AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review

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It highlights the challenges in distinguishing drug-induced liver injury from authentic autoimmune liver disease. It also points out the importance of considering autoimmune liver disease as a potential diagnosis revealed by the setting of drug-induced liver injury." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-1270", "name": "AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report..." } } ] } Home Browse AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Tababi R, Hela K, Zehani A et al. AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 3; peer review: 1 approved] . F1000Research 2025, 13 :1270 ( https://doi.org/10.12688/f1000research.157997.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Clinical Practice Article Revised AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 3; peer review: 1 approved] Previously titled: Autoimmune liver disease revealed by Tuberculosis treatment: report of two cases and literature review Ramzi Tababi https://orcid.org/0009-0006-1330-6887 1 , Kchir Hela 1 , Alia Zehani 2 , [...] Imen Aouinti 3 , Hajer Hassine https://orcid.org/0000-0002-4077-8373 1 , Ahmed Nefzi https://orcid.org/0000-0002-6160-4620 1 , Khadija Bellil 2 , Slim Haouet 2 , Habiba Debbabi 1 , Nadia Maamouri 1 Ramzi Tababi https://orcid.org/0009-0006-1330-6887 1 , Kchir Hela 1 , [...] Alia Zehani 2 , Imen Aouinti 3 , Hajer Hassine https://orcid.org/0000-0002-4077-8373 1 , Ahmed Nefzi https://orcid.org/0000-0002-6160-4620 1 , Khadija Bellil 2 , Slim Haouet 2 , Habiba Debbabi 1 , Nadia Maamouri 1 PUBLISHED 31 Mar 2025 Author details Author details 1 Gastroenterology Department B, Rabta University Hospital, Tunis, Tunis, Tunisia 2 Pathology Department, Rabta University Hospital, Tunis, Tunis, Tunisia 3 Pharmacovigilance Department, Faculty of Medicine of Tunis, Tunis, Tunisia Ramzi Tababi Roles: Conceptualization, Data Curation, Resources, Writing – Original Draft Preparation, Writing – Review & Editing Kchir Hela Roles: Conceptualization, Data Curation, Investigation, Resources, Supervision, Validation, Visualization, Writing – Review & Editing Alia Zehani Roles: Writing – Review & Editing Imen Aouinti Roles: Writing – Review & Editing Hajer Hassine Roles: Supervision, Validation, Writing – Review & Editing Ahmed Nefzi Roles: Data Curation, Resources, Writing – Review & Editing Khadija Bellil Roles: Data Curation, Resources, Visualization Slim Haouet Roles: Data Curation, Resources, Visualization Habiba Debbabi Roles: Supervision, Validation, Writing – Review & Editing Nadia Maamouri Roles: Conceptualization, Investigation, Project Administration, Supervision, Validation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract This article presents two patients who were diagnosed with genuine autoimmune liver disease (autoimmune hepatitis and primary biliary cholangitis overlap syndrome) during anti-tuberculosis therapy, which is a rarely reported occurrence. It highlights the challenges in distinguishing drug-induced liver injury from authentic autoimmune liver disease. It also points out the importance of considering autoimmune liver disease as a potential diagnosis revealed by the setting of drug-induced liver injury. READ ALL READ LESS Keywords Tuberculosis, Drug-induced Liver Injury, Autoimmune Hepatitis, Primary Biliary Cholangitis, Overlap Syndrome Corresponding Author(s) Ramzi Tababi ( [email protected] ) Close Corresponding author: Ramzi Tababi Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Tababi R et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Tababi R, Hela K, Zehani A et al. AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 3; peer review: 1 approved] . F1000Research 2025, 13 :1270 ( https://doi.org/10.12688/f1000research.157997.3 ) First published: 24 Oct 2024, 13 :1270 ( https://doi.org/10.12688/f1000research.157997.1 ) Latest published: 31 Mar 2025, 13 :1270 ( https://doi.org/10.12688/f1000research.157997.3 ) Revised Amendments from Version 2 In this revised version, the author list has been revised to better reflect the contributions to the manuscript. Two authors, Alia Zehani (Pathology) and Imen Aouinti (Pharmacology), have been added for their valuable expertise in reviewing the histopathological findings and drug-related aspects. Additionally, the publication year of reference 19 has been corrected from 2015 to 2016. No other changes have been made to the manuscript. In this revised version, the author list has been revised to better reflect the contributions to the manuscript. Two authors, Alia Zehani (Pathology) and Imen Aouinti (Pharmacology), have been added for their valuable expertise in reviewing the histopathological findings and drug-related aspects. Additionally, the publication year of reference 19 has been corrected from 2015 to 2016. No other changes have been made to the manuscript. See the authors' detailed response to the review by Rolf Teschke READ REVIEWER RESPONSES Introduction Tuberculosis (TB) remains a significant public health challenge in numerous countries worldwide, raising concerns about the potential risks associated with anti-TB drugs. Specifically, these drugs have been implicated in drug-induced liver injury (DILI) with a reported incidence ranging from 2% to 28%. 1 DILI can manifest as mild liver enzyme elevation to life-threatening liver failure, commonly resulting from an idiosyncratic reaction involving either metabolic or immune-mediated mechanisms. 