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Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD), in the context of autoimmune hepatitis (AIH) among liver transplantation (LT) candidates or recipients remains poorly understood. This study compares waitlist and post‐LT outcomes in patients with MASLD/AIH to MASLD and AIH alone. Methods: Using the united network organ sharing database (2002–2022), we compared waitlist outcomes and post‐LT survival among patients with MASLD/AIH (n = 282), AIH (n = 5812), and MASLD (n = 33 331). Competing risk, Kaplan Meier estimates and Cox proportional hazard analyses were performed. Results: MASLD/AIH group had the highest rates of encephalopathy and ascites, and highest MELD scores. MASLD/AIH patients had higher transplantation incidence (adjusted subdistribution hazard ratio [aSHR] 1.64, 95% CI 1.44–1.85; p <.001) and lower waitlist removal risk (aSHR.30, 95% CI.20–.44; p <.001) compared to MASLD alone. One‐year post‐LT survival favoured MASLD compared to AIH (patient: 92% vs. 91%, p <.001; graft: 89% vs. 88%, p <.001) and MASLD/AIH (patient: 92% vs. 90%, p =.008; graft: 89% vs. 88%, p =.023). Recipients with MASLD/AIH showed no significant difference in survival at 10‐year post‐LT compared to MASLD (patient: 63% vs. 61%, p =.68; graft 60% vs. 59%, p =.83) and AIH (patient: 63% vs. 70%, p =.07; graft: 60% vs. 64%, p =.42). Conclusions: Our study showed that MASLD/AIH patients demonstrate higher LT incidence and lower dropout rates. Long‐term post‐LT outcomes did not significantly differ between groups. Further prospective multicenter studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Background and Aims: The European Reference Network on Hepatological Diseases (ERN RARE‐LIVER) launched the prospective, multicentre, quality‐controlled R‐LIVER registry on rare liver diseases. The aim of this study was to assess the presentation and outcome of autoimmune hepatitis (AIH) after 1 year of treatment. Methods: Data were prospectively collected at the time of diagnosis and after 6 and 12 months follow‐up. Complete biochemical response (CBR) was defined as normalization of alanine aminotransferase (ALT) and immunoglobulin G (IgG) serum levels. Results: A total of 231 patients from six European centres were included in the analysis. After 6 months of treatment 50% (106/212), and after 12 months 63% (131/210) of patients reached CBR with only 27% (56/211) achieving a steroid‐free CBR within the first year. Overall, 16 different treatment regimens were administered. Change of treatment, mostly due to intolerance, occurred in 30.4% within the first 6 months. In multivariate analysis, younger age at diagnosis (odds ratio [OR] = 1.03 [95% confidence interval (CI) 1.01–1.05]; p =.007), severe fibrosis (OR.38 [95%.16–.89], p =.026) and change of treatment within the first 6 months (OR.40 [95% CI.2–.86]; p =.018) were associated with a lesser chance of ALT normalization at 12 months follow‐up. Conclusion: The landscape of AIH treatment in Europe is highly heterogeneous, even between expert centres. The results from this first European multicentre prospective registry reveal several unmet needs, highlighted by the overall low rates of CBR and the frequent failure to withdraw corticosteroids. [ABSTRACT FROM AUTHOR]

Drug‐induced liver injury (DILI) presents unique challenges in clinical practice. While some types of DILI are mild and resolve quickly after removing the drug, other situations are more complex, with competing aetiologies or underlying liver disease. Guidelines from professional societies agree that the liver biopsy retains a role in understanding and managing DILI in certain situations. Liver biopsy allows characterization of the histological pattern of injury as well as assessment of severity. Inflammatory infiltrates, bile duct injury or loss and vascular injury are all revealed by liver biopsy. Communication between the hepatopathologist and clinical team with clinicopathological correlation of the findings is necessary for the best determination of causality and differentiation from other diseases of exclusion, like autoimmune hepatitis and graft‐versus‐host disease. This review highlights important aspects of the role of liver biopsy in DILI evaluation. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) in patients with alcohol‐associated hepatitis (AH) has rapidly increased following the coronavirus disease 2019 pandemic and the implementation of the Acuity Circle policy, raising questions of equity and utility. Waitlist mortality among high (≥37) Model for End‐Stage Liver Disease LT candidates with AH and post‐transplant survival were assessed with a semiparametric survival regression and a generalized linear mixed‐effect model with LT centre‐ and listing date‐level random intercepts. These models demonstrate a lower mortality for the candidates listed with AH (adjusted sub‐hazard ratio.58_.72_.90 and odds ratio.44_.66_.99) when compared to other diagnoses (autoimmune hepatitis, metabolic dysfunction‐associated fatty liver disease and primary biliary cholangitis). Post‐LT survival was comparable. This study highlights the limitations of current tools in characterizing the risk of mortality, and thus need for the modifications in prioritizing LT candidates with AH. Policy revision may be needed to ensure equivalent access to LT regardless of diagnosis. [ABSTRACT FROM AUTHOR]

Background and Aims: Small series suggest that rituximab could be effective as treatment for autoimmune hepatitis (AIH), although data are scarce. We aimed to evaluate the efficacy and safety of rituximab in different cohorts of patients with AIH. Methods: Multicentre retrospective analysis of the 35 patients with AIH and its variant forms treated with rituximab and included in the ColHai registry between 2015 and 2023. Results: Most patients were female (83%), 10 (29%) had cirrhosis and four (11.4%) variant forms of AIH. Indication for rituximab were as follows: 14(40%) refractory AIH, 19(54%) concomitant autoimmune or haematological disorder, 2(6%) intolerance to prior treatments. In three (9%) subjects with a concomitant disorder, rituximab was the first therapy for AIH. Overall, 31 (89%) patients achieved or maintained complete biochemical response (CBR), including the three in first‐line therapy. No difference in CBR was observed according to rituximab indication (refractory AIH 86% vs. concomitant disorders 90%, p =.824) or cirrhosis (80% vs. 92%, p =.319). Rituximab was associated with a significant reduction in corticosteroids (median dose: prior 20 vs. post 5 mg, p <.001) and the discontinuation of ≥1 immunosuppressant in 47% of patients. Flare‐free rate at 1st, 2nd and 3rd year was 86%, 73% and 62% respectively. Flares were not associated with the development of liver failure and were successfully managed with repeated doses of rituximab and/or increased corticosteroids. Three (9%) patients experienced infusion‐related adverse events (1 anaphylaxis and 2 flu‐like symptoms) and five (14%) infections. Conclusion: Rituximab is safe and effective in patients with refractory AIH and those treated due to concomitant autoimmune or haematological disorders. [ABSTRACT FROM AUTHOR]

