Immunology Highlights of Four Major Idiosyncratic DILI Subtypes Verified by the RUCAM: A New Evidence-Based Classification
Abstract
:1. Introduction
2. Literature Search and Search Terms
3. RUCAM
4. Definition of Four Major Autoimmune and Immune Drug-Induced Liver Injury Types
4.1. Type 1: Idiosyncratic Autoimmune DILI
4.2. Type 2: HLA-Based Drug-Induced Autoimmune Hepatitis
4.3. Type 3: Idiosyncratic Anti-CYP Autoimmune DILI
4.4. Type 4: Idiosyncratic Immune Rather than Autoimmune DILI
5. Clinical Characteristics of Four Idiosyncratic Autoimmune and Immune DILI Types
5.1. Type 1: Drug-Induced Autoimmune Hepatitis (DIAIH)
5.2. Type 2: Idiosyncratic Autoimmune HLA-Based DILI
5.3. Type 3: Idiosyncratic Autoimmune Anti-CYP-Based DILI
5.4. Type 4: Idiosyncratic Immune DILI Combined with SJS and TEN
6. Perspectives
7. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Serum Autoimmune Parameter | RUCAM Used | Clinical Details of DIAIH Cases and Comments | Drugs and Drug Groups | References |
---|---|---|---|---|
AMA ANA ASMA | YES | At the start of the hospital stay, jaundice was a common initial finding. Portal inflammation and infiltration with lymphoplasmacytic cells were evident in the liver histology specimen. | Antimicrobials | Licata, 2014 [60] |
ANA ASMA | YES | This excellent study provided results of serum autoantibodies in cohorts with careful exclusion of confounding cases that had nothing to do with DIAIH but had to be diagnosed as common, non-immune DILI caused, for instance, by antibiotics. | Adalimumab Certolizumab Infliximab | Shelton, 2015 [61] |
ANA | YES | In Japan, DIAIH was rarely attributed to chemical drugs as opposed predominantly to herbal TCMs, making the term DIAIH incorrect because herbal products are in no way chemical drugs. | Clarithromycin NSAIDs | Hisamochu, 2016 [62] |
ANA ASMA | YES | Initial therapy started with prednisone given as a sole drug, while later, sometimes, azathioprine was provided alone or combined with prednisone. Under these treatment regimes, there was no lethality due to liver disease and no necessity for liver transplantation. | Nitrofurantoin NSAIDs | Yeong, 2016 [63] |
ANA | YES | The female gender prevailed with 93% of cases. Improvement was seen in 40% after drug cessation. | Imatinib Infliximab Nitrofurantoin | Björnsson, 2017 [64] |
ANA ASMA | NO | With 91%, females were in the majority. Patients were symptomatic with icterus, pruritus, exanthema, and increased body temperature. Eosinophilia was a typical laboratory abnormality in the affected patients. The liver pattern was mostly of the hepatocellular injury type. | Hydralazine Methyldopa Minocycline Nitrofurantoin | de Boer 2017 [65] |
ANA | YES | Menotrophin was given as a hormonal fertility medication. | Menotrophin | Alqrinawi, 2019 [66] |
AMA ANA ASMA | YES | Steroids and immunomodulators provided an efficient therapy. This was an excellent clinical study on the DIAIH study from Latin America. | Nitrofurantoin NSAIDs | Martinez-Casas, 2018 [67] |
ALKMA AMA ANA ASMA | YES | The decline of serum ALT activities one week following starting the treatment with steroid therapy was more evident in the DIAIH cases than in patients with genuine AIH, seen as another diagnostic parameter that could help differentiate DIAIH from AIH. | Atorvastatin Dabigatran Diclofenac Ezetimibe Metamizole Rivaroxaban | Weber, 2019 [68] |
