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Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4+CD25- cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor (TNF)-α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-γ and PD-1 expression in AIH, where control over CD4+CD25- cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4+CD25- cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs. [ABSTRACT FROM AUTHOR]

Introduction In autoimmune hepatitis (AIH), the extent of CD4 effector immune responses is associated with defective CD4CD25 regulatory T-cells (T-regs). Engagement of T-cell-immunoglobulin-and-mucin-domain-3 (Tim3) on Th1-cells by galectin-9, expressed by T-regs, induces Th1-cell apoptosis. In AIH, Tim3 is down-regulated on CD4 effector cells. Whether the reduced Tim3 expression renders CD4 T-cells less susceptible to T-reg control is unknown. Aim To evaluate whether Tim3 expression is associated with the ability of CD4 effector cells to be regulated by T-regs in AIH. Method 18 ANA/SMA+ patients (median age: 14.9 years, 11 females) and 6 healthy subjects (HS, median age: 28.4, 5 females) were studied. T-regs and CD4CD25 effector cells were purified from PBMCs using immunomagnetic beads. CD25 cells were further purified into Tim3 and Tim3 cell fractions and used as targets in co-culture experiments with T-regs. Target cell proliferation was assessed after 5-day culture by H-thymidine incorporation and expressed as mean cpm count. Results Proliferation of unfractionated CD25 cells (HS: 37 745±5015; AIH: 6160+714) was lower than that of Tim3 (HS: 115 488±8348, p=0.001; AIH: 9659+1041, p=0.02) and higher than that of Tim3 (HS: 29 382±2323, p=0.03; AIH: 4604±1177, p=0.004) cells. Addition of T-regs reduced cell proliferation by 51% (P<0.001) in HS and by 26% (p=NS) in AIH when unfractionated CD25 cells were used as targets; by 25% (p=0.14) and 23% (p=NS) when Tim3 cells were the targets and by 62% (p=0.04) and 43% (p=0.03) when the targets were Tim3 cells. Since Tim3 cells produce higher levels of IFN-gamma than Tim3 cells, we investigated the effect of IFN-gamma neutralisation on the ability of Tim3 and Tim3 cells to be regulated by T-regs. While treatment with anti-IFN-gamma neutralising antibodies did not change Tim3 cell susceptibility to T-reg control, it decreased it in Tim3 cells, inhibition of proliferation being 17% in HS and nil in AIH following T-reg addition. Conclusion Compared to unfractionated CD25 and Tim3 cells, Tim3 effectors display higher ability to proliferate and are less susceptible to T-reg control especially in AIH. Down-regulation of Tim3 renders CD4 effectors less amenable to immune regulation and therefore more likely to inflict and perpetuate liver damage. The decreased ability of T-regs to suppress proliferation of anti-IFN-gamma-treated Tim3 cells suggests that IFN-gamma production is needed in order for these cells to be effectively regulated. [ABSTRACT FROM PUBLISHER]

