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Macro-creatine kinase: a neglected cause of elevated creatine kinase F. Aljuani, A. Tournadre, S. Cecchetti, M. Soubrier and J. J. Dubost Department of Rheumatology, G. Montpied Hospital, Clermont-Ferrand University, Clermont-Ferrand, France

Key words macro-CK, creatine kinase, inflammatory myositis, neoplasm. Correspondence Jean-Jacques Dubost, Department of Rheumatology, G. Montpied Hospital, Clermont-Ferrand University, Service de Rhumatologie, 58, rue Montalembert, 63003 Clermont-Ferrand cedex 1, France. Email: [email protected]

Abstract Macro-creatine kinase (macro-CK) is a neglected cause of raised CK. Over a 10-year period, we observed five cases. Three patients had macro-CK type 1. One patient with fibromyalgia underwent several explorations to find a muscular pathology; another, who had elevated CK-MB (muscle–brain fraction) activity, was referred to a cardiologist, and statin therapy was erroneously discontinued in two patients. Two patients had macro-CK type 2: a man with a neuroendocrine carcinoma and a woman with rheumatoid arthritis. Diagnosis of type 1 obviates the need to carry out pointless and expensive investigations seeking a neuromuscular or cardiac pathology, and also, the unwarranted discontinuation of statin therapy. Type 2 must prompt investigations for a neoplasm.

Received 19 September 2014; accepted 5 February 2015. doi:10.1111/imj.12710

As part of the investigation of a painful condition, an increase in the activity of creatine kinase (CK) directs efforts towards a muscular pathology, notably an inflammatory myopathy. However, increased CK has several possible causes and the presence of a macro-CK is a cause often neglected by clinicians.1 Macro-CK are macroenzymes, defined as enzymemacromolecule complexes of high molecular weight and prolonged half-life, giving rise to an artefactual increase in their serum activity.2 Two types of macro-CK are distinguished. Macro-CK type 1 enzymes are complexes formed by one of the CK isoenzymes and an immunoglobulin. They are found in a diverse range of pathologies and also in healthy subjects, and their pathological significance has not been clearly demonstrated. Macro-CK type 2 enzymes are made up of mitochondrial-derived CK polymers. They may be associated with neoplasms. Over a 10-year period, we observed five cases of macro-CK associated with problematic diagnoses. A 71-year-old woman was referred to us in 2012 for diffuse pain in her limbs and spine that had been evolving over several years with a recent finding of elevated CK. Discontinuation of rosuvastatin, which she had been taking for several years for dyslipidaemia, did not

Funding: None. Conflict of interest: None.

improve her condition. An increase in CK levels to between 446 and 566 IU/l (n < 145) was observed on three occasions over a 9-month period. The examination did not find any evidence in support of a muscular or neurological pathology, and notably, there was no motor deficit. The electromyography did not show myopathic changes, whereas magnetic resonance imaging (MRI) of the shoulder and pelvic girdles did not show abnormal muscle signals. Laboratory tests did not find an elevated C-reactive protein level or sedimentation rate; levels of alanine aminotransferase, aspartate aminotransferase, aldolase and thyroid-stimulating hormone (TSH) were normal and antinuclear antibodies were 1:160 without anti-DNA or myositis-associated antibodies. CK electrophoresis revealed macro-CK type 1 (Fig. 1). A diagnosis of fibromyalgia was established, and 18 months later, the symptoms had remained stable. A 54-year-old woman was referred to us in 2010 for management of rheumatic disease. For 1 year, she had been experiencing brief flare-ups affecting the joints of her hands and feet, and this was suggestive of palindromic rheumatism. Anti-cyclic citrullinated peptide antibody testing was positive, and X-rays showed erosion of metatarsal heads. A diagnosis of rheumatoid arthritis was made and the patient was treated with methotrexate. In view of the persistence of the joint attacks, concomitant treatment with hydroxychloroquine was initiated with successful results. A routine assessment showed a persistent