Background and Aims: The International AIH Pathology Group (IAIH‐PG) put forward the new histological criteria of autoimmune hepatitis (AIH) in 2022, which have not undergone adequate verification. In this study, we verified the applicability of the new histological criteria in the population of Chinese patients with chronic liver disease, comparing it with the simplified criteria. Methods: The gold standard for diagnosis in all patients was based on histological findings, combined with clinical manifestations and laboratory tests and determined after a follow‐up period of at least 3 years. A total of 640 patients with various chronic liver diseases from multiple centres underwent scoring using the new histological criteria and the simplified criteria, comparing their diagnostic performance. Results: In this study, the new histological criteria showed a sensitivity of 73.6% and 100% for likely and possible AIH, with specificities of 100% and 69.0% respectively. The coincidence rates of possible AIH for the new histological criteria, simplified histological criteria and simplified score were 81.7%, 72.8% and 69.7% respectively. For likely AIH, the rates were 89.2%, 75.9% and 65.6% respectively. Based on the new histological criteria, all patients with AIH were correctly diagnosed. Specifically, 73.6% were diagnosed with likely AIH and 26.4% were possible AIH. Additionally, the simplified histological criteria achieved a diagnosis rate of 98.6% for AIH, while the simplified score could only diagnose 53.8% of AIH. Conclusions: Compared with the simplified score and simplified histological criteria, the sensitivity and specificity of the new histological criteria for AIH were significantly improved. The results indicate that the new histological criteria exhibit high sensitivity and specificity for diagnosing AIH in China. [ABSTRACT FROM AUTHOR]

Background and Aims: Autoimmune hepatitis (AIH) in children presenting in acute liver failure (ALF) can be fatal and often requires liver transplantation (LTx). This individual patient data meta‐analysis (IPD) aims to examine management and outcomes of this population, given the lack of large cohort studies on paediatric AIH first presenting as ALF (AIH‐ALF). Methods: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta‐Analyses of IPD statement using PubMed and Excerpta Medica dataBASE, and included English studies published between 2000 and 2020. The study included patients under 21 years of age, diagnosed with type 1 or 2 AIH and presenting with ALF. Data extracted included clinical and biochemical characteristics, interventions, and outcomes. Results: Three hundred and thirty eligible patients from 61 studies were identified, with an additional five patients from our institution. The majority were female (66.8%), with a median age of 10. Overall, 59.7% achieved native liver survival (NLS), 35% underwent LTx, and 5% died before LTx. The use of corticosteroids with non‐steroid immunomodulators increased the likelihood of NLS by 2.5‐fold compared to corticosteroids alone. AIH‐1 was associated with 3.3‐fold odds for NLS, compared to AIH‐2. However, on multivariate analysis, only AIH‐1 was identified as an independent predictor for NLS (OR 3.8 [95% CI 1.03–14.2], p =.04). Conclusion: While corticosteroids and non‐steroid immunomodulators treatment may offer enhanced probability of achieving NLS, treatment regimens for AIH‐ALF may need to consider patient‐specific factors, especially AIH type. This highlights the potential for NLS in AIH‐ALF and suggest a need to identify biomarkers which predict the need for combination immunosuppression to avoid LTx. [ABSTRACT FROM AUTHOR]

Background and Aims: During recent years, there have been major insight into the pathogenesis, diagnosis and treatment of autoimmune hepatitis (AIH). We aim to evaluate modifications of the clinical‐epidemiological phenotype of AIH patients from 1980 to our days. Methods: Single‐centre, tertiary care retrospective study on 507 consecutive Italian patients with AIH. Patients were divided into four subgroups according to the decade of diagnosis: 1981–1990, 1991–2000, 2001–2010 and 2011–2020. We assessed clinical, laboratory and histological features at diagnosis, response to treatment and clinical outcomes. Acute presentation is defined as transaminase levels >10‐fold the upper limit and/or bilirubin >5 mg/dL. Complete response is defined as the normalization of transaminases and IgG after 12 months. Clinical progression is defined as the development of cirrhosis in non‐cirrhotic patients and hepatic decompensation/hepatocellular carcinoma development in compensated cirrhosis. Results: Median age at diagnosis increased across decades (24, 31, 39, 52 years, p <.001). Acute onset became more common (39.6%, 44.4%, 47.7%, 59.5%, p =.019), while cirrhosis at diagnosis became less frequent (36.5%, 16.3%, 10.8%, 8.7%, p <.001). Complete response rates rose (11.1%, 49.4%, 72.7% 76.2%, p <.001) and clinical progression during follow‐up decreased (54.3%, 29.9%, 16.9%, 11.2%, p <.001). Anti‐nuclear antibodies positivity increased (40.7%, 52.0%, 73.7%, 79.3%, p <.001), while IgG levels/upper limit progressively decreased (1.546, 1.515, 1.252, 1.120, p <.001). Liver‐related death and liver transplantation reduced from 17.1% to 2.1% (p <.001). Conclusions: In the new millennium, the typical AIH patient in Italy is older at diagnosis, more often presents with acute hepatitis, cirrhosis is less frequent and response to treatment is more favourable. [ABSTRACT FROM AUTHOR]

Background and Aims: Patients with some chronic liver diseases have increased risk of diabetes. Whether this is also the case for patients with autoimmune liver diseases is unknown. The study aimed to calculate risk and worldwide prevalence of diabetes in patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Methods: We performed a case–control study using data from the United Kingdom Biobank (UKB) and compared frequency of type 1 diabetes (T1D) and type 2 diabetes (T2D) in AIH and PBC with age‐, sex‐, BMI‐ and ethnicity‐matched controls. Next, we performed a systematic review and proportional meta‐analysis searching PubMed, Embase, Cochrane Library and Web of Science (inception to 1 May 2022 [AIH]; 20 August 2022 [PBC]; 11 November 2022 [PSC]). The pooled prevalence of diabetes was calculated using an inverse method random effects model. Results: Three hundred twenty‐eight AIH patients and 345 PBC patients were identified in UKB and risk of T1D and T2D significantly increased compared with matched controls. Our systematic search identified 6914 records including the UKB study. Of these, 77 studies were eligible for inclusion comprising 36 467, 39 924 and 4877 individuals with AIH, PBC and PSC, respectively. The pooled prevalence of T1D was 3.8% (2.6%–5.7%), 1.7% (0.9%–3.1%), 3.1% (1.9%–4.8%) and of T2D 14.8% (11.1%–19.5%), 18.1% (14.6%–22.2%), 6.3% (2.8%–13.3%) in patients with AIH, PBC and PSC, respectively. Conclusions: Patients with autoimmune liver diseases have increased risk of diabetes. Increased awareness of diabetes risk in patients with autoimmune liver diseases is warranted. [ABSTRACT FROM AUTHOR]

