Creatine Kinase (CK), Total Plus Isoenzymes

Overview:

Diagnose myocardial infarction (MI). Three fractions normally may be found, each an isoenzyme:

• MM is found in normal serum.

• MB is the myocardial fraction associated with MI and occurs in certain other states. MB can be used in estimation of infarct size.

MB increases have been reported with entities that cause damage to the myocardium, such as myocarditis, some instances of cardiomyopathy, and with extensive rhabdomyolysis, Duchenne muscular dystrophy, malignant hyperthermia, polymyositis, dermatomyositis, mixed connective tissue disease, myoglobinemia, Rocky Mountain spotted fever, Reye syndrome, and rarely in rheumatoid arthritis with high titer RF.2 CK-MB does not generally abruptly rise and fall in such nonacute MI settings, as it does in acute myocardial infarct (AMI).

• BB is rarely present. BB has been described as a marker for adenocarcinoma of the prostate, breast, ovary, colon, adenocarcinomas of gastrointestinal tract, and for small cell anaplastic carcinoma of lung. BB has been reported with severe shock and/or hypothermia, infarction of bowel,3 brain injury, stroke, as a genetic marker in some families with malignant pyrexia, and with MB in alcoholic myopathy. Exercise, intramuscular injections, myxedema, grand mal seizures, prior trauma or surgery, and acute MI very early or late lead to the combination of increased total CK but usually normal CK-MB. Increased CK-MB has been described in marathon runners without MI.4 CK isoenzyme analysis is not usually practical when the total CK is very low, although in elderly people with low muscle mass, the use of sensitive mass concentration assays may be useful. A single CK isoenzyme examination may be misleading. One should look for a pattern in serial CK isoenzyme analyses and seek confirmation with the isoenzymes of LD (LDH), ideally beginning with onset to establish the baseline. LD isoenzyme 1:2 flip is most consistently found about two days after onset of acute infarction of myocardium. The diagnosis of myocardial injury should not be based solely on MB isoenzyme, but rather should be supported by clinical findings, ECG, and often other laboratory parameters (ie, confirmation by LD isoenzymes).1 CK-MB is found in much higher concentrations in cardiac muscle than in ordinary skeletal muscle.

CK-MB is usually not elevated in exercise (total CK elevated); myxedema (total CK elevated in about half of cases); injections into muscle (total CK elevated); strokes, CVA, and other brain disorders in which total CK may be increased; pericarditis; pneumonias or other lung diseases; pulmonary embolus; seizures (CK may be very high but no great MB increase, if any). Although CK-MB is not usually increased in angina, some CK-MB elevations are recognized in angina patients, depending partly on laboratory methodology.

Atypical forms of CK occur. Macro CK type 1 is usually a complex of CK-BB and IgG (or rarely CK-MM with IgA) and created via an antigen-antibody reaction. It can lead to the false-positive diagnosis of acute myocardial infarction by CK-MB interference in some immunoassay techniques. In quantitative total CK assays, macro CK is indistinguishable from normal CK and can cause an elevation of the total CK, although total CK may also be normal. Macroenzymes should be suspected when enzyme levels are persistently raised with relatively constant levels and there is no obvious clinical explanation or other laboratory abnormality. The clinical relevance of macro CK type 1 is not clearly established. It is not associated with a particular type of disease and has been observed in patients with various diseases, as well as in apparently healthy individuals. Occurring more often in women than men and in patients older than 70 years than in the 20 to 69 year age group, it is likely a marker or consequence of cellular damage in a minority of predisposed individuals, predominantly women and elderly people. There are several reported disease associations, including hypothyroidism, neoplasia, autoimmune disease, myositis, and cardiovascular disease. The last two have the strongest reported associations and may support the diagnosis of an autoimmune process, but this may in part be explained by a higher frequency of requests for CK levels in these groups of patients.5 Myositis, including autoimmune myositis, polymyositis, malignancy-associated dermatomyositis, and drug-induced myositis, has been diagnosed in >50% of the patients with macro CK type 1.6

Macro CK type 2 is an oligomeric mitochondrial CK complex that migrates cathodically, or close to CK-MM. It is found primarily in adults who are severely ill with malignancies or liver disease or in children who have myocardial disease. It occurs transiently in about 1% of hospitalized patients and indicates a poor prognosis, except in children.6

Characteristic Findings in Patients With Macro CK*

	Type 1	Type 2
Total CK	Usually high (>500 U/L) ~ 2/3 of cases	Usually low (<100 U/L) ~3/4 of cases
CK-BB	Rarely detectable: ~1/30 of cases	Present relatively often: ~1/3 of cases
CK-MB	Often present (>4/5 of cases) Increased (>1/2 of cases)	May be present (~1/4 of cases) Increased (~1/10 of cases)
Macro CK	~10% of total	~25% of total
Myositis	Very common	Uncommon
Malignancy	Uncommon	Very common
*Adapted from Lee KN, Csako G, Bernhardt P, Elin RJ. Relevance of macro creatine kinase type 1 and type 2 isoenzymes to laboratory and clinical data. Clin Chem. 1994 Jul; 40(7 Pt 1):1278-1283.

1. Pappas NJ Jr. Enhanced cardiac enzyme profile. Clin Lab Med. 1989 Dec; 9(4):689-716. PubMed 2686909

2. Wolf PL. Common causes of false-positive CK-MB test for acute myocardial infarction. Clin Lab Med. 1986 Sep; 6(3):577-581. PubMed 3742986

3. Fried MW, Murthy UK, Hassig SR, Woo J, Oates RP. Creatine kinase isoenzymes in the diagnosis of intestinal infarction. Dig Dis Sci. 1991 Nov; 36(11):1589-1593. PubMed 1935497

4. Seigel AJ, Silverman LM, Evans WJ. Elevated skeletal muscle creatine kinase MB isoenzyme levels in marathon runners. JAMA. 1983 Nov 25; 250(20):2835-2837. PubMed 6644963

5. Laureys M, Sion JP, Slabbynck H, et al. Macromolecular creatine kinase type 1: A serum marker associated with disease. Clin Chem. 1991 Mar; 37(3):430-434. PubMed 2004451

6. Lee KN, Csako G, Bernhardt P, Elin RJ. Relevance of macro creatine kinase type 1 and type 2 isoenzymes to laboratory and clinical data. Clin Chem. 1994 Jul; 40(7 Pt 1):1278-1283. PubMed 8013099