Drug-Induced Autoimmune Hepatitis by Varenicline and Infliximab as a Continuous Disease Spectrum with Two Different Flares: Acute Liver Injury Followed by Hepatic Autoimmunity
Abstract
1. Introduction
2. Strategy of Literature Search
3. Causality Assessment of Drug-Induced Autoimmune Hepatitis
3.1. RUCAM
3.2. Simplified AIH Score
3.3. Sequential Use of the Diagnostic Algorithms
3.4. Approaches Unifying Diagnostic Causality Assessment Algorithms
4. Definitions
4.1. Drug-Induced Autoimmune Hepatitis (DIAIH)
4.2. Idiosyncratic Drug-Induced Liver Injury (iDILI)
4.3. Idiopathic Autoimmune Hepatitis (AIH)
5. Quality of DIAIH Cases Essential for Analysis
5.1. Search for Appropriate DIAIH Study Cohorts
5.2. Cautionary Note on Unqualified DIAIH Cases Due to Incomplete Causality Assessment
6. Continuous Disease Spectrum of DIAIH with Two Injurious Flares
6.1. Basic Aspects
6.2. DIAIH Due to the Smoking Cessation Agent Varenicline
6.3. DIAIH Due to TNF-α Antagonist Infliximab
7. Molecular and Mechanistic Sequelae of the Two Flares Caused by Varenicline in the DIAIH Cases
7.1. Acute Liver Injury by Varenicline as First Flare of DIAIH
7.1.1. General Metabolic Aspects of Varenicline
7.1.2. Non-CYP Pathways in iDILI
7.1.3. Role of Hepatic Non-CYP Enzymes in Acute Liver Injury by Varenicline
7.1.4. Molecular and Mechanistic Sequelae Causing the First Flare of DIAIH by Varenicline
7.2. Autoimmune Liver Injury by Varenicline as Second Flare of DIAIH
7.2.1. Tentative Compounds Triggering the Autoimmunity
7.2.2. Molecular and Mechanistic Autoimmune Processes
8. Conceptual Considerations Regarding the Two Sequential Flares of DIAIH by Varenicline and Infliximab
8.1. Varenicline
8.2. Infliximab
9. Conclusions
Funding
Data Availability Statement
Conflicts of Interest
References
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Drugs and Drug Groups | Cases (n) | References |
---|---|---|
Adalimumab | 1 1 | Martínez-Casas, 2018 [82] Chung, 2024 [83] |
Allopurinol | 1 | Chung, 2024 [83] |
Amitriptyline | 1 | Weber, 2019 [84] |
Amoxicillin-clavulanate | 2 | García-Cortés, 2023 [85] |
Amoxicillin-clavulanate + ceftriaxone | 3 | Licata, 2014 [86] |
Amoxicillin + erythromycin | 1 | Chung, 2024 [83] |
Amoxicillin + metronidazole | 1 | Chung, 2024 [83] |
Anabolic steroid | 1 | Chung, 2024 [83] |
Atorvastatin | 2 2 2 1 1 | Yeong, 2016 [87] Weber, 2019 [84] García-Cortés, 2023 [85] Tan, 2022 [88] Tse, 2023 [89] |
Candesartan | 1 | Hassoun, 2023 [90] |
Cephalexin + amoxicillin | 1 | Chung, 2024 [83] |
Ciprofloxacin | 1 1 | García-Cortés, 2023 [85] Chung, 2024 [83] |
Cyproterone acetate | 2 | García-Cortés, 2023 [85] |
Dabigatran | 1 | Weber, 2019 [84] |
Dexketoprofen | 1 | García-Cortés, 2023 [85] |
Diclofenac | 1 2 3 | Yeong, 2016 [87] Martínez-Casas, 2018 [82] Weber, 2019 [84] |
Ebrotidine | 1 | García-Cortés, 2023 [85] |
Efalizumab | 1 | García-Cortés, 2023 [85] |
Enalapril maleate | 1 | Hassoun, 2023 [90] |
Etanercept | 1 | Valgeirsson, 2019 [91] |
Ezetimibe | 1 | García-Cortés, 2023 [85] |
Fluvastatin | 4 | García-Cortés, 2023 [85] |
