Creatine Phosphokinase


Creatine phosphokinase (CPK), also known by the name creatine kinase (CK), is the enzyme that catalyzes the reaction of creatine and adenosine triphosphate (ATP) to phosphocreatine (PCr) and adenosine diphosphate (ADP).[1] This CPK enzyme reaction is reversible; thus, ATP can be generated from PCr and ADP. The phosphocreatine created from this reaction is used to supply tissues and cells that require substantial amounts of ATP, like the brain, skeletal muscles, and the heart, with their required ATP.[2] Creatine phosphokinase (CPK) is a central controller of cellular energy homeostasis. Many conditions can cause derangement in CPK levels, including rhabdomyolysis, heart disease, kidney disease, or even certain medications.[3]



Creatine phosphokinase (CPK) is a compact enzyme of around 82 kDa that is found in both the cytosol and mitochondria of tissues where energy demands are high.[4] In the cytosol, CPK is composed of two polypeptide subunits of around 42 kDa, and two types of subunits are found: M (muscle type) and B (brain type).[5] The genes for these subunits are located on different chromosomes: B on 14q32 and M on 19q13. These subunits allow the formation of three tissue-specific isoenzymes: CPK-MB (cardiac muscle), CPK-MM (skeletal muscle), and CPK-BB (brain). Typically, the ratio of subunits varies with muscle type: skeletal muscle: 98% MM and 2% MB; cardiac muscle: 70 to 80% MM and 20 to 30% MB, while the brain predominantly has BB.[6] In mitochondria, there are two specific forms of mitochondrial CK (Mt-CK): a non-sarcomeric type called ubiquitous Mt-CK expressed in various tissues such as the brain, smooth muscle, and sperm, and a sarcomeric Mt-CK expressed in cardiac and skeletal muscle. The functional entity of the mitochondrial CK isoforms is an octamer consisting of four dimers each.[7] While mitochondrial creatine kinase is directly involved in forming phosphocreatine from mitochondrial ATP, cytosolic CK regenerates ATP from ADP using PCr. This happens at intracellular sites where ATP is used in the cell, with CK acting as an in situ ATP regenerator.[8]

Mitochondrial (Mt-CK) and cytosolic CK are connected in a so-called PCr/Cr-shuttle or circuit.[9] Phosphocreatine (PCr) generated by Mt-CK in mitochondria is shuttled to cytosolic CK that is coupled to ATP-dependent processes, e.g., ATPases, such as actomyosin ATPase and calcium ATPase involved in muscle contraction, and sodium/potassium ATPase involved in sodium retention in the kidney.[10] The bound cytosolic CK accepts the PCr shuttled through the cell and uses ADP to regenerate ATP, which can then be used as an energy source by the ATPases (CK is associated intimately with the ATPases, forming a functionally coupled microcompartment).[8] Phosphocreatine (PCr) is not only an energy buffer but also a cellular transport form of energy between subcellular sites of energy (ATP) production (mitochondria and glycolysis) and those of energy utilization (ATPases).[11]

Normally, creatine phosphokinase occurs in heart tissue, skeletal muscles, the brain, etc. However, upon muscular injury, there is leakage of CPK into the bloodstream. Thus, CPK is indicative of muscular damage. CPK-MB is a more specific indicator of myocardial muscle damage, while CPK-MM is more indicative of skeletal muscle damage.[12] The CPK activity in the serum of healthy people is due almost exclusively to MM activity (though small amounts of CPK-MB may be present) and is the result of the physiological turnover of muscle tissue.[13]

When electrophoresed, CPK-MM runs closest to the cathode, CPK-MB has intermediate mobility, and CPK-BB moves farthest from the point of application toward the anode. Mt-CK, which runs more cathodal than the MM fraction, is usually associated with tissue necrosis that accompanies severe anoxic shock and severe liver disease.[14] CK activity may also be found in a macromolecular form—the so-called macro-CK. Macro-CK is found, often transiently, in sera of up to 6% of hospitalized patients, but only a small proportion of these have increased CK activities in serum.[15] It exists in two forms, types 1 and 2. Macro-CK type 1 is a complex of CK, typically CK-BB, and an immunoglobulin, often IgG.[16] It often occurs in women older than 50. Macro-CK type 2 is oligomeric Mt-CK found predominantly in adults who are severely ill with malignancies or in children who have notable tissue distress.[17]