Background: The Baveno VII guidelines were proposed to identify which patients could safely avoid screening esophagogastroduodenoscopy (EGD) for gastroesophageal varices. We aimed to evaluate the frequency of gastric neoplasia in compensated advanced chronic liver disease (cACLD) patients who underwent EGD for screening of gastroesophageal varices (GOEV) compared to a healthy population., Methods: Retrospective study that enrolled all cACLD patients who underwent EGD for GOEV screening (January 2008-June 2018) in a tertiary reference center. cACLD patients were compared with asymptomatic healthy individuals who underwent EGD in a private hospital setting (April 2017-March 2018)., Results: We evaluated 1845 patients (481 cACLD patients, 1364 healthy individuals). A significantly higher frequency of gastric neoplasia was observed in patients with cACLD compared to healthy individuals (4.0% vs. 1.0 %; p < 0.001). Rare histopathological subtypes (WHO Classification) accounted for 28.7 % of gastric carcinoma cases in the cACLD cohort. Seven cases of gastric neoplasia (36.8 % of gastric neoplasia cases in the cACLD patients) were diagnosed in patients who, according to the Baveno VII criteria, would have not been submitted to EGD., Conclusion: We found an increased frequency of gastric neoplasia in patients with cACLD in comparison with healthy individuals. In countries with intermediate-high risk for GC, continuing to perform EGD could be beneficial., Competing Interests: Conflict of interest None., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: A limited number of drugs are used as standard or alternative therapies in autoimmune hepatitis (AIH). No specific recommendations are available for patients failing to respond to these therapies. We analyzed the efficacy and safety of infliximab in patients with AIH., Approach and Results: We performed a retrospective study of 42 patients with AIH who received infliximab at 21 liver centers in 12 countries. Patients were categorized according to the reason for infliximab therapy. Patients in group 1 (n=20) had failed standard, second-line (mycophenolate mofetil and 6-mercaptopurine) or third-line (tacrolimus or cyclosporine) therapy. In group 2 (n=22), infliximab was given for treatment of concomitant extrahepatic autoimmune diseases. Patients received a median of 17 (range: 3-104) infliximab infusions. Complete biochemical response (CR) was achieved or maintained in 33 (78%) patients during infliximab therapy. In group 1, infliximab induced CR in 11 of 20 (55%) patients. In group 2, 16 patients with CR prior to infliximab maintained remission, and the remaining 6 patients with active AIH (5 on standard and 1 on both second-line and third-line therapy) showed CR following infliximab therapy. Infliximab led to CR in 75% (6/8) of nonresponders to second-line and in 46% (6/13) of failing third-line therapy. Overall, 65% (17/26) of the patients with active AIH achieved CR on infliximab. Infliximab was discontinued in 3 patients of group 1. One patient had a severe allergic reaction and 2 developed anti-infliximab autoantibodies., Conclusions: Our study suggests that infliximab may be an effective and safe rescue therapy in AIH., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Aim: Metabolic syndrome (MetS) is associated with higher cardiovascular and metabolic risks, as well as with psychosocial disorders. Data regarding quality of life (QoL) in patients with MetS, point towards a significative association between MetS and a worse QoL. It remains unclear whether MetS components and non-alcoholic fatty liver disease (NAFLD) are associated with QoL in these individuals. We aimed to evaluate the association between QoL of patients with MetS and prespecified metabolic parameters (anthropometric, lipidic and glucose profiles), the risk of hepatic steatosis and fibrosis, and hepatic elastography parameters., Methods: Cross-sectional study including patients from microDHNA cohort. This cohort includes patients diagnosed with MetS, 18 to 75 years old, followed in our tertiary center. The evaluation included anamnesis, physical examination, a QoL questionnaire (Short-Form Health Survey, SF-36), blood sampling and hepatic elastography. We used ordered logistic regression models adjusted to sex, age and body mass index to evaluate the associations between the QoL domains evaluated by SF-36 and the prespecified parameters., Results: We included a total of 65 participants with MetS, with 54% being female and the mean age 61.9 ± 9.6 years old. A worse metabolic profile, specifically higher waist circumference, lower HDL, higher triglycerides, and more severe hepatic steatosis, were associated with worse QoL scores in several domains. We found no significant association of hepatic fibrosis with QoL., Conclusion: Our data suggests that there is a link between a worse metabolic profile (specifically poorer lipidic profile and presence of hepatic steatosis) and a worse QoL in patients with MetS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: The International Autoimmune Hepatitis Group retrospective registry (IAIHG-RR) is a web-based platform with subjects enrolled with a clinical diagnosis of autoimmune hepatitis (AIH). As prognostic factor studies with enough power are scarce, this study aimed to ascertain data quality and identify prognostic factors in the IAIHG-RR cohort., Methods: This retrospective, observational, multicenter study included all patients with a clinical diagnosis of AIH from the IAIHG-RR. The quality assessment consisted of external validation of completeness and consistency for 29 predefined variables. Cox regression was used to identify risk factors for liver-related death and liver transplantation (LT)., Results: This analysis included 2559 patients across 7 countries. In 1700 patients, follow-up was available, with a completeness of individual data of 90% (range: 30-100). During a median follow-up period of 10 (range: 0-49) years, there were 229 deaths, of which 116 were liver-related, and 143 patients underwent LT. Non-White ethnicity (HR 4.1 95% CI: 2.3-7.1), cirrhosis (HR 3.5 95% CI: 2.3-5.5), variant syndrome with primary sclerosing cholangitis (PSC) (HR 3.1 95% CI: 1.6-6.2), and lack of complete biochemical response within 6 months (HR 5.7 95% CI: 3.4-9.6) were independent prognostic factors., Conclusions: The IAIHG-RR represents the world's largest AIH cohort with moderate-to-good data quality and a relevant number of liver-related events. The registry is a suitable platform for patient selection in future studies. Lack of complete biochemical response to treatment, non-White ethnicity, cirrhosis, and PSC-AIH were associated with liver-related death and LT., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: In patients with portal hypertension (PH), the differential diagnosis between porto-sinusoidal vascular disease (PSVD) and cirrhosis is challenging. This study aims to evaluate the diagnostic accuracy of the SSM/LSM index in the diagnosis of PSVD., Methods: Prospective study of patients with PH and PSVD or cirrhosis. Transient liver and spleen elastography were performed and the ratio between spleen stiffness measurement (SSM) and liver stiffness measurement (LSM) was calculated. The relation of SSM/LSM with the diagnosis of PSVD was evaluated., Results: Forty-four patients with PSVD and 44 patients with cirrhosis were evaluated. Median age was 57.5 (IQR 49.0-64.5) years, 66.3% were males. In patients with PSVD, median SSM was 59.4 (33.5-77.7) kPa, median LSM was 6.2 (5.2-10.2) kPa and median SSM/LSM was 5.62 (3.15-9.68). In patients with cirrhosis, median SSM was 47.3 (24.3-60.3) kPa, median LSM was 27.8 (17.7-53.9) kPa and median SSM/LSM was 1.55 (1.06-3.24). The SSM/LSM AUROC was 0.940 (p<0.001). Using 2 as a cut-off, we obtained good sensitivity (86.5%), specificity (92.7%), and accuracy (89.7%) for the diagnosis of PSVD., Conclusion: The SSM/LSM index is useful in the differential diagnosis between liver cirrhosis and PSVD. Using the cut-off of 2 we achieved a good sensitivity and specificity for diagnosing PSVD., Competing Interests: Conflict of Interest None of the authors acted as Reviewer or Editor of this article. There are no conflicts of interest or financial ties to disclose. All authors disclosed no financial relationships relevant to this publication., (Copyright © 2022. Published by Elsevier Ltd.)

