Gut Microbiota-Derived Butyrate Induces Epigenetic and Metabolic Reprogramming in Myeloid-Derived Suppressor Cells to Alleviate Primary Biliary Cholangitis.

BACKGROUND & AIMS: Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC. METHODS: We measured fecal short-chain fatty acids levels using targeted gas chromatography-mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and chromatin immunoprecipitation-quantitative polymerase chain reaction), and metabolic (untargeted liquid chromatography-mass spectrometry, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in a 2-octynoic acid-bovine serum albumin-induced cholangitis murine model. RESULTS: Decreased butyrate levels and defective MDSC function were found in patients with incomplete response to ursodeoxycholic acid, compared with those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid ß-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced acetylation of lysine 27 on histone H3 at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from ursodeoxycholic acid nonresponders, and their impaired suppressive function was restored by butyrate. CONCLUSIONS: We identify a critical role for butyrate in modulation of MDSC homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC.

Treatment response and clinical event-free survival in autoimmune hepatitis: A Canadian multicentre cohort study.

BACKGROUND & AIMS: Treatment outcomes for people living with autoimmune hepatitis (AIH) are limited by a lack of specific therapies, as well as limited well-validated prognostic tools and clinical trial endpoints. We sought to identify predictors of outcome for people living with AIH. METHODS: We evaluated the clinical course of people with AIH across 11 Canadian centres. Biochemical changes were analysed using linear mixed-effect and logistic regression. Clinical outcome was dynamically modelled using time-varying Cox proportional hazard modelling and landmark analysis. RESULTS: In 691 patients (median age 49 years, 75.4% female), with a median follow-up of 6 years (25th-75th percentile, 2.5-11), 118 clinical events occurred. Alanine aminotransferase (ALT) normalisation occurred in 63.8% of the cohort by 12 months. Older age at diagnosis (odd ratio [OR] 1.19, 95% CI 1.06-1.35) and female sex (OR 1.94, 95% CI 1.18-3.19) were associated with ALT normalisation at 6 months, whilst baseline cirrhosis status was associated with reduced chance of normalisation at 12 months (OR 0.52, 95% CI 0.33-0.82). Baseline total bilirubin, aminotransferases, and IgG values, as well as initial prednisone dose, did not predict average ALT reduction. At baseline, older age (hazard ratio [HR] 1.25, 95% CI 1.12-1.40), cirrhosis at diagnosis (HR 3.67, 95% CI 2.48-5.43), and elevated baseline total bilirubin (HR 1.36, 95% CI 1.17-1.58) increased the risk of clinical events. Prolonged elevations in ALT (HR 1.07, 95% CI 1.00-1.13) and aspartate aminotransferase (HR 1.13, 95% CI 1.06-1.21), but not IgG (HR 1.01, 95% CI 0.95-1.07), were associated with higher risk of clinical events. Higher ALT at 6 months was associated with worse clinical event-free survival. CONCLUSION: In people living with AIH, sustained elevated aminotransferase values, but not IgG, are associated with poorer long-term outcomes. Biochemical response and long-term survival are not associated with starting prednisone dose. IMPACT AND IMPLICATIONS: Using clinical data from multiple Canadian liver clinics treating autoimmune hepatitis (AIH), we evaluate treatment response and clinical outcomes. For the first time, we apply mixed-effect and time-varying survival statistical methods to rigorously examine treatment response and the impact of fluctuating liver biochemistry on clinical event-free survival. Key to the study impact, our data is 'real-world', represents a diverse population across Canada, and uses continuous measurements over follow-up. Our results challenge the role of IgG as a marker of treatment response and if normalisation of IgG should remain an important part of the definition of biochemical remission. Our analysis further highlights that baseline markers of disease severity may not prognosticate early treatment response. Additionally, the initial prednisone dose may be less relevant for achieving aminotransferase normalisation. This is important for patients and treating clinicians given the relevance and importance of side effects.

Prognostic scores for ursodeoxycholic acid-treated patients predict graft loss and mortality in recurrent primary biliary cholangitis after liver transplantation.