Both M and B subunits have a C-terminal lysine residue, but only the former is hydrolyzed by the action of carboxypeptidases present in the blood. Carboxypeptidases B or N sequentially hydrolyze the lysine residues from CKMM to produce two CK-MM isoforms—CK-MM2 (one lysine residue removed) and CK-MM1 (both lysine residues removed).[18] The loss of the positively charged lysine produces a more negatively charged CK molecule with greater anodic mobility at electrophoresis. Because CK-MB has only one M subunit, the dimer coded by the M and B genes is named CK-MB2, and the lysine-hydrolyzed dimer is named CK-MB1. The assay of the CK isoforms requires special techniques, such as high-voltage electrophoresis (with gel cooling), HPLC, chromatofocusing, or immunoassay.[19]

Specimen Requirements and Procedure

Specimens for CK analysis include serum and plasma heparin. Anticoagulants, other than heparin, should not be used in collection tubes because they inhibit CK activity. The collection of specimens in gel separator tubes does not appear to affect CK activity compared to tubes not containing gel.[20] CK activity in serum is relatively unstable and rapidly lost during storage. Average stabilities are less than 8 hours at room temperature, 48 hours at 4 C, and one month at −20 C.[21] Therefore, the serum specimen should be stored at −80 C if the analysis is delayed for more than 30 days. 

Fresh serum, free from hemolysis, is the specimen of choice for analysis of the CK isoenzyme pattern.[22] Of the three commonly seen isoenzymes, CK-BB activity is the least stable. Adding a thiol such as 2-mercaptoethanol to the serum improves its stability.CK-MB activity is not significantly reduced when the separated serum is stored for up to 48 hours at 4 C or one month at −20 C. Since the mass measurement is not subject to the loss of enzymatic activity, CK-MB protein concentration in serum is stable for weeks when the specimen is stored under refrigeration and for several years if stored at −20 C.[23]

Testing Procedures

Numerous photometric, fluorometric, and coupled-enzyme methods have been developed for the assay of CK activity, using either the forward (Cr --> CRP) or the reverse (Cr <-- CRP) reaction.[24] Currently, all commercial assays for total CK are based on the reverse reaction that proceeds about six times faster than the forward reaction. The ATP produced is measured by hexokinase (HK)/glucose-6-phosphate dehydrogenase (G6PD) coupled reactions that ultimately convert NADP+ to NADPH, which is monitored spectrophotometrically at 340 nm.[4] The rate of increase in absorbance is a measure of CK activity present in the specimen.

The techniques most commonly used for the analysis of CK isoenzyme are electrophoresis and various immunological methods.[25] Electrophoretic methods are useful for the separation of all of the CK isoenzymes. The isoenzyme bands are visualized by incubating the support (e.g., agarose or cellulose acetate) with a concentrated CK assay mixture using the reverse reaction. The NADPH formed in this reaction is then detected by observing the bluish-white fluorescence after excitation by long-wave (360 nm) ultraviolet light. NADPH may be quantified by fluorescence densitometry, which is capable of detecting bands of 2 to 5 U/L. The mobility of CK isoenzymes at pH 8.6 toward the anode is BB > MB > MM, with the MM remaining cathodic to the point of application.[26] The discriminating power of electrophoresis also allows the detection of abnormal CK bands (e.g., macro-CK). The disadvantages of electrophoresis include that the turnaround time is relatively long, the procedure is highly labor intensive and not adaptable to clinical chemistry analyzers in emergency situations, and interpretative skills are required.[27]