Fosfomycin | 1 | Hassoun, 2023 [90] |
Ibandronate | 1 | Hassoun, 2023 [90] |
Ibuprofen | 5 1 | Hassoun, 2023 [90] García-Cortés, 2023 [85] |
Imatinib | 1 1 1 | Björnsson, 2017 [92] Weber, 2019 [84] Valgeirsson, 2019 [91] |
Infliximab | 8 7 1 1 1 | Björnsson, 2017 [92] Valgeirsson, 2019 [91] Chung, 2024 [83] García-Cortés, 2023 [85] Weber, 2019 [84] |
Interferon beta | 1 | Weber, 2019 [84] |
Irbesartan | 1 | García-Cortés, 2023 [85] |
Isotretinoin | 1 | García-Cortés, 2023 [85] |
Lansoprazole | 1 | Chung, 2024 [83] |
Lymecycline | 2 | Chung, 2024 [83] |
Mefenamic acid | 1 | Hassoun, 2023 [90] |
Menotropin | 1 | Alqrinawi, 2019 [93] |
Metamizole | 3 | Weber, 2019 [84] |
Methocarbamol | 1 | Weber, 2019 [84] |
Nimesulide + ketoprofen | 6 | Licata, 2014 [86] |
Minocycline | 4 4 1 | García-Cortés, 2023 [85] Chung, 2024 [83] Weber, 2019 [84] |
NSAIDs + antibiotics | 1 | Chung, 2024 [83] |
Natalizumab | 1 | Valgeirsson, 2019 [91] |
Nitrofurantoin | 8 7 5 4 3 1 | Martínez-Casas, 2018 [82] Chung, 2024 [83] García-Cortés, 2023 [85] Yeong, 2016 [87] Björnsson, 2017 [92] Hassoun, 2023 [90] |
Olmesartan | 1 | Hassoun, 2023 [90] |
Orlistat | 1 | García-Cortés, 2023 [85] |
Pembrolizumab | 1 | Weber, 2019 [84] |
Propylthiouracil | 1 | Martínez-Casas, 2018 [82] |
Rivaroxaban | 1 | Weber, 2019 [84] |
Rosuvastatin | 1 | García-Cortés, 2023 [85] |
Simvastatin | 1 1 | Yeong, 2016 [87] García-Cortés, 2023 [85] |
Sorafenib | 1 | Tan, 2022 [88] |
Trazodone | 2 | Hassoun, 2023 [90] |
Valsartan | 1 | Hassoun, 2023 [90] |
Drugs | Cases (n) | ALT (U/L) | ALP (U/L) | Autoimmune Parameters | References |
---|---|---|---|---|---|
Adalimumab | 1 | 562 | NR | ANA | Martínez-Casas, 2018 [82] |
Amitriptyline | 1 | NR | NR | Not specified | Weber, 2019 [84] |
Amoxicillin-clavulanate | 2 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Amoxicillin-clavulanate + ceftriaxone | 3 | NR | NR | Not specified | Licata, 2014 [86] |
Amoxicillin + erythromycin | 1 | NR | NR | Not specified | Chung, 2024 [83] |
Amoxicillin + metronidazole | 1 | NR | NR | Not specified | Chung, 2024 [83] |
Anabolic steroid | 1 | NR | NR | Not specified | Chung, 2024 [83] |
Atorvastatin | 2 2 2 1 1 | 721 NR NR 696 385 | NR NR NR 107 163 | ANA, ASMA Not specified Not specified Unremarkable ANA | Yeong, 2016 [87] Weber, 2019 [84] García-Cortés, 2023 [85] Tan, 2022 [88] Tse, 2023 [89] |
Candesartan | 1 | NR | NR | Not specified | Hassoun, 2023 [90] |
Cefalexin + amoxicillin | 1 | NR | NR | Not specified | Chung, 2024 [83] |
Ciprofloxacin | 1 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Cyproterone acetate | 2 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Dabigatran | 1 | NR | NR | Not specified | Weber, 2019 [84] |
Dexketoprofen | 1 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Diclofenac | 1 2 3 | 3489 1491 NR | NR NR NR | ANA, ASMA ANA, ASMA, SLA Not specified | Yeong, 2016 [87] Martínez-Casas, 2018 [82] Weber, 2019 [84] |
Ebrotidine | 1 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Efalizumab | 1 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Ezetimibe | 1 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Enalapril maleate | 1 | NR | NR | Not specified | Hassoun, 2023 [90] |
