Liver Damage in Patients with Polymyositis and Dermatomyositis

Original Contribution Kitasato Med J 2016; 46: 40-46

Liver damage in patients with polymyositis and dermatomyositis

Tatsuhiko Wada, Gakurou Abe, Takeo Kudou, Eisuke Ogawa, Tatsuo Nagai, Sumiaki Tanaka, Shunsei Hirohata

Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine

Objective: To clarify the prevalence of liver damage associated with polymyositis (PM) and dermatomyositis (DM) Methods: Forty-two patients with PM/DM were exhaustively studied. Six patients showed liver diseases of known etiology, including drug-induced hepatitis, fatty liver, metastatic liver tumor, primary biliary cirrhosis and autoimmune hepatitis. As a control, 8 patients with miscellaneous diseases who showed elevation of the creatine kinase (CK) due to extreme exercise were studied. Serum levels of aspirate aminotransferase (AST), alanine aminotransferase (ALT) and CK, as well as the ratios of AST/CK, ALT/CK and AST/ALT were evaluated. Results: ALT levels were significantly elevated in PM/DM compared with control group. The ratios of AST/CK and ALT/CK were significantly elevated in PM/DM compared with the control group. AST/ALT ratios in PM/DM were significantly lower than those in control group (P < 0.0001). Twenty- six of 36 patients (72.2%) with PM/DM showed AST/ALT ratios below the minimum value of AST/ ALT ratios in the control patients. Additionally, 10 of 26 patients (38.5%) showed hepatocellular liver damage. There were no significant differences in the levels of AST, ALT or CK, or in the ratios of AST/CK, ALT/CK or AST/ALT between PM and DM. Conclusions: The results indicate that a disproportionate elevation of ALT takes places in patients with PM/DM. These data, therefore, strongly suggest that PM/DM might cause liver damage.

Key words: Liver damage, polymyositis, dermatomyositis

marginally elevated in myopathies.4 By contrast, several Introduction case reports revealed that disproportionate elevations of olymyositis (PM) is an inflammatory muscle disease ALT were observed in patients with PM or DM.5 These P of unknown etiology, characterized by the presence cases suggest the possible presence of liver damage of proximal muscle weakness as a prominent symptom, caused by PM/DM. muscle enzyme elevation including creatine kinase (CK) Noteworthy, liver damage has been known to and lymphocytic infiltration into muscular tissues.1 In sometimes reflect the activity of connective tissue diseases addition to these muscular manifestations, (CTDs) itself other than various causes, including drug- dermatomyositis (DM) frequently presents with specific induced hepatitis, fatty liver, and viral hepatitis.6,7 In a cutaneous symptoms such as Gottron's sign and heliotrope previous histopathological investigation of 160 patients rash.1,2 The prevalence and incidence of PM/DM are with CTDs, including 18 patients with PM/DM, hepatic 10−13 per 100,000 populations and 10−13 per arteritis was observed in 27 patients with the incidence 1,000,000 person-years, respectively, in Japan.3 Therefore, of 100% in polyarteritis nodosa and 8.3%−25% in other PM/DM are rather common. CTDs.8 Furthermore, CD8-positive T cell infiltration Elevation of liver enzyme aspartate aminotransferase was found to infiltrate in the interstitium of both liver (AST) is often seen along with elevation of CK in a and muscle tissues, indicating the pathogenic potential variety of muscle diseases, including PM/DM. Because roles of CD8-poisitive T cell in liver injuries.5 The present alanine aminotransferase (ALT) is contained in skeletal study was designed to explore whether or not liver muscles at much lower quantities than is AST, it is damage, not related with drug-induced liver dysfunction,

Received 8 August 2015, accepted 27 October 2015 Correspondence to: Tatsuhiko Wada, Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan E-mail: [email protected]