A study published in Liver International examined changes in the clinical and epidemiological features of autoimmune hepatitis (AIH) patients in Italy over the past 40 years. The study found that the median age at diagnosis increased, acute onset AIH became more common, and cirrhosis at diagnosis became less frequent. Complete response rates improved, and clinical progression during follow-up decreased. The study also noted an increase in anti-nuclear antibodies positivity and a decrease in IgG levels. The findings suggest that acute onset AIH has become the most frequent clinical phenotype in recent years. However, the study's retrospective nature and single-center focus were acknowledged as limitations. The authors emphasized the importance of long-term, detailed data from experienced liver units for clinical hepatologists. They also highlighted the need for a universal definition of acute onset and severe disease in AIH. [Extracted from the article]

Background & aims: Idiosyncratic drug‐induced liver injury (DILI) with autoimmune features is a liver condition with laboratory and histological characteristics similar to those of idiopathic autoimmune hepatitis (AIH), which despite being increasingly reported, remains largely undefined. We aimed to describe in‐depth the features of this entity in a large series of patients from two prospective DILI registries. Methods: DILI cases with autoimmune features collected in the Spanish DILI Registry and the Latin American DILI Network were compared with DILI patients without autoimmune features and with an independent cohort of patients with AIH. Results: Out of 1,426 patients with DILI, 33 cases with autoimmune features were identified. Female sex was more frequent in AIH patients than in the other groups (p =.001). DILI cases with autoimmune features had significantly longer time to onset (p <.001) and resolution time (p =.004) than those without autoimmune features. Interestingly, DILI patients with autoimmune features who relapsed exhibited significantly higher total bilirubin and transaminases at onset and absence of peripheral eosinophilia than those who did not relapse. The likelihood of relapse increased over time, from 17% at 6 months to 50% 4 years after biochemical normalization. Statins, nitrofurantoin and minocycline were the drugs most frequently associated with this phenotype. Conclusions: DILI with autoimmune features shows different clinical features than DILI patients lacking characteristics of autoimmunity. Higher transaminases and total bilirubin values with no eosinophilia at presentation increase the likelihood of relapse in DILI with autoimmune features. As the tendency to relapse increases over time, these patients will require long‐term follow‐up. [ABSTRACT FROM AUTHOR]

Autoimmune hepatitis (AIH) is a rare autoimmune liver disease that is characterised by a chronic inflammatory immune reaction directed against hepatocytes. The disease results in a substantial reduction in quality of life and potentially leads to liver‐related complications or death. The International Autoimmune Hepatitis Group (IAIHG) initiated a series of research workshops to uncover the scientific gaps and opportunities in AIH. This review summarises the results of the latest workshop in Maastricht in 2022 and reviews the current challenges in adult AIH, particularly in relation to four important aspects of AIH: diagnostics; new immunomodulatory therapies; clinical trial design; and unmet clinical needs. This review also summarises the progress made since the AIH workshop in 2017. Patients and patient representatives were actively involved in the parallel working groups alongside clinicians and researchers. Despite 40 years of experience with diagnosing and treating AIH, false diagnoses occur and treatment is still based on nonselective immunosuppression. In addition to the need for more specific diagnostic tests, prognostic markers and tailor‐based treatments, a major unmet clinical need was identified in areas of care delivery and health‐related quality of life. [ABSTRACT FROM AUTHOR]

Backgrounds/Aims: Liver diseases may affect the liver heterogeneously, especially in autoimmune hepatitis (AIH). Hence, the aim of this study was to assess the added benefit of double biopsy of both liver lobes during minilaparoscopy in guiding treatment decisions in patients with AIH. Methods: We identified all patients with AIH or variant syndromes (AIH/PBC and AIH/PSC) at our center, who underwent a double biopsy of both liver lobes via minilaparoscopy between 01/2016 and 12/2020. Results: A total of 114 patients received a biopsy of both liver lobes (AIH: N = 83, AIH/PBC: N = 26, AIH/PSC: N = 7). Differences in inflammatory activity as assessed by Ishaks's modified hepatitis activity index (mHAI) were observed in 72 (63%) patients. The difference was ≥2/18 points and ≥3/18 points in 32 (28%) and 11 (10%) patients, respectively. Starting or intensification of immunosuppression should be discussed at a mHAI of 4–5, while a mHAI≥6 prompts intensified immunosuppression in most cases. In 19/114 (17%) and 17/114 (15%) patients mHAI ≥4 or ≥6 was found in only one liver lobe, respectively. In ten patients, severe fibrosis (≥F3) was only found in one liver biopsy. Overall, therapeutically relevant histological differences were observed in 39/114 (34%) patients, which had a direct impact on treatment decisions in 24 patients (21%). No major adverse outcome occurred by taking biopsies from both liver lobes. Conclusions: Obtaining a double biopsy of both liver lobes is a safe procedure during minilaparoscopy that results in more accurate grading and staging and that may impact on treatment decisions in patients with AIH. [ABSTRACT FROM AUTHOR]

Background & Aims: Autoimmune hepatitis (AIH) is a rare indication for liver transplantation (LT). The aims of this study were to evaluate long‐term survival after LT for AIH and prognostic factors, especially the impact of recurrent AIH (rAIH). Methods: A multicentre retrospective nationwide study including all patients aged ≥16 transplanted for AIH in France was conducted. Early deaths and retransplantations (≤6 months) were excluded. Results: The study population consisted of 301 patients transplanted from 1987 to 2018. Median age at LT was 43 years (IQR, 29.4–53.8). Median follow‐up was 87.0 months (IQR, 43.5–168.0). Seventy‐four patients (24.6%) developed rAIH. Graft survival was 91%, 79%, 65% at 1, 10 and 20 years respectively. Patient survival was 94%, 84% and 74% at 1, 10 and 20 years respectively. From multivariate Cox regression, factors significantly associated with poorer patient survival were patient age ≥58 years (HR = 2.9; 95% CI, 1.4–6.2; p = 0.005) and occurrence of an infectious episode within the first year after LT (HR = 2.5; 95% CI, 1.2–5.1; p = 0.018). Risk factors for impaired graft survival were: occurrence of rAIH (HR = 2.7; 95% CI, 1.5–5.0; p = 0.001), chronic rejection (HR = 2.9; 95% CI, 1.4–6.1; p = 0.005), biliary (HR = 2.0; 95% CI, 1.2–3.4; p = 0.009), vascular (HR = 1.8; 95% CI, 1.0–3.1; p = 0.044) and early septic (HR = 2.1; 95% CI, 1.2–3.5; p = 0.006) complications. Conclusion: Our results confirm that survival after LT for AIH is excellent. Disease recurrence and chronic rejection reduce graft survival. The occurrence of an infectious complication during the first year post‐LT identifies at‐risk patients for graft loss and death. [ABSTRACT FROM AUTHOR]