SMA | YES | In line with previous reports, the treatment with immunosuppressive agents was efficient. | Infliximab | Valgareisson 2019 [69] |
ANA ASMA | YES | Normal IgG levels were reported as well as serum ANA and ASMA positivity in 32% of patients. | ICIs | Riveiro-Barciela, 2020 [70] |
AMA ANA ASMA | YES | RUCAM-based liver injury pattern was hepatocellular in 92% of cases. Females predominated with 62%. | Antibacterials Statins | Stephens, 2021 [71] |
ALKMA ANA ASLA ASMA | YES | This immuno-allergic phenotype was based on a rash, facial edema, lymphadenopathy, fever, and eosinophilia in a range of 11–27% and of 70–75% in cases with jaundice. An elevated serum IgG level was a common finding. Specimens of the liver showed histological signs of portal inflammation, plasma cell infiltrates, rosettes, and focal necrosis. | Atorvastatin Diclofenac Etanercept Infliximab Methyldopa Minocycline Nitrofurantoin Rosuvastatin | Tan, 2022 [72] |
ANA ASMA | YES | In 18% of patients, seronegativity was observed, and cirrhosis in 25% of cases. | Infliximab Minocycline Nitrofurantoin | Chung, 2023 [73] |
ANA SMA | YES | At baseline, all patients had jaundice and elevated serum ALT and AST activities. | Ibuprofen Trazodone | Hassoun, 2023 [74] |
AMA ANA | YES | The cohort was inhomogeneous due to mixing with non-drugs such as herbs and undetermined classification. | Antibiotics Hormones | Kakisaka 2023 [75] |
ANA | YES | A positive test was reported after unintentional reexposure to the same drug. | Atorvastatin | Tse, 2023 [76] |
ANA | YES | After drug cessation, a decline in ALT and AST was observed, with an increase on day 10. | Ornidazole | Memiş, 2024 [77] |
Drug | HLA Allele | RUCAM-Based iDILI Cases (n) | References |
---|---|---|---|
Amoxicillin | A*01:01 C*03:02 B*58:01 DPB1*01:01 | 15 | Nicoletti, 2019 [78] |
Amoxicillin-clavulanate | A*02:01 DQB1*06:02 | 201 | Lucena, 2011 [79] |
Amoxicillin-clavulanate | A*30:02 B*18:01 DRB1*15:01 DQB1*06:02 | 75 | Stephens, 2013 [80] |
Amoxicillin-clavulanate | DRB1*15:01 | 14 | O’Donohue, 2000 [81] |
Antituberculotics + antiretrovirals | B*57:02 B*57:03 | 46 | Petros, 2017 [82] |
Carbamazepine | A*31:01 | 29 | Nicoletti, 2019 [83] |
Dapsone | B*13:01 | 4 | Devarbhavi, 2022 [84] |
Enalapril | A*33:01 | 4 | Nicoletti, 2017 [85] |
Erythromycin | A*33:01 | 10 | Nicoletti, 2017 [85] |
Fenofibrate | A*33:01 | 7 | Nicoletti, 2017 [85] |
Flucloxacillin | B*5701 | 51 | Daly, 2009 [86] |
Flucloxacillin | B*57:01 | 6 | Monshi, 2013 [87] |
Flucloxacillin | B*57:01 B*57:03 | 197 | Nicoletti, 2019 [78] |
Flucloxacillin | B*57:01 | 1 | Teixera, 2020 [88] |
Flupirtine | DRB1*16:01-DQB*05:02 | 11 | Nicoletti, 2016 [89] |
Infliximab | B*39:01 | 18 | Bruno, 2020 [90] |
Isoxazolyl penicillins | C*07:04 DQB1*06:09 | 6 | Nicoletti, 2019 [78] |
Methimazole | C*03:02 | 40 | Li, 2019 [91] |
Methyldopa | A*33:01 | 4 | Nicoletti, 2017 [85] |
Minocycline | B*35:02 | 25 | Urban, 2017 [92] |
Nitrofurantoin | A*33:01 DQB1*02:02 A*30:02 DQA1*02:01 DRB1*07:01 DPB1*16:01 C*06:02 | 26 | Daly, 2023 [93] |
Sertaline | A*33:01 | 5 | Nicoletti, 2017 [85] |
Terbinafine | A*33:01 | 14 | Nicoletti, 2017 [85] |
Ticlopidine | A*33:01 | 5 | Nicoletti, 2017 [85] |
Trimethoprim-sulfamethoxazole | B*14:01 B*14:02 B*35:01 | 86 | Li, 2021 [94] |