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Figure 2 Electrophoresis of serum creatine kinase (CK) of case 2. Figure 1 Electrophoresis of serum creatine kinase (CK) of case 1.

elevation of CK to values between 341 and 458 IU/l. The examination did not find signs suggestive of a muscular pathology. Liver function tests and TSH were normal, antinuclear antibodies were positive at 1:80 with no antiDNA nor myositis-associated antibodies. CK electrophoresis revealed the presence of macro-CK type 2 (Fig. 2). Investigations for a neoplasm, including mammography, gynaecological assessment, chest/abdomen/pelvis computed tomography (CT) scan and gastrointestinal endoscopy were negative. At 4-year follow-up, CK was stable, and no other pathology had developed. A 51-year-old man was hospitalised in 2006 for recurrent episodes of fever with myalgia. He had elevated C-reactive protein level (69 mg/l) and mild elevation of CK at 167 IU/l. Electrophoresis revealed macro-CK type 2 accounting for 43% of CK. The clinical examination was unremarkable. The CT scan demonstrated the presence of a lung nodule, several bone defects in the vertebral column and pelvis, and also pleural nodules in contact with costal arches. On MRI, some of the locations appeared necrotic. Biopsy of a pleural nodule revealed a neuroendocrine carcinoma. A 63-year-old woman was referred to us in 2004 for elevated CK discovered during evaluation of her fatigue. The CK remained continually elevated, at values between 176 and 369 IU/l, over a period of 9 months. In view of the increase in CK-MB levels, her doctor referred

her to a cardiologist who ruled out cardiomypathy. The clinical examination and TSH levels were normal, and there were no antinuclear antibodies. CK electrophoresis revealed macro-CK type 1 accounting for 10% of the CK. A 70-year-old man was referred to us in 2009 for low-back pain in association with increased CK, which had been discovered 6 months earlier and verified on five occasions, with levels varying between 270 and 296 IU/l. The levels were not influenced by discontinuation of pravastatin. The clinical examination did not demonstrate any neurological or muscular signs. TSH was normal, and there were no antinuclear antibodies. CK electrophoresis revealed macro-CK type 1 accounting for 80% of the CK. The conclusion was low-back pain secondary to lumbar facet joint osteoarthritis. The unexplained increase in CK demonstrated in these five patients was linked to macro-CK (3 macro-CK type 1 and 2 macro-CK type 2). CK electrophoresis is the preferred technique for the detection of macro-CK.3 It permits separation of isoenzymes MM (skeletal muscle), MB (myocardium) and BB (brain). Macro-CK type 1 enzymes, complexes formed from an isoenzyme (most often BB) and immunoglobulin (most often IgG), usually migrate between isoenzymes MB and MM.4 Macro-CK type 2 enzymes, formed from mitochondrial CK polymers, migrate more cathodically and appear earlier than CK-MM. Estimated prevalences are between 0.5% and 2.5% of hospitalised © 2015 Royal Australasian College of Physicians

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patients for CK type 1 and up to 3.7 % for CK type 2 in this same patient group.4–6 Macro-CK type 1 does not have a clearly demonstrated pathological significance. It can occur in healthy subjects and also in association with varied pathologies, notably myositis, hypothyroidism or cardiovascular pathologies, conditions for which measurement of CK activity is frequently ordered.4 Recently, it has been described in association with ulcerative colitis, but not with Crohn disease.7 Macro-CK type 2 is associated with diverse neoplasms, often metastatic and are believed to be released during cell lysis or produced by the tumour.4,6 In observation 3, the patient had a neuroendocrine carcinoma with multiple metastases, some of which appeared necrotic on MRI. This macro-CK type is also associated with liver diseases notably cirrhosis.6 More recently, it has also been described in patients infected with human immunodeficiency virus and treated with antiretroviral agents.8 It also occurs in children.6 The increase in CK activity is usually moderate and lower than 500 IU/l, as in our patients. However, the CK

