What is the differential diagnosis (DDx) for elevated creatine kinase (CK) in a patient?

Differential Diagnosis of Elevated Creatine Kinase

Elevated CK requires systematic evaluation across cardiac, muscular, traumatic, drug-induced, and systemic causes, with the clinical context and degree of elevation guiding the diagnostic approach.

Cardiac Causes

• Acute myocardial infarction remains a critical diagnosis, though troponin has replaced CK-MB as the primary marker for MI diagnosis 1, 2
• CK-MB retains utility for detecting reinfarction due to its shorter half-life compared to troponin, and for diagnosing periprocedural MI 1, 2
• In one medical department study, acute MI accounted for 32% of CK elevations 3

Traumatic and Rhabdomyolysis-Related Causes

• Severe limb trauma and crush injuries cause marked CK elevation, with levels >5 times normal indicating rhabdomyolysis 2
• Crush syndrome with CK >75,000 IU/L carries >80% risk of acute kidney injury 2
• Falls and hematomas are common causes, found in 24% and 17% of hospitalized patients with elevated CK respectively 3
• Intramuscular injections account for 16% of cases 3

Drug-Induced Causes

• Statin therapy is a frequent culprit, with non-specific muscle aches in ~5% of users, though most have mild or no CK elevation 2
• Severe statin myositis (CK >10× upper limit) is rare but requires immediate cessation 2
• Rhabdomyolysis from statins is exceedingly rare (<1 death per million prescriptions), occurring most with CYP3A4 inhibitors, fibrates, macrolide antibiotics, and cyclosporine 2
• Immune checkpoint inhibitors can cause myositis with markedly elevated CK, often requiring high-dose corticosteroids 1
• Drug intake broadly accounted for 32% of CK elevations in hospitalized patients 3

Inflammatory and Autoimmune Myopathies

• Immune checkpoint inhibitor-associated myositis presents with proximal weakness and markedly elevated CK, potentially fatal if involving myocardium 1
• Idiopathic inflammatory myopathies show elevated CK with proximal muscle weakness 2
• Immune-mediated necrotizing myopathy demonstrates particularly high elevations (>10× upper limit), especially in statin-induced cases with anti-HMGCR antibodies 2
• Polymyalgia rheumatica-like syndromes present with severe myalgia but CK levels should be normal, differentiating from true myositis 1

Genetic Myopathies

• Duchenne muscular dystrophy should be considered in any male child with CK >10,000 U/L, with permanently elevated levels that don't fluctuate with exercise 4
• Becker muscular dystrophy shows progressive proximal weakness with respiratory impairment and elevated CK 4
• Pompe disease demonstrates elevated CK in ~95% of late-onset cases and highest levels in infantile-onset (up to 2000 IU/L) 4, 2
• Malignant hyperthermia susceptibility may present with persistently elevated CK or recurrent rhabdomyolysis triggered by exercise or anesthesia 2
• Muscular dystrophies are found in only 2% of medical department admissions with elevated CK 3

Benign and Physiologic Causes

• Exercise-induced elevation is common in athletes, with CK peaking 24-120 hours post-exercise depending on modality 2, 5
• Ethnicity affects baseline CK: Black individuals demonstrate higher baseline levels than South Asian or white individuals due to larger muscle mass 2, 5
• Macro-CK type 1 (CK-immunoglobulin complex) causes persistent elevation without pathology, obviating need for extensive workup and preventing unwarranted statin discontinuation 6, 7
• Macro-CK type 2 (CK-mitochondrial oligomers) should prompt investigation for malignancy 6, 7

Other Systemic Causes

• Malignancy accounted for 11% of CK elevations in hospitalized patients 3
• Hypothyroidism can cause CK elevation with muscle symptoms
• Seizures and other neurological conditions may elevate CK
• In 61% of hospitalized patients, multiple potential causes coexist, making CK elevation relatively nonspecific 3

Critical Diagnostic Approach

For CK >10,000 U/L in males: Proceed directly to genetic testing for dystrophinopathies 4

For suspected rhabdomyolysis: Check CK, myoglobin, renal function, and urine myoglobin; myoglobin may be more sensitive for early AKI risk 2

For statin users with muscle symptoms: Severe myositis requires immediate cessation if CK >10× upper limit 2

For immune checkpoint inhibitor patients: Monitor CK with ESR/CRP; elevated CK with weakness warrants holding therapy and considering high-dose corticosteroids 1

To exclude exercise effect: Re-measure CK after 48-72 hours of complete rest; persistently elevated levels (as in DMD) are not exercise-related 4

To identify macro-CK: Consider when CK-MB is disproportionately elevated relative to total CK, preventing unnecessary cardiac or neuromuscular workup 6, 7