Background and Aims: Autoimmune hepatitis (AIH) is a rare indication (<5%) for liver transplantation (LT). The aim of this study was to describe the early outcome after LT for AIH. Methods: A multicenter retrospective nationwide study including all patients aged ≥16 transplanted for AIH in France was conducted. Occurrences of biliary and vascular complications, rejection, sepsis, retransplantation and death were collected during the first year after LT. Results: A total of 344 patients (78.8% of women, 17.0% of (sub)fulminant hepatitis and 19.2% of chronic liver diseases transplanted in the context of acute‐on‐chronic liver failure [ACLF]) were included, with a median age at LT of 43.6 years. Acute rejection, sepsis, biliary and vascular complications occurred in respectively 23.5%, 44.2%, 25.3% and 17.4% of patients during the first year after LT. One‐year graft and patient survivals were 84.3% and 88.0% respectively. The main cause of early death was sepsis. Pre‐LT immunosuppression was not associated with an increased risk for early infections or surgical complications. Significant risk factors for septic events were LT in the context of (sub)fulminant hepatitis or ACLF, acute kidney injury at the time of LT (AKI) and occurrence of biliary complications after LT. AKI was the only independent factor associated with graft (HR = 2.5; 95% CI: 1.1–5.4; p =.02) and patient survivals (HR = 2.6; 95% CI: 1.0–6.5; p =.04). Conclusion: Early prognosis is good after LT for AIH and is not impacted by pre‐LT immunosuppression but by the presence of AKI at the time of LT. [ABSTRACT FROM AUTHOR]

Background and Aims: While some articles describe outcome of pregnancy in autoimmune hepatitis (AIH), there are less data evaluating influence of AIH control on maternal and perinatal outcomes. This study analysed outcomes of pregnancy and related possible risk factors in AIH. Method: A retrospective multicentre cohort study on pregnancy in AIH was performed in 11 hospitals in the Netherlands. Maternal and neonatal outcomes were collected from records and completed by interview. Risk factors—including incomplete response, relapse and cirrhosis—for adverse outcomes were identified using logistic regression analysis. Results: Ninety‐seven pregnancies in 50 women resulted in 70 deliveries (72%) with a live birth rate of 98.5%. AIH relapse occurred in 6% during pregnancy, and in 27% of post‐partum episodes. Absence of complete biochemical response at conception was identified as risk factor for the occurrence of gestational and post‐partum relapses. Relapse of AIH in the year before conception was a risk factor for the occurrence of both gestational relapses and post‐partum relapses. No complete biochemical response increased the risk for hypertensive disorders during pregnancy and intrahepatic cholestasis of pregnancy (ICP). Cirrhosis was found to be a risk factor for miscarriages, but not for other outcomes. Conclusion: Pregnancy in AIH is related to an increased incidence of maternal and fetal/neonatal complications; in most cases, outcome is good. Incomplete biochemical response at conception or relapse in the year before conception are risk factors for gestational and post‐partum relapses, for hypertensive disorders and for ICP. Cirrhosis was a risk factor for miscarriages. [ABSTRACT FROM AUTHOR]

Background and Aims: Autoimmune liver diseases (AILDs) are associated with impaired health‐related quality of life (HrQoL). The aim of this project was to identify potentially modifiable factors related to HrQoL in a large transnational cohort of patients with AILDs. Methods: A cross‐sectional online survey was conducted on patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) or primary sclerosing cholangitis from 15 European countries. HrQoL was measured with EQ‐5D‐5L and EQ visual analogue scale (EQ‐VAS) and analysed in relation to demographic, psychosocial, disease‐ and treatment‐related factors. A Patient Health Questionnaire‐2 score >3 indicated relevant depression. Multivariable linear regression analyses were used to identify potentially modifiable factors associated with HrQoL and confidence in treatment whilst adjusting for known confounders. Results: A group of 1178 European patients (79% female, mean age 48 ± 14 years) participated in the study. HrQoL was impaired in all three diseases (mean EQ‐5D‐5L = 0.75, mean EQ VAS = 68.9), most markedly in PBC (mean EQ‐5D‐5L = 0.73, mean EQ‐VAS = 66.2). Relevant depression, which was detected in 17% of patients, was prominently associated with impaired HrQoL. In the regression analysis, treatment confidence was identified as an important modifiable factor positively contributing to HrQoL. This influence was observable even after adjusting for other covariates including depression. Management in a transplant centre, treatment with azathioprine in AIH, and with ursodeoxycholic acid in PBC, was associated with increased treatment confidence. Finally, improved patient‐physician relationships contributed to treatment confidence. Conclusion: Treatment confidence is a relevant modifiable determinant of HrQoL and should be further investigated to improve the standards of care for patients with AILDs. [ABSTRACT FROM AUTHOR]

Background & aims: To explore the humoral and T‐cell response to the third COVID‐19 vaccination in autoimmune hepatitis (AIH). Methods: Anti‐SARS‐CoV‐2 antibody titers were prospectively determined in 81 AIH patients and 53 healthy age‐ and sex‐matched controls >7 days (median 35) after the first COVID‐19 booster vaccination. The spike‐specific T‐cell response was assessed using an activation‐induced marker assay (AIM) in a subset of patients. Results: Median antibody levels were significantly lower in AIH compared to controls (10 908 vs. 25 000 AU/ml, p <.001), especially in AIH patients treated with MMF (N = 14, 4542 AU/ml, p =.004) or steroids (N = 27, 7326 AU/ml, p =.020). Also, 48% of AIH patients had antibody titers below the 10% percentile of the healthy controls (9194 AU/ml, p <.001). AIH patients had a high risk of failing to develop a spike‐specific T‐cell response (15/34 (44%) vs. 2/16 (12%), p =.05) and showed overall lower frequencies of spike‐specific CD4 + T cells (median: 0.074% vs 0.283; p =.01) after the booster vaccination compared to healthy individuals. In 34/81 patients, antibody titers before and after booster vaccination were available. In this subgroup, all patients but especially those without detectable/low antibodies titers (<100 AU/ml) after the second vaccination (N = 11/34) showed a strong, 148‐fold increase. Conclusion: A third COVID‐19 vaccination efficiently boosts antibody levels and T‐cell responses in AIH patients and even seroconversion in patients with the absent immune response after two vaccinations, but to a lower level compared to controls. Therefore, we suggest routinely assessing antibody levels in AIH patients and offering additional booster vaccinations to those with suboptimal responses. [ABSTRACT FROM AUTHOR]