BACKGROUND & AIMS: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC. METHODS: A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. RESULTS: During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival. CONCLUSION: Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. IMPACT AND IMPLICATIONS: One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.

Genetic association and causal relationship between multiple modifiable risk factors and autoimmune liver disease: a two-sample mendelian randomization study.

BACKGROUND: The intricate etiology of autoimmune liver disease (AILD) involves genetic, environmental, and other factors that yet to be completely elucidated. This study comprehensively assessed the causal association between genetically predicted modifiable risk factors and AILD by employing Mendelian randomization. METHODS: Genetic variants associated with 29 exposure factors were obtained from genome-wide association studies (GWAS). Genetic association data with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) were also obtained from publicly available GWAS. Univariate and multivariate Mendelian randomization analyses were performed to identify potential risk factors for AILD. RESULTS: Genetically predicted rheumatoid arthritis (RA) (OR = 1.620, 95%CI 1.423-1.843, P = 2.506 × 10- 13) was significantly associated with an increased risk of AIH. Genetically predicted smoking initiation (OR = 1.637, 95%CI 1.055-2.540, P = 0.028), lower coffee intake (OR = 0.359, 95%CI 0.131-0.985, P = 0.047), cholelithiasis (OR = 1.134, 95%CI 1.023-1.257, P = 0.017) and higher C-reactive protein (CRP) (OR = 1.397, 95%CI 1.094-1.784, P = 0.007) were suggestively associated with an increased risk of AIH. Genetically predicted inflammatory bowel disease (IBD) (OR = 1.212, 95%CI 1.127-1.303, P = 2.015 × 10- 7) and RA (OR = 1.417, 95%CI 1.193-1.683, P = 7.193 × 10- 5) were significantly associated with increased risk of PBC. Genetically predicted smoking initiation (OR = 1.167, 95%CI 1.005-1.355, P = 0.043), systemic lupus erythematosus (SLE) (OR = 1.086, 95%CI 1.017-1.160, P = 0.014) and higher CRP (OR = 1.199, 95%CI 1.019-1.410, P = 0.028) were suggestively associated with an increased risk of PBC. Higher vitamin D3 (OR = 0.741, 95%CI 0.560-0.980, P = 0.036) and calcium (OR = 0.834, 95%CI 0.699-0.995, P = 0.044) levels were suggestive protective factors for PBC. Genetically predicted smoking initiation (OR = 0.630, 95%CI 0.462-0.860, P = 0.004) was suggestively associated with a decreased risk of PSC. Genetically predicted IBD (OR = 1.252, 95%CI 1.164-1.346, P = 1.394 × 10- 9), RA (OR = 1.543, 95%CI 1.279-1.861, P = 5.728 × 10- 6) and lower glycosylated hemoglobin (HbA1c) (OR = 0.268, 95%CI 0.141-0.510, P = 6.172 × 10- 5) were positively associated with an increased risk of PSC. CONCLUSIONS: Evidence on the causal relationship between 29 genetically predicted modifiable risk factors and the risk of AIH, PBC, and PSC is provided by this study. These findings provide fresh perspectives on the management and prevention strategies for AILD.

Blockade of neutrophil extracellular trap components ameliorates cholestatic liver disease in Mdr2 (Abcb4) knockout mice.