2 DILI may exhibit autoimmune features, creating diagnostic challenges, particularly in differentiating it from idiopathic autoimmune liver diseases (ALD) such as autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). This article presents two cases of genuine ALD, specifically AIH-PBC overlap syndrome, uncovered during TB therapy, while navigating the differential diagnosis of an autoimmune-phenotype DILI. We additionally conducted a review of the literature, seeking insights into the intricate relationship between TB treatment and ALD. Case 1 A 49-year-old Caucasian woman, with atopic background and no alcohol intake, was diagnosed with abdominal lymph node and peritoneal tuberculosis (TB). She was started on first-line anti-TB therapy with Isoniazid (INH), Rifampicin (RIF), Pyrazinamide (PZA) and Ethambutol (EMB) following normal pre-treatment liver function tests (LFTs). A month after starting the treatment, the patient presented with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome attributed to EMB. DRESS syndrome was diagnosed based on a pruritic macular-papular skin rash, fever, eosinophilia (3100/mm 3 ), immunoallergic leukocytoclastic skin vasculitis, and significantly elevated liver enzymes including Aspartate Aminotransferase (AST) at 9 times the upper limit of normal (ULN), Alanine Aminotransferase (ALT) at 4 xULN, Alkaline Phosphatase (ALP) at 2.6 xULN, and Gamma Glutamyl Transferase (GGT) at 7 xULN, with normal bilirubin levels (BIL). Anti-TB drugs were suspended, and DRESS syndrome resolved within a month, allowing for the restart of a modified treatment regimen, replacing EMB with a fluoroquinolone: Levofloxacin (LFX) with INH-RIF-PZA during 2 months followed by 6 months of INH-RIF. However, by the 8th month of anti-TB treatment (INH-RIF), the patient exhibited clinical signs of acute hepatocellular injury, presenting with jaundice and significantly elevated levels of AST (18xULN), ALT (10xULN), ALP (1.3xULN), GGT (3xULN), and BIL (12 mg/dl) predominantly conjugated bilirubin (CBIL: 9 mg/dl), with normal factor V levels (84%). There were no clinical or biological signs of hypersensitivity, and abdominal ultrasound (US) showed no abnormalities. Aetiological investigation for liver injury ruled out a viral hepatitis A, B and C, as well as HIV infection (negative anti-HAV IgM, negative HBsAg, positive anti-HBc, negative DNA-HBV, negative anti-HCV and negative HIV serology). Meanwhile, immunological assessment revealed positivity for anti-nuclear antibody (ANA) with a titre of 1/400, anti-Smooth Muscle Antibody (ASMA), anti-Mitochondrial M2 antibody (AMA-M2) and anti-gp210 antibody. The rest of the Liverdot was negative (anti-sp100, anti-LKM1, anti-LC1, anti-SLA/LP). Additionally, the patient had mild hypergammaglobulinaemia (1750 mg/dl) with normal levels of IgA, IgM, and IgG. At this stage, DILI with autoimmune features was considered; however, a RUCAM score (Roussel Uclaf Causality Assessment Method) of 2 made the diagnosis unlikely ( Table 1 ). Nevertheless, anti-TB drugs were permanently discontinued, as TB was declared cured. Table 1. Updated Roussel Uclaf Causality Assessment Method (RUCAM) for Hepatocellular pattern of drug-induced liver injury * . Criteria Points Case 1 Case 2 Time to onset from beginning of drug/herb: • 5 – 90 days (rechallenge: 1 – 15 days) • 90 days (rechallenge: > 15 days) Alternative: Time to onset from cessation of drug/herb: • ≤15 days (except for slowly metabolised chemicals: >15 days) +2 +1 +1 x x Course of ALT after cessation of drug/herb: • Decrease ≥50% within 8 days • Decrease ≥50% within 30 days • No information or continued drug use • Decrease ≥50% after the 30 th day • Decrease <50% after the 30 th day or recurrent increase +3 +2 0 0 -2 x x Risk factors: • Alcohol use • Age ≥ 55 years +1 +1 x Concomitant drugs/herbs: • None or no information • Concomitant drug/herb with incompatible time to onset • Concomitant drug/herb with compatible or suggestive time to onset • Concomitant drug/herb known as hepatotoxin and with compatible or suggestive time to onset • Concomitant drug/herb with evidence for its role in this case (positive re-challenge or validated test) 0 0 -1 -2 -3 x x Search for alternative causes ** : • All causes reasonably ruled-out (group I and II) • The 7 causes of group I ruled-out • 5 – 6 causes of group I ruled-out • < 5 causes of group I ruled-out • Alternative cause highly probable +2 +1 0 -2 -3 x x x Previous hepatotoxicity to the drug/herb: • Reaction labelled in the product characteristics • Reaction published but unlabelled • Reaction unknown +2 +1 0 x x Response to unintentional re-exposure: • Doubling of ALT with drug/herb alone (if ALT <5 xULN before re-exposure) • Doubling of ALT with the drug/herb already given at time of first reaction • Increase of ALT but < 5 ULN in the same conditions as for first administration • Other situations +3 +1 -2 0 Total score 2 2 Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. * The updated RUCAM for hepatocellular injury of drug-induced liver injury, adapted from Danan and Teschke. 19 ** Group I causes include viral hepatitis A, B, C, and E, biliary and vascular obstruction (on imaging), alcohol consumption, and acute arterial hypotension. Group II causes include complications of underlying diseases such as sepsis, metastatic malignancy, chronic hepatitis B or C, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, or genetic liver diseases, as well as viral infections like cytomegalovirus, herpes simplex virus, Epstein-Barr virus, or varicella-zoster virus. Total score and corresponding causality grading: ≤0 = excluded, 1–2 = unlikely, 3–5 = possible, 6–8 = probable, ≥9 = highly probable. At follow-up, LFTs returned to normal levels within 2 months. However, the patient complained of persistent right upper quadrant abdominal discomfort without pruritus or fatigue. Immunological assessment at 3 months showed the same previous findings with an increased ANA titre of 1/800. Abdominal US at 6 months revealed a dysmorphic liver with surface irregularity, right lobe hypotrophy, and left lobe hypertrophy, but no signs of portal hypertension or impaired liver function. Transient elastography using Fibroscan ® revealed a median liver elasticity of 12.2 kPa. Subsequently, a liver biopsy was performed for diagnostic and prognostic purposes, which demonstrated septal fibrosis, interface hepatitis ( Figure 1 ), hepatic rosette formation, and non-suppurative destructive lymphocytic cholangitis (florid duct lesions). Figure 1. Liver biopsy of the patient in the first