Creatine Kinase

Normal findings

Total creatine phosophokinase (CPK) ^[1] :

Adult/elderly:

• Male: 55-170 units/L or 55-170 units/L (SI units)
• Female: 30-135 units/L or 30-135 units/L (SI units)

(Values are higher following exercise.)

Newborn: 68-580 units/L (SI units) ^[1]

Isoenzymes ^[1] :

• Creatine kinase-MM (CK-MM): 100%
• CK-MB: 0%
• CK-BB: 0%

However, serum CK levels can vary among healthy subjects, even when correcting for muscle mass. Age, gender, race, and, as stated, physical activity can affect CK. CK is higher among black males, as well as newborns. ^[2] Moreover, CK reference ranges are varied with different assays and reference temperatures.

CK is found in the mitochondria and cytoplasm of skeletal muscle (predominantly), cardiac muscle, brain, and other visceral tissues. Its main function is in the generation and facilitation of transportation of high-energy phosphates. CK is a dimeric molecule, composed of M and B subunits. The 2 subunits can form 3 isozymes: CK-MM, CK-MB, and CK-BB. Skeletal muscle, myocardium, and neuronal tissue are the main sources of CK-MM, CK-MB, and CK-BB, respectively. ^[3]

Increased CK is predominantly used to diagnose neuromuscular diseases and acute myocardial infarction. Neuromuscular disorders include myopathies, muscular dystrophy, rhabdomyolysis, drug-induced myopathies, neuroleptic malignant syndrome, malignant hyperthermia, and periodic paralyses.

CK can also be elevated in the absence of neuromuscular diseases or cardiac injury, such as after strenuous exercise, intramuscular injection, and with renal disease.

Because the major source of CK-MB is myocardium, an elevated CK-MB level reflects myocardial injury, including acute myocardial infarction, myocarditis, cardiac trauma, cardiac surgery, and endomyocardial biopsy. However, CK-MB makes up 5-7% of CK in skeletal muscle. Therefore, skeletal muscle injury can sometimes cause elevated CK-MB levels, leading to misinterpretation. ^[3] In addition, recent study shows that CK-MB is related to elevated blood pressure, as elevated adenosine triphosphate in endothelium can cause vasoconstriction and antagonize nitric mediated vasodilatation. ^[4]

The clinical application of CK-BB is still limited. The elevated CK-BB in cerebrospinal fluid is a useful predictor of hypoxic brain injury after cardiac arrest. ^[5] Reduced CK-BB can be seen with Huntington disease, multiple sclerosis, and amyotrophic lateral sclerosis. ^{[6, 7, 8]}

Serum CK can be drawn at any time of the day, and the subject need not fast. Collecting the blood sample an hour before or after an intramuscular injection is important in order to avoid misinterpretation.

Both serum gel separator and red top tubes, which contains clot activator, are preferred for CK and CK-MB analysis. CK is found to be stable in both 4^o C and 24^o C for 72-hours storage. ^[9] Importantly, the plasma reference levels of CK-MB are different from serum reference levels. If the heparinized plasma (green-top tube) is used, the plasma level should be referenced to each manufacturer laboratory assay. ^{[10, 11]}

Description

CK, formerly known as creatinine phosphokinase, is an important protein enzyme catalyzing the reversible phosphorylation reaction.

ADP + creatine phosphate → ATP + creatine

CK is a dimeric molecule composed of M and/or B subunits. Two protein subunits form into 3 different isozymes: CK-MM, CK-MB, and CK-BB. CK-MM and CK-BB are abundantly found in skeletal muscle and the brain, respectively. CK-MB is found predominantly in the myocardium (making up 15-30% of the CK in the heart muscle), while a much smaller proportion is found in the skeletal muscle (making up only 5-7% of the CK in the skeletal muscle). ^[3] As CK is found in the inner mitochondrial membrane and cytoplasm, it can be released into the blood through cell membrane disruption and death.

CK-MB is sensitive and specific to myocardial injury. CK-MB begins to rise 4-6 hours after the onset of acute myocardial injury and returns to baseline level after 36-48 hours. ^{[12, 13]} Thus, CK-MB is also a useful marker of reinfarction or infarct extension. However, a small percentage of B-subunit can be found in skeletal muscle. Thus, muscle breakdown can also increase the both total CK and CK-MB level.