Primary sclerosing cholangitis (PSC) is an (auto)immune-mediated cholestatic liver disease with a yet unclear etiology. Increasing evidence points to an involvement of neutrophils in chronic liver inflammation and cirrhosis but also liver repair. Here, we investigate the role of the neutrophil extracellular trap (NET) component myeloperoxidase (MPO) and the therapeutic potential of DNase I and of neutrophil elastase (NE) inhibitor GW311616A on disease outcome in the multidrug resistance 2 knockout (Mdr2-/-) mouse, a PSC animal model. Initially, we observed the recruitment of MPO expressing cells and the formation of NETs in liver biopsies of PSC patients and in Mdr2-/- livers. Furthermore, sera of Mdr2-/- mice contained perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA)-like reactivity similar to PSC patient sera. Also, hepatic NE activity was significantly higher in Mdr2-/- mice than in wild type littermates. Flow cytometry analyses revealed that during disease development a highly active neutrophil subpopulation established specifically in the liver of Mdr2-/- mice. However, absence of their MPO activity, as in MPO-deficient Mdr2-/- mice, showed no effect on hepatobiliary disease severity. In contrast, clearance of extracellular DNA by DNase I reduced the frequency of liver-resident neutrophils, plasmacytoid dendritic cells (pDCs) and CD103+ conventional DCs and decreased cholangiocyte injury. Combination of DNase I with a pDC-depleting antibody was additionally hepatocyte-protective. Most importantly, GW311616A, an orally bioavailable inhibitor of human NE, attenuated hepatobiliary injury in a TNFα-dependent manner and damped hyperproliferation of biliary epithelial cells. Further, hepatic immigration and activity of CD11b+ DCs as well as the secretion of IFNγ by hepatic CD4 and CD8 T cells were reduced. Our findings delineate neutrophils as important participants in the immune cell crosstalk that drives cholestatic liver disease and identify NET components as potential therapeutic targets.

Association between autoimmune liver diseases and chronic hepatitis B: A multivariable Mendelian randomization study in European population.

BACKGROUND: Observational studies have indicated a link between autoimmune liver diseases (AILD) and chronic hepatitis B (CHB) through observational studies. The association between AILD and CHB remains indeterminate. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted to scrutinize the causal nexus between AILD and CHB utilizing summary statistics derived from extensive genome-wide association studies (GWASs) in European populations. The primary statistical methodology employed was the inverse variance-weighted (IVW) method to deduce the causal connection of AILD on CHB. This study incorporated primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) as subtypes of AILD. Additionally, we conducted a multivariable MR (MVMR) analysis to account for the potential confounding effects of smoking, alcohol consumption, body mass index (BMI), and some autoimmune diseases. RESULTS: Our MR investigation encompassed a cohort of 725,816 individuals. The MR analysis revealed that genetically predicted PSC significantly correlated with a reduced risk of CHB (IVW OR = 0.857; 95%CI: 0.770-0.953, P = 0.005). Conversely, the reverse MR analysis suggested that genetic susceptibility to PSC might not modify the risk of CHB (IVW OR = 1.004; 95% CI: 0.958-1.053, P = 0.866). Genetically proxied PBC and AIH exhibited no discernible causal association with CHB in the MR analysis using the IVW method (P = 0.583; P = 0.425). The MVMR analysis still indicated a decreased risk of CHB associated with PSC (OR = 0.853, P = 0.003). CONCLUSION: Our study elucidates a causal relationship between PSC and a diminished risk of CHB.

Only repeatedly elevated IgG4 levels in primary sclerosing cholangitis may distinguish a particular patient phenotype.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic liver disease leading to inflammation with scaring and strictures of bile ducts, which can lead to liver cirrhosis. A subtype of PSC characterized by high serum IgG4 (sIgG4) levels has been reported to be associated with poor outcomes, but the exact role and the longitudinal development of sIgG4 levels in PSC progression remains to be clarified. The aim of this study was to investigate if subsequent analysis of sIgG4 levels allows the identification of the PSC phenotype with high sIgG4. METHODS: sIgG4 values were repeatedly analysed in a well-characterized European PSC cohort of 110 individuals. Biochemical parameters, clinical endpoints, death and liver transplantation were compared between PSC subgroups. RESULTS: 12.7% (n = 14) of PSC patients showed increased sIgG4 levels (PSC-IgG4). The values normalized in 57.1% (n = 8; PSC-IgG4norm) during follow-up measurements, whereas the values remained permanently elevated in 42.9% (n = 6; PSC-IgG4const). Serum values of AP and γGT were significantly higher in PSC-IgG4const compared to PSC-IgG4norm at final blood sampling. Furthermore, mean age at PSC diagnosis was markedly lower in PSC-IgG4const compared to PSC-IgG4norm. CONCLUSIONS: This is the first study analyzing longitudinal development of sIgG4 in PSC. Our data indicate that only sequential determination of sIgG4 levels allow to accurately distinguish between the PSC phenotype with high sIgG4 and PSC with low sIgG4.

