Positive troponin T without cardiac involvement in inclusion body myositis

Human Pathology (2005) 36, 917 – 921

www.elsevier.com/locate/humpath

Positive troponin T without cardiac involvement in inclusion body myositis Josef D. Schwarzmeier MDa,b,*,1, Ahmad Hamwi MDc,1, Martin Preisel MDa, Christoph Resl MDa, Matthias Preusser MDd, Elfriede Sluga MDd,f, Ernst Horcher MDe, Medhat M. Shehata MDa,b,1 a

Hematology Department, Internal Medicine I, Medical University of Vienna, A-1097 Vienna, Austria Boltzmann Institute for Cytokine Research, Medical University of Vienna, A-1097 Vienna, Austria c Institute of Laboratory Diagnosis, Medical University of Vienna, A-1097 Vienna, Austria d Institute of Neurology, Medical University of Vienna, A-1097 Vienna, Austria e Department of Surgery, Medical University of Vienna, A-1097 Vienna, Austria f Rudolfinerhaus-Hospital, A-1190 Vienna, Austria b

Keywords: cTnT; cTnI; Myopathies; Myocardial infarction; Differential diagnosis

Summary Cardiac troponin T (cTnT) is considered as a specific marker for acute myocardial infarction. Here, we present a case with elevated cTnT, determined by a third-generation assay, without signs of a myocardial lesion. Routine investigation of a 66-year-old female patient with indolent B-cell lymphoma revealed increased serum levels of creatine kinase (CK), MB fraction of CK (CK-MB), and cTnT, although she did not complain of cardiac symptoms. Electrocardiographic monitoring, echocardiography, magnetic resonance computed angiography, and percutaneous coronary angiography excluded myocardial damage. However, the close follow-up showed a steady increase of CK-MB and cTnT levels and gradual development of weakness in both thighs. A biopsy of the right quadriceps muscle led to the diagnosis of inclusion body myositis. In contrast to cTnT, cardiac troponin I could not be detected retrospectively in any of her serum samples. These results demonstrate for the first time that cTnT is elevated in patients with inclusion body myositis. D 2005 Published by Elsevier Inc.

1. Introduction

T Corresponding author. Clinic of Internal Medicine I, L. Boltzmann Institute for Cytokine Research, Medical University of Vienna, A-1090 Vienna, Austria. E-mail addresses: [email protected] (J.D. Schwarzmeier)8 [email protected] (M.M. Shehata). 1 M. Shehata, J. D. Schwarzmeier, and A. Hamwi contributed equally to this work. 0046-8177/$ – see front matter D 2005 Published by Elsevier Inc. doi:10.1016/j.humpath.2005.06.009

In the absence of clinical symptoms or relevant electrocardiographic (ECG) changes, the diagnosis of acute myocardial infarction (AMI) relies on biochemical markers such as glutamic oxalacetic transaminase, lactate dehydrogenase, creatine kinase (CK), CK-MB, cardiac-specific lactate dehydrogenase, and cardiac troponins T (cTnT) and I (cTnI) [1]. The subunits of these troponins, T and I, are considered to have the best diagnostic value because of their specificity and sensitivity in the detection of myocardial

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Fig. 1 Alterations of cTnT, cTnI, and CK-MB levels during a period of 2.5 years in relation to the influence of therapy with high doses of prednisone (P I-III) and immunoglobulins (Ig). Arrows represent the start of therapies. cTnT was analyzed using the third-generation troponin T STAT assay run on an Elecsys 2010 system (Roche Diagnostics, Basel, Switzerland); cTnI was determined by an AxSYM analyzer (Abbott Laboratories, Abbott Park, Ill). Asterisk represents splenectomy.

damage. According to the redefinition of myocardial infarction, as proposed by a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee in April 2000 [2], any amount of myocardial necrosis caused by ischemia should be labeled as an infarct. At present, cardiac troponins are considered as the cornerstone of the new definition of myocardial infarction because they can detect bminimal myocardial damageQ (also termed binfarctletQ or bnecrosetteQ) when other cardiac markers are still within the normal range. Moreover, cardiac troponins gained great importance in risk stratification and prospective management of coronary artery disease. Elevations of cTnT have also been reported in chronic muscle diseases such as dermatomyositis (DM) or polymyositis (PM) and Duchenne muscle dystrophy (DMD) without clinical evidence for myocardial damage [3,4]. However, elevated cTnT in inclusion body myositis (IBM) has not been reported before. Here, we describe a patient with IBM and indolent B-cell lymphoma who presented with elevated cTnT levels. Although the measurement was performed with a third-generation cTnT assay, highly specific for AMI, no myocardial damage could be detected in this patient.