Background & Aims: No multi‐national prospective study of drug‐induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short‐term outcomes of the cases and controls is reported. Methods: Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016–2021. DILI cases or non‐DILI acute liver injury controls following causality assessment were enrolled. Results: Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre‐existing liver disease. DILI cases and non‐DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin‐clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug‐induced autoimmune‐like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver‐related death), and another six received liver transplantation. Conclusions: In this first multi‐national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI. [ABSTRACT FROM AUTHOR]

Background and Aims: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with an increased prevalence of extrahepatic autoimmune diseases and an increased mortality compared with the general population. The contribution of extrahepatic autoimmune diseases to the increased mortality has not been clarified. Our aim was to determine the effect of extrahepatic autoimmune diseases on mortality in AIH patients. Methods: This nationwide register‐based cohort study included all Danish patients diagnosed with AIH between 1995 and 2019. We examined the presence of extrahepatic autoimmune diseases and compared the mortality between AIH patients with and without extrahepatic autoimmune diseases. We adjusted our analysis for age, sex, calendar year of AIH diagnosis, cirrhosis, cancer, chronic obstructive pulmonary disease and ischaemic heart disease. Results: We included 2479 AIH patients of whom 19.8% had one extrahepatic autoimmune disease and 3.3% had multiple. The adjusted 10‐year cumulative mortality was 27.2% (95% confidence interval [CI]: 25.2–29.4) for patients with extrahepatic autoimmune diseases and 21.6% (95% CI: 19.9–23.6) for patients without. The adjusted mortality hazard ratio was 1.30 (95% CI: 1.12–1.52) for AIH patients with versus without extrahepatic autoimmune diseases; it was 1.25 (95% CI: 1.06–1.48) for patients with one extrahepatic autoimmune disease and 1.54 (95% CI: 1.15–2.05) for those with more than one. Conclusions: Extrahepatic autoimmune diseases increased the mortality in patients with AIH. Patients with multiple extrahepatic autoimmune diseases had a higher mortality than patients with just one extrahepatic autoimmune disease. [ABSTRACT FROM AUTHOR]

Background and Aims: Wilson disease (WD) has diverse presentations that frequently mimic other liver diseases. Distinguishing WD from non‐alcoholic fatty liver disease (NAFLD) and autoimmune hepatitis (AIH), can be difficult and has critical implications for medical management. This study aimed to examine the utility of histological features of WD in children compared to those with NAFLD and AIH. Methods: A review of liver biopsy slides was performed in children with a clinical and/or genetic diagnosis of WD, seen at the Hospital for Sick Children between 1981 and 2019 and compared to controls with NAFLD and AIH. 37 children with WD and 37 disease controls (20 NAFLD; 17 AIH) were included. Three pathologists, blind to clinical details and diagnosis, reviewed all liver biopsies to reach consensus. Clinical and histopathologic features were compared between groups. Results: Most WD cases displayed steatosis or steatohepatitis on histology (34/37), active AIH‐pattern in 1 and inactive cirrhosis in 2 cases. Electron microscopy (EM) findings of mitochondrial abnormalities including dilated tips of cristae, pleomorphism, membrane duplication and dense matrix were more frequent in the WD group as compared to disease controls (p < 0.0001). In WD, dilated tips of mitochondrial cristae had a sensitivity of 91% and specificity of 86%, best among EM features. Conclusions: Light microscopic findings display considerable overlap among children with WD, NAFLD and AIH. Ultrastructural findings of mitochondrial abnormalities are important to distinguish WD from NAFLD and AIH. EM examination should be considered essential in the diagnostic work‐up of paediatric liver biopsies. [ABSTRACT FROM AUTHOR]

Background and Aims: Prior studies suggested that patients with autoimmune liver diseases (AiLDs) had an increased risk of cancer, whereas the causal effect remained unclear. Methods: Meta‐analyses concerning the relationship between AiLD and cancer risk were performed to calculate the pooled relative risk (RR) and corresponding 95% confidence intervals (CIs). Then, the associations with a p value of <.05 were further validated by two‐sample Mendelian randomization studies. Results: A total of 37 cohort studies covering more than 34 558 patients were included, and we observed an increased risk of overall cancers (pooled RR = 3.64, 95% CI: 2.64–5.03, p <.001) and cancer‐related death (pooled RR = 2.48, 95% CI: 1.73–3.53, p <.001) for patients with AiLD. Besides, overall and several site‐specific cancers risk were found in patients with primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC) (p <.05). However, associations between genetically predisposed AIH, PBC, and PSC and the risk of specific cancers did not reach a significant level, except for PBC and gastric cancer (OR = 0.96, 95% CI: 0.93–0.99; p =.02). Conclusions: In addition to hepatobiliary cancer, results from the meta‐analyses suggest that patients with AiLD might have an increased risk of several extrahepatobiliary cancers. However, the causal role of AiLD in cancer development needs to be further investigated. [ABSTRACT FROM AUTHOR]

Rare diseases, also known as orphan diseases, are a group of diseases that affect a relatively small number of people. Low incidence rates, atypical symptoms, imperfect diagnosis criteria and few treatment options impose medical, psychological and financial stress on the local healthcare system. The spectrum of liver diseases in China has changed in the past decades due to successful control of once highly prevalent viral hepatitis B and C. Furthermore, the increased awareness and improved availability of specific laboratory tests have also facilitated the diagnosis of rare diseases such as autoimmune, cholestatic and genetic liver diseases. Finally, considering the huge population, the total number of many rare liver diseases in China is not as rare as once deemed. In this mini-review article, we will outline the current clinical and epidemiological profiles of some rare liver diseases that are no longer rare in China. [ABSTRACT FROM AUTHOR]

