What conditions are associated with elevated Creatinine Phosphokinase (CPK) levels?

What Creatine Phosphokinase (CPK) Identifies

Creatine phosphokinase (CPK, also called creatine kinase or CK) is primarily used to identify muscular dystrophies—especially Duchenne muscular dystrophy—and other neuromuscular disorders involving muscle or lower motor neuron disease. 1

Primary Diagnostic Applications

Muscular Dystrophies

• Duchenne muscular dystrophy (DMD) is the most important condition identified by CPK testing, with levels typically exceeding 1000 U/L and often reaching significantly higher values 1
• The American Academy of Pediatrics recommends measuring serum CPK concentration as initial testing for all children with motor delay and low tone, specifically to screen for DMD 1
• Becker muscular dystrophy, which is allelic to DMD, also presents with elevated CPK levels but typically in older children with milder symptoms 1
• CPK elevation can help identify female carriers of X-linked muscular dystrophies, though sensitivity is imperfect 2, 3

Other Neuromuscular Disorders

• CPK testing helps identify diseases of peripheral motor nerves or muscles including myotonic dystrophy, spinal muscular atrophy, mitochondrial disorders, and congenital myasthenia gravis 1
• In motor neuron diseases like amyotrophic lateral sclerosis (ALS), CPK is elevated in 50-75% of patients, typically 5-6 times normal, with values up to 1000 IU/L compatible with the diagnosis 4

Inflammatory Muscle Diseases

Myositis and Inflammatory Myopathies

• Dermatomyositis and polymyositis present with elevated CPK levels coupled with symmetric proximal muscle weakness 1
• Immune-mediated necrotizing myopathy (IMNM) shows high CPK elevations greater than 10 times the upper limit of normal 1
• Statin-induced necrotizing myopathy is associated with markedly elevated CPK and has been linked to anti-HMGCR antibodies 1

Drug-Induced Myositis

• Immune checkpoint inhibitor-associated myositis requires urgent CPK testing when patients present with proximal muscle weakness, as this can be severe and fatal, particularly when involving the myocardium 1
• All patients with suspected myositis presenting with muscle weakness and elevated CK should be referred to rheumatology or neurology, as this can be life-threatening 1
• CPK levels should generally be within normal limits in polymyalgia-like syndromes, helping differentiate this condition from true myositis 1

Important Clinical Caveats

Distinguishing True Pathology from Benign Elevations

• Physical activity significantly affects CPK levels and must be considered when interpreting results 5, 4
• In patients with motor neuron disease, moderate exercise can increase CPK to 1.71 times baseline, while 24 hours of bedrest decreases it to 0.58 of baseline 4
• For patients with atypical CPK values, having them rest 48 hours before repeating the test is recommended 4

Drug-Related CPK Elevations

• JAK inhibitors occasionally cause CPK elevations without weakness, usually with occasional myalgia but typically without clinical repercussions, though rhabdomyolysis has been reported in rare cases 1
• In the rare event of symptoms with JAK inhibitor therapy, CPK should be tested, although routine monitoring is not necessary 1
• BRAF and MEK inhibitors used in melanoma treatment can cause blood CPK increases as a documented toxicity 1

Sporadic Inclusion Body Myositis

• This condition is distinctive because muscle enzyme levels such as CK may be only minimally elevated despite significant clinical weakness, occurring typically after age 50 years with a 3:1 male predominance 1

Other Conditions

• Growth hormone treatment in patients with multiple pituitary hormone deficiency can cause CPK elevation to more than 500 U/L, particularly in those with complete GH deficiency and pituitary stalk transection 6
• Markedly elevated CK (>2,500 U/L) in meningitis patients should prompt aggressive management of cerebral edema with consideration of ICP monitoring, and requires monitoring renal function due to risk of acute kidney injury 7

Diagnostic Algorithm

When CPK is elevated:

1. Assess clinical context: presence of muscle weakness, tone abnormalities, age of presentation, and family history 1
2. If significantly elevated (>1000 U/L) with weakness and low tone in children, pursue DMD gene sequencing 1
3. If elevated with proximal weakness in adults, consider inflammatory myopathies and obtain EMG, autoantibody panels, and potentially muscle biopsy 1
4. Rule out medication effects (statins, immune checkpoint inhibitors, JAK inhibitors) and recent physical activity 1, 5
5. For persistent unexplained elevations, refer to neurology or rheumatology for electrodiagnostic testing and specific genetic testing 1