case. Haematoxylin and eosin staining showing in (A), on x100 magnification, a portal tract enlarged with fibrosis along with fibrous bands separating clusters of hepatocytes with an annular tendency. This fibrosis contains lymphoplasmacytic and polymorphic inflammatory infiltrate disrupting the limiting plate and extending to periportal hepatocytes, resulting in interface hepatitis (arrows). Ballooned hepatocytes are also visible (*). Lobular inflammatory infiltrate with necrosis (#) is also noted in (B) and in x200 magnification (C). The definitive diagnosis of AIH-PBC overlap syndrome was established, rather than DILI, based on the “Paris criteria”, meeting two of the three key criteria for each disease. For PBC, these included AMA-M2 positivity and florid bile duct lesions on biopsy; for AIH, ASMA positivity and moderate interface hepatitis on biopsy. Accordingly, the patient was started on ursodeoxycholic acid (UDCA) 15 mg/kg/day and azathioprine 1.2 mg/kg/day with good treatment adherence and tolerability. Given that LFTs were normal, no corticosteroids were prescribed, and LFTs remained normal during a 7-month follow-up period. Case 2 A 64-year-old Caucasian man with no prior medical history and no alcohol intake was diagnosed with pulmonary TB following a positive sputum polymerase chain reaction result. Pre-treatment LFTs showed AST levels at 1.5 xULN with normal levels of ALT, ALP, GGT, and BIL. He received initial anti-TB therapy (INH, RIF, PZA, and EMB) for two months. At the end of this period, the patient developed jaundice due to acute hepatitis, with levels of AST at 15 xULN, ALT at 4 xULN, ALP at 1.6 xULN, GGT at 5 xULN, BIL at 2 mg/dl, and prothrombin time (PT) at 51%. The treatment was consequently discontinued. However, an acute liver injury (ALI) was settled, as indicated by the decline in PT to 46% alongside hypertransaminasemia worsening (AST at 22 xULN, ALT at 8 xULN) and a rise in BIL levels to 3 mg/dl. An aetiological investigation revealed active hepatitis B (positive AgHBs, negative AgHBe, and a viral load of 8,000,000 IU/ml). Other viral causes were excluded (negative IgM HAV, negative IgM HEV, negative anti-HCV, negative HIV serology, and previous immunity to EBV, CMV, and HSV 1 and 2). The patient was started on entecavir 0.5 mg/d. Disease assessment showed a dysmorphic liver on ultrasound with irregular contours and the presence of oesophageal varices on endoscopy. Within one week of initiating entecavir, LFTs continued to worsen, with AST reaching 26 xULN, ALT reaching 9 xULN, BIL increasing to 3.5 mg/dl, and PT dropping to 30%. Further immunological assays showed positive ANA at 1/100 and ASMA at 1/100. Other liver-related autoantibodies were negative. DILI with autoimmune features was suspected; however, LFTs worsening despite discontinuation of anti-TB drugs, and a RUCAM score (Table 1) of 2 made DILI unlikely. Nonetheless, the patient was started on oral corticosteroids (prednisolone 30 mg/d) following negative sputum bacilloscopy tests and an expert opinion. In 3 weeks, LFTs significantly improved (AST at 5 xULN, ALT at 2 xULN, BIL at 2 mg/dl, and PT at 48%), with persistent cholestasis (ALP at 1.6 xULN, GGT at 5 xULN). A liver biopsy revealed portal and periportal extensive fibrosis with regenerative nodules, lymphoplasmocytic infiltrate in the portal tract extending into the lobule with hepatic rosette formation, and a marked interface hepatitis. Florid bile duct lesions with evident ductopenia were also observed. Several ground glass hepatocytes and central ballooning degeneration were found, attesting to active hepatitis B infection. This reflected an overall aspect of chronic liver disease with severe activity (A3-F4, Metavir). In light of these findings, the diagnosis of AIH-PBC overlap syndrome was confirmed based on the “Paris criteria”: ASMA positivity and severe interface hepatitis for AIH, and GGT ≥ 5× ULN and florid bile duct lesions for PBC. Accordingly, the patient was kept on entecavir and corticosteroids, and UDCA was started at a 15 mg/kg/d. LFTs continuously improved within two months. Nevertheless, expert opinion recommended no anti-TB restart until the total normalisation of liver enzymes, given that TB symptoms and radiographic lesions had considerably recovered. Immunosuppressive therapy was allowed at that point. Therefore, the patient was started on azathioprine (50 mg/d, then 100 mg/d) alongside tapering corticosteroids (5 mg/3 weeks), with good compliance and tolerability to the treatment. After six months, biological findings showed complete normalisation of LFTs, and the viral load of HBV was 40 IU/ml. Discussion Though the manifestation of authentic AIH-PBC overlap syndrome during anti-TB treatment is uncommon and rarely reported, drug-induced autoimmune liver disease (DIALD), which encompasses various combinations of AIH and DILI, has been increasingly studied. DIALD can be classified into three main types 3 ( Table 2 ). First, “AIH with DILI” includes patients already diagnosed with AIH, who reactivate their quiescent disease upon the introduction of a new drug, often with advanced fibrosis. Second, “drug-induced AIH” (DI-AIH) involves patients with undiagnosed low-grade disease or genetically predisposed to develop AIH, where the drug generates an immune reaction sustaining AIH, leading to chronic inflammation and requiring continuous immunosuppressive therapy. DI-AIH patients usually carry typical HLA-DR haplotypes associated with AIH. The third type is “immune-mediated DILI” (IM-DILI), where the drug triggers an adverse immune reaction with hypersensitivity. The liver injury in IM-DILI can be acute or chronic, and it may resolve or remain quiescent after drug cessation. IM-DILI is the most common DIALD type and is also referred to as drug-induced AIH-like injury. It often resembles idiopathic AIH, showing a complete response to corticosteroid treatment, yet with no relapse. 