40 Liver damage in patients with polymyositis and dermatomyositis fatty liver, viral hepatitis, or malignancy is prevalent in research issued by the Ministry of Education, Culture, patients with PM and DM. Sports, Science and Technology and the Ministry of Health, Labour and Welfare of the Japanese Government.14 Methods Patients Statistical analyses Forty-two patients with PM/DM, who had been admitted Comparison of various parameters between PM/DM and to the Department of Rheumatology and Infectious the control group and between PM and DM was carried Diseases, Kitasato University Hospital, between January out by the Mann-Whitney U-test, and comparison of the 2006 and October 2011, were included in the present AST/ALT ratio of the patients with PM/DM between before study. These patients were diagnosed with PM/DM or and after 4 weeks of treatment with immunosuppressive amyopathic DM based on Bohan and Peter's or agents was carried out by the Wilcoxon matched-pairs Sontheimer's criteria.9,10 Among the 42 patients, 6 patients signed rank test, using GraphPad Prism 6 for Microsoft showed liver diseases of known etiology, including drug- Windows, GraphPad Software, San Diego, CA, USA. induced hepatitis (1 patient), fatty liver (1 patient), metastatic liver tumor (1 patient), primary biliary cirrhosis (PBC) (1 patient) and autoimmune hepatitis (AIH) (2 Results patients). The diagnosis of fatty liver was evaluated by Demographic data of the patients abdominal ultrasonography (US) and computed Clinical characteristics of 36 patients with PM/DM and tomography (CT). Metastatic liver tumor was diagnosed 8 control patients are shown in Table 1. Control patients by US and CT findings and histopathological showed elevation of CK due to extreme exercise, which manifestation. The diagnoses of PBC and AIH were subsided spontaneously without any immunosuppressive based on the criteria provided by Sasaki et al.11 and by therapy. Although there were no significant differences the International Autoimmune Hepatitis Group12, in clinical and demographic features between 10 patients respectively. These 6 patients were excluded from the with PM and 26 patients with DM, a larger number of analyses. None of the other 36 patients were positive for patients with DM received cyclosporin A, intravenous HBs antigen, HBs antibody, HBc antibody, or hepatitis cyclophosphamide pulse therapy and tacrolimus. C antibody. As a control, 8 patients with various diseases who showed elevation of CK due to extreme exercises Liver enzymes and CK in sera from patients with PM/ were studied (2 HIV patients, 1 fibromyalgia patient, 2 DM polymyalgia rheumatica patients, 1 rheumatoid arthritis We initially compared the serum levels of AST, ALT and patient, 1 systemic sclerosis patient, and 1 Beçhet's disease CK in PM/DM with those in the control group. ALT patient ). levels were significantly elevated in PM/DM compared with the control group (P=0.0132), whereas there were Data recording and the definition of liver damage no significant differences in the levels of AST and CK Serum levels of AST, ALT, alkaline phosphatase (ALP) (Figure 1). As shown in Figure 2, the ratios of AST/CK and CK were measured before treatment. The normal and ALT/CK were significantly elevated in PM/DM ranges of AST, ALT, ALP, and CK were 10−35 U/l, 5 compared with those in the control group, indicating that −40 U/l, 115−359 U/l and 60−247 U/l, respectively. the levels of AST and ALT were disproportionately higher In the present study, a liver biopsy was not performed in than expected by the values of CK in PM/DM. patients with PM/DM and control. Therefore, we defined Furthermore, AST/ALT ratios in PM/DM were liver damage as an increase of more than twice that of the significantly lower than those in the control group. The upper normal range of ALT. We compared the AST/ results indicate that ALT was disproportionately elevated ALT ratio between PM/DM and the control group. The in patients with PM/DM. Because ALT is present at patients with PM/DM, who showed AST/ALT ratio below much lower levels than AST in muscle tissues15, the data the minimum value of the AST/ALT ratio in the control strongly suggest that the damage in liver tissue occurs in patients, were defined as patients with liver damage. PM/DM. Twenty-six of 36 patients (72.2%) with PM/ Furthermore, the prevalence of hepatocellular liver DM showed AST/ALT ratios below the minimum value damage for these patients was examined. This study was of AST/ALT ratios in the control patients. Additionally, carried out in compliance with the Declaration of among those 26 patients, 10 patients (38.5%) had liver Helsinki13, and the ethical guideline for epidemiological damage, which was considered hepatocellular, and 1 41 Wada, et al.

Table 1. Clinical characteristics of the patients

Control Polymyositis Dermatomyositis* n = 8 n = 10 n = 26

Age(y) 55.6 ± 21.8 51.8 ± 10.7 52.9 ± 12.8 Female : Male 1 : 7 7 : 3 21 : 5 Interstitial pneumonia 0 7 (70.0%) 19 (73.0%) Hepatic encephalopathy 0 0 0 Hepatic cirrhosis with ascites 0 0 0 Laboratory findings Total bilirubin (mg/dl) 0.6 ± 0.2 0.4 ± 0.1 0.4 ± 0.2 Albumin (g/dLl 4.1 ± 0.5 3.4 ± 0.6 3.4 ± 0.5 Prothrombin time (%) - 87.5 ± 9.2 96.6 ± 12.6 Activated partial thromboplastin time (sec) - 34.7 ± 5.9 38.5 ± 9.9 Therapy Predonisolone, initial dose(mg/day) - 47.7 ± 9.0 52.1 ± 14.3 Methyl-predonisolone pulse(case) - 4 (40.0%) 9 (34.6%) Other immunosuppressant agents Cyclosporin A - 3 (30.0%) 12 (46.2%) Methotrexate - 3 (30.0%) 5 (19.2%) IVCY - 0 6 (23.1%) IVIG - 1 (10.0%) 0 Tacrolimus - 0 3 (11.5%)

