Clinical Case: A Patient with Weakness, Skin Rashes, Increased Transaminase Activity and Bilirubin Levels

Aim: to increase physicians’ awareness of differential diagnosis of autoimmune hepatitis and diffuse connective tissue disease using a clinical case as an example.
Key points. The article describes a clinical observation of a 34-year-old patient with dermatomyositis occurring against the background of atopic dermatitis and Gilbert’s syndrome, imitating autoimmune liver disease and complicated by the development of drug-induced liver injury. The complexity of diagnosis was determined by the development of skin lesions against the background of changes already present as a result of the atopic dermatitis, laboratory data (increased transaminase activity, bilirubin levels, and detection of antinuclear and anti-smooth muscle autoantibodies indicating a suspected liver disease), and the disappearance of a number of typical signs of the disease as a result of previously prescribed immunosuppressive therapy. The diagnosis was established through a thorough retrospective analysis of the clinical manifestations and anamnesis of the disease (a change in the nature of skin rashes and the predominance of increased activity of aspartate transaminase were noteworthy); the key moment for making the diagnosis was the detection of increased activity of creatine kinase and myositis-specific antibodies Jo-1. Morphological examination of liver tissue did not find signs of autoimmune hepatitis and liver fibrosis, but revealed centrilobular intracellular cholestasis and lymphohistiocytic infiltration, proliferative changes in the biliary epithelium, probably caused by drug-induced liver injury due to azathioprine intake. The issues of diagnostics and differential diagnosis of autoimmune hepatitis are considered, the strict necessity of morphological examination of the liver for diagnosis is discussed. Secondary liver injury in diffuse connective tissue disease and azathioprineinduced liver injury are analyzed.
Conclusion. Differential diagnosis of elevated serum transaminases should include not only liver disease, but also muscle tissue injury. When diagnosing autoimmune hepatitis, histological examination plays a key role, and verification of the diagnosis is impossible without morphological data.

1. Atopic dermatitis: Clinical guidelines. 2024. (In Russ.). URL: https://www.medznat.ru/uploads/file/post/ru/9359/17297545049359.pdf

2. Severity scoring of atopic dermatitis: The SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23–31. DOI: 10.1159/000247298

3. Kim H.J., Zeidi M., Bonciani D., Pena S.M., Tiao J., Sahu S., et al. Itch in dermatomyositis: The role of increased skin interleukin-31. Br J Dermatol. 2018;179(3):669–78. DOI: 10.1111/bjd.16498

4. Xu A., Fu Q. Heliotrope rash. BMJ. 2023;382:e075978. DOI: 10.1136/bmj-2023-075978

5. Trisvetova E.L. Diagnosis of interstitial lung diseases in systemic connective tissue diseases. Meditsinskie novosti. 2021;7(322):22–8. (In Russ.).

6. Isenberg D.A., Allen E., Farewell V., Ehrenstein M.R., Hanna M.G., Lundberg I.E., et al.; International Myositis and Clinical Studies Group (IMACS). International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology (Oxford). 2004;43(1):49–54. DOI: 10.1093/rheumatology/keg427

7. Lundberg I.E., Tjärnlund A., Bottai M., Werth V.P., Pilkington C., de Visser M., et al.; International Myositis Classification Criteria Project Consortium, the Euromyositis Register, and the Juvenile Dermatomyositis Cohort Biomarker Study and Repository (UK and Ireland). 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Arthritis Rheumatol. 2017;69(12):2271–82. DOI: 10.1002/art.40320

8. Bohan A., Peter J.B. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292(8):403–7. DOI: 10.1056/NEJM197502202920807

9. Lohse A.W., Sebode M., Bhathal P.S., Clouston A.D., Dienes H.P., Jain D., et al. Consensus recommendations for histological criteria of autoimmune hepatitis from the International AIH Pathology Group: Results of a workshop on AIH histology hosted by the European Reference Network on Hepatological Diseases and the European Society of Pathology: Results of a workshop on AIH histology hosted by the European Reference Network on Hepatological Diseases and the European Society of Pathology. Liver Int. 2022;42(5):1058–69. DOI: 10.1111/liv.15217

10. Manns M.P., Czaja A.J., Gorham J.D., Krawitt E.L., Mieli-Vergani G., Vergani D., et al.; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51(6):2193–213. DOI: 10.1002/hep.23584

11. Woodward J., Neuberger J. Autoimmune overlap syndromes. Hepatology. 2001;33(4):994–1002. DOI: 10.1053/jhep.2001.23316

12. Hounoki H., Shinoda K., Ogawa R., Taki H., Tsuneyama K., Tobe K. Simultaneously developed polymyositis and autoimmune hepatitis. BMJ Case Rep. 2011;2011:bcr0920114763 DOI: 10.1136/bcr.09.2011.4763

13. Hirschfield G.M., Gill P., Neuberger J. The liver in systemic disease: A clinician's guide to abnormal liver tests. Hoboken, NJ: John Wiley & Sons, Inc.; 2023. DOI: 10.1002/9781119802181

14. De Santis M., Crotti C., Selmi C. Liver abnormalities in connective tissue diseases. Best Pract Res Clin Gastroenterol. 2013;27(4):543–51. DOI: 10.1016/j.bpg.2013.06.016

15. Vergani D., Alvarez F., Bianchi F.B., Cançado E.L., Mackay I.R., Manns M.P., et al.; International Autoimmune Hepatitis Group. Liver autoimmune serology: A consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol. 2004;41(4):677–83. DOI: 10.1016/j.jhep.2004.08.002