DRUG | HLA Allele | RUCAM-Based iDILI Cases (n) | RUCAM-Based Causality | References |
---|---|---|---|---|
Flucloxacillin | B*57:01 | 51 | 4/51 patients had a possible causality, 18 a probable one, and 29 a highly probable causality one | Daly, 2009 [86] |
Flucloxacillin | B*57:01 | 6 | 2/6 patients had a possible causality, 2 a probable, and 2 a highly probable causality | Monshi, 2013 [87] |
Flucloxacillin | B*57:01 B*57:03 | 197 | 22/197 of the patients had a possible causality, 90 a probable, and 85 a highly probable causality grading | Nicoletti, 2019 [83] |
Flucloxacillin | B*57:01 | 1 | RUCAM score of 8, equivalent to a probable causality grading | Teixera, 2020 [88] |
Autoimmune Parameter | Details of RUCAM-Based iDILI Cases | Drug | References |
---|---|---|---|
Serum anti-CYP 2E1 | Patients experiencing iDILI attributed to the volatile anesthetic sevoflurane use exhibited positive serum titers of anti-CYP 2E1 in cases with highly probable causalities and well-described clinical features. Among these were flu-like symptoms, fever, jaundice, vomiting, right upper quadrant abdominal pain, reduced appetite, rash, and myalgias, all described after the second anesthesia. In the liver histology, centrilobular necrosis with hemorrhage and rosetting of liver cells prevailed. | Sevoflurane | Nicoll, 2012 [104] |
Serum anti-CYP 2E1 | Clinical case details of the RUCAM-based iDILI were published as a result of volatile anesthetic use in combination. Considering alternative causes such as hypotension and DILI by antibiotics or paracetamol was highly appreciated for reasons of clarity and transparency. | Sevoflurane + Desflurane | Bishop, 2019 [47] |
Serum anti-TFA | Aditional valuable insight into the mechanistic steps involved in iDILI with a verified diagnosis by RUCAM was evident in patients with detected toxic intermediates in the form of trifluoroacetate (TFA) halide, produced during the drug metabolism via CYP 2E1. This provided clues of irreversible protein adduct formation and free radical generation, resulting in detectable anti-TFA antibodies as a sign of an immune process. | Sevoflurane + Desflurane | Nicoll, 2012 [104] Bishop, 2019 [47] |
Drugs/Drug Classes | Cases (n) | Causality Algorithm Use | Outcome | References |
---|---|---|---|---|
Allopurinol | 2 | RUCAM + ALDEN + | All survived | Devarbhavi, 2016 [58] |
Allopurinol | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Amoxicillin | N.A. | RUCAM + ALDEN − | Cases of acute liver failure, outcome unknown | Ortega-Alonso, 2017 [117] |
Ampicillin | N.A. | RUCAM + ALDEN − | Cases of acute liver failure, outcome unknown | Ortega-Alonso, 2017 [117] |
Aspirin | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Carbamazepine | 2 | RUCAM + ALDEN + | All died | Devarbhavi, 2016 [58] |
Carbamazepine | 8 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Carbamazepine | 36 | RUCAM + ALDEN + | 4/36 died | Devarbhavi, 2023 [118] |
Ceftazidime | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Ceftriaxone | 1 | RUCAM + ALDEN + | Lethal outcome | Devarbhavi, 2016 [58] |
Ceftriaxone | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Celecoxib | N.A. | RUCAM + ALDEN − | No cases of acute liver failure | Ortega-Alonso, 2017 [117] |
Clobazam | 2 | RUCAM + ALDEN + | 1/3 died | Devarbhavi, 2023 [118] |