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that mainly injures the hepatocytes. The autoimmune disease might be involved in its aetiology, but this remains to be confirmed. Recently epidemiological studies of AIH in Asia have been broadly conducted, revealing characteristics and management of AIH patients in Asia. In East Asia, most AIH patients are type 1, and type 2 AIH is very rare. However, type 2 AIH in South Asia is as frequent as in Europe and the USA. HLA-DR4 is associated with the characteristics of type 1 AIH in East Asia, whereas HLA-DR3 occurs in AIH patients from South Asia. AIH prevalence worldwide is increasing, and several studies have reported a prevalence of 19.44, 22.80 and 12.99 per 100 000 people in Europe, the USA and Asia respectively. A meta-analysis of studies on AIH showed similar annual incidence rates for all regions, with 1.31, 1.37 and 1.00 per 100 000 people in Asia, Europe and the USA respectively. The increase in the rates could be attributable to the increased awareness of disease concepts and diagnosis. In South Asia, most cases were diagnosed as AIH only after having progressed to cirrhosis, which may cause a higher mortality rate in South Asia than in East Asia. Therefore, the early diagnosis and treatment of AIH patients can improve the current situation in Asia. [ABSTRACT FROM AUTHOR]

Rare diseases, also known as orphan diseases, are a group of diseases that affect a relatively small number of people. Low incidence rates, atypical symptoms, imperfect diagnosis criteria and few treatment options impose medical, psychological and financial stress on the local healthcare system. The spectrum of liver diseases in China has changed in the past decades due to successful control of once highly prevalent viral hepatitis B and C. Furthermore, the increased awareness and improved availability of specific laboratory tests have also facilitated the diagnosis of rare diseases such as autoimmune, cholestatic and genetic liver diseases. Finally, considering the huge population, the total number of many rare liver diseases in China is not as rare as once deemed. In this mini‐review article, we will outline the current clinical and epidemiological profiles of some rare liver diseases that are no longer rare in China. [ABSTRACT FROM AUTHOR]

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that mainly injures the hepatocytes. The autoimmune disease might be involved in its aetiology, but this remains to be confirmed. Recently epidemiological studies of AIH in Asia have been broadly conducted, revealing characteristics and management of AIH patients in Asia. In East Asia, most AIH patients are type 1, and type 2 AIH is very rare. However, type 2 AIH in South Asia is as frequent as in Europe and the USA. HLA‐DR4 is associated with the characteristics of type 1 AIH in East Asia, whereas HLA‐DR3 occurs in AIH patients from South Asia. AIH prevalence worldwide is increasing, and several studies have reported a prevalence of 19.44, 22.80 and 12.99 per 100 000 people in Europe, the USA and Asia respectively. A meta‐analysis of studies on AIH showed similar annual incidence rates for all regions, with 1.31, 1.37 and 1.00 per 100 000 people in Asia, Europe and the USA respectively. The increase in the rates could be attributable to the increased awareness of disease concepts and diagnosis. In South Asia, most cases were diagnosed as AIH only after having progressed to cirrhosis, which may cause a higher mortality rate in South Asia than in East Asia. Therefore, the early diagnosis and treatment of AIH patients can improve the current situation in Asia. [ABSTRACT FROM AUTHOR]

Background: With few data regarding treatment and outcome of patients with AIH outside of large centres we present such a study of patients with AIH in 28 UK hospitals of varying size and facilities. Methods: Patients with AIH were identified in 14 University and 14 District General hospitals; incident cases during 2007–2015 and prevalent cases, presenting 2000–2015. Treatment and outcomes were analysed. Results: In 1267 patients with AIH, followed up for 3.8 (0–15) years, 5‐ and 10‐year death/transplant rates were 7.1 ± 0.8% and 10.1 ± 1.3% (all‐cause) and 4.0 ± 0.6% and 5.9 ± 1% (liver related) respectively. Baseline parameters independently associated with death/transplantation for all causes were: older age, vascular/respiratory co‐morbidity, cirrhosis, decompensation, platelet count, attending transplant centre and for liver related: the last four of these and peak bilirubin. All‐cause and liver‐related death/transplantation was independently associated with: non‐treatment with corticosteroids, non‐treatment with a steroid‐sparing agent (SSA), non‐treatment of asymptomatic or non‐cirrhotic patients and initial dose of Prednisolone >35 mg/0.5 mg/kg/day (all‐cause only), but not with type of steroid (Prednisolone vs. Budesonide) or steroid duration beyond 12 months. Subsequent all‐cause and liver‐death/transplant rates showed independent associations with smaller percentage fall in serum ALT after 1 and 3 months, but not with failure to normalise levels over 12 months. Conclusions: We observed higher death/transplant rates in patients with AIH who were untreated with steroids (including asymptomatic or non‐cirrhotic subgroups), those receiving higher Prednisolone doses and those who did not receive an SSA. Similar death/transplant rates were seen in those receiving Prednisolone or Budesonide, those continuing steroids after 12 months and patients attaining normal ALT within 12 months versus not. [ABSTRACT FROM AUTHOR]

Background and Aims: Little is known about the impact of DNA methylation modifications on autoimmune hepatitis (AIH) pathogenesis and therapeutic response. We investigated the potential alterations of DNA methylation in AIH peripheral lymphocytes at diagnosis and remission. Methods: Ten AIH patients at diagnosis (time‐point 1; AIH‐tp1), 8/10 following biochemical response (time‐point 2; AIH‐tp2), 9 primary biliary cholangitis (PBC) and 10 healthy controls (HC) were investigated. Peripheral CD19(+) and CD4(+) cells were isolated. Global DNA methylation (5mC)/hydroxymethylation (5hmC) was studied by ELISAs. mRNA of DNA methylation (DNMT1/3A/3B) and their counteracting hydroxymethylation enzymes (TET1/2/3) was determined by quantitative RT‐PCR. Epigenome wide association study (EWAS) was performed in CD4(+) cells (Illumina HumanMethylation 850 K array) in AIH and HC. Total 5mC/5hmC was also assessed by immunohistochemistry (IHC) on paraffin‐embedded liver sections. Results: Reduced TET1 and increased DNMT3A mRNA levels characterized CD19(+) and CD4(+)‐lymphocytes from AIH‐tp1 compared to HC and PBC, respectively, without affecting global DNA 5mC/5hmC. In AIH‐tp1, CD4(+) DNMT3A expression was negatively correlated with serum IgG (P =.03). In remission, DNMT3A decreased in both CD19(+) and CD4(+) cells compared to AIH‐tp1 (P =.02, P =.03 respectively). EWAS in CD4(+) cells from AIH patients confirmed important modifications in genes implicated in immune responses (HLA‐DP, TNF, lnRNAs and CD86). IHC showed increased 5hmC staining of periportal infiltrating lymphocytes in AIH‐tp1 compared to HC and PBC. Conclusion: Altered TET1 and DNMT3A expressions, characterize peripheral lymphocytes in AIH. DNMT3A was associated with disease activity and decreased following remission. Gene DNA methylation modifications affect immunological pathways that may play an important role in AIH pathogenesis. [ABSTRACT FROM AUTHOR]