4 – 6 Table 2. Clinical characteristics of drug-induced autoimmune liver disease subtypes. Predisposed subjects Mechanism/Presentation Advanced fibrosis on histology Long-term immunosuppression AIH with DILI Diagnosed AIH, in quiescent state Disease flare-up when introducing a new drug. Proving causality is however difficult due to potential coincidences Often present Required DI-AIH Undiagnosed low-grade disease or genetic predisposition to AIH (usually carry typical HLA-DR haplotypes associated with AIH) The drug induces an immune response that results in chronic inflammation, sustaining AIH Possible Required DI-ALH (IM-DILI) Genetic susceptibility to DILI The most frequent drug-induced liver immune reaction caused by drugs. Hypersensitivity features (fever, rash, eosinophilia). Resembles idiopathic AIH (AIH-like) Usually absent Typically resolves after drug withdrawal ± CS. Usually complete response to CS treatment with no relapse The immunopathogenesis of DILI with autoimmune features is not fully understood. It has been hypothesised that these idiosyncratic adverse events involve reactive drug metabolites, primarily produced by CYP450, which bind covalently to this enzyme, forming neoantigens that activate humoral and cellular immune reactions, leading to liver injury. 2 , 4 Distinguishing classical AIH from DIALD is challenging as no specific feature is exclusive to either entity. Certain characteristics favour drug-induced AIH-like liver injury, including the presence of hypersensitivity features (in up to 30% of cases), absence of advanced fibrosis or cirrhosis at presentation, and no relapse after steroids discontinuation. 4 – 6 As both conditions can share similar clinical, biochemical, and serological patterns, histological findings may not always be helpful in distinguishing between the two diagnoses. Nevertheless, Suzuki et al. 7 found that certain features such as portal and intra-acinar plasma cells, rosette formation, and emperipolesis, along with more severe histological inflammation scores (Ishak score), supported the diagnosis of AIH. On the other hand, portal neutrophils and intracellular cholestasis were more prevalent in DILI. However, interface hepatitis, emperipolesis, and rosette formation were also present in 89%, 34%, and 40% of DILI cases, respectively. Recently, Lammert et al. 8 suggested that autoantibody profiling could be a promising and useful tool to distinguish idiopathic AIH and DILI with AIH-like phenotype. Among 65 patients with autoimmune phenotype DILI and 17 patients with de novo AIH, they found that the former group had elevated IgM (55%) but not IgG autoantibodies, whereas the latter group had elevated IgG (46%) and IgM (70%) autoantibodies, theorising the unique IgG autoantibodies signature in authentic AIH. Based on this, they developed a model incorporating IgG autoantibodies directed against centromere protein B, myosin, mitochondrial antigen, and nucleosome antigen, which accurately predicted de novo AIH, distinguishing it from autoimmune DILI, with an area under the receiver operating characteristic (ROC) curve of 0.88. A study by Björnsson et al. 9 included 216 patients with AIH, of which 9.2% were drug-induced, and both groups showed similar clinical and histological characteristics. Notably, overlap syndromes with PBC were excluded from this study. They found that nitrofurantoin and minocycline accounted for more than 90% of the drug-induced AIH cases. Anti-TB drugs are the leading cause of DILI in India and China, given the prevalence of TB in these countries. 10 , 11 The reported incidence of DILI due to anti-TB drugs varies between 2% and 28%. 1 Isoniazid, pyrazinamide, and rifampicin are recognised as potentially hepatotoxic drugs. Isoniazid, in particular, is notorious for causing hepatocellular injury and has been incriminated in some cases of idiosyncratic DILI. It ranks second among antimicrobials responsible for DILI (11.7%) in the United States DILI Network registry 12 and is considered to have a probable association with liver injuries resembling AIH. 5 Previous literature has reported cases of DILI with autoimmune features due to anti-TB treatment, applying RUCAM score for assessing causality. 13 , 14 Certain risk factors have been suggested to predict DILI, including age, female gender, malnutrition, alcohol intake, and pre-existing liver disease. 12 Slow acetylator status and specific genetic polymorphisms have also been associated with DILI occurrence due to isoniazid. 2 , 15 , 16 Additionally, polymorphisms of drug-metabolising enzymes, mainly CYP, and major histocompatibility complex (MHC) are plausible genetic factors for autoimmune DILI susceptibility. 2 , 4 An interesting study conducted by Lucena et al. 17 reported that 9 out of 742 patients experienced a second episode of DILI caused by a different offending agent than the first one. Among these 9 patients, four had a presentation of AIH. The authors concluded that recurrent DILI is likely to be associated with autoimmune features. However, the mystery remains unresolved whether the episode was a DILI unmasking an authentic AIH or an IM-DILI. Immune-mediated hepatotoxicity can also present with a cholestatic phenotype, characterised by small bile duct injury. This type of DILI is more common in elderly patients and typically exhibits delayed recovery and a tendency to become chronic even after drug withdrawal. 4 , 12 , 15 In some cases, it may progress to ductopenia, known as vanishing bile duct syndrome (VBDS), and biliary cirrhosis. This DILI phenotype is well established with amoxicillin-clavulanic acid association. 4 , 12 , 15 Notably, chronic cholestatic hepatitis, or VBDS, has not been linked to anti-TB drugs (INH, RIF, PZA, EMB) according to LiverTox database. Ultimately, both of our patients were diagnosed with authentic AIH-PBC overlap syndrome, based on the “Paris criteria”, as recommended by guidelines. 