Immunochemical methods apply to the direct measurement of CK-MB. In the immunoinhibition technique, an anti-CK-M subunit antiserum is used to inhibit both M subunits of CK-MM and the single M subunit of CK-MB, thus allowing the determination of the enzyme activity of the B subunit of CK-MB, the B subunits of CK-BB, and macro-CKs. To determine CK-MB, this technique assumes the absence of CK-BB (and of the other sources of interference such as macro-CKs) from the tested serum.[28] Because the CK-B subunit accounts for half of the CK-MB activity, the change in absorbance should be doubled to obtain CK-MB activity. This results in a significant decrease in the analytical sensitivity of the method. If present, atypical macro-CK may result in falsely elevated CK-MB results. Owing to its low sensitivity and specificity, the immunoinhibition technique has been largely supplanted by mass assays of CKMB.[29]

In contrast with immunoinhibition, which measures the CK-MB isoenzyme by determination of its catalytic activity, mass immunoassays measure CK-MB protein concentrations.[30] A number of mass assays using various labels are now commercially available and are used for routine determination of CK-MB. Measurements use the “sandwich” technique, in which one antibody specifically recognizes only the MB dimer. The sandwich technique ensures that only CK-MB is estimated because neither CK-MM nor CK-BB reacts with both antibodies. Mass assays are more sensitive than activity-based methods, with a limit of detection for CK-MB usually <1 μg/L.[31] Other advantages include sample stability, noninterference with hemolysis, drugs, or other catalytic activity inhibitors, full automation, and fast turnaround time.[32]

Interfering Factors

A moderate degree of hemolysis (up to 0.32 g/dL of hemoglobin) does not significantly influence the measured CK activity because erythrocytes contain no CK activity.[33] However, severely hemolyzed specimens are unsatisfactory because enzymes and intermediates (AK, ATP, and glucose-6-phosphate) liberated from the erythrocytes may affect the lag phase and the side reactions occurring in the assay system. Turbid and icteric samples can be analyzed; appropriate values are obtained if the starting absorbance is not too high.[34]

Results, Reporting, Critical Findings

Serum CK activity is subject to a number of physiological variations. Sex, age, muscle mass, physical activity, and race all interact to affect measured serum activity. Males generally have a larger muscle mass, which results in higher serum CK activities than those in females. The racial type also has an effect on CK activities, and the mean activity in White individuals is 66% of the mean activity in Black individuals.[34] In White subjects, the reference interval is found to be 46 to 171 U/L for males and 34 to 145 U/L for females when measured with an assay traceable to the IFCC 37 C reference procedure.

Newborns generally have higher CK activities resulting from skeletal muscle trauma during birth. Serum CK in infants decreases to the adult reference interval by 6 to 10 weeks.CK-BB may be elevated in neonates, particularly in newborns with brain-damaged or very low birth weight.[35] The presence of CK-BB in blood, usually at low concentrations, may, however, represent a physiological finding in the first days of life. The suggested upper reference limits when standardized methods for CK determination are employed are males up to 170 U/L and females up to 145 U/L. 

With the CK-MB mass assay, the upper reference limit for males is 5.0 μg/L, with values for females being less than for males. However, many laboratories use a single reference interval (male).[36] Sustained exercise, such as in well-trained, long-distance runners, increases the CK-MB content of skeletal muscle, which may produce abnormal serum CK-MB concentrations to better separate non-myocardial infarction from myocardial infarction patients; a “relative index” (RI) is necessary.[37] The RI relates CK-MB mass concentration in μg/L to measured total CK activity in U/L.[38] Results are expressed as a percentage: Physiological: ≤3%,equivocal: 3 to 5%,consistent with myocardial necrosis: >5%.[39] To appropriately use the RI, blood sampling between 8 and 36 hours from symptom onset is necessary.