Background & Aims: Diagnostic histological criteria for autoimmune hepatitis (AIH) have not been clearly established. Previously published criteria focused mainly on chronic AIH, in which inflammatory changes mainly occur in portal/periportal regions and may not be applicable to acute presentation of AIH, in which inflammatory changes are typically predominantly lobular in location. International consensus criteria for the diagnosis and assessment of disease severity in both acute and chronic AIH are thus urgently needed. Methods: Seventeen expert liver pathologists convened at an international workshop and subsequently used a modified Delphi panel approach to establish consensus criteria for the histopathological diagnosis of AIH. Results: The consensus view is that liver biopsy should remain standard for diagnosing AIH. AIH is considered likely, if there is a predominantly portal lymphoplasmacytic hepatitis with more than mild interface activity and/or more than mild lobular hepatitis in the absence of histological features suggestive of another liver disease. AIH is also considered likely if there is predominantly lobular hepatitis with or without centrilobular necroinflammation and at least one of the following features: portal lymphoplasmacytic hepatitis, interface hepatitis or portal‐based fibrosis, in the absence of histological features suggestive of another liver disease. Emperipolesis and hepatocellular rosettes are not regarded as being specific for AIH. Conclusions: The criteria proposed in this consensus statement provide a uniform approach to the histological diagnosis of AIH, which is relevant for patients with an acute as well as a chronic presentation and to more accurately reflect the current understanding of liver pathology in AIH. [ABSTRACT FROM AUTHOR]

Background and Aims: Neuropsychiatric symptoms in hepatitis C (HCV) patients resemble those of patients with autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), whilst the mechanisms behind them are unknown. Here we looked for cerebral metabolic and/or microstructural alterations in patients with HCV, AIH or PBC as possible causes behind these symptoms. Methods: Patients with HCV infection (n = 17), AIH (n = 14) or PBC (n = 11) and age‐adjusted healthy controls (n = 18) underwent brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and psychometric assessment of memory and attention. Brain relative proton density (PD) and T2 relaxation time (T2) were determined in 17 regions of interest (ROIs), as were the concentrations of N‐acetyl‐aspartate, choline, creatine, myo‐inositol and glutamine + glutamate in frontal‐ (fWM) and parietal white matter (pWM). One‐way analysis of variance and Kruskal‐Wallis tests were used for group comparison. Correlations between altered neuropsychological findings and MRI/MRS observations were estimated with the Spearman ρ test. Results: HCV, AIH and PBC patients revealed similar alterations in brain PD and metabolites compared to controls: significantly decreased PD in 7/17 ROIs in the HCV group, 16/17 ROIs in the PBC group and 14/17 ROIs in the AIH group, significantly increased N‐acetyl‐aspartate in fWM in all patients, significantly increased choline in the PBC group in both fWM and pWM, in the AIH group only in pWM and with a trend in the HCV group in pWM. Correlation analysis did not reveal significant associations between MRI/MRS alterations and neuropsychological dysfunction. Conclusion: The findings suggest similar pathophysiological mechanisms behind neuropsychiatric symptoms associated with HCV infection, AIH and PBC. [ABSTRACT FROM AUTHOR]

Background: We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID‐19) in autoimmune hepatitis (AIH). Patients and methods: Data of AIH patients with laboratory confirmed COVID‐19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID‐19 were compared to patients who were not on AIH medication. The clinical courses of COVID‐19 were classified as (i)‐no hospitalization, (ii)‐hospitalization without oxygen supplementation, (iii)‐hospitalization with oxygen supplementation by nasal cannula or mask, (iv)‐intensive care unit (ICU) admission with non‐invasive mechanical ventilation, (v)‐ICU admission with invasive mechanical ventilation or (vi)‐death and analysed using ordinal logistic regression. Results: We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17‐85) years. At the onset of COVID‐19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12‐25.89) and thiopurines (aOR 4.78, 95% CI 1.33‐23.50) for AIH was associated with worse COVID‐19 severity, after adjusting for age‐sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76‐20.56) and tacrolimus (aOR 4.09, 95% CI 0.69‐27.00) were also associated with more severe COVID‐19 courses in a smaller subset of treated patients. Conclusion: Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID‐19 was significantly associated with COVID‐19 severity in patients with AIH. [ABSTRACT FROM AUTHOR]

Background: Patients with autoimmune hepatitis (AIH) and primary or autoimmune sclerosing cholangitis are at nutritional risk; their body composition and has not been extensively studied. We aimed to describe their body composition and identify clinical links. Methods: Using magnetic resonance imaging (MRI), two reviewers segmented total psoas muscle area (tPMSA), visceral fat area (VFA) and subcutaneous fat area (mm2) and measured visceral and subcutaneous thickness (mm). Clinical, laboratory and quality of life (QoL; using PedsQL) data were collected. Sarcopenia was defined as tPMSA ≤5th percentile. Analysis of variance, Wilcoxon rank test and multivariable modelling were performed. A paediatric cohort with non‐alcoholic fatty liver disease (NAFLD) was used as a comparator following propensity score matching. Results: Fifty‐eight patients with autoimmune liver disease (AILD) (33 [57%] with AIH) were included: median age 16 years (interquartile range [IQR]: 13‐18), 33 (57%) male. Median time from diagnosis to MRI was 15 months (IQR: 2‐39 months). Two patients (3%) had a BMIz indicative of mild malnutrition. tPMSA was measurable in 52 subjects (90%). Of those, 25 (48%) had sarcopenia. Sarcopenic patients had a lower blood urea nitrogen compared to non‐sarcopenic (median [IQR]: 9.5 [8.0, 12.0] vs 11 [10, 14] mg/dL; P =.023). There was no difference in corticosteroid use between groups. The VFA of sarcopenic patients was higher (3156 [2064, 7492]) vs 2084 [688, 3092]) mm2; P =.005). Patient‐reported QoL negatively associated with VFA and general health negatively associated with VFA. Compared with NAFLD, the odds ratio for sarcopenia with AILD was 14.5 (95% confidence interval: 2.3‐90.7). Conclusion: In autoimmune liver diseases, sarcopenia is highly prevalent, associated with increased visceral fat and QoL. [ABSTRACT FROM AUTHOR]

