Rheumatology Department and
1 Department of Clinical Chemistry, Queen Alexandra Hospital, Cosham, Portsmouth PO6 3LY and
2 Biochemistry Department, Southend Hospital, Westcliff-on-Sea, Essex SSO ORY, UK
SIR, in this report we present two cases that caused diagnostic confusion. Although a rare diagnosis was ultimately confirmed in each case, several costly investigations could potentially have been avoided had this diagnosis been considered earlier.
Patient 1 was a 59-yr-old man who was admitted with central chest pain. His ECGs and laboratory tests were normal apart from a raised creatine kinase (CK) of 600 IU/l. As CK levels remained elevated over several months, cardiology consultation and investigations were undertaken and ischaemic heart disease was excluded. Additional features, including night sweats and muscle cramps, were noted after referral to the rheumatology department. Physical examination revealed no evidence of myopathy or connective tissue disease. Investigations were normal apart from a lymphocytosis of 7.4x109/l, CK of 852 IU/l and an erythrocyte sedimentation rate of 78 mm/h. Serum protein electrophoresis demonstrated an immunoglobulin (Ig) M kappa paraprotein. A low-grade non-Hodgkin's lymphoma (NHL) was diagnosed on bone marrow examination after referral to the haematologists. A neurologist with an interest in muscle diseases also assessed this patient. Electromyographic studies and CK electrophoresis were requested. The former were normal but the latter showed the presence of a macro CK. The macro CK was then subcategorized to the type 2 form. The final diagnosis was a NHL causing an IgM paraprotein and macro CK type 2.
Patient 2 was a 79-yr-old lady who was admitted with chest pain. Her ECG showed paroxysmal atrial tachycardia that settled spontaneously. Blood tests were normal over the next few days, apart from a persistently raised CK of 2000 IU/l. Further investigations to elicit the cause of the raised CK were unremarkable. A year later a referral was made to rheumatology following an admission with a vasovagal attack and left shoulder pain. CK was again raised, at 1400 IU/l, despite no history of fall or muscle injury. There was no evidence of myopathy or connective tissue disease. Macro CK was considered as a possible diagnosis and was confirmed by gel filtration chromatography. The macro CK was subcategorized to the type 1 form.
Macroenzymes are enzymes with higher molecular mass than the corresponding enzyme normally found in serum [13]. Several macroenzymes have been reported, the most common being macro CK (two types), macro amylase, macro lactate dehydrogenase and macro aspartate transaminase. All except macro CK type 2 consist of a normal enzyme complexed with an immunoglobulin, most commonly IgG or IgA. The complexed enzyme has reduced blood clearance, resulting in increased circulating amounts of the higher-than-normal molecular weight form of the relevant enzyme. When quantitative total CK assays are used, macro CK is indistinguishable from normal CK, causing an elevation of the total CK. Macroenzymes should be suspected when the enzyme levels are persistently raised with relatively constant levels and there is no obvious clinical explanation or other laboratory abnormality.
Creatine kinase is a muscle enzyme responsible for the regeneration of ATP and has three recognized isoenzymes of cytoplasmic origin: CKMM (skeletal muscle), CKMB (myocardium) and CKBB (brain); each of these enzymes has a molecular weight of 80 kDa. Macro CK has a molecular weight of over 200 kDa, which results in different electrophoretic and chromatographic mobility [1, 4, 5].
Two types of macro CK have been described. Macro CK type 1 is an isoenzymeIg complex created via an antigenantibody reaction. The most common form of type 1 macro CK is a CKBBIgG complex. Less is known about the composition of macro CK type 2. It is believed to be of mitochondrial rather than cytoplasmic origin.
Diagnosis can most readily be made by CK electrophoresis [3, 4], immunoinhibition [2, 6] and chromatographic [3, 7] techniques. When CK electrophoresis is used, the diagnosis is confirmed through the different electrophoretic mobility of the macro CK compared with the other CK isoenzymes (Fig. 1, left). Gel filtration chromatography and protein G affinity chromatography were used to establish the diagnosis in the two cases reported (Fig. 1
, right). Having confirmed macro CK activity, protein G affinity chromatography is used to subclassify the macro CK into type 1 or 2.
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Macro CK type 2 has a reported prevalence rate of 0.53.7% [1, 6], the higher rates being reported from in-patient populations. Macro CK type 2 is less readily identified and is therefore likely to be under-reported as the total CK level will be raised in only 1020% of cases [4, 6]. In the remaining 8090% the main potential marker for the presence of macro CK type 2 is an elevation in the CKMB isoenzyme above 50% of the total CK concentration; even in individuals who have had a recent myocardial infarction this isoenzyme rarely makes up more than 30% of the total CK concentration [2].
Unlike type 1, macro CK type 2 has been reported in predominantly ill patients [1, 46], most commonly in association with malignancy (colonic carcinoma [10]) and liver disease [1, 46]. It is associated with high mortality [4, 6] and when present in children can be a marker of myocardial disease [5]. Lee et al. [4] found a three-fold higher incidence of malignancy in patients with macro CK type 2 compared with patients having type 1.
One proposed mechanism for the association of macro CK type 2 with malignancy is the direct release of the enzyme from malignant or necrotic cells. Stein et al. [6] found the mitochondrial macroenzyme in fractions of primary and metastatic prostatic tumours examined at necropsy, and suggested that the neoplasm and its metastases can release macro CK type 2 directly.
Macro CK reportedly causes only a minimal elevation (<500 IU/l) in CK or a high CKMB/CK ratio with no elevation of the total CK. Although Lee et al. [4] reported CK levels up to 12000 IU/l associated with macro CK, several of his patients were found to suffer from co-existent polymyositis. Our patients had CK levels of 10002000 IU/l that were attributable only to macro CK.
Macro CK can occur as an incidental finding in healthy individuals and it is important to recognize it in order to avoid unnecessary specialist consultations and investigations. Had the diagnosis of macro CK been considered earlier in the two cases reported, several tests and consultations could have been avoided. Macro CK should always be considered in patients with a raised CK for which there is no obvious clinical explanation and when the CKMB isoenzyme makes up more than 50% of the total CK. If macro CK type 2 is identified, further investigations for malignancy and liver disease should be considered.
This report focuses on macro CK but other macroenzymes may also cause diagnostic confusion and may result in potentially unnecessary investigations being undertaken.
Notes
Correspondence to: J. M. Ledingham. E-mail: Jo.Ledingham{at}qmail01.porthosp.swest.nhs.uk
References
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