What are the causes of elevated Creatine Kinase (CK) levels in a patient?

Causes of Elevated Creatine Kinase (CK)

Elevated CK levels result from muscle damage through pathological conditions (myositis, muscular dystrophy, drug-induced myopathy, rhabdomyolysis), physiological stress (exercise, particularly eccentric contractions), or non-muscular sources (cardiac injury, medications, infections). 1

Pathological Causes

Inflammatory Muscle Disease

• Myositis presents with muscle inflammation, weakness, and elevated CK, with potential life-threatening involvement of respiratory muscles or myocardium 2
• Immune-mediated necrotizing myopathy (IMNM) is characterized by proximal muscle weakness and persistently elevated CK despite statin discontinuation, with positive anti-HMG CoA reductase antibodies 3, 4
• Dermatomyositis can cause CK elevation in symptomatic girls and should be considered in the differential 5

Drug-Induced Myopathy

• Statins are the most common medication causing CK elevation, with risk factors including age ≥65 years, uncontrolled hypothyroidism, renal impairment, and higher dosages 3
• Statin-associated myopathy warrants discontinuation if CK >10× ULN with muscle symptoms 1, 3
• Immune checkpoint inhibitors can cause rapidly progressive myositis requiring immediate intervention 2, 1
• Drug interactions through CYP3A4 inhibition (cyclosporine, gemfibrozil, certain antivirals, azole antifungals, macrolides) increase myopathy risk 3
• Lipid-modifying doses of niacin (>1 gram/day), fibrates, and colchicine increase rhabdomyolysis risk 3

Rhabdomyolysis

• CK levels can range from 10,000 to 200,000 U/L or higher, with exceptionally severe cases reaching nearly 1 million U/L 6
• Multiple etiologic factors (cocaine, alcohol, infections like Legionella, sepsis, trauma) can cause massive rhabdomyolysis with significant morbidity 6
• Acute conditions predisposing to renal failure (sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic/endocrine/electrolyte disorders, uncontrolled epilepsy) warrant temporary statin discontinuation 3

Genetic Muscle Disorders

• Muscular dystrophy, including Duchenne/Becker carriers in girls, must be considered regardless of symptom presentation 5
• Sarcoglycanopathy (LGMDR4) and calpainopathy (LGMDR1) can present with persistent CK elevation 5
• Myoadenylate deaminase deficiency may present with cramp-like muscle pain and weakness without significant CK elevation 4
• Persistently elevated CK in apparently healthy individuals may represent pre-clinical stages of muscle disease 7, 8

Physiological Causes

Exercise-Induced Elevation

• Strenuous exercise, particularly eccentric contractions (downhill running, weight-bearing exercises), causes the highest post-exercise CK elevations 2, 7
• CK peaks approximately 24 hours post-exercise and gradually returns to baseline with rest 2, 7
• Ultradistance running can cause up to 152-fold CK increases 2
• Athletes may have chronically elevated baseline CK levels, with individual variability in response ("high responders" vs "low responders") 2, 1, 7
• CK elevations should not be attributed solely to exercise without excluding pathological causes 1

Non-Muscular Causes

Cardiac Involvement

• Myocardial injury causes CK-MB elevation and requires evaluation for acute coronary syndrome with troponin and ECG 1
• Troponin assessment is essential to evaluate myocardial involvement in suspected myositis 2

Other Contributing Factors

• CK levels depend on age, gender, race, muscle mass, physical activity, and climatic conditions 7
• Infections (particularly Legionella pneumophila) can contribute to rhabdomyolysis 6
• Hypothyroidism increases myopathy risk 3

Diagnostic Approach by CK Level

Mild Elevation (<3× ULN)

• Consider exercise-induced elevation, medication effects, or early muscle disease 1
• Repeat testing after 48-72 hours of rest from strenuous activity 8

Moderate Elevation (3-10× ULN)

• Check additional muscle enzymes (aldolase, AST, ALT, LDH) and inflammatory markers (ESR, CRP) 2, 1
• Consider temporary discontinuation of causative medications 1
• Evaluate for immune checkpoint inhibitor-related myositis if applicable 2

Severe Elevation (>10× ULN)

• Discontinue causative medications immediately and consider hospitalization 1, 3
• Assess for rhabdomyolysis with renal function monitoring and aggressive hydration 1, 6
• Evaluate for myocardial involvement with troponin and ECG 1

Critical Pitfalls

• Never continue statins when CK >10× ULN with symptoms, as this risks progression to rhabdomyolysis 1
• Checkpoint inhibitor myositis can be rapidly fatal and requires immediate recognition and intervention 1
• Muscle weakness (particularly proximal) is more typical of myositis than pain alone and requires urgent evaluation 2
• In girls with persistent CK elevation, muscular dystrophy including DMD/BMD carriers must be considered even without symptoms 5
• Early myopathy may be asymptomatic, with symptoms manifesting only after exercise 7