Clinicopathological characteristics of autoimmune‑like hepatitis after drug‑induced liver injury

Ikeda,Kohei; Fukui,Shunsuke; Kobayashi,Mayu; Shimada,Yasuaki; Nakazawa,Yuichi; Mizutani,Hiroki; Nisiura,Yuki; Suga,Daisuke; Moritani,Isao; Yamanaka,Yutaka; Inoue,Hidekazu; Fukutome,Kazuo; Shiraki,Katsuya

doi:10.3892/br.2025.1953

Clinicopathological characteristics of autoimmune‑like hepatitis after drug‑induced liver injury

Authors:
- Kohei Ikeda
- Shunsuke Fukui
- Mayu Kobayashi
- Yasuaki Shimada
- Yuichi Nakazawa
- Hiroki Mizutani
- Yuki Nisiura
- Daisuke Suga
- Isao Moritani
- Yutaka Yamanaka
- Hidekazu Inoue
- Kazuo Fukutome
- Katsuya Shiraki
View Affiliations

Affiliations: Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510‑8561, Japan, Department of Pathology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510‑8561, Japan
Published online on: February 25, 2025 https://doi.org/10.3892/br.2025.1953
Article Number: 75
Copyright: © Ikeda et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Autoimmune hepatitis (AIH) can be induced by drugs, but the underlying mechanisms remain unclear. The present study attempted to elucidate the clinicopathological characteristics of autoimmune‑like hepatitis following drug‑induced liver injury (DILI‑ALH). The medical records of 57 patients diagnosed with AIH at Mie General Medical Center (Yokkaichi, Japan) were retrospectively reviewed, paying particular attention to the history of drug administration. Patients were classified into three groups: De novo AIH, drug‑induced ALH (DI‑ALH) and DILI‑ALH. DILI‑ALH was newly defined as cases in which the patient had a history of DILI and where the liver injury initially improved after drug discontinuation, but later worsened and was diagnosed as AIH. Of the 57 patients diagnosed with AIH, 42 patients were included in this study. De novo AIH was diagnosed in 29 patients, DI‑ALH in 10 patients and DILI‑ALH in 3 patients. Suspected causative drugs for drug‑related pathologies were variable, including statins, health foods and supplements. No significant differences in sex or mean age were observed for DI‑ALH and DILI‑ALH compared with those for AIH. Distinguishing DI‑ALH or DILI‑ALH from AIH serologically and pathologically is difficult. No significant differences in the number of steroids used or the recurrence rate were observed between any groups. These findings suggest that drugs may present a more diverse cause of ALH than generally predicted. In particular, some AIH cases clearly present with DILI‑ALH. Clarifying the involvement of drugs in the pathogenesis of AIH and establishing guidelines for diagnosis and treatment represent important issues for the future.

