens it. Phosphate and uric acid rise, and a high-anion-gap acidosis develops. Calcium falls early as calcium phosphate precipitates in necrotic muscle; in recovery the deposits mobilize and calcitriol rises, so hypercalcemia can follow.

Give calcium only for symptomatic hypocalcemia or hyperkalemia with ECG changes; extra calcium deposits in damaged muscle and feeds the later rebound.

Management

Toxic, endocrine and metabolic myopathies

Statin necrotizing myopathy. Statins can provoke autoantibodies against HMG-CoA reductase, the enzyme they inhibit and whose expression they upregulate. This immune-mediated necrotizing myopathy causes progressive proximal weakness with CK in the thousands to above 10,000 U/L and necrotic fibers with scant inflammation. Unlike toxic statin myopathy, it persists after the statin stops and needs immunosuppression.

Glucocorticoid myopathy. Chronic glucocorticoids or Cushing syndrome cause painless hip-girdle weakness (trouble rising from a chair) with a normal CK and type 2 fiber atrophy. In a patient treated for myositis, a normal CK favors steroid myopathy over a flare.

Other culprits. Hypothyroidism raises CK and statin toxicity. Colchicine binds tubulin and disrupts microtubule-dependent autophagy (vacuolar neuromyopathy), especially with CKD, clarithromycin or cyclosporine. Zidovudine inhibits mitochondrial DNA polymerase γ, and abnormal mitochondria clump under the sarcolemma as ragged-red fibers on Gomori trichrome.

Contrast: inflammatory and inclusion body myositis

Polymyositis and dermatomyositis. Symmetric proximal weakness over weeks to months, a high CK, antibodies such as anti-Jo-1 (anti-Mi-2 is specific for dermatomyositis) and a good response to glucocorticoids; perifascicular atrophy marks dermatomyositis.

Inclusion body myositis. IBM is the most common acquired myopathy after age 50 and mostly affects men. Weakness progresses over years, is often asymmetric, and targets the deep finger flexors (weak grip) and quadriceps (falls); dysphagia is common. CK is normal or mildly raised. Biopsy shows rimmed vacuoles and endomysial CD8⁺ T cells invading non-necrotic fibers. Immunosuppression fails.

Older man, weak grip, frequent falls, no response to prednisone: inclusion body myositis, not polymyositis.