Evaluation of autoimmune liver disease natural history in patients referred to Middle East Liver Diseases (MELD) center.

BACKGROUND: Autoimmune liver diseases (AILD) are increasing and common forms of chronic liver disease (CLD) with different clinical responses and characteristics which can result in cirrhosis. This study aimed to investigate the natural history and characteristics of AILD in an Iranian population. METHODS: Patients with AILD [Autoimmune Hepatitis (AIH), Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC) and Overlap Syndrome (OS)] referred to Middle East Liver Diseases (MELD) center, Tehran, Iran, between January 2002 and December 2022 were included in this retrospective cohort study. The main features of natural history (the trends of liver functional tests (LFT), Auto-Antibodies, response to treatment and cirrhotic status) along with demographic data were studied. RESULTS: Two hundred sixty-five patients (160 (60.4%) AIH, 37 (14.0%) PBC, 20 (7.5%) PSC, 48 (18.1%) overlap syndrome) with a median follow-up time of 5 years (IQR 4 to 8 years) were included. Baseline laboratory tests revealed that patients with AIH exhibit elevated transaminase levels. However, patients suffering from PBC and PSC displayed increased alkaline phosphatase levels. Conversely, in overlap syndrome patients, both transaminases and alkaline phosphatase were observed at high levels. Autoantibodies represented themselves as important diagnostic markers for the AIH and PBC but not for PSC. The complete response occurred in 112 (70%) of and 28 (58.4%) patients with AIH and overlap syndrome respectively and 21 patients 11 (6.9%) of AIH and 10 (20.8%) of overlap syndrome) were non-responders. Other patients in these two categories were considered as insufficient responders. On the other side, 32 (91.9%) and 8 (40%) of patients with PBC and PSC biochemically responded to Ursodeoxycholic Acid (UDCA). Unpredictably, cirrhosis regression was observed in some AIH and PBC patients. CONCLUSION: Appropriate medication management for AILD patients may leads to regression from cirrhosis and improvement of manifestations; while discontinuation of medication may cause relapses. However, patient suffering from PSC showed limited response to treatment.

Safety and effectiveness of SARS-CoV-2 vaccines for patients with intractable hepatobiliary diseases: A multicenter, questionnaire-based, cross-sectional study.

AIM: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease. METHODS: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected. RESULTS: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination. CONCLUSION: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases.

Evaluation of four chatbots in autoimmune liver disease: A comparative analysis.

INTRODUCTION AND OBJECTIVES: Autoimmune liver diseases (AILDs) are rare and require precise evaluation, which is often challenging for medical providers. Chatbots are innovative solutions to assist healthcare professionals in clinical management. In our study, ten liver specialists systematically evaluated four chatbots to determine their utility as clinical decision support tools in the field of AILDs. MATERIALS AND METHODS: We constructed a 56-question questionnaire focusing on AILD evaluation, diagnosis, and management of Autoimmune Hepatitis (AIH), Primary Biliary Cholangitis (PBC), and Primary Sclerosing Cholangitis (PSC). Four chatbots -ChatGPT 3.5, Claude, Microsoft Copilot, and Google Bard- were presented with the questions in their free tiers in December 2023. Responses underwent critical evaluation by ten liver specialists using a standardized 1 to 10 Likert scale. The analysis included mean scores, the number of highest-rated replies, and the identification of common shortcomings in chatbots performance. RESULTS: Among the assessed chatbots, specialists rated Claude highest with a mean score of 7.37 (SD = 1.91), followed by ChatGPT (7.17, SD = 1.89), Microsoft Copilot (6.63, SD = 2.10), and Google Bard (6.52, SD = 2.27). Claude also excelled with 27 best-rated replies, outperforming ChatGPT (20), while Microsoft Copilot and Google Bard lagged with only 6 and 9, respectively. Common deficiencies included listing details over specific advice, limited dosing options, inaccuracies for pregnant patients, insufficient recent data, over-reliance on CT and MRI imaging, and inadequate discussion regarding off-label use and fibrates in PBC treatment. Notably, internet access for Microsoft Copilot and Google Bard did not enhance precision compared to pre-trained models. CONCLUSIONS: Chatbots hold promise in AILD support, but our study underscores key areas for improvement. Refinement is needed in providing specific advice, accuracy, and focused up-to-date information. Addressing these shortcomings is essential for enhancing the utility of chatbots in AILD management, guiding future development, and ensuring their effectiveness as clinical decision-support tools.