Fluvastatin | 4 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Fosfomycin | 1 | NR | NR | Not specified | Hassoun, 2023 [90] |
Ibandronate | 1 | NR | NR | Not specified | Hassoun, 2023 [90] |
Ibuprofen | 5 1 | NR NR | NR NR | Not specified Not specified | Hassoun, 2023 [90] García-Cortés, 2023 [85] |
Imatinib | 1 1 | 1212 NR | 205 NR | ANA Not specified | Björnsson, 2017 [92] Weber, 2019 [84] |
Infliximab | 10 8 1 1 | 1658 NR NR NR | 493 NR NR NR | ANA ASMA Not specified Not specified | Björnsson, 2017 [92] Valgeirsson, 2019 [91] García-Cortés, 2023 [85] Weber, 2019 [84] |
Interferon beta | 1 | NR | NR | Not specified | Weber, 2019 [84] |
Irbesartan | 1 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Isotretinoin | 1 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Lansoprazole | 1 | NR | NR | Not specified | Chung, 2014 [83] |
Lymecycline | 2 | NR | NR | Not specified | Chung, 2024 [83] |
Mefenamic acid | 1 | NR | NR | Not specified | Hassoun, 2023 [90] |
Menotropin | 1 | 504 | 366 | ANA | Alqrinawi, 2019 [93] |
Metamizole | 3 | NR | NR | Not specified | Weber, 2019 [84] |
Methocarbamol | 1 | NR | NR | Not specified | Weber, 2019 [84] |
Minocycline | 4 4 1 | NR NR NR | NR NR NR | Not specified Not specified Not specified | García-Cortés, 2023 [85] Chung, 2024 [83] Weber, 2019 [84] |
Nimesulide + ketoprofen | 6 | NR | NR | Not specified | Licata, 2014 [86] |
Nitrofurantoin | 8 7 5 4 3 1 | 2059 NR NR 587 1974 NR | NR NR NR NR 204 NR | ANA, ASMA Not specified Not specified ANA, ASMA ANA Not specified | Martínez-Casas, 2018 [82] Chung, 2024 [83] García-Cortés, 2023 [85] Yeong, 2016 [87] Björnsson, 2017 [92] Hassoun, 2023 [90] |
NSAIDs + antibiotics | 1 | NR | NR | Not specified | Chung, 2024 [83] |
Olmesartan | 1 | NR | NR | Not specified | Hassoun, 2023 [90] |
Orlistat | 1 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Pembrolizumab | 1 | NR | NR | Not specified | Weber, 2019 [84] |
Propylthiouracil | 1 | 754 | NR | ANA | Martínez-Casas, 2018 [82] |
Rivaroxaban | 1 | NR | NR | Not specified | Weber, 2019 [84] |
Rosuvastatin | 1 | NR | NR | Not specified | García-Cortés, 2023 [85] |
Simvastatin | 1 1 | 1245 NR | NR NR | ANA, ASMA Not specified | Yeong, 2016 [87] García-Cortés, 2023 [85] |
Sorafenib | 1 | 1004 | 190 | Unremarkable | Tan, 2022 [88] |
Trazodone | 2 | NR | NR | Not specified | Hassoun, 2023 [90] |
Valsartan | 1 | NR | NR | Not specified | Hassoun, 2023 [90] |
Drugs | Cases (n) | Response to Drug Cessation/Therapy | References |
---|---|---|---|
Adalimumab | 1 1 | CR with PRED/AZA CR with cessation of the culprit drug | Martínez-Casas, 2018 [82] Chung, 2024 [83] |
Allopurinol | 1 | CR with IS | Chung, 2024 [83] |
Amoxicillin + erythromycin | 1 | CR with IS | Chung, 2024 [83] |
Amoxicillin + metronidazole | 1 | CR with IS | Chung, 2024 [83] |
Anabolic steroid | 1 | CR with IS | Chung, 2024 [83] |
Atorvastatin | 1 2 | CR with PRED CR with cessation of the culprit drug | Tan, 2022 [88] Tse, 2023 [89] |