View Figures

View References

1	Björnsson E, Talwalkar J, Treeprasertsuk S, Kamath PS, Takahashi N, Sanderson S, Neuhauser M and Lindor K: Drug-induced autoimmune hepatitis: Clinical characteristics and prognosis. Hepatology. 51:2040–2048. 2010.PubMed/NCBI View Article : Google Scholar
2	Liberal R, Longhi MS, Mieli-Vergani G and Vergani D: Pathogenesis of autoimmune hepatitis. Best Pract Res Clin Gastroenterol. 25:653–664. 2011.PubMed/NCBI View Article : Google Scholar
3	Manns MP, Lohse AW and Vergani D: Autoimmune hepatitis-update 2015. J Hepatol. 62 (Suppl 1):S100–S111. 2015.PubMed/NCBI View Article : Google Scholar
4	Sebode M, Schulz L and Lohse AW: ‘Autoimmune(-like)’ drug and herb induced liver injury: New insights into molecular pathogenesis. Int J Mol Sci. 18(1954)2017.PubMed/NCBI View Article : Google Scholar
5	Lammert C, Chalasani SN, Atkinson EJ, McCauley BM and Lazaridis KN: Environmental risk factors are associated with autoimmune hepatitis. Liver Int. 41:2396–2403. 2021.PubMed/NCBI View Article : Google Scholar
6	Chalasani NP, Maddur H, Russo MW, Wong RJ and Reddy KR: Practice Parameters Committee of the American College of Gastroenterology. ACG clinical guideline: Diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 116:878–898. 2021.PubMed/NCBI View Article : Google Scholar
7	European Association for the Study of the Liver. EASL clinical practice guidelines: Autoimmune hepatitis. J Hepatol. 63:971–1004. 2015.PubMed/NCBI View Article : Google Scholar
8	European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL clinical practice guidelines: Drug-induced liver injury. J Hepatol. 70:1222–1261. 2019.PubMed/NCBI View Article : Google Scholar
9	Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH and Czaja AJ: 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. 72:671–722. 2020.PubMed/NCBI View Article : Google Scholar
10	Weiler-Normann C and Schramm C: Drug induced liver injury and its relationship to autoimmune hepatitis. J Hepatol. 55:747–749. 2011.PubMed/NCBI View Article : Google Scholar
11	Castiella A, Zapata E, Lucena MI and Andrade RJ: Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease. World J Hepatol. 6:160–168. 2014.PubMed/NCBI View Article : Google Scholar
12	de Boer YS, Kosinski AS, Urban TJ, Zhao Z, Long N, Chalasani N, Kleiner DE and Hoofnagle JH: Drug-Induced Liver Injury Network. Features of autoimmune hepatitis in patients with drug-induced liver injury. Clin Gastroenterol Hepatol. 15:103–112.e2. 2017.PubMed/NCBI View Article : Google Scholar
13	Lammert C, Zhu C, Lian Y, Raman I, Eckert G, Li QZ and Chalasani N: Exploratory study of autoantibody profiling in drug-induced liver injury with an autoimmune phenotype. Hepatol Commun. 4:1651–1663. 2020.PubMed/NCBI View Article : Google Scholar
14	Tan CK, Ho D, Wang LM and Kumar R: Drug-induced autoimmune hepatitis: A minireview. World J Gastroenterol. 28:2654–2666. 2022.PubMed/NCBI View Article : Google Scholar
15	Björnsson ES, Medina-Caliz I, Andrade RJ and Lucena MI: Setting up criteria for drug-induced autoimmune-like hepatitis through a systematic analysis of published reports. Hepatol Commun. 6:1895–1909. 2022.PubMed/NCBI View Article : Google Scholar
16	Andrade RJ, Aithal GP, de Boer YS, Liberal R, Gerbes A, Regev A, Terziroli Beretta-Piccoli B, Schramm C, Kleiner DE, De Martin E, et al: Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report. J Hepatol. 79:853–866. 2023.PubMed/NCBI View Article : Google Scholar
17	Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, Devarbhavi H, Merz M, Lucena MI, Kaplowitz N and Aithal GP: Drug-induced liver injury. Nat Rev Dis Primers. 5(58)2019.PubMed/NCBI View Article : Google Scholar
18	Lucena MI, Kaplowitz N, Hallal H, Castiella A, García-Bengoechea M, Otazua P, Berenguer M, Fernandez MC, Planas R and Andrade RJ: Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: The dilemma of the relationship to autoimmune hepatitis. J Hepatol. 55:820–827. 2011.PubMed/NCBI View Article : Google Scholar