5 , 6 An undiagnosed quiescent AIH, unmasked by anti-TB treatment, appeared to be a more plausible explanation than a de novo IM-DILI. The presence of advanced fibrosis, characteristic histology findings, and the association with PBC support this conclusion. Furthermore, PBC is known for its progressive nature and slow onset. Additionally, the positivity of AMA-M2 and anti-gp210, as well as the presence of florid bile duct lesions, strongly suggest PBC and argue against a cholestatic DILI. In cases of AIH-like DILI, the backbone of the treatment is cessation of the causative drugs and close monitoring of liver enzymes until recovery, which typically occurs within a month. 5 Corticosteroid therapy should be initiated for severe hepatitis or if lab tests do not improve or worsen after drug withdrawal. 5 , 6 Corticosteroids may also be prescribed for severe hypersensitivity reactions, DRESS syndrome, and when autoimmune features are observed on liver biopsy. 15 Typically, glucocorticoids lead to a response with no relapse after discontinuation. Unlike authentic AIH, long-term immunosuppression is not required. Therefore, follow-up can help differentiate AIH and DILI. 5 , 6 UDCA might be beneficial in cases of DILI with prolonged cholestasis. 4 , 15 In the cases of our patients, both of them required immunosuppressive therapy, along with UDCA, given that they were diagnosed with AIH-PBC overlap syndrome. In the first case, discontinuation of anti-TB drugs led to resolution of liver injury without the need for corticosteroids. Instead, the decision to prescribe immunosuppressants was based on histological disease activity and advanced fibrosis. As for the second patient, the withdrawal of anti-TB drugs and the use of entecavir were not sufficient to induce remission of ALI until steroids were introduced. Subsequently, normalisation of cholestasis was slowly achieved with UDCA treatment. In conclusion, our article emphasises the significance of monitoring for DILI during TB therapy. It also highlights the importance of considering authentic ALD, despite overlapping features with DILI, which can make accurate diagnosis challenging. A comprehensive understanding of these entities, aided by histological findings, is essential for initiating appropriate treatment strategies. Ethical approval Ethical approval was not required for this study. Consent Written informed consent for publication of their clinical details and/or clinical images was obtained from the patients. Data availability No data are associated with this article. Reporting guidelines Zenodo Repository: CARE checklist for ‘Autoimmune Liver Disease Revealed by Tuberculosis Treatment: Report of Two Cases and Literature Review’. DOI: https://doi.org/10.5281/zenodo.13934956 . 18 Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). Acknowledgements No acknowledgments to declare. References 1. Wang N, Chen X, Hao Z, et al. : Incidence and Temporal Trend of Antituberculosis Drug-Induced Liver Injury: A Systematic Review and Meta-Analysis. J Trop Med. 2022; 2022 : 1–10. PubMed Abstract | Publisher Full Text | Free Full Text 2. Soedarsono S, Riadi ARW: Tuberculosis Drug-Induced Liver Injury. J Respirasi. 2020; 6 (2): 49–54. Publisher Full Text 3. Agustin Castiella EZ, Andrade l J: Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease. World J Hepatol. 2014; 6 (4): 160–168. PubMed Abstract | Publisher Full Text | Free Full Text 4. Liu ZX, Kaplowitz N: Immune-mediated drug-induced liver disease. Clin Liver Dis. 2002; 6 (3): 755–774. Publisher Full Text 5. Mack CL, Adams D, Assis DN, 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. PubMed Abstract | Publisher Full Text 6. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015; 63 (4): 971–1004. Publisher Full Text 7. Suzuki A, Brunt EM, Kleiner DE, et al. : The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology. 2011; 54 (3): 931–939. PubMed Abstract | Publisher Full Text | Free Full Text 8. Lammert C, Zhu C, Lian Y, et al. : Exploratory Study of Autoantibody Profiling in Drug-Induced Liver Injury with an Autoimmune Phenotype. Hepatol Commun. 2020; 4 (11): 1651–1663. PubMed Abstract | Publisher Full Text | Free Full Text 9. Björnsson E, Talwalkar J, Treeprasertsuk S, et al. : Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatol Baltim Md. 2010; 51 (6): 2040–2048. PubMed Abstract | Publisher Full Text 10. Devarbhavi H, Dierkhising R, Kremers WK, et al. : Single-Center Experience With Drug-Induced Liver Injury From India: Causes, Outcome, Prognosis, and Predictors of Mortality. Off J Am Coll Gastroenterol ACG. 2010; 105 (11): 2396–2404. Publisher Full Text Reference Source 11. Zhou Y, Yang L, Liao Z, et al. : Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21 789 patients. Eur J Gastroenterol Hepatol. 2013; 25 (7): 825–829. PubMed Abstract | Publisher Full Text Reference Source 12. Sandhu N, Navarro V: Drug-Induced Liver Injury in GI Practice. Hepatol Commun. 2020; 4 (5): 631–645. PubMed Abstract | Publisher Full Text | Free Full Text 13. Mosqueira JR, Anicama S, Ríos JDL: A Severe Autoimmune-like Anti-Tuberculosis Drug-induced Liver Injury: Case Report and Review. J Microbiol Infect Dis. 2018; 08 (03): 128–134. Publisher Full Text 14. Rangel MA, Pinto Pais I, Duarte R, et al. : Antituberculosis Drug-Induced Liver Injury with Autoimmune Features: Facing Diagnostic and Treatment Challenges. Case Rep Pediatr. 2017; 2017 : 1–4. PubMed Abstract | Publisher Full Text | Free Full Text 15. Fontana RJ, Liou I, Reuben A, et al. : AASLD practice guidance on drug, herbal, and dietary supplement–induced liver injury. Hepatology. 2022; 77 (n/a): 1036–1065. PubMed Abstract | Publisher Full Text | Free Full Text 16. Mushiroda T, Yanai H, Yoshiyama T, et al. : Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients. Hum Genome Var. 2016; 3 (1): 16014. PubMed Abstract | Publisher Full Text | Free Full Text 17. Lucena MI, Kaplowitz N, Hallal H, et al. : Recurrent Drug-Induced Liver Injury (DILI) with different drugs in the Spanish Registry: The dilemma of the relationship to autoimmune hepatitis. J Hepatol. 