Systemic lupus erythematosus and autoimmune hepatitis overlap disease in a hospitalized systemic lupus erythematosus cohort.

Liver dysfunction in systemic lupus erythematosus (SLE) is caused by disease activity or secondary conditions like coexistent autoimmune liver diseases. In Taiwan, despite sporadically reported cases of SLE-autoimmune hepatitis (AIH) overlap disease, larger-scale monocentric investigations for such overlapping patients are not available. Retrospective analyses were performed in a hospitalized SLE cohort with 805 patients for identifying co-existent AIH from 2014 to 2023, focusing on distinct therapeutic modalities and differential diagnosis between SLE-AIH overlap and lupus hepatitis (LH). There were 5 cases (a 0.6% occurrence), all females aged 25-58 years (44 ± 13). Ages for the SLE diagnosis were 19-51 years (30 ± 13), while ages for the AIH diagnosis were 22-57 years (36 ± 14). Contradictory to interface hepatitis in SLE-AIH overlap, liver biopsy only demonstrated non-specific abnormalities in LH. Liver cirrhosis was identified in SLE-AIH overlap but not in LH. After corticosteroids/azathioprine therapy, there were normalized liver function in all LH. In 2 SLE-AIH overlap cases refractory to such therapy, one received B-cell depletion therapy (annual rituximab infusion, 375 mg/m2 weekly × 4) and another accepted living-donor liver transplantation from sibling due to advanced liver cirrhosis, leading to improved hepatic dysfunction in both.

SARS-CoV-2 and the liver: clinical and immunological features in chronic liver disease.

SARS-CoV-2 infection may affect the liver in healthy individuals but also influences the course of COVID-19 in patients with chronic liver disease (CLD). As described in healthy individuals, a strong SARS-CoV-2-specific adaptive immune response is important for the outcome of COVID-19, however, knowledge on the adaptive immune response in CLD is limited.Here, we review the clinical and immunological features of SARS-CoV-2 infection in individuals with CLD. Acute liver injury occurs in many cases of SARS-CoV-2 infection and may be induced by multiple factors, such as cytokines, direct viral infection or toxic effects of COVID-19 drugs. In individuals with CLD, SARS-CoV-2 infection may have a more severe course and promote decompensation and particularly in patients with cirrhosis. Compared with healthy individuals, the SARS-CoV-2-specific adaptive immune responses is impaired in patients with CLD after both, natural infection and vaccination but improves at least partially after booster vaccination.Following SARS-CoV-2 vaccination, rare cases of acute vaccine-induced liver injury and the development of autoimmune-like hepatitis have been reported. However, the concomitant elevation of liver enzymes is reversible under steroid treatment.

Long-term outcomes of patients with type 1 or 2 autoimmune hepatitis presenting in childhood.