19	Yeong TT, Lim KH, Goubet S, Parnell N and Verma S: Natural history and outcomes in drug induced autoimmune hepatitis. Hepatol Res. 46:E79–E88. 2016.PubMed/NCBI View Article : Google Scholar
20	Björnsson ES, Stephens C, Atallah E, Robles-Diaz M, Alvarez-Alvarez I, Gerbes A, Weber S, Stirnimann G, Kullak-Ublick G, Cortez-Pinto H, et al: A new framework for advancing in drug-induced liver injury research. The prospective European DILI registry. Liver Int. 43:115–126. 2023.PubMed/NCBI View Article : Google Scholar
21	Ueno M, Takabatake H, Kayahara T, Morimoto Y, Notohara K and Mizuno M: Long-term outcomes of drug-induced autoimmune-like hepatitis after pulse steroid therapy. Hepatol Res. 53:1073–1083. 2023.PubMed/NCBI View Article : Google Scholar
22	Sugimoto K, Ito T, Yamamoto N and Shiraki K: Seven cases of autoimmune hepatitis that developed after drug-induced liver injury. Hepatology. 54:1892–1893. 2011.PubMed/NCBI View Article : Google Scholar
23	Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ, et al: International autoimmune hepatitis group report: Review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 31:929–938. 1999.PubMed/NCBI View Article : Google Scholar
24	Benichou C, Danan G and Flahault A: Causality assessment of adverse reactions to drugs-II. An original model for validation of drug causality assessment methods: Case reports with positive rechallenge. J Clin Epidemiol. 46:1331–1336. 1993.PubMed/NCBI View Article : Google Scholar
25	Ichida F, Tsuji T, Omata M, Ichida T, Inoue K, Kamimura T, Yamada G, Hino K, Yokosuka O and Suzuki H: New Inuyama classification; new criteria for histological assessment of chronic hepatitis. Int Hepatol Commun. 6:112–119. 1996.
26	Kanda Y: Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 48:452–458. 2013.PubMed/NCBI View Article : Google Scholar
27	Huppertz HI, Triechel U, Gassel AM, Jeschke R and Büschenfelde KHMZ: Autoimmune hepatitis following hepatitis A virus infection. J Hepatology. 23:204–208. 1995.PubMed/NCBI View Article : Google Scholar
28	Singh G, Palaniappan S, Rotimi O and Hamlin PJ: Autoimmune hepatitis triggered by hepatitis A. Gut. 56(304)2007.PubMed/NCBI View Article : Google Scholar
29	Rigopoulou EI, Zachou K, Gatselis N, Koukoulis GK and Dalekos GN: Autoimmune hepatitis in patients with chronic HBV and HCV infections: Patterns of clinical characteristics, disease progression and outcome. Ann Hepatol. 13:127–135. 2013.PubMed/NCBI
30	Pischke S, Gisa A, Suneetha PV, Wiegand SB, Taubert R, Schlue J, Wursthorn K, Bantel H, Raupach R, Bremer B, et al: Increased HEV seroprevalence in patients with autoimmune hepatitis. PLoS One. 9(e85330)2014.PubMed/NCBI View Article : Google Scholar
31	Zellos A, Spoulou V, Roma-Giannikou E, Karentzou O, Dalekos GN and Theodoridou M: Autoimmune hepatitis type-2 and Epstein-Barr virus infection in a toddler: Art of facts or an artifact? Ann Hepatol. 12:147–151. 2013.PubMed/NCBI
32	Martínez-Casas OY, Díaz-Ramírez GS, Marín-Zuluaga JI, Muñoz-Maya O, Santos O, Donado-Gómez JH and Restrepo-Gutiérrez JC: Differential characteristics in drug-induced autoimmune hepatitis. JGH Open. 2:97–104. 2018.PubMed/NCBI View Article : Google Scholar
33	Stephens C, Robles-Diaz M, Medina-Caliz I, Garcia-Cortes M, Ortega-Alonso A, Sanabria-Cabrera J, Gonzalez-Jimenez A, Alvarez-Alvarez I, Slim M, Jimenez-Perez M, et al: Comprehensive analysis and insights gained from long-term experience of the Spanish DILI registry. J Hepatol. 75:86–97. 2021.PubMed/NCBI View Article : Google Scholar
34	Takahashi A, Arinaga-Hino T, Ohira H, Torimura T, Zeniya M, Abe M, Yoshizawa K, Takaki A, Suzuki Y, Kang JH, et al: Autoimmune hepatitis in Japan: Trends in a nationwide survey. J Gastroenterol. 52:631–640. 2017.PubMed/NCBI View Article : Google Scholar
35	Wang H, Fu J, Liu G, Wang L, Yan A and Wang G: Drug induced autoimmune hepatitis (DIAIH): Pathological and clinical study. Biomed Res. 28:6028–6034. 2017.