2011; 55 (4): 820–827. PubMed Abstract | Publisher Full Text 18. Tababi R: CARE checklist for “Autoimmune Liver Disease Revealed by Tuberculosis Treatment: Report of Two Cases and Literature Review.” [Dataset]. Published online October 15, 2024. Publisher Full Text 19. Danan G, Teschke R: RUCAM in Drug and Herb Induced Liver Injury: The Update. Int J Mol Sci. 2016; 17 (1): 14. Publisher Full Text Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 24 Oct 2024 ADD YOUR COMMENT Comment Author details Author details 1 Gastroenterology Department B, Rabta University Hospital, Tunis, Tunis, Tunisia 2 Pathology Department, Rabta University Hospital, Tunis, Tunis, Tunisia 3 Pharmacovigilance Department, Faculty of Medicine of Tunis, Tunis, Tunisia Ramzi Tababi Roles: Conceptualization, Data Curation, Resources, Writing – Original Draft Preparation, Writing – Review & Editing Kchir Hela Roles: Conceptualization, Data Curation, Investigation, Resources, Supervision, Validation, Visualization, Writing – Review & Editing Alia Zehani Roles: Writing – Review & Editing Imen Aouinti Roles: Writing – Review & Editing Hajer Hassine Roles: Supervision, Validation, Writing – Review & Editing Ahmed Nefzi Roles: Data Curation, Resources, Writing – Review & Editing Khadija Bellil Roles: Data Curation, Resources, Visualization Slim Haouet Roles: Data Curation, Resources, Visualization Habiba Debbabi Roles: Supervision, Validation, Writing – Review & Editing Nadia Maamouri Roles: Conceptualization, Investigation, Project Administration, Supervision, Validation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (3) version 3 Revised Published: 31 Mar 2025, 13:1270 https://doi.org/10.12688/f1000research.157997.3 version 2 Revised Published: 17 Jan 2025, 13:1270 https://doi.org/10.12688/f1000research.157997.2 version 1 Published: 24 Oct 2024, 13:1270 https://doi.org/10.12688/f1000research.157997.1 Copyright © 2025 Tababi R et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Tababi R, Hela K, Zehani A et al. AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 3; peer review: 1 approved] . F1000Research 2025, 13 :1270 ( https://doi.org/10.12688/f1000research.157997.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 17 Jan 2025 Revised Views 0 Cite How to cite this report: Teschke R. Reviewer Report For: AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 3; peer review: 1 approved] . F1000Research 2025, 13 :1270 ( https://doi.org/10.5256/f1000research.176587.r360163 ) The direct URL for this report is: https://f1000research.com/articles/13-1270/v2#referee-response-360163 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 25 Jan 2025 Rolf Teschke , Goethe University, Hanau, Germany Approved VIEWS 0 https://doi.org/10.5256/f1000research.176587.r360163 Yes, paper can be accepted but ensure that in the ... Continue reading READ ALL Yes, paper can be accepted but ensure that in the reference list ref 19: 2015 should be replaced by 2016. Competing Interests: No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Teschke R. Reviewer Report For: AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 3; peer review: 1 approved] . F1000Research 2025, 13 :1270 ( https://doi.org/10.5256/f1000research.176587.r360163 ) The direct URL for this report is: https://f1000research.com/articles/13-1270/v2#referee-response-360163 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 31 Mar 2025 Ramzi Tababi , Gastroenterology Department B, Rabta University Hospital, Tunis, Tunisia 31 Mar 2025 Author Response Thank you for your feedback. The year for reference 19 has been corrected from 2015 to 2016 as requested. Competing Interests: No competing interests were disclosed. Thank you for your feedback. The year for reference 19 has been corrected from 2015 to 2016 as requested. Thank you for your feedback. The year for reference 19 has been corrected from 2015 to 2016 as requested. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 31 Mar 2025 Ramzi Tababi , Gastroenterology Department B, Rabta University Hospital, Tunis, Tunisia 31 Mar 2025 Author Response Thank you for your feedback. The year for reference 19 has been corrected from 2015 to 2016 as requested. Competing Interests: No competing interests were disclosed. Thank you for your feedback. The year for reference 19 has been corrected from 2015 to 2016 as requested. Thank you for your feedback. The year for reference 19 has been corrected from 2015 to 2016 as requested. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 24 Oct 2024 Views 0 Cite How to cite this report: Teschke R. Reviewer Report For: AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 3; peer review: 1 approved] . F1000Research 2025, 13 :1270 ( https://doi.org/10.5256/f1000research.173527.r345335 ) The direct URL for this report is: https://f1000research.com/articles/13-1270/v1#referee-response-345335 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 16 Dec 2024 Rolf Teschke , Goethe University, Hanau, Germany Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.173527.r345335 This paper requires complete re-writing. Major points: It seems that you are describing Drug induced autoimmune hepatitis (DIAIH), if this is correct, cases need two different diagnostic approaches. One for the DILI part, using the ... Continue reading READ ALL This paper requires complete re-writing. Major points: It seems that you are describing Drug induced autoimmune hepatitis (DIAIH), if this is correct, cases need two different diagnostic approaches. One for the DILI part, using the updated RUCAM of 2016, and one for the AIH part using the simplified AIH score of Hennes. Provide scores of both methods in the abstract and the text. The focus should be on DIAIH diagnosis. This should be clarified in the title with details in the abstract and under keywords. Authors should discuss the importance of DIAIH and the need to evaluate this disorder characterized by disrupting drugs. Author should include in the discussion DIAIH cases by other drugs and should analyze how these published reports has been assessed for causality. Is the background of the cases’ history and progression described in sufficient detail? No Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No Is the conclusion balanced and justified on the basis of the findings? Partly Competing