Clinical Significance

Creatine kinase activity is one of the oldest markers of acute myocardial infarction (AMI).[40] Creatine kinase activity begins to rise within 12 hours of AMI symptoms, peaks at 24 to 36 hours, and normalizes after 48 to 72 hours. The issue with measuring creatine kinase activity for AMI is that it is not specific to the heart. CK activity can increase in several conditions, such as rhabdomyolysis, chronic muscle diseases, burns, and even after strenuous exercise.[41] Thus, the CK-MB isoenzyme started being used to aid in the diagnosis of AMI.[42] Although the CK-MB measurement is an improvement over just CK, it can still increase in other conditions such as acute muscle injury, congestive cardiac failure, and arrhythmias.[43]

Elevated levels of CK-MB have long been used to diagnose a case of AMI. Although many centers are now going by troponin levels instead of CK-MB, there is a newer, more specific CK-MB method.[44] The new testing method involves measuring the values of the CK-MB1 and CK-MB2 isoforms. In a normal patient, the ratio of CK-MB2 to CK-MB1 should be at 1 to 1. In the case of AMI, the ratio will be at its peak within 4 hours of the infarction. However, some evidence of AMI can be detected as early as 1-2 hours after the infarction.[45] To diagnose AMI, the ratio of CK-MB2 to CK-MB1 should be greater than 1.7 to 1. However, even a ratio of more than or equal to 1.5 to 1 points strongly to a diagnosis of AMI. Other cardiac conditions have been reported to increase serum CK and CK-MB in the serum (e.g., coronary artery bypass surgery, cardiac transplantation, myocarditis, and pulmonary embolism).[46]

Serum CK activity is greatly elevated in all types of muscular dystrophy.[47] In progressive muscular dystrophy (particularly Duchenne sex-linked muscular dystrophy), enzyme activity in serum is highest in infancy and childhood (7 to 10 years of age) and may be increased long before the disease is clinically apparent. Serum CK activity characteristically falls as patients get older and as the mass of functioning muscles diminishes with the progression of the disease. About 50% to 80% of the asymptomatic female carriers of Duchenne dystrophy show threefold to sixfold increases in CK activity.[48][49] High CK values are noted in viral myositis, polymyositis, and similar muscle diseases. However, in neurogenic muscle diseases, such as myasthenia gravis, multiple sclerosis, poliomyelitis, and parkinsonism, serum enzyme activity is not increased.[50] Patients with Alzheimer disease and Pick disease may have decreased CPK activity in the brain. The BB-CK activity primarily decreased in these patients, resulting in an overall decrease in total CPK activity.[51]

CPK levels also elevate in patients with rhabdomyolysis[52]. Rhabdomyolysis may result from a crush injury, drug use, viral infections, and strenuous exercise. It typically presents with muscle pain and weakness alongside dark-colored urine. There is a breakdown of skeletal muscle, which leads to a release of CPK along with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and electrolytes.[53] The reason for the dark urine is due to myoglobinuria. A CPK level that increases to more than 1000 IU/L is indicative of rhabdomyolysis; values over 5000 IU/L indicate severe rhabdomyolysis. Patients with sickle cell trait who suddenly start a new strenuous exercise program such as spin class are also at an increased risk of rhabdomyolysis, with reported levels of creatine kinase higher than 70000 IU/L in some cases.[54] The most common complication resulting from rhabdomyolysis is acute kidney injury.[55] Therefore, any patient with suspected rhabdomyolysis should receive prompt treatment with intravenous fluids to preserve kidney function.[56]

Patients on statins such as simvastatin may have an adverse effect of significantly elevated CPK levels, potentially leading to rhabdomyolysis.[57] This adverse effect becomes amplified if the patient also receives a concurrent drug that inhibits cytochrome P450-3A4 (CYP3A4).[58] Some common medications to avoid in patients on statin therapy include clarithromycin, erythromycin, verapamil, tamoxifen, and many antifungal agents.[57] Low levels of CPK can be present in patients with connective tissue diseases such as rheumatoid arthritis or systemic lupus erythematosus. There may also be low levels in patients with reduced physical activity, such as elderly bedridden patients.[59] A low level of serum CK is associated with an increased risk of death in a CKD population.[60] A creatine kinase before the start of peritoneal dialysis between 111 and 179 IU/L is associated with a lower risk of death than a higher or lower creatine kinase level.[61]