16. Tkachenko O.Yu., Lapin S.V., Mazing A.V., Totolian Areg A. Russian-language version of the International Nomenclature of International Consensus on Antinuclear Antibody (ANA) Patterns (ICAP). Medical Immunology (Russia). 2020;6:1195–214. (In Russ.). DOI: 10.15789/1563-0625-RVO-2067

17. Damoiseaux J., von Mühlen C.A., Garcia-De La Torre I., Carballo O.G., de Melo Cruvinel W., Francescantonio P.L., et al. International consensus on ANA patterns (ICAP): The bumpy road towards a consensus on reporting ANA results. Auto Immun Highlights. 2016;7(1):1. DOI: 10.1007/s13317-016-0075-0

18. Galaski J., Weiler-Normann C., Schakat M., Zachou K., Muratori P., Lampalzer S., et al. Update of the simplified criteria for autoimmune hepatitis: Evaluation of the methodology for immunoserological testing. J Hepatol. 2021;74(2):312–20. DOI: 10.1016/j.jhep.2020.07.032

19. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015;63(4):971–1004. DOI: 10.1016/j.jhep.2015.06.030

20. Vinnitskaya E.V., Sandler Yu.G., Abdurakhmanov D.T., Bakulin I.G., Belousova E.A., Buyeverov A.O., et al. Main provisions of the Russian consensus on diagnosis and treatment of autoimmune hepatitis. Farmateka. 2017;5(17):47–55. (In Russ.).

21. Vinnitskaya E.V., Sandler Yu.G., Bakulin I.G., Parfenov A.I., Ilchenko L.Yu, Nikitin I.G., et al. Important problems in the diagnosis and treatment of autoimmune hepatitis (based on the Russian consensus 2017). Terapevticheskii arkhiv. 2018;90(2):12–8. (In Russ.). DOI: 10.26442/terarkh201890212-18

22. Mack C.L., Adams D., Assis D.N., Kerkar N., Manns M.P., Mayo M.J., et al. Diagnosis and management of autoimmune hepatitis in adults and children: 2019 Practice guidance and guidelines from the American Association for the Study of Liver Diseases. Hepatology. 2020;72(2):671–722. DOI: 10.1002/hep.31065

23. Hennes E.M., Zeniya M., Czaja A.J., Pares A., Dalekos G.N., Krawitt E.L., et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48(1):169–76. DOI: 10.1002/hep.22322

24. Takahashi A., Takeda I., Kanno T., Nakahara T., Odajima H., Kasukawa R. CD8-positive T cell-induced liver damage was found in a patient with polymyositis. Intern Med. 2006;45(18):1059–63. DOI: 10.2169/internalmedicine.45.1710

25. Takahashi A., Abe K., Yokokawa J., Iwadate H., Kobayashi H., Watanabe H., et al. Clinical features of liver dysfunction in collagen diseases. Hepatol Res. 2010;40(11):1092–7. DOI: 10.1111/j.1872-034X.2010.00707.x

26. Wada T., Abe G., Kudou T., Ogawa E., Nagai T., Tanaka S., et al. Liver damage in patients with polymyositis and dermatomyositis. Kitasato Med J. 2016;46:40–6.

27. Noda S., Asano Y., Tamaki Z., Takekoshi T., Sugaya M., Sato S. A case of dermatomyositis with “liver disease associated with rheumatoid diseases” positive for anti-liver-kidney microsome-1 antibody. Clin Rheumatol. 2010;29(8):941–3. DOI: 10.1007/s10067-010-1397-3

28. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Azathioprine. Last Update: August 21, 2017. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. URL https://www.ncbi.nlm.nih.gov/books/NBK548332/

29. Björnsson E.S., Gu J., Kleiner D.E., Chalasani N., Hayashi P.H., Hoofnagle J.H.; DILIN Investigators. Azathioprine and 6-mercaptopurine-induced liver injury: Clinical features and outcomes. J Clin Gastroenterol. 2017;51(1):63–9. DOI: 10.1097/MCG.0000000000000568

30. Kleiner D.E., Chalasani N.P., Lee W.M., Fontana R.J., Bonkovsky H.L., Watkins P.B., et al.; Drug-Induced Liver Injury Network (DILIN). Hepatic histological findings in suspected drug-induced liver injury: Systematic evaluation and clinical associations. Hepatology. 2014;59(2):661–70. DOI: 10.1002/hep.26709

31. Rinella M.E., Lazarus J.V., Ratziu V., Francque S.M., Sanyal A.J.; Kanwal F., et al.; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966–86. DOI: 10.1097/HEP.0000000000000520

32. Liebe R., Esposito I., Bock H.H., Vom Dahl S., Stindt J., Baumann U., et al. Diagnosis and management of secondary causes of steatohepatitis. J Hepatol. 2021;74(6):1455–71. DOI: 10.1016/j.jhep.2021.01.045

33. Hayashi P.H., Lucena M.I., Fontana R.J. RECAM: A new and improved, computerized causality assessment tool for DILI diagnosis. Am J Gastroenterol. 2022;117(9): 1387–9. DOI: 10.14309/ajg.0000000000001836

34. Danan G., Benichou C. Causality assessment of adverse reactions to drugs — I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323–30. DOI: 10.1016/0895-4356(93)90101-6