Interests: No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Teschke R. Reviewer Report For: AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 3; peer review: 1 approved] . F1000Research 2025, 13 :1270 ( https://doi.org/10.5256/f1000research.173527.r345335 ) The direct URL for this report is: https://f1000research.com/articles/13-1270/v1#referee-response-345335 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 17 Jan 2025 Ramzi Tababi , Gastroenterology Department B, Rabta University Hospital, Tunis, Tunisia 17 Jan 2025 Author Response Thank you for your valuable feedback. To clarify, the cases presented in our report describe genuine AIH-PBC overlap syndrome, which was only revealed upon the initiation of anti-TB drugs. While ... Continue reading Thank you for your valuable feedback. To clarify, the cases presented in our report describe genuine AIH-PBC overlap syndrome, which was only revealed upon the initiation of anti-TB drugs. While drug-induced autoimmune hepatitis (DIAIH) was initially considered as a differential diagnosis, it was ultimately ruled out based on the updated RUCAM scores for both cases, which indicated that DILI was unlikely. The final diagnosis of AIH-PBC overlap syndrome was made according to the "Paris criteria", as recommended by international guidelines, which are more appropriate for diagnosing overlap syndrome than the simplified or older AIH criteria. We have revised the manuscript to explicitly clarify these points, including the updated RUCAM scores (as per your recommendation) and the use of the "Paris criteria", to prevent any misunderstanding and provide a clearer understanding of our diagnostic approach and conclusions. In the discussion, we have provided a detailed explanation supporting our diagnosis, highlighting the presence of advanced fibrosis, characteristic histological findings, and the association with PBC, all of which reinforce our conclusion of AIH-PBC overlap syndrome, while also addressing the literature on autoimmune-phenotype DILI. To clarify once again, this report is not about drug-induced autoimmune hepatitis; rather, it describes true AIH-PBC overlap syndrome that was unmasked by the initiation of anti-TB drugs. That's why the title was also changed to convey the accurate focus of the manuscript. Thank you for your valuable feedback. To clarify, the cases presented in our report describe genuine AIH-PBC overlap syndrome, which was only revealed upon the initiation of anti-TB drugs. While drug-induced autoimmune hepatitis (DIAIH) was initially considered as a differential diagnosis, it was ultimately ruled out based on the updated RUCAM scores for both cases, which indicated that DILI was unlikely. The final diagnosis of AIH-PBC overlap syndrome was made according to the "Paris criteria", as recommended by international guidelines, which are more appropriate for diagnosing overlap syndrome than the simplified or older AIH criteria. We have revised the manuscript to explicitly clarify these points, including the updated RUCAM scores (as per your recommendation) and the use of the "Paris criteria", to prevent any misunderstanding and provide a clearer understanding of our diagnostic approach and conclusions. In the discussion, we have provided a detailed explanation supporting our diagnosis, highlighting the presence of advanced fibrosis, characteristic histological findings, and the association with PBC, all of which reinforce our conclusion of AIH-PBC overlap syndrome, while also addressing the literature on autoimmune-phenotype DILI. To clarify once again, this report is not about drug-induced autoimmune hepatitis; rather, it describes true AIH-PBC overlap syndrome that was unmasked by the initiation of anti-TB drugs. That's why the title was also changed to convey the accurate focus of the manuscript. Competing Interests: No competing interests to disclose. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 17 Jan 2025 Ramzi Tababi , Gastroenterology Department B, Rabta University Hospital, Tunis, Tunisia 17 Jan 2025 Author Response Thank you for your valuable feedback. To clarify, the cases presented in our report describe genuine AIH-PBC overlap syndrome, which was only revealed upon the initiation of anti-TB drugs. While ... Continue reading Thank you for your valuable feedback. To clarify, the cases presented in our report describe genuine AIH-PBC overlap syndrome, which was only revealed upon the initiation of anti-TB drugs. While drug-induced autoimmune hepatitis (DIAIH) was initially considered as a differential diagnosis, it was ultimately ruled out based on the updated RUCAM scores for both cases, which indicated that DILI was unlikely. The final diagnosis of AIH-PBC overlap syndrome was made according to the "Paris criteria", as recommended by international guidelines, which are more appropriate for diagnosing overlap syndrome than the simplified or older AIH criteria. We have revised the manuscript to explicitly clarify these points, including the updated RUCAM scores (as per your recommendation) and the use of the "Paris criteria", to prevent any misunderstanding and provide a clearer understanding of our diagnostic approach and conclusions. In the discussion, we have provided a detailed explanation supporting our diagnosis, highlighting the presence of advanced fibrosis, characteristic histological findings, and the association with PBC, all of which reinforce our conclusion of AIH-PBC overlap syndrome, while also addressing the literature on autoimmune-phenotype DILI. To clarify once again, this report is not about drug-induced autoimmune hepatitis; rather, it describes true AIH-PBC overlap syndrome that was unmasked by the initiation of anti-TB drugs. That's why the title was also changed to convey the accurate focus of the manuscript. Thank you for your valuable feedback. To clarify, the cases presented in our report describe genuine AIH-PBC overlap syndrome, which was only revealed upon the initiation of anti-TB drugs. While drug-induced autoimmune hepatitis (DIAIH) was initially