Background and aims: Immunoglobulin G4‐associated cholangitis (IAC) is characterized by distinctly elevated immunoglobulin G4 in serum (sIgG4) and responds well to corticosteroid therapy. Primary Sclerosing Cholangitis (PSC) is a progressive liver disease without causal treatment options usually not responding to immunosuppression. Increased serum levels of sIgG4 in patients with PSC, that do not meet criteria of IAC, have been reported in 10%‐25%. Therefore, we aimed to characterize this subgroup of patients in a retrospective, multicenter study. Methods: sIgG4 values of 289 patients with PSC from three German university hospitals were analysed. Patients with elevated sIgG4 levels were identified and further characterized by clinical and biochemical parameters and by cholangiographic presentation. Clinical endpoints, death and liver transplantation were compared between groups. Parameters associated with outcome were identified with Cox regression analysis. Results: 14.5% of patients with PSC showed increased sIgG4 levels (PSC‐IgG4), presented with significantly higher (P <.02) albumin, aspartate‐aminotransferase, bilirubin and alkaline phosphatase and had a significant lower prevalence of a concomitant autoimmune hepatitis (P =.025). Cholangiogram obtained via ERC showed extrahepatic dominant strictures more often in the PSC‐IgG4 subgroup (P =.047). The disease severity models Amsterdam‐Oxford‐Score (P =.018) and Mayo‐Risk‐Score (P =.025) predicted lower survival rates for the PSC‐IgG4 subgroup. Transplant‐free survival after first diagnosis of PSC was shorter in patients with elevated sIgG4 (11.6 vs 15.1 years, P =.001). Conclusion: Patients with PSC and elevated sIgG4 should be considered as a distinct subgroup, characterized by different clinical and cholangiographical features and are associated with an inferior outcome. [ABSTRACT FROM AUTHOR]

Background: Previous studies investigating the prevalence of celiac disease (CD) in individuals with autoimmune hepatitis (AIH) have shown highly variable results. We therefore aimed to examine the prevalence of CD in individuals with AIH. Methods: Two professional librarians searched PubMed, EMBASE, Cochrane and Web of Science Core Collection up until 7 February 2020. The search terms included 'celiac disease', 'celiac', 'transglutaminases', 'gluten', 'gliadin', 'EMA', 'TTG' and 'villous' combined with 'autoimmune', 'hepatitis', 'ANA', 'SMA' and 'LKM'. This search yielded 2419 unique publications. A systematic review based on the PRISMA guidelines resulted in 31 articles eligible for full text review. Fifteen articles were deemed relevant, with 8 being included in our main analysis. A fixed‐effect inverse variance‐weighted model was used, and heterogeneity was calculated. Results: Our main analysis included 567 individuals with AIH from eight studies, where biopsy‐verified CD (equivalent to Marsh III) was seen in 23 individuals (4.1%). The pooled prevalence of CD in AIH was 3.5% (95% CI = 1.6%‐5.3%) (heterogeneity: P =.874; I2 = 0.0%), which is clearly higher than the 1% CD seen in most general populations. When also including studies where CD had been diagnosed through positive serology without biopsy (15 studies: n = 1817 individuals with AIH), the pooled prevalence of CD was 2.9% (95% CI = 2.1%‐3.8%) (heterogeneity: P <.001; I2 = 66.8%). Conclusion: Our results demonstrate a higher prevalence of CD in individuals with AIH compared to the general population. CD screening may be considered in patients with AIH. [ABSTRACT FROM AUTHOR]

Background: Failure of immunologic homeostasis and resultant hepatocyte destruction in autoimmune hepatitis (AIH) is likely the result of environmental triggers within a permissive genetic architecture. Aims: We aimed to identify risk factors associated with AIH in a well‐phenotyped AIH cohort. Methods: We prospectively collected environmental questionnaires from 358 AIH cases and 563 healthy controls. Response frequencies were compared using logistic regression, adjusting for age at recruitment, sex and education. Results: AIH cases were more likely to ever have a urinary tract infection (UTI) (53.6% vs 33.9%, P <.001) and recurrent UTI (more than 1 per year) (23.5% vs 15.9%, P =.002) compared to controls. Female cases more frequently had ever used oral contraceptives (83.0% vs 73.7%, P =.006), fewer pregnancies (median = 1 vs 3, P <.001) and less often used hormone replacement therapy compared to controls (28.5% vs 60.1%, P <.001). Current smoking was more prevalent in cases (18.9% vs 7.4%, P =.022), yet no difference according to historical smoking behaviours was observed. Finally, cases were less likely to have history of mumps (32.4% vs 53.1%, P =.011) and rheumatic fever (1.1% vs 4.4%, P =.028), but reported higher vaccination frequency to chicken pox (38% vs 28.1%), measles (66.5% vs 39.3%), mumps (58.7% vs 34.6%), rubella (55.3% vs 32.7%), pertussis (59.8% vs 40.1%) and pneumococcus (47.2% VS 39.4%) (P <.002). Conclusions: Environmental factors are important in AIH pathogenesis. Replication of these findings and prospective examination may provide new insight into AIH onset and outcomes. [ABSTRACT FROM AUTHOR]

Background & Aims: Autoimmune hepatitis (AIH) affects both sexes and all age groups. However, very few studies have focused specifically on the characteristics and outcome of AIH in patients aged 70 y or older. Methods: 25/234 patients with well‐established AIH and disease onset at ≥70‐y (median: 73‐y) were analysed and compared to the rest patients (median: 47 y). Treatment response was assessed in all patients from both groups who were eligible for treatment (n = 202). Results: Disease presentation was mainly insidious in both groups (19/25, 76% vs. 134/209, 64.1%; P =.313). At diagnosis, older patients had lower alaninoaminotrasferase (101[433] vs. 199[441] IU/L, P <.05) but were more frequently cirrhotic (12/25, 48% vs. 57/209, 27.3%; P =.03). Importantly, similar rates of on‐treatment response (16/18, 89% vs. 154/184, 84%; P =.565), corticosteroid withdrawal (10/16, 62.5% vs. 113/154, 73.4%; P =.355) and complete withdrawal of immunosuppression (1/16, 6.3% vs. 40/154, 26%; P =.122) were achieved in both groups. Treatment‐related adverse events were evenly observed between groups (6/18, 33% vs. 54/184, 29