Background and Aim: Amyloidosis is a systemic disease characterized by extracellular deposition of amyloid protein, most commonly in the heart and kidney. Hepatic amyloidosis is a rare form of presentation that ranges from mild hepatomegaly and altered liver biochemical tests to acute liver failure. The aims of this study were to evaluate the prevalence of amyloidosis in patients undergoing liver biopsy and describe its main clinical characteristics and prognostic impact., Methods: A retrospective analysis of all patients with a histological diagnosis of hepatic amyloidosis between January 2010 and December 2019 was performed., Major Results: A total of 7 patients were identified from a total of 1773 liver biopsy procedures (0.4%), with a female predominance (6/7) and median age of diagnosis of 62 years. The most common clinical manifestations included hepatomegaly (4/7), jaundice (2/7) and peripheral edema (2/7), whereas 3/7 patients were asymptomatic. Every patient presented abnormalities in liver biochemical tests, more commonly cholestasis (6/7), but also cytolysis (4/7) or hyperbilirubinemia (2/7). Abnormal imaging findings included hepatomegaly, steatosis or parenchymal heterogeneity. In most patients (5/7), other organs were involved, most commonly with nephrotic syndrome (3/7) and infiltrative cardiomyopathy (3/7). The most common type was AA amyloidosis (3/7) followed by AL amyloidosis (2/7). The 1-year mortality rate was 43% and the median survival was 24 months., Conclusions: We report a low prevalence (0.4%) of amyloidosis among patients undergoing liver biopsy. Although rare, hepatic amyloidosis is associated with a dismal prognosis and a high index of suspicion is crucial to achieve an early diagnosis. .

Backround: In acute severe autoimmune hepatitis (AS-AIH), the early identification of predictors of non-response to corticosteroids and the optimal timing for liver transplantation (LT) remains controversial., Aims: To determine early predictors of non-response to corticosteroids and to assess the usefulness of severity scores, namely the recently developed SURFASA., Methods: Retrospective multicentre cohort study including consecutive patients admitted for AS-AIH between 2016 and 2020. Definitions- response to corticosteroids: LT-free survival at 90 days (D90); SURFASA score: -6.8 + 1.92x(D0-INR)+1.94xINR[(D3-D0)/D0]+1.64xbilirubin[(D3-D0)/D0]., Results: We included 26 patients [median age 56 (45-69) years; 22 (84.6%) women]. All patients underwent corticosteroid therapy. Overall survival reached 73%. amongst the non-responders, 2 (7.8%) underwent LT and 5 (19.2%) died. The interval between admission and initiation of corticosteroids was not different between responders and non- responders [13 (7-23) vs. 8 (3-10), P:0.06], respectively. SURFASA and MELD-Na + (D3) scores showed an AUROC of 0.96 (0.87-1) and 0.92 (0.82-0.99), respectively, for prediction of non-response. SURFASA >-2.5 had a sensitivity of 85.7% and a specificity of 100% and MELD-Na + (D3) >26 had sensitivity of 85.7% and a specificity of 78% for the prediction of non-response., Conclusions: SURFASA and MELD-Na + at D3 scores are useful in early identification of non-responders to corticosteroids., Competing Interests: Conflict of interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