Clonazepam | 2 | RUCAM + ALDEN + | All survived | Devarbhavi, 2023 [118] |
Cotrimoxazole | 3 | RUCAM + ALDEN + | All survived | Devarbhavi, 2016 [58] |
Dapsone | 5 | RUCAM + ALDEN + | 3/5 died | Devarbhavi, 2016 [58] |
Fluoxetine | 1 | RUCAM + ALDEN + | Survived | Agrawal, 2019 [119] |
Gabapentin | 1 | RUCAM + ALDEN + | Survived | Devarbhavi, 2023 [118] |
Ibuprofen | N.A. | RUCAM + ALDEN − | Cases of acute liver failure, outcome unknown | Ortega-Alonso, 2017 [117] |
Lamotrigine | 1 | RUCAM + ALDEN + | Lethal outcome | Devarbhavi, 2016 [58] |
Lamotrigine | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Lamotrigine | 3 | RUCAM + ALDEN + | 1/3 died | Devarbhavi, 2023 [118] |
Leflunomide | 3 | RUCAM + ALDEN + | All died | Devarbhavi, 2016 [58] |
Leflunomide | 2 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Levitericetam | 1 | RUCAM + ALDEN + | Lethal outcome | Devarbhavi, 2016 [58] |
Levitericetam | 3 | RUCAM + ALDEN + | All survived | Devarbhavi, 2023 [118] |
Levofloxacin | 1 | RUCAM + ALDEN + | Survived | Devarbhavi, 2016 [58] |
Nevirapine | 6 | RUCAM + ALDEN + | All survived | Devarbhavi, 2016 [58] |
Omeprazole | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Oxacarbazepine | 1 | RUCAM + ALDEN + | Survived | Devarbhavi, 2016 [58] |
Oxacarbazepine | 2 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Oxacarbazepine | 2 | RUCAM + ALDEN + | All survived | Devarbhavi, 2023 [118] |
Paracetamol | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Penicillin | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Phenobarbitone | 2 | RUCAM + ALDEN + | 1/2 died | Devarbhavi, 2016 [58] |
Phenobarbitone | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Phenobarbitone | 8 | RUCAM + ALDEN + | 2/8 died | Devarbhavi, 2023 [118] |
Phenylbutazone | 2 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Phenytoin | 2 | RUCAM + ALDEN + | 1/2 died | Devarbhavi, 2016 [58] |
Phenytoin | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Phenytoin | 71 | RUCAM + ALDEN + | 4/71 died | Devarbhavi 2023 [118] |
Tegafur | 1 | RUCAM + ALDEN + | N.A. | Zhang, 2020 [116] |
Terbinafine | N.A. | RUCAM + ALDEN − | Cases of acute liver failure, outcome unknown | Ortega-Alonso, 2017 [117] |
Topiramate | 1 | RUCAM + ALDEN + | Survived | Devarbhavi, 2023 [118] |
Valproate | 14 | RUCAM + ALDEN + | 1/14 died | Devarbhavi, 2023 [118] |
Warfarin | 1 | RUCAM + ALDEN + | Survived | Xiong 2021 [120] |
Zonisamide | 1 | RUCAM + ALDEN + | Survived | Devarbhavi, 2023 [118] |
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Teschke, R. Immunology Highlights of Four Major Idiosyncratic DILI Subtypes Verified by the RUCAM: A New Evidence-Based Classification. Livers 2025, 5, 8. https://doi.org/10.3390/livers5010008
Teschke R. Immunology Highlights of Four Major Idiosyncratic DILI Subtypes Verified by the RUCAM: A New Evidence-Based Classification. Livers. 2025; 5(1):8. https://doi.org/10.3390/livers5010008
Chicago/Turabian StyleTeschke, Rolf. 2025. "Immunology Highlights of Four Major Idiosyncratic DILI Subtypes Verified by the RUCAM: A New Evidence-Based Classification" Livers 5, no. 1: 8. https://doi.org/10.3390/livers5010008
APA StyleTeschke, R. (2025). Immunology Highlights of Four Major Idiosyncratic DILI Subtypes Verified by the RUCAM: A New Evidence-Based Classification. Livers, 5(1), 8. https://doi.org/10.3390/livers5010008