2. Case report and pathological findings In July 2001, routine laboratory investigations in a 66-year-old female patient, who had been diagnosed 10 years earlier with an indolent B-cell lymphoma and had recently received 6 cycles of chemotherapy (COP

protocol: cyclophosphamide, Oncovin, prednisone), revealed an elevation of CK to 350 U/L (normal, b70 U/L), CK-MB to 38 U/L (normal, b10 U/L), and a positive test for cTnT (considering the cutoff value for acute coronary artery disease of 0.1 lg/L). The ECG, however, was normal and the patient did not complain of symptoms suggestive of coronary insufficiency or myocardial infarction. Echocardiography, magnetic resonance computed angiography, and percutaneous coronary angiography were performed, but the results did not support a diagnosis of myocardial damage. A close follow-up within the first few weeks (Fig. 1) showed a steady increase of CK-MB and cTnT levels, accompanied by the gradual development of weakness in both thighs. Although the nerve conduction velocity was normal, an electromyogram showed pathological results. Because of the underlying disease of an indolent B-cell lymphoma, a test for antimyelin antibodies against myelinassociated glycoprotein was performed and it was negative. Therefore, a muscle biopsy of the right quadriceps muscle was carried out. The histological investigation resulted in the diagnosis of IBM (Fig. 2). The picture revealed features of a moderate inflammatory myopathy, and there were focal endomysial aggregates of mononuclear inflammatory cells (Fig. 2A) as well as invasion of intact muscle fibers by CD8 immunoreactive lymphocytes. In addition, characteristic rimmed vacuoles were evident in the sarcoplasms of numerous muscle fibers (Fig. 2B). Electron microscopy identified these vacuoles as autophagic vacuoles filled with a variety of membranous and laminated bodies and amorphous material (Fig. 2C). Near the vacuoles, filamentous inclusions with diameters of up to 20 nm were found (Fig. 2D).

Positive troponin T without cardiac involvement

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Fig. 2 The muscle biopsy of the right musculus quadriceps revealed an inflammatory myopathy with pathognomonic features of IBM. A, Focal endomysial infiltrates by mononuclear inflammatory cells (hematoxylin-eosin, original magnification 200). B, Rimmed vacuoles in the sarcoplasm of a muscle fiber (Gomori trichrome, original magnification 600). C, Myelin-like whorls and amorphous material in an autophagic vacuole (electron microscopy, original magnification 7000). D, Aggregates of bpaired helical filamentsQ (*) with diameters of up to 20 nm in the surroundings of autophagic vacuoles (electron microscopy, original magnification 20 000).

Treatment with oral prednisone (100 mg/d for 5 days) resulted in significant improvement of muscular symptoms and reduction of CK, CK-MB, and cTnT values (Fig. 1). Although IBM is usually refractory to corticosteroids, the observed response in our patient is in agreement with the published reports that some cases of IBM, particularly those with autoimmune component, benefit from prednisone therapy [5,6]. This might be because of the effect of prednisone on the inflammatory cells in the endomysial infiltrates (Fig. 2A), which results in a decrease in muscle damage. However, the remission duration was short, and after 3 cycles with prednisone (each of 5 days’ duration), this therapy was discontinued. The aggravation of muscular weakness and the occurrence of dysphagia then led to initiation of treatment with high doses of immunoglobulins [7]. After 2 cycles with immunoglobulins (each 140 g of Octagam; Octapharma, Vienna, Austria), a dramatic improvement of clinical symptoms as well as a marked decrease in CK and troponin levels was observed. Because of a steady increase in spleen size, there was a decrease in platelet counts, and because a causal relationship between IBM and B-cell lymphoma could not be ruled out, a splenectomy was performed. Although this intervention led to a reduction of tumor mass and normalization of platelet levels, cTnT and CK serum concentrations remained

high. This argued against a causal relation between B-cell lymphoma and elevated cTnT levels. To affirm the absence of subclinical myocardial damage, cTnI was retrospectively evaluated. In contrast to cTnT, however, cTnI could not be detected in any of the serum samples collected since the original detection of increased cardiac markers. A new series of 3 cycles of high-dose immunoglobulin therapy led to normalization of CK-MB levels and resolution of muscular symptoms. Cardiac troponin T was reduced considerably, but remained higher than normal values. Since the last high-dose immunoglobulin therapy, the patient remains, with regard to the myositis and the B-cell lymphoma, in stable condition.

