What are the causes of elevated creatine kinase (CK) levels in patients?

Causes of Elevated Creatine Kinase

Elevated CK results from muscle injury through traumatic causes (crush injuries, severe limb trauma), non-traumatic causes (medications, exercise, infections, inflammatory myopathies, genetic disorders), and cardiac causes (myocardial infarction), with non-traumatic causes now being at least 5 times more frequent than traumatic causes. 1, 2

Medication-Induced Causes

Statins are the most common medication cause of CK elevation, ranging from asymptomatic mild elevation to severe rhabdomyolysis with CK >10× upper limit of normal (ULN). 1, 3

• Statin-associated myopathy occurs in approximately 5% of users in clinical practice, though severe myositis with CK >10× ULN is rare (<1 death per million prescriptions). 4
• Risk increases dramatically with drug interactions involving CYP3A4 inhibitors, fibrates (particularly gemfibrozil), macrolide antibiotics, azole antifungals, and cyclosporine. 3
• Immune-mediated necrotizing myopathy (IMNM) is a rare autoimmune complication characterized by proximal muscle weakness, persistently elevated CK despite statin discontinuation, and positive anti-HMGCR antibodies. 3

Antipsychotic medications can cause massive CK elevations (ranging from 1,206 to 177,363 IU/L) in approximately 10% of treated patients, including clozapine, risperidone, olanzapine, haloperidol, and loxapine. 5 These elevations typically occur 5 days to 2 years after treatment initiation and are usually self-limiting within 4-28 days. 5

Exercise-Related Causes

Exercise, particularly eccentric contractions or unaccustomed high-intensity activity, commonly elevates CK levels, with peaks occurring 24-120 hours post-exercise. 1, 4, 6

• Healthy individuals can reach CK levels >3,000 U/L after maximal resistance training without pathological significance. 1
• Exertional rhabdomyolysis (CK ≥1,000 U/L from exercise) represents 2.1% of all rhabdomyolysis cases, with strength training at the gym being the most common trigger (38.1% of exertional cases). 7
• Athletes show highly individual CK responses, with some being "high responders" showing chronically elevated levels and others being "low responders" with persistently low levels despite similar training. 6
• Black individuals demonstrate higher baseline CK levels than South Asian or white individuals due to larger muscle mass and higher tissue CK activity. 4, 6

Traumatic Causes

Trauma is the single most common cause of rhabdomyolysis overall, accounting for 37.1% of all cases. 7

• Crush injuries and severe limb trauma cause CK elevations >5× ULN, meeting criteria for rhabdomyolysis. 4
• CK levels exceeding 75,000 IU/L in crush syndrome patients are associated with >80% incidence of acute kidney injury. 4
• Impact trauma can dramatically increase CK without reflecting internal muscle stress. 1

Infectious Causes

Legionella pneumophila infection can cause massive rhabdomyolysis with exceptionally high CK levels (documented cases reaching nearly 1 million U/L). 8

• Sepsis and critical illness can elevate CK through multiple mechanisms. 1
• Post-viral myositis causes transient CK elevation, though this is less common without preceding upper respiratory symptoms. 1

Inflammatory Myopathies

Idiopathic inflammatory myopathies present with elevated CK alongside proximal muscle weakness. 4

• Immune-mediated necrotizing myopathy shows particularly high CK elevations (>10× ULN), especially in statin-induced cases with anti-HMGCR antibodies. 4
• Immune checkpoint inhibitor-related myositis can cause rapidly progressive and potentially fatal myopathy requiring immediate intervention. 1
• Polymyalgia rheumatica typically presents with bilateral shoulder/hip pain and morning stiffness but usually has normal CK levels, distinguishing it from inflammatory myopathies. 1

Genetic and Metabolic Causes

Pompe disease consistently demonstrates elevated CK, with infantile-onset cases showing the highest elevations (up to 2,000 IU/L) and approximately 95% of late-onset cases having elevated CK. 4

• Malignant hyperthermia susceptibility may present with persistently elevated CK or recurrent rhabdomyolysis triggered by exercise or anesthesia. 4
• Recurrent rhabdomyolysis warrants investigation for genetic myopathies or autoimmune diseases. 2

Cardiac Causes

Myocardial infarction elevates CK-MB, though troponin has replaced CK-MB as the primary diagnostic marker. 4

• CK-MB remains useful for detecting reinfarction or periprocedural MI due to its shorter half-life compared to troponin. 1
• Periprocedural MI related to coronary bypass is diagnosed by biomarker elevation >5-10× the 99th percentile of normal. 1

Other Medical Causes

• Acute kidney injury can show chronic significant CK elevations, though creatinine interpretation is complicated by reduced hepatic creatine synthesis and increased muscle creatinine release. 1, 4
• Severe acute neurological events (stroke, subarachnoid hemorrhage) can cause CK elevation. 1
• Infiltrative diseases (amiloidosis, sarcoidosis) may elevate CK. 1
• Hypothyroidism (particularly uncontrolled) increases myopathy risk. 3

Critical Interpretation Factors

CK elevation magnitude and timing are crucial for diagnosis: CK >5× ULN indicates rhabdomyolysis; CK >10× ULN with muscle symptoms suggests pathological elevation requiring immediate intervention. 1, 4

• CK does not peak immediately post-injury but rather 24-120 hours later depending on the cause. 1, 6
• Day-to-day variability is high, influenced by physical activity, dietary protein intake, hydration status, and metabolic perturbations. 9
• Myoglobin measurement may be more sensitive than CK for early identification of acute kidney injury risk. 4

Common Pitfalls

Do not attribute CK elevation solely to exercise in athletes without excluding pathological causes, as persistently elevated CK at rest may indicate subclinical muscle disease that becomes symptomatic only with training loads. 6

Do not continue statins when CK >10× ULN with symptoms, as this risks progression to rhabdomyolysis with acute kidney injury. 1, 3

Do not overlook drug interactions when prescribing statins—concomitant use with cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir is contraindicated. 3