Serum CK activity demonstrates an inverse relationship with thyroid activity. About 60% of hypothyroid subjects show an average elevation of CK activity fivefold more than the upper reference limit. [62]The major isoenzyme present is CK-MM, suggesting muscular involvement. Even in subclinical hypothyroidism, there is some degree of dysfunction in skeletal muscle metabolism.[63][64] Strenuous, prolonged exercise will result in large increases in serum CK activities.[65] In untrained persons, serum CK appears to increase proportionately to the duration and intensity of the exercise; however, conditioned persons often show smaller changes in serum CK activity. Sustained exercise, such as in well-trained, long-distance runners, increases the CK-MB content of skeletal muscle, owing to the phenomenon of “fetal reversion,” in which fetal patterns of protein synthesis reappear.[66][67] Thus serum CK-MB isoenzyme may increase in such circumstances. This explanation may also account for the elevated CK-MB values sometimes observed in chronic renal failure (uremic myopathy).[68]

Plasma creatine kinase activity is significantly associated with blood pressure in the general population and is thought to contribute to hypertension by increasing vascular contractility and renal sodium retention.[69][70] Similar to the association in the general population, plasma creatine kinase activity measured in early pregnancy is associated with blood pressure during pregnancy.[71] It is also associated with severe gestational hypertension diagnosed before 34 weeks of gestation but not with preeclampsia and HELLP, which is considered suggestive of a difference in pathophysiology between these entities.[72]

Quality control and Lab Safety

For non-waived tests, laboratory regulations require, at the minimum, analysis of at least two levels of control materials once every 24 hours. Laboratories can assay QC samples more frequently if deemed necessary to ensure accurate results. Quality control samples should be assayed after calibration or maintenance of an analyzer to verify the correct method performance.[73] To minimize QC when performing tests for which manufacturers’ recommendations are less than those required by the regulatory agency (such as once per month), the labs can develop an individualized quality control plan (IQCP) that involves performing a risk assessment of potential sources of error in all phases of testing and putting in place a QC plan to reduce the likelihood of errors.[74] Westgard multi rules are used to evaluate the quality control runs, and in case of any violation of a rule, proper corrective and preventive action should be taken before patient testing is performed.[74]

Enhancing Healthcare Team Outcomes

Creatine phosphokinase is an important enzyme in diagnosing rhabdomyolysis than AMI in the current medical setting. It is essential in patients with sickle cell anemia or sickle cell trait. It requires careful management with an interprofessional team consisting of a pediatrician and a geneticist. The geneticist should assess the type of sickle cell disease during newborn screening.[75] The pediatrician should advise the child's parents that there are increased chances of rhabdomyolysis from strenuous exercise in children with sickle cell anemia and sickle cell trait.

In a patient who already presents with rhabdomyolysis after an increased creatine phosphokinase level, an interprofessional team consisting of a nephrologist, surgeon, and nurse may manage the condition. The nephrologist would be working to increase kidney function in such patients, as acute kidney injury is the most common complication of rhabdomyolysis. The surgeon may need to surgically repair any damaged muscle or tissue that leads to the condition. The nurse should teach the patient about managing their condition and how to avoid having an attack of rhabdomyolysis again. The healthcare team can also consult with the pharmacist to verify that any patient's medications are not potential sources for elevated CPK.[76] Any hospital staff working in the emergency department should know that intravenous fluid therapy should be started promptly to curb acute kidney injury in patients with suspected rhabdomyolysis.[77]

(Click Image to Enlarge)
Creatine kinase levels after an MI
Creatine kinase levels after an MI
Image courtesy O.Chaigasame
Article Details

Article Author

Ravinder S. Aujla

Article Editor:

Roshan Patel


10/24/2022 9:25:46 AM

PubMed Link:

Creatine Phosphokinase



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