*Three of 26 patients with dermatomyositis were diagnosed as clinically amyopathic dermatomyositis. IVCY: intravenous cyclophosphamide, IVIG: intravenous immunoglobulin

Figure 1. Serum levels of AST, ALT, and CK in PM/DM Each symbol represents 1 subject. The shaded area represents the normal range of AST, ALT, and CK. Horizontal lines show the mean, and error bars show the SEM. Statistical analysis was carried out by the Mann-Whitney U-test. The mean ± SD for AST, ALT, and CK were 85 ± 81.2, 40.5 ± 42.3, and 4,396.4 ± 5,387.5 in the 8 control subjects. These in 36 patients with PM/DM were 146.1 ± 173.6, 108.4 ± 105, and 2,425.2 ± 3,155.4, respectively. ALT, alanine aminotransferase: AST, aspartate aminotransferase: CK, creatine kinase

42 Liver damage in patients with polymyositis and dermatomyositis

Figure 2. The ratios of AST/CK, ALT/CK and AST/ALT ratios in PM/DM The mean ± SD for AST/CK, ALT/CK, and AST/ALT were 0.029 ± 0.016, 0.012 ± 0.006, and 2.41 ± 0.99 in the 8 control subjects. These in 36 patients with PM/DM were 0.33 ± 0.64, 0.23 ± 0.4, and 1.37 ± 0.46, respectively. Each symbol represents 1 subject. Horizontal lines show the mean, and error bars show the SEM. Statistical analysis was carried out by the Mann-Whitney U-test.

Figure 3. Comparison of the levels of AST, ALT and CK between PM and DM The mean ± SD for AST, ALT, and CK were 147.7 ± 136.8, 125.4 ±89.1, and 3,608.9 ± 3,450.4 in 10 patients with PM. These in 26 patients with DM were 145.5 ± 188.3, 101.9 ± 111.4, and 1,970 ± 2,979.5, respectively. The shaded area represents the normal range of AST, ALT, and CK. Horizontal lines show the mean; error bars show the SEM. Statistical analysis was carried out by the Mann- Whitney U-test.

Figure 4. Comparison of the AST/CK, ALT/CK and AST/ALT between PM and DM The mean ± SD for AST/CK, ALT/CK, and AST/ALT were 0.075 ± 0.06, 0.06 ± 0.037, and 1.31 ± 0.73 in 10 patients with PM. These in 26 patients with DM were 0.43 ± 0.73, 0.3 ± 0.45, and 1.39 ± 0.32, respectively. Horizontal lines show the mean, and error bars show the SEM. Statistical analysis was carried out by the Mann-Whitney U-test.