3. Discussion Elevated levels of CK-MB are indicators of potential myocardial damage, even in patients without ECG abnormalities or typical clinical symptoms. For further diagnosis, additional tools, including invasive techniques, are frequently used. These procedures, however, are time-consuming, expensive, and potentially hazardous. They could be avoided if highly specific blood tests were available to definitely rule out cardiac involvement. At present, cardiac

920 troponins are generally accepted as the criterion standard in the diagnosis of coronary artery disease. Cardiac troponin consists of 3 subunits: cTnT, cTnI, and cTnC. These proteins regulate the calcium-mediated interaction of actin and myosin [8]. Because cTnC is also found in skeletal muscle, it is not suitable for AMI diagnosis. Troponins T and I exist in 3 different isoforms: one for slowtwitch skeletal muscle, one for fast-twitch skeletal muscle, and one for cardiac muscle. Because these isoforms are encoded by different genes, cTnT and cTnI have the potential for high cardiac specificity [9]. A consensus document of the European Society of Cardiology and the American College of Cardiology defined any amount of myocardial necrosis caused by ischemia, as detected by the highly sensitive cTnT or cTnI, as an infarct [2]. In our patient, significant elevations of CK, CK-MB, and cTnT strongly suggested the diagnosis of myocardial infarction. In the absence of typical clinical symptoms, however, and in the light of the negative ECG, echocardiography, myocardial scintigraphy, and coronary arteriography results, the diagnosis of AMI appeared to be highly unlikely. Because cTnT can also be released during unstable angina resulting from minimal myocardial damage, as well as in cases of myocardial damage of nonischemic nature, including pericarditis, myocarditis, uremic cardiomyopathy, or toxic reaction to chemotherapeutic drugs [10-15], the patient was thoroughly examined with regard to these conditions. There was, however, no evidence for any of these diseases. Because cTnI levels tested during disease progression and retrospectively in frozen samples collected at the beginning of the illness were negative at all time points, a previous or recent myocardial damage was ruled out. As regenerating skeletal muscle reexpresses fetal genes, cTnT isoforms might theoretically be reexpressed in chronic degenerating and regenerating skeletal muscle, leading to detectable cTnT in blood without concomitant myocardial damage [16,17]. In fact, cTnT could be detected not only in skeletal muscles of patients with DM or DMD, but even in healthy muscular tissue [18]. In contrast to cTnT, cTnI is not expressed in fetal and healthy or diseased adult human skeletal muscle [19]. With the more specific secondgeneration cTnT assays for AMI, no cross-reactivity with troponin T purified from skeletal muscle could be detected and no false-positive cTnT was measured in sera of healthy marathon runners or patients with severe skeletal muscle damage [20]. On the other hand, elevated cTnT values were measured in patients with DMD, although no reexpression of cTnT could be demonstrated in the diseased skeletal muscle [4]. Therefore, a subclinical cardiac involvement with release of cTnT into the blood has been discussed in patients with DM or PM [21,22]. In our patient, an elevated cTnT was not due to a subclinical involvement since cTnI was negative. A possible cross-reactivity of cTnT with skeletal muscle isoforms, which has sometimes been observed with older assay systems, was also improbable because a very specific third-generation cTnT assay [20,23] was used.

J.D. Schwarzmeier et al. The histological examination of a muscle biopsy confirmed the diagnosis of IBM (Fig. 2). This disease represents a subset of inflammatory myopathies with insidious progression, primarily affecting older individuals [24]. Our patient showed the typical symptoms of IBM including focal and distal weakness as well as dysphagia, which occurs in more than 20% of the patients as a late but severe symptom. To our knowledge, this is the first case showing significant cTnT elevations in a patient with IBM without cardiac involvement. Taking into consideration that CK-MB and cTnT are used in daily clinical practice to diagnose myocardial necrosis, false interpretation could occur with inflammatory muscle diseases or muscular dystrophy, as has been demonstrated in DM [25], PM [3], DMD [4], and now in IBM. Therefore, the specificity of cTnT in relation to myocardial damage needs to be interpreted with caution, particularly in patients without typical clinical symptoms of AMI.

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