Cefalexin + amoxicillin | 1 | CR with IS | Chung, 2024 [83] |
Ciprofloxacin | 1 | CR with IS | Chung, 2024 [83] |
Diclofenac Diclofenac + ibuprofen | 1 1 | CR with PRED/AZA IR with PRED/AZA/TAC/UCDA | Martínez-Casas, 2018 [82] Chung, 2024 [83] |
Infliximab | 1 2 | CR with IS CR with cessation of the culprit drug | Chung, 2024 [83] Chung, 2024 [83] |
Lansoprazole | 1 | CR with IS | Chung, 2024 [83] |
Menotropin | 1 | CR with PRED/AZA | Alqrinawi, 2019 [93] |
Minocycline | 1 | CR with IS | Chung, 2024 [83] |
NSAIDs + Antibiotics | 1 | CR with IS | Chung, 2024 [83] |
Nitrofurantoin | 8 7 | CR with PRED/AZA CR with IS | Martínez-Casas, 2018 [82] Chung, 2024 [83] |
Propylthiouracil | 1 | CR with PRED/AZA | Martínez-Casas, 2018 [82] |
Sorafenib | 1 | CR with cessation of the culprit drug | Tan, 2022 [88] |
Drugs | Cases (n) | RUCAM Causality Algorithm Used | Simplified Criteria of AIH Score Used | DIAIH Diagnosis Verified by Both RUCAM and Simplified AIH Score | Literature |
---|---|---|---|---|---|
Adalimumab | 1 1 | Yes No | No Yes | No No | Ghabril, 2013 [94] Rodrigues, 2015 [95] |
Atorvastatin | 1 | Yes | No | No | Khan, 2020 [96] |
Cephalexin | 1 | No | Yes | No | Björnsson, 2010 [97] |
Etanercept | 2 | Yes | No | No | Ghabril, 2013 [94] |
Hydralazine | 7 | No | No | No | de Boer, 2017 [98] |
Infliximab | 25 8 3 | Yes No Yes | No Yes No | No No No | Björnsson, 2022 [99] Rodrigues, 2015 [95] Ghabril, 2013 [94] |
Methyldopa | 10 | No | No | No | de Boer, 2017 [98] |
Minocycline | 19 10 1 | No No No | No Yes No | No No No | de Boer, 2017 [98] Björnsson, 2010 [97] Harmon, 2018 [100] |
Nitrofurantoin | 24 10 | No No | No Yes | No No | de Boer, 2017 [98] Björnsson, 2010 [97] |
Pirfenidone | 1 | Yes | No | No | Fortunati, 2024 [101] |
Prometrium | 1 | No | Yes | No | Björnsson, 2010 [97] |
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Teschke, R. Drug-Induced Autoimmune Hepatitis by Varenicline and Infliximab as a Continuous Disease Spectrum with Two Different Flares: Acute Liver Injury Followed by Hepatic Autoimmunity. Int. J. Mol. Sci. 2025, 26, 9574. https://doi.org/10.3390/ijms26199574
Teschke R. Drug-Induced Autoimmune Hepatitis by Varenicline and Infliximab as a Continuous Disease Spectrum with Two Different Flares: Acute Liver Injury Followed by Hepatic Autoimmunity. International Journal of Molecular Sciences. 2025; 26(19):9574. https://doi.org/10.3390/ijms26199574
Chicago/Turabian StyleTeschke, Rolf. 2025. "Drug-Induced Autoimmune Hepatitis by Varenicline and Infliximab as a Continuous Disease Spectrum with Two Different Flares: Acute Liver Injury Followed by Hepatic Autoimmunity" International Journal of Molecular Sciences 26, no. 19: 9574. https://doi.org/10.3390/ijms26199574
APA StyleTeschke, R. (2025). Drug-Induced Autoimmune Hepatitis by Varenicline and Infliximab as a Continuous Disease Spectrum with Two Different Flares: Acute Liver Injury Followed by Hepatic Autoimmunity. International Journal of Molecular Sciences, 26(19), 9574. https://doi.org/10.3390/ijms26199574