BACKGROUND & AIMS: In children with autoimmune hepatitis, uncertainties include outcomes associated with type 2 hepatitis, the possibility of and criteria for attempting withdrawal of treatment, and long-term outcomes. We report our experience on these issues. METHODS: From 1973 to 2002, 117 children with type 1 (n = 65) or type 2 (n = 52) hepatitis, excluding fulminant hepatitis, were treated, primarily with prednisone and azathioprine. Median follow-up was 20 years in survivors. RESULTS: Normalisation of aminotransferases and prothrombin ratio were observed in 93% and 84% of children, respectively; sustained remission after treatment withdrawal was recorded in 24% of the entire population, with a median follow-up of 7 years. Sustained treatment-free remission was obtained in 11 of 24 children with follow-ups of 4-22 years based on durable normalisation of aminotransferases (without histological assessment). Gastrointestinal bleeding from varices and the emergence of extrahepatic autoimmune disorders occurred in 10 and 22 patients, respectively. Liver transplantation was performed in 23 patients at a median age of 21 years. The 30-year probabilities of overall and native liver survival were 81% and 61%, respectively. No differences were observed between type 1 and 2 hepatitis for any of the component parts of outcome. In the multivariate analysis, a persistent abnormal prothrombin ratio was associated with worse probabilities of overall and native liver survival. CONCLUSIONS: In terms of liver outcome, type 2 hepatitis is not different from type 1. Withdrawal of treatment is possible without prior liver histology. A persistent abnormal prothrombin ratio identifies patients who will require liver transplantation in adolescence or early adulthood. IMPACT AND IMPLICATIONS: In children with autoimmune hepatitis, there are conflicting reports on the differences in outcome between type 1 and type 2 hepatitis, and on the possibility of treatment withdrawal, before which liver histology is required; data concerning >10-year overall and native liver survival rates are limited. In this study, we found no differences in outcomes between type 1 and 2 hepatitis; a durable treatment-free state was achieved in 19% of all patients throughout childhood and early adulthood, and in 45% of children for whom treatment withdrawal was attempted without prior liver histology; prothrombin was found to be predictive of 30-year overall and native liver survival. The results allow for a less-strict approach to treatment withdrawal in children, avoiding the risks of a liver biopsy, and they provide a tool to help anticipate the need for liver transplantation before complications occur.

Primary sclerosing cholangitis and overlap features of autoimmune hepatitis: A coming of age or an age-ist problem?

Autoimmune liver diseases are siloed into three syndromes that define clinical practice. These classifiers can, and are, challenged by variant presentations across all ages, something inevitable to disease definitions that rely on interpreting (inherently variable) semi-quantitative/qualitative clinical, laboratory, pathological or radiological findings. Furthermore this categorisation is premised on an ongoing absence of definable disease aetiologies. Clinicians thus encounter individuals with biochemical, serological, and histological manifestations that are common to both primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH), often labelled as 'PSC/AIH-overlap'. In childhood the term 'autoimmune sclerosing cholangitis (ASC)' may be used, and some propose this to be a distinct disease process. In this article we champion the concept that ASC and PSC/AIH-overlap are not distinct entities. Rather, they represent inflammatory phases of PSC frequently manifesting earlier in the disease course, most notably in younger patients. Ultimately, disease outcomes remain similar to those of a more classical PSC phenotype observed in later life. Thus, we argue that it is now time to align disease names and descriptions used by clinicians across all patient subpopulations, to help unify care. This will enhance collaborative studies and ultimately contribute to rational treatment advances.

Postinfantile Giant Cell Hepatitis in Native and Allograft Livers: A Multi-Institutional Clinicopathologic Study of 70 Cases.