Background and Aims: A few case reports of autoimmune hepatitis-like liver injury have been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We evaluated clinical features, treatment response and outcomes of liver injury following SARS-CoV-2 vaccination in a large case series., Approach and Results: We collected data from cases in 18 countries. The type of liver injury was assessed with the R-value. The study population was categorized according to features of immune-mediated hepatitis (positive autoantibodies and elevated immunoglobulin G levels) and corticosteroid therapy for the liver injury. We identified 87 patients (63%, female), median age 48 (range: 18-79) years at presentation. Liver injury was diagnosed a median 15 (range: 3-65) days after vaccination. Fifty-one cases (59%) were attributed to the Pfizer-BioNTech (BNT162b2) vaccine, 20 (23%) cases to the Oxford-AstraZeneca (ChAdOX1 nCoV-19) vaccine and 16 (18%) cases to the Moderna (mRNA-1273) vaccine. The liver injury was predominantly hepatocellular (84%) and 57% of patients showed features of immune-mediated hepatitis. Corticosteroids were given to 46 (53%) patients, more often for grade 3-4 liver injury than for grade 1-2 liver injury (88.9% vs. 43.5%, p = 0.001) and more often for patients with than without immune-mediated hepatitis (71.1% vs. 38.2%, p = 0.003). All patients showed resolution of liver injury except for one man (1.1%) who developed liver failure and underwent liver transplantation. Steroid therapy was withdrawn during the observation period in 12 (26%) patients after complete biochemical resolution. None had a relapse during follow-up., Conclusions: SARS-CoV-2 vaccination can be associated with liver injury. Corticosteroid therapy may be beneficial in those with immune-mediated features or severe hepatitis. Outcome was generally favorable, but vaccine-associated liver injury led to fulminant liver failure in one patient., (© 2022 American Association for the Study of Liver Diseases.)

Introduction: Celiac disease has been associated with abnormal liver function tests at diagnosis that usually resolve with a gluten-free diet (GFD). The aim of this study was to assess the evolution of liver involvement and possible long-term complications in patients on a GFD., Methods: Retrospective and single-center study, which included all individuals with Celiac disease followed in specialized consultation in a tertiary referral hospital., Results: A total of 162 patients were included, most of them female (77.8%) with a median age of 24 years (IQR, 7-39). Seventy-four (45.7%) patients had abnormal liver function tests at diagnosis. These individuals had higher anti-tissue transglutaminase IgA (tTG-IgA) antibody titers (126 vs. 29 IU/L; P  = 0.003). There were no significant differences in the Marsh classification ( P  = 0.599). During follow-up, most celiac hepatitis patients had normalization of liver function tests and tTG-IgA antibodies. At the last follow-up, all the patients had fibrosis-4 index &lt;2.4 and an aspartate aminotransferase-to-platelet ratio index score &lt;0.6. Vibration-controlled transient elastography showed values &lt;6.4 kPa in all cases. On the other hand, it was found that 42.9% of the individuals had a controlled attenuation parameter &gt;206.5 db/m., Conclusions: In our cohort, liver function tests normalized in the vast majority of celiac hepatitis patients on a GFD, with no progression to chronic liver disease. It should be noted the high number of individuals who present hepatic steatosis during follow-up, which may be related to a diet that tends to be hyperlipidemic and hypercaloric., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: The "gut homing" hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here, we examine "the gut homing theory" in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases., Approach and Results: Expression of MAdCAM-1, CCL25, and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from patients with CLD undergoing OLT and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T cells was assessed using flow cytometry. Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was up-regulated in all CLDs compared with normal liver. There were no differences between disease groups. Frequencies of α4β7, αEβ7, CCR9, and GPR15 expressing hepatic T cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. β7 expressing hepatic T cells displayed an increased inflammatory phenotype compared with β7 negative cells, although this inflammatory cytokine profile was present in both the inflamed and normal liver., Conclusions: These findings refute the widely accepted "gut homing" hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T cells is not unique to PSC, but is a panetiological feature of CLD., (© 2021 American Association for the Study of Liver Diseases.)

Introduction: Wilson disease is an autosomal recessive disease of liver copper metabolism with predominant hepatic and neurological manifestations. Long-term data on the clinical follow-up and treatment efficacy are limited due to the low frequency of the disease. We evaluated a large cohort of Wilson disease patients from Northern Portugal during a 20-year follow-up period., Methods: Twenty-four patients, diagnosed from 1975 to 2020 in a tertiary care center in Portugal, were retrospectively evaluated according to their clinical presentation, therapies and outcomes., Results: Most of the patients were males (54%), with a median age at diagnosis of 19 years old (interquartile range 15-25). The main manifestations of Wilson disease were hepatic (71%) and neurological (25%). Family history was positive in 5 (21%) patients. Four patients (17%) presented with acute liver failure and fifteen (63%) individuals had cirrhosis at diagnosis. Penicillamine therapy was used by 11 (46%) patients, while trientine and zinc were given to 8 (33%) and 1 (4%) patient, respectively. Ten (42%) individuals underwent liver transplantation. The majority of patients (83%) had stable disease or improved outcomes during follow-up., Conclusion: This is the largest cohort of adult patients with Wilson disease reported in Northern Portugal. We show that Wilson disease has favorable outcomes with long overall survival, assuming adherence to therapy and lack of other insults to their liver., (© 2022. The Author(s).)