References 1 Silvestri NJ, Wolfe GI. Asymptomatic/pauci-symptomatic creatine kinase elevations (hyperckemia). Muscle Nerve 2013; 4: 805–15. 2 Sturk A, Sanders GT. Macroenzymes: prevalence, composition, detection and clinical relevance. J Clin Chem Clin Biochem 1990; 28: 65–81. 3 Wyness SP, Hunsaker JJ, La’ulu SL, Rao LV, Roberts WL. Detection of macro-creatine kinase and macroamylase by polyethylene glycol precipitation and ultrafiltration methods. Clin Chim Acta 2011; 412: 2052–7. 4 Lee KN, Csako G, Bernhardt P, Elin RJ. Relevance of macro creatine kinase type1 and type 2 isoenzymes to laboratory and clinical data. Clin Chem 1994; 40: 278–83. 5 Fahie-Wilson MN, Burrows S, Lawson GJ, Gordon T, Wong W, Dasgupta B.

level may be normal especially with macro-CK type 2.4,6,9 Given that macro-CK enzymes are not inhibited by anti-M antibodies, CK-MB activity is often falsely elevated when determined by immunoinhibition and may be higher than total CK activity, a finding suggestive of macro-CK.4 Elevated CK-MB activity leads to suspicions of ischaemic cardiopathy, as in patient 4 and in other observations in the literature.9–11 Ambiguity can be rapidly eliminated by the quantitative determination of CK-MB or troponin. Awareness of macro-CK enzymes is low. They should be suspected and sought in all cases of persistent and unexplained CK elevation. The discovery of macro-CK type 1 prevents the performance of pointless and expensive investigations seeking a neuromuscular or even a cardiac pathology and also the unwarranted discontinuation of statins as in patients 1 and 5.12 Presence of macro-CK type 2 should prompt investigations for a neoplasm.

Prevalence of increased serum creatine kinase activity due to macro-creatine kinase and experience of screening programmes in district general hospitals. Ann Clin Biochem 2007; 44: 377–83. 6 Stein W, Bohner J, Renn W, Maulbetsch R. Macro creatine kinase type 2: Results of a prospective study in hospitalized patients. Clin Chem 1985; 31: 1959–64. 7 Hoffmann KM, Grillitsch M, Deutschmann A, Högenauer C, Stojakovic T, Hauer AC. Serum macromolecular creatine kinase type 1 as a diagnostic clue in inflammatory bowel disease? Eur J Pediatr 2013; 172: 699–701. 8 Schmid H, Tokarska-Schlattner M, Füeßl B, Röder M, Kay L, Attia S et al. Macro CK2 accumulation in tenofovir-treated HIV patients is facilitated by CK oligomer stabilization but is not predictive for pathology. Antivir Ther 2013; 18: 193–204.

9 Galarraga B, Sinclair D, Fahie-Wilson MN, McCrae FC, Hull RG, Ledingham JM. A rare but important cause for a raised serum creatine kinase concentration: two case reports and a literature review. Rheumatology (Oxford) 2003; 42: 186–8. 10 Schulenburg D, De Lange W, Van Jaarsveld H, Kuyl JM. Persistently elevated CKMB and negative troponin T in a patient at ischaemic risk with chest pain. Cardiovasc J Afr 2010; 21: 47–8. 11 Liu C-Y, Lai Y, Wu Y, Tzeng C-H, Lee S. Macroenzyme creatine kinase in the era of modern laboratory medicine. J Chin Med Assoc 2010; 73: 35–9. 12 Loh TP, Ang YH, Neo SF, Yin C, Wong MS, Leong SM et al. Immunoglobulin-associated creatine kinase masquerading as macro-creatine kinase type 2 in a statin user. Intern Med 2012; 51: 1061–4.

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Macro-creatine kinase: a neglected cause of elevated creatine kinase.

Macro-creatine kinase (macro-CK) is a neglected cause of raised CK. Over a 10-year period, we observed five cases. Three patients had macro-CK type 1...
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