Postinfantile giant cell hepatitis (PIGCH) is a rare hepatitis pattern in adults with variable etiologies and clinical outcomes. We conducted a multi-institutional retrospective study to define the clinicopathologic characteristics of patients with PIGCH. A total of 70 PIGCH cases were identified and reviewed for pathological features, including fibrosis, cholestasis, inflammation, steatosis, necrosis, and apoptosis, as well as the distribution of giant cells and the maximum number of giant cells per high-power field. Demographic and clinical data, including age, sex, laboratory results, etiologies, and follow-up results, were recorded. Among the 70 cases, 40% (28/70) were associated with autoimmune liver diseases, followed by 9 (13%) with unknown etiology, 8 (11%) with viral infection, 5 (7%) with medications, 5 with combined etiologies, and 4 (6%) with malignancies (mostly chronic lymphocytic leukemia). Notably, another 16% were de novo PIGCH in liver allografts, most of which occurred after a rejection event. During follow-up, 26 (37%) patients died of the disease and 44 (63%) were alive. Deceased patients were characterized by older age (mean age, 54.9 vs 45.5 years; P = .02), higher alkaline phosphatase level (mean value, 253.3U/L vs 166.3 U/L; P = .03), higher fibrosis stage (stage 3-4 vs stage 0-2, 57.7% vs 29.6%; P = .03), being more likely to have de novo PIGCH after transplantation (23.1% vs 11.4%; P = .04), and being less likely to have primary autoimmune liver disease etiology (26.9% vs 47.7%; P = .04). These results indicate that PIGCH is a rare pattern of liver injury associated with different etiologies and variable clinical outcomes. Autoimmune liver disease with PIGCH is associated with better survival, whereas de novo PIGCH in allografts is associated with poorer survival. Older age, higher alkaline phosphatase level, and advanced fibrosis are adverse prognostic factors.

The Albumin-Bilirubin Score as a Predictor of Liver-Related Mortality in Primary Biliary Cholangitis with Compensated Cirrhosis.

BACKGROUND: Although several prognostic scores have been reported to correlate with the prognosis of primary biliary cholangitis (PBC) patients, there are limited tools to predict the prognosis of PBC with compensated cirrhosis. This study aimed to evaluate the prognostic performance of the albumin-bilirubin (ALBI) score in PBC patients with compensated cirrhosis. METHODS: We conducted a retrospective longitudinal study of 219 patients with compensated PBC cirrhosis to evaluate the prognostic performance of the ALBI using Cox regression model, receiver operating characteristic (ROC) curve, and Kaplan-Meier method. RESULTS: During follow-up, a total of 19 subjects (8.7%) met the primary endpoint of liver-related death or liver transplantation (LT). Patients who died/underwent LT have higher ALBI score (-1.06 vs. -2.06, p < 0.001) at baseline than those who survived. ALBI score (hazard ratio: 15.011, 95% confidence interval [CI]: 5.045-44.665, p < 0.001) was associated with an increase in liver-related mortality or LT. ALBI score had the best discriminative capacity to predict the 5-year liver-related mortality (area under the ROC curve: 0.871, 95% CI [0.820, 0.913]) compared with other prognostic scores. The ROC curve showed that the best cut-off value of ALBI score was -1.47, with 90.0% sensitivity and 76.6% specificity. Also, the probability of transplant-free survival decreased with increasing ALBI grade (log-rank p = 0.003). The 5-year transplant-free survival rates of patients in grade 1, grade 2, and grade 3 were 100.0%, 96.4%, and 89.4%, respectively. CONCLUSION: ALBI score is a simple and effective predictive factor estimating the clinical outcome of patients with compensated PBC cirrhosis and provides better prognostic performance compared with other prognostic scores.

Correlation between hepatic venous pressure gradient and portal pressure gradient in patients with autoimmune cirrhotic portal hypertension and collateral branches of the hepatic vein.

AIM: To assess the correlation and agreement between hepatic venous pressure gradient (HVPG) and portal pressure gradient (PPG) in patients with autoimmune liver diseases (ALD) and portal hypertension, and to investigate the extent to which hepatic vein collateralization affects the accuracy of this assessment. METHODS: Ninety-eight patients with ALD between 2017 and 2021 who underwent transjugular intrahepatic portosystemic shunt with conventional and innovative 15 mL pressurized contrast were selected to measure wedged hepatic venous pressure (WHVP) and portal venous pressure and to calculate the HVPG and PPG. Pearson's correlation was used for correlation analysis between the two groups. Bland-Altman plots were plotted to estimate the agreement between paired pressures. RESULTS: The r values of PPG and HVPG in the early, middle, late, and portal venous visualization were 0.404, 0.789, 0.807, and 0.830, respectively, and the R2 values were 0.163, 0.622, 0.651, and 0.690, respectively. The p value for the r and R2 values in the early group was 0.015, and the p values in the remaining groups were less than 0.001. Bland-Altman plots showed that patients in the portal venous visualization group had the narrowest 95% limits of agreement. The mean value of the difference was close to the zero-scale line. CONCLUSIONS: In patients with ALD, the correlation between the HVPG and PPG was good, and the later the collateral development, the better the correlation. Hepatic vein collateral was an essential factor in underestimating WHVP and HVPG, and the earlier the collateral appeared, the more obvious the underestimation.

