Creatine Kinase

Creatine kinase (CK) catalyses the transfer of phosphate from phosphocreatine to ADP, regenerating ATP in tissues with a high energy demand. It is a dimer of M and B subunits. CK-MM, mainly from skeletal muscle, makes up almost all normal serum activity. CK-MB is found in heart muscle, and CK-BB in brain and smooth muscle. Total CK is measured by an enzymatic coupled assay, and isoenzymes are measured by immunoinhibition, immunoassay (CK-MB mass) or electrophoresis.

CK is the principal marker of skeletal muscle injury. It is used to diagnose rhabdomyolysis, to assess myopathy and muscular dystrophy, and to monitor muscle toxicity from drugs. High sensitivity troponin has replaced CK-MB for myocardial injury.

Mildly raised CK is common in the general population and is most often due to exercise, muscle mass or ancestry. Idiopathic hyperCKaemia without symptoms is found in about 1 in 50 to 100 adults. Rhabdomyolysis accounts for about 5 to 10% of acute kidney injury in some series.

Indications. Muscle pain or weakness, dark urine after exertion, trauma or prolonged immobilisation, suspected myopathy or dystrophy, statin or fibrate treatment with muscle symptoms, seizures, hyperthermia, suspected neuroleptic malignant syndrome or malignant hyperthermia, unexplained raised AST, delayed motor milestones in a boy, and family history of muscle disease.

Specimen. Serum or heparin plasma. Haemolysis has little effect on CK activity, though adenylate kinase from red cells can raise results in some assays. CK is stable for about 7 days at 2 to 8 °C. Avoid strenuous exercise for 72 hours before testing, and avoid intramuscular injections.

Reference range (total CK, 37 °C). Men about 40 to 320 U/L, women about 25 to 200 U/L. Upper limits are higher in muscular people and athletes, and roughly 1.5 to 2 times higher in people of African ancestry. Local ranges take precedence.

Kinetics. After muscle injury, CK rises within 2 to 12 hours, peaks at 24 to 72 hours and falls by about half each day when the injury stops (half life about 1.5 days). A CK that stays raised beyond 5 to 7 days after the insult indicates continuing injury.

Magnitude and cause.

• Under 5 times the upper limit: exercise, intramuscular injection, mild trauma, hypothyroidism, drugs, ancestry, idiopathic.
• 5 to 10 times: significant muscle injury, inflammatory myopathy, statin myopathy, infection, hypokalaemia.
• Over 10 times (over about 2000 to 3000 U/L): rhabdomyolysis, muscular dystrophy, necrotising immune mediated myopathy, seizures, crush injury, heat stroke.
• Over 10 000 U/L: usually rhabdomyolysis, or Duchenne dystrophy in a boy.

Rhabdomyolysis. Muscle pain, weakness and dark urine, with CK over 5 times the upper limit (usually over 1000 U/L), a positive urine dipstick for blood without red cells on microscopy, and raised potassium, phosphate, urate and creatinine with low calcium early on. The risk of acute kidney injury rises steeply when CK is over 5000 U/L and is high over 15 000 U/L, particularly with sepsis, dehydration and acidosis.

CK-MB. A raised CK-MB with raised total CK indicates cardiac muscle injury, but skeletal muscle injury, regenerating muscle and chronic myopathy also raise it. A relative index (CK-MB mass divided by total CK, multiplied by 100) of 2.5 to 3% or more favours cardiac origin. It is used for reinfarction only when troponin is unavailable.

Causes of raised CK.

• Skeletal muscle injury: exercise (especially eccentric), intramuscular injection, trauma, crush injury, burns, electrical injury, immobilisation after a fall, surgery, seizures, delirium tremens.
• Hyperthermia and drug reactions: heat stroke, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome.
• Drugs and toxins: statins, fibrates, colchicine, zidovudine, daptomycin, propofol, glucocorticoids, alcohol, cocaine, amphetamines, MDMA, snake venom.
• Infection: influenza, COVID-19, EBV, HIV, pyomyositis.
• Metabolic and endocrine: hypothyroidism, hypokalaemia, hypophosphataemia, hypernatraemia and hyponatraemia, diabetic ketoacidosis, hyperosmolar state.
• Inflammatory and inherited myopathy: dermatomyositis, polymyositis, necrotising immune mediated myopathy (anti-HMGCR, anti-SRP), Duchenne and Becker dystrophy, limb girdle dystrophies, Pompe disease, McArdle disease, CPT2 deficiency, mitochondrial myopathy.
• Other: myocardial infarction, myocarditis, cardioversion, stroke, pulmonary embolism, kidney failure, macro-CK, labour and the early postpartum period.

Causes of low CK. Low muscle mass, older age, sedentary habit, corticosteroid therapy, alcoholic liver disease, rheumatoid arthritis, and early pregnancy. Low values have no diagnostic use.

Statin treatment. Muscle symptoms with CK over 10 times the upper limit, or rhabdomyolysis, need the statin stopped. Mild symptoms with CK under 4 times the upper limit allow continuation under monitoring. Persistent raised CK after stopping needs assessment for necrotising immune mediated myopathy.

Critical values and findings needing immediate action. Triggers vary by laboratory.

• CK over 5000 U/L, or any rise with dark urine, oliguria, hyperkalaemia, arrhythmia, tense swollen limbs (compartment syndrome) or rising creatinine.
• CK rise with fever, rigidity and altered consciousness (neuroleptic malignant syndrome, serotonin syndrome, malignant hyperthermia).
• Raised CK with chest pain and an abnormal ECG, which needs troponin and cardiac assessment.

Interferences and pitfalls.

• Strenuous exercise within 72 hours, intramuscular injections, recent seizures and alcohol raise CK, and an asymptomatic raised result is repeated after 7 days of rest.
• Ancestry, sex and muscle mass shift reference limits, and a single upper limit misclassifies many people.
• Macro-CK (type 1, CK-BB bound to immunoglobulin, and type 2, mitochondrial CK) gives a persistent isolated rise, often in older women, and needs isoenzyme analysis.
• Haemolysis and high bilirubin cause small errors in some methods.
• CK can fall to normal while a myopathy is active, particularly in late dystrophy with muscle replaced by fat, and in inflammatory myopathy treated with steroids.

Special groups.

• Neonates and infants: CK is higher in the first days of life and falls over weeks.
• Children: a boy with delayed walking, calf hypertrophy or a Gowers manoeuvre and CK over 10 times the upper limit needs urgent assessment for Duchenne dystrophy. Female carriers can have mildly raised CK.
• Pregnancy: CK is lower in the first trimester and rises in labour.
• Older adults: a long lie after a fall, and statin or colchicine toxicity, are common causes of marked rise.
• Athletes: baseline values are higher, and values over 1000 U/L can follow exertion with no kidney injury.
• Regions: crush injury after earthquakes and building collapse, snake envenomation and heat stroke are significant causes.

Follow up tests. Repeat CK after rest, urea and electrolytes including potassium, calcium and phosphate, urate, urine dipstick and urinary myoglobin, liver function tests, lactate dehydrogenase, thyroid function tests, troponin, ECG, myositis and necrotising myopathy antibodies (anti-Jo-1, anti-Mi-2, anti-SRP, anti-HMGCR), antinuclear antibodies, dystrophin gene analysis, muscle MRI, electromyography, muscle biopsy, acylcarnitine profile, toxicology screen, CK isoenzymes with polyethylene glycol precipitation for macro-CK.