considered as a differential diagnosis, it was ultimately ruled out based on the updated RUCAM scores for both cases, which indicated that DILI was unlikely. The final diagnosis of AIH-PBC overlap syndrome was made according to the "Paris criteria", as recommended by international guidelines, which are more appropriate for diagnosing overlap syndrome than the simplified or older AIH criteria. We have revised the manuscript to explicitly clarify these points, including the updated RUCAM scores (as per your recommendation) and the use of the "Paris criteria", to prevent any misunderstanding and provide a clearer understanding of our diagnostic approach and conclusions. In the discussion, we have provided a detailed explanation supporting our diagnosis, highlighting the presence of advanced fibrosis, characteristic histological findings, and the association with PBC, all of which reinforce our conclusion of AIH-PBC overlap syndrome, while also addressing the literature on autoimmune-phenotype DILI. To clarify once again, this report is not about drug-induced autoimmune hepatitis; rather, it describes true AIH-PBC overlap syndrome that was unmasked by the initiation of anti-TB drugs. That's why the title was also changed to convey the accurate focus of the manuscript. Competing Interests: No competing interests to disclose. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 24 Oct 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 3 (revision) 31 Mar 25 Version 2 (revision) 17 Jan 25 read Version 1 24 Oct 24 read Rolf Teschke , Goethe University, Hanau, Germany Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Teschke R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 25 Jan 2025 | for Version 2 Rolf Teschke , Goethe University, Hanau, Germany 0 Views copyright © 2025 Teschke R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Yes, paper can be accepted but ensure that in the reference list ref 19: 2015 should be replaced by 2016. Competing Interests No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 31 Mar 2025 Ramzi Tababi, Gastroenterology Department B, Rabta University Hospital, Tunis, Tunisia Thank you for your feedback. The year for reference 19 has been corrected from 2015 to 2016 as requested. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Teschke R. Peer Review Report For: AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 3; peer review: 1 approved] . F1000Research 2025, 13 :1270 ( https://doi.org/10.5256/f1000research.176587.r360163) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1270/v2#referee-response-360163 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Teschke R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 16 Dec 2024 | for Version 1 Rolf Teschke , Goethe University, Hanau, Germany 0 Views copyright © 2024 Teschke R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This paper requires complete re-writing. Major points: It seems that you are describing Drug induced autoimmune hepatitis (DIAIH), if this is correct, cases need two different diagnostic approaches. One for the DILI part, using the updated RUCAM of 2016, and one for the AIH part using the simplified AIH score of Hennes. Provide scores of both methods in the abstract and the text. The focus should be on DIAIH diagnosis. This should be clarified in the title with details in the abstract and under keywords. Authors should discuss the importance of DIAIH and the need to evaluate this disorder characterized by disrupting drugs. Author should include in the discussion DIAIH cases by other drugs and should analyze how these published reports has been assessed for causality. Is the background of the cases’ history and progression described in sufficient detail? No Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No Is the conclusion balanced and justified on the basis of the findings? Partly Competing Interests No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 17 Jan 2025 Ramzi Tababi, Gastroenterology Department B, Rabta University Hospital, Tunis, Tunisia Thank you for your valuable feedback. To clarify, the cases presented in our report describe genuine AIH-PBC overlap syndrome, which was only revealed upon the initiation of anti-TB drugs. While drug-induced autoimmune hepatitis (DIAIH) was initially considered as a differential diagnosis, it was ultimately ruled out based on the updated RUCAM scores for both cases, which indicated that DILI was unlikely. The final diagnosis of AIH-PBC overlap syndrome was made according to the "Paris criteria", as recommended by international guidelines, which are more appropriate for diagnosing overlap syndrome than the simplified or older AIH criteria. We have revised the manuscript to explicitly clarify these points, including the updated RUCAM scores (as per your recommendation) and the use of the "Paris criteria", to prevent any misunderstanding and provide a clearer understanding of our diagnostic approach and conclusions. In the discussion, we have provided a detailed explanation supporting our diagnosis, highlighting the presence of advanced fibrosis, characteristic histological findings, and the association with PBC, all of which reinforce our conclusion of AIH-PBC overlap syndrome, while also addressing the literature on autoimmune-phenotype DILI. To clarify once again, this report is not about drug-induced autoimmune hepatitis; rather, it describes true AIH-PBC overlap syndrome that was unmasked by the initiation of anti-TB drugs. That's why the title was also changed to convey the accurate focus of the manuscript. View more View less Competing Interests No competing interests to disclose. reply Respond Report a concern Teschke R. Peer Review Report For: AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 3; peer review: 1 approved] . F1000Research 2025, 13 :1270 ( https://doi.org/10.5256/f1000research.173527.r345335) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1270/v1#referee-response-345335 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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