Liver abnormalities in celiac disease and response to gluten free diet: A systematic review and meta-analysis.

BACKGROUND AND AIM: Liver involvement in celiac disease (CeD) is known but its various etiologies and the effect of gluten free diet (GFD) on it is understudied. METHODS: We searched PubMed, Medline and Embase databases from date of inception to March 7, 2022, to look for studies reporting on CeD and liver abnormalities. Pooled proportion of CeD patients with deranged transaminases, etiologies of various other liver diseases with CeD and the response to GFD were estimated. Subgroup analyses based on the age group, geographic distribution and duration of GFD were also carried out. RESULTS: Total 42 studies (8976 patients) reported hyper-transaminasemia in patients with celiac disease. The pooled proportion of patients with elevated transaminases was 21.42% (95% CI: 17.02-26.59, I2  = 94%) overall, with similar prevalence among adults (21.20%) and children (21.51%). The commonest etiology was celiac hepatitis at 49.23% (95% CI: 30.09-68.59, I2  = 87%). Compliance with GFD was noted in 90.27%. The proportion of CeD patients with liver abnormalities who showed response to GFD was 86.39% (95% CI: 80.04-90.95, I2  = 74%) overall. CONCLUSION: Liver involvement was noted in 21.42% of CeD patients. Celiac hepatitis was reported in nearly half of them. Good compliance and response were noted with GFD.

Relapse and Need for Extended Immunosuppression: Novel Features of Drug-Induced Autoimmune Hepatitis.

BACKGROUND: Drug-induced autoimmune hepatitis (DI-AIH) has been proposed as a distinct phenotype of drug-induced liver injury (DILI), and frequently has been associated with specific drugs, such as minocycline and nitrofurantoin. However, no clear definition of DI-AIH has been established thus far. OBJECTIVES: We aimed to identify features distinguishing DI-AIH from DILI and idiopathic autoimmune hepatitis (AIH) in an attempt to further define a DI-AIH phenotype. METHOD: A cohort of 38 previously reported DILI and AIH patients who were prospectively recruited at our tertiary centre and who received corticosteroid was analysed regarding the phenotypical presentation and outcome of DI-AIH, DILI, and AIH. RESULTS: AIH (n = 19), DILI (n = 8), and DI-AIH (n = 11) patients presented with similar clinical features at onset, with the only difference being a higher Roussel Uclaf Causality Assessment Method (RUCAM) score in the DILI and DI-AIH patients. Post-treatment AIH scores were lower and a more rapid decrease of alanine aminotransferase in the first week of corticosteroid treatment was observed in both DILI groups when compared to AIH patients, while no significant differences were observed between DI-AIH and DILI patients. Relapse occurred in DI-AIH but not in DILI patients (36% vs. 0%) with a more frequent need for long-term immunosuppression (27% vs. 13%). CONCLUSIONS: Our data show that relapse after cessation of corticosteroids and need for further immunosuppressive treatment does occur in a substantial proportion of DI-AIH patients. However, no other phenotypical differences between DILI due to agents commonly associated with DI-AIH and DILI due to other drugs were identified.

Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation.

BACKGROUND & AIMS: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival. METHODS: We included 736 patients (77% female, mean age 42±1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis. RESULTS: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT ≤42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001). CONCLUSION: Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH. LAY SUMMARY: Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition.