Creatine Kinase (CK)

Creatine kinase (CK) is an enzyme that catalyzes the reversible phosphorylation of creatine by ATP. The end product, phosphocreatine, is a readily available energy source for cells.  CK is present in many tissues but skeletal and heart muscles contain the highest concentrations. CK released from skeletal muscle accounts for almost all of the CK activity detected in the plasma of healthy individuals. Circulating CK is cleared by degradation in the liver and reticuloendothelial system and has a circulating half-life of 12 hours. 

Historically, CK was most often measured to diagnose acute myocardial infarction. In May 2001, the American College of Cardiologists recommended that total CK no longer be included as a cardiac marker. Today, CK is primarily ordered to screen for statin induced myopathy. Statin induced myopathy has been defined as an elevation of CK levels to more than 10 times the upper limit of the normal range with myalgia or weakness. Approximately 0.2% of treated patients have high CK elevations greater than 10 times the upper limit of normal and 0.6% has mild elevations, defined as 3 to 10 times the upper limit of normal. 

Plasma CK levels are helpful in diagnosing rhabdomyolysis, because objective clinical signs are often absent. CK is a more sensitive marker of skeletal muscle injury than urine myoglobin. CK levels may exceed 100,000 U/L. CK levels above 6000 U/L are associated with an increased risk of acute tubular necrosis. 

Chronic muscle disease, such as the muscular dystrophies and polymyositis/dermatomyositis, elevate plasma CK levels, but not to the same extent as rhabdomyolysis.  Muscle trauma and burns also significantly elevate CK.  Intramuscular injections and noncardiac surgery also can elevate CK. Plasma CK activity is not usually elevated by mild exercise, unless a person is in poor physical conditioning, but severe or prolonged exercise can increase levels.

Some patients may have subnormal CK levels, which may result from reduced muscle mass due to aging, wasting or cachexia. Another explanation is decreased physical activity caused by illness or advanced age. Alcoholics often have low CK levels due to reduced muscle mass. Patients with viral hepatitis may have low levels from reduced physical activity. Some patients with connective tissue disease have low CK activity, but the mechanism is unknown. Patients with thyrotoxicosis and Cushing’s disease frequently have low plasma CK activity, presumably due to altered membrane permeability and diminished enzyme efflux. A similar mechanism may be responsible for the subnormal enzyme activity in patients receiving steroids, estrogens, oral contraceptives, and tamoxifen. Captopril, an antihypertensive drug, produces low plasma CK levels by interfering with disulfide bond formation. Patients with septicemia often have low CK levels due to glutathione depletion, which is necessary for preservation of enzyme activity in the plasma. 

The reference range is very broad and skewed toward the top end.  A  study from the Netherlands convincingly demonstrated that the reference range should be stratified by gender and race. Black men have much higher CK levels than non-black men or black women, who have higher levels than white or Asian women. Differences in muscle mass were believed to account for these gender and racial differences. This stratification should help to prevent the misdiagnosis of myopathy in black individuals.

In the United States, the reference range varies by age and gender. For each age interval, values are higher for males than females. For example, the reference range for adults between the ages of 18 and 50 years is 49-439 U/L for males and 32-182 U/L for females. 

 It is important to remember that CK levels may be even higher in the physically fit, due to their greater muscle mass and that CK levels gradually decline with age or chronic illness due to a reduction in muscle mass. The reference range for males older than 80 years is 30-208 U/L for males and 26-161 for females. 

References

Brewster LM, Mairuhu G, Sturk A, van Montfrans GA. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J. 2007;154(4):655-61.

Kim EJ, Wierzbicki AS, Investigating raised creatine kinase, BMJ 2021;373:n1486

Brancaccio P, Maffulli N, Limongelli FM. Creatine kinase monitoring in sport medicine. British Medical Bulletin. 2007;81-82(1):209–230.

Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: rhabdomyolysis—an overview for clinicians. Critical Care. 2005;9(2):158–169.

Baird MF, Graham SM, Baker JS, Bickerstaff GF. Creatine-kinase- and exercise-related muscle damage implications for muscle performance and recovery. J Nutr Metab. 2012;2012:960363.