43 Wada, et al.

−3, although the elevation of ALT levels was delayed in comparison with AST levels.17 Accordingly, in the present study, AST/ALT ratios in the control group were above 2. By contrast, the average of AST/ALT ratios in PM/DM was 1.38, which was significantly lower than that in control. These findings indicate that serum levels of ALT in PM/DM were elevated disproportionally against serum AST levels. It should be noted that the amount of ALT contained in muscle was much lower than AST,15 and that ALT is mainly present in liver.18,19 Figure 5. Comparison of the AST/ALT ratio in 26 patients with It is, therefore, most likely that the disproportionate PM/DM between before and after 4 weeks of treatment of elevation of ALT along with the decreased AST/ALT immunosuppressive agents ratios might be a result of liver damage in PM/DM The mean± SD for AST/ALT ratio before and after 4 weeks of patients. Because the decrease in AST/ALT ratios returned treatment were 1.56 ± 0.70 and 0.79 ± 0.39, respectively. to normal after treatment with immunosuppressive agents Horizontal lines show the mean, and error bars show the SD. (Figure 5), the liver damage was likely caused by PM/ Statistical analysis was carried out by the Wilcoxon matched- DM. pairs signed rank test. Takahashi et al.7 previously reported that 9 of 27 patients presented with hepatitis associated directly with PM/DM. However, the prevalence of liver damage with patient (12.5%) showed liver damage in the control group. PM/DM was higher in the present cohort of patients. We then examined whether or not there was any This might be due to differences in the assessment of difference in liver damage between PM and DM, because liver damage. Thus, Takahashi et al.7 defined liver some studies suggest differences in their pathogenesis.1,16 damage as an elevation of at least 2 of ALT, alkaline There were no significant differences in the levels of phosphatases (ALP), and γ-glutamyl transpeptidase. It AST, ALT and CK nor in the ratios of AST/CK, ALT/ should be noted that ALT levels in PM/DM in their study7 CK and AST/ALT between PM and DM (Figures 3, 4), were comparable to those in the present study. Moreover, although the ratios of AST/CK and ALT/CK appeared to ALP levels were the lowest among various CTDs in their be higher in DM than those in PM. Altogether, these study.7 Therefore, it is possible that liver damage might data indicate that serum ALT disproportionately elevated be underestimated in their study. liver damage is prevalent in PM as well as in DM. Major histocompatibility complex (MHC) class 1 is Furthermore, comparison of the AST/ALT ratio in 26 known to be overexpressed within the inflammatory patients with PM/DM between before and after 4 weeks myofasia and muscle fibers in patients with myositis.20-22 of treatment with immunosuppressive agents is shown in It is, therefore, suggested that CD8-positive T cells Figure 5. Immunosuppressive therapy significantly invading the muscle tissues might recognize some improved the AST/ALT ratio in patients with PM/DM. antigens presented by MHC class 1, leading to muscle injuries, although the nature of such antigens that trigger immune responses remains unknown. Notably, Discussion Takahashi et al.5 reported a case of PM with liver injury In the present study, we examined the prevalence of liver without secondary hepatitis, in which CD8-positive T damage in PM and DM. It should be noted that PBC and cell infiltration was found simultaneously both in the AIH were complicated in 1 and 2 patients, respectively, liver and in the muscle.5 It is, therefore, possible that among the 42 patients in the study. Therefore, the such CD8-positive T cells might recognize the antigens prevalence of PBC and AIH in this series of patients was that were expressed commonly in the liver as well as in comparable to a previous studies.7 More importantly, the muscle in the patient. Further studies are warranted the data in the present study have disclosed that to identify such antigens. approximately 72.2% of patients with PM/DM have liver On the other hand, a number of reports have revealed damage, as evidenced by the disproportionate elevation that patients with viral hepatitis, including HAV, HBV, of ALT as well as by the decrease in AST/ALT ratios. In and HCV hepatitis developed PM/DM.23-26 It is possible Japanese healthy-young subjects, AST/ALT ratios after that infection of these hepatitis viruses induce some 96 hours post-exercise have been found to rise above 2 unknown antigens or viral antigens in the context of MHC 44 Liver damage in patients with polymyositis and dermatomyositis class 1 in hepatocytes as well as in muscle tissues, against 8. Matsumoto T, Kobayashi S, Shimizu H, et al. The which CD8-positive T cells might respond and cause liver in collagen diseases: pathologic study of 160 tissue damage. cases with particular reference to hepatic arteritis, The major limitation of this study is that we did not primary biliary cirrhosis, autoimmune hepatitis and nodular regenerative hyperplasia of the liver. Liver perform liver biopsies for control and PM/DM patients. 2000; 20: 366-73. A liver biopsy may facilitate the pathological and 9. Bohan A, Peter JB. Polymyositis and dermatomyositis immunological assessment. Other limitations of this study (first of two parts). N Engl J Med 1975; 292: 344-7. are the relatively small size of the control population of 10. Sontheimer RD. Would a new name hasten the patients, especially more women, would support our acceptance of amyopathic dermatomyositis conclusions more convincingly. (dermatomyositis siné myositis) as a distinctive subset In summary, these data demonstrate that liver damage within the idiopathic inflammatory dermatomyopathies was much more prevalent than expected in patients with spectrum of clinical illness? J Am Acad Dermatol PM/DM. Further studies designed to investigate such 2002; 46: 626-36. antigens that are commonly expressed in liver and muscle 11. Sasaki H, Inoue K, Higuchi K, et al. Primary biliary would be important for a more complete understanding cirrhosis in Japan: national survey by the Subcommittee on Autoimmune hepatitis. Gastroenterol Jpn 1985; of the mechanisms of liver damage in PM/DM. 20: 476-85. 12. Alvarez F, Berg PA, Bianchi FB, et al. International Conflict of interest Autoimmune Hepatitis Group. International All authors declare that they have no conflicts of interest. Autoimmune Hepatitis Group Report: review of This study was carried out in compliance with the criteria for diagnosis of autoimmune hepatitis. J Declaration of Helsinki,13 and the ethical guideline for Hepatol 1999; 31: 929-38. epidemiological research issued by the Ministry of 13. World Medical Association. World Medical Education, Culture, Sports, Science and Technology, and Association declaration of Helsinki Ethical principles the Ministry of Health, Labour and Welfare of the for medical research involving human subjects. Japanese Government.14 Informed consent was obtained Available at: http://www.wma.net/en/30publications/ from all patients included in the study. 10policies/b3/. Accessed July 31, 2015. 14. Ethical guidelines for epidemiological research. 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