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

Causes of Elevated Creatine Kinase (CK)

Elevated CK levels arise from muscle injury (exercise, trauma, myopathy, rhabdomyolysis), cardiac causes (myocardial infarction), medications (especially statins), and systemic conditions (renal failure, sepsis, neurological emergencies), with the clinical significance determined by the magnitude of elevation and accompanying symptoms. 1

Primary Muscle-Related Causes

Exercise and Physical Activity

• Unaccustomed exercise, particularly involving eccentric contractions, commonly elevates CK with peaks occurring 24-120 hours post-exercise depending on exercise modality 1
• CK levels can reach >3000 U/L after maximal resistance training in healthy individuals without pathological significance 1
• Athletes may have chronically elevated baseline CK levels, with some being "high responders" showing greater CK elevations after exercise 2, 3
• Prolonged exercise such as ultradistance marathon running or downhill running produces the highest post-exercise serum CK activities 3

Traumatic Muscle Injury

• Impact trauma can drastically increase CK levels without reflecting internal muscle stress 1
• CK >5 times the upper limit of normal indicates rhabdomyolysis 1
• CK >75,000 IU/L associates with >80% incidence of acute kidney injury in crush syndrome patients 1
• In severe cases with multiple etiologic factors, CK can reach exceptionally high levels approaching 1 million U/L 4

Myopathies and Muscular Dystrophies

• Inflammatory myopathies (polymyositis, dermatomyositis) cause CK elevation with proximal muscle weakness 2
• Muscular dystrophies, including Duchenne/Becker carriers in females, must be considered even in asymptomatic patients with persistent hyperCKemia 5
• Limb-girdle muscular dystrophies (sarcoglycanopathy, calpainopathy) present with elevated CK in both symptomatic and asymptomatic girls 5
• Persistently increased CK in apparently healthy individuals may represent pre-clinical stages of muscle disease 3

Medication-Induced Causes

Statins

• Statins cause dose-dependent myopathy ranging from asymptomatic CK elevation to severe rhabdomyolysis 1, 2
• Severe myositis with CK >10 times the upper limit of normal requires immediate statin discontinuation 1
• Myositis occurs more frequently when statins combine with cyclosporine, fibrates, macrolide antibiotics, antifungal drugs, or niacin 1
• Cerivastatin had a 16-80 times higher rate of fatal rhabdomyolysis compared to other statins 1

Tyrosine Kinase Inhibitors (TKIs)

• Several TKIs (brigatinib, binimetinib, cobimetinib-vemurafenib, aumolertinib, sunvozertinib) have >35% incidence of CK elevation 6
• TKI-induced CK elevation can manifest as myopathy, myositis, inclusion body myositis, cardiotoxicity, or rhabdomyolysis 6

Immune Checkpoint Inhibitors

• Checkpoint inhibitor-related myositis can be rapidly fatal and requires immediate recognition 2
• Grade 2 myositis (CK 3-10× ULN with moderate symptoms) requires holding therapy and initiating prednisone 0.5-1 mg/kg daily 2
• Any myocardial involvement mandates permanent discontinuation of checkpoint inhibitor therapy 2

Cardiac Causes

• CK-MB is useful for diagnosing early infarct extension due to its short half-life compared to troponin 1
• Myocardial infarction related to coronary bypass is diagnosed by biomarker elevation >5-10 times the 99th percentile of normal 1
• Cardiac evaluation including troponin and ECG should be performed immediately when myocardial involvement is suspected 2

Systemic and Metabolic Causes

Renal Failure

• Chronic kidney disease can cause significant chronic CK elevations 1
• Hemodialysis patients may have abnormally elevated CK-MB even without acute myocardial necrosis, with approximately 29% showing subform analysis consistent with myocardial infarction despite no cardiac symptoms 7
• Drug dosing must account for GFR to avoid accumulation of renally excreted medications that may contribute to myopathy 2

Neurological Emergencies

• Severe acute neurological diseases including stroke or subarachnoid hemorrhage can cause CK elevations 1

Infiltrative Diseases

• Amiloidosis and sarcoidosis can cause CK elevations 1

Critical Illness

• Sepsis and critically ill patients may have CK elevations 1

Important Confounding Factors

Demographic Variables

• Ethnicity affects CK levels, with Black individuals having higher baseline CK than South Asian and White individuals due to greater muscle mass and higher tissue CK activity 1
• Positive relationship exists between total muscle mass and baseline CK activity 1
• Age, gender, race, and climatic conditions influence total CK levels 3

Timing Considerations

• CK does not peak immediately post-injury but rather 24-120 hours later depending on the cause 1
• CK is markedly elevated for 24 hours after exercise and gradually returns to baseline with rest 3

Diagnostic Approach Algorithm

Initial Assessment Based on CK Level

• CK >10× ULN with muscle symptoms: Suggests pathological elevation requiring immediate evaluation 1, 2
• CK >5× ULN: Suggests rhabdomyolysis; check myoglobin, potassium, creatinine, and renal function 1
• CK 3-10× ULN with symptoms: Consider temporary discontinuation of causative medications 2
• CK <5× ULN without weakness: Close monitoring often sufficient without specific intervention 2

Distinguishing Muscle vs. Liver Injury

• Check creatine phosphokinase, aldolase, or other muscle enzymes to confirm non-hepatic origin when ALT/AST are elevated in patients on statins or exercising intensively 1
• This is particularly important in NASH patients where muscle injury can mimic liver injury 1

When to Suspect Inflammatory Myopathy

• Consider autoimmune panels if immune-mediated myopathy is suspected 1
• Progressive proximal muscle weakness requires urgent evaluation 2
• Red flags include dysphagia, dysarthria, dysphonia, and dyspnea suggesting severe myositis requiring immediate attention 2

Special Population Considerations

• In girls with persistent hyperCKemia, muscular dystrophy including Duchenne/Becker carriers must be considered regardless of symptom presentation 5
• In athletes with high CK at rest after absolute rest without predisposing factors, perform full diagnostic workup for signs of muscle weakness indicating subclinical muscle disease 3