The normal value for CK-MB is 3-5% of total CK, but peak CK-MB level can range from 15-30% of total CK in post-myocardial infarction. Therefore, percentage criteria were proposed to distinguish between skeletal muscle and myocardial damage. However, these criteria were found to have decreased sensitivity for acute myocardial infarction in trauma patients and decreased specificity in patients with chronic skeletal muscle abnormalities. Therefore, the measurement of troponin is recommended in these patients. ^[14]

CK is degraded by proteolysis either locally or in lymph nodes. ^[15] Hypothyroidism can retard this CK degradation. ^[14]

Indications/Applications

Because the greatest amount of CK is found in skeletal muscle, CK is a useful marker of skeletal muscle breakdown. Therefore, CK is most commonly used for diagnosis and monitoring among patients with neuromuscular disorders including the following:

• Inflammatory myopathies such as polymyositis, dermatomyositis

• Infectious myopathies

• Dystrophinopathies such as Duchenne and Becker muscular dystrophy

• Rhabdomyolysis

• Drugs-induced myopathies resulting from statins, fibrates, colchicines, antimalarials, and cocaine

• Neuroleptic malignant syndrome

• Malignant hyperthermia

• Endocrine myopathies such as hypothyroidism

• Periodic paralyses

CK-MB is found mostly in myocardium. Therefore, CK-MB is a useful marker for acute myocardial injury. CK-MB can be elevated in the following:

• Acute myocardial infarction

• Myocarditis

• Cardiac trauma or contusion

• Cardiac surgery

• Endomyocardial biopsy

• Defibrillation or cardioversion

As stated in the 2004 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, serial measurement of CK-MB can be useful in indicating the success of reperfusion after fibrinolysis in conjunction with clinical variables. ^{[16, 17, 18, 19]} Because CK-MB has a short half-life and returns to baseline level within 48 hours after acute myocardial infarction, CK-MB can be used as a marker for reinfarction in conjunction with clinical chest pain and EKG changes after 18 hours from the onset of a myocardial infarction. ^{[19, 20]}

Moreover, studies have demonstrated a relationship between CK-MB level and clinical outcome among patients with acute coronary syndromes. Specifically, increased CK-MB is related to higher mortality after both non-ST and ST elevation myocardial infarction. ^{[21, 22, 23]}

Furthermore, serial sampling CK-MB can be used to estimate the infarct size by formulating time activity curves and using mathematic model of the amount depleted from the myocardium. However, this is not routinely done because multiple blood samples are required to avoid the likelihood of missing the peak enzyme concentration. Moreover, CK-MB can underestimate infarct size in a large doughnut infarct pattern because reduced blood flow limits CK-MB efflux. ^{[24, 25, 26]}

Considerations

CK is a useful test for diagnosing and monitoring of neuromuscular diseases. Because CK can rise in any condition causing muscle injury, considering this possibility is important to prevent misdiagnosis in the following circumstances: ^[2]

• Recent strenuous exercise

• Repeated intramuscular injection or needle electromyography (EMG)

• Recent trauma with muscle injury

• Epileptic seizure or severe dystonia

• High fever accompanied by shivering

• Systemic disorders such as viral infection, connective tissue disorder, celiac disease, renal failure, or critically ill patients

CK-MB is found almost exclusively in myocardium. It is widely used as a marker for acute myocardial infarction. However, 5-7% of CK-MB is found in skeletal muscle. Thus, skeletal muscle injury can also cause elevated CK-MB, which can lead to misinterpretation. Note that other noncoronary conditions that can cause elevated CK-MB level include asthma, renal failure, pulmonary embolism, muscle disease, and hypothyroidism. ^[27]

Despite less sensitivity and specificity for acute myocardial infarction compared to troponin, CK-MB is still a useful cardiac marker. CK-MB rises and returns to baseline more rapidly, which make it a preferred marker for reinfarction. Moreover, CK-MB can be used to indicate successful reperfusion after fibrinolysis, to estimate the infarct size, and to predict infarct-related mortality. In addition, elevated CK-MB level post percutaneous coronary intervention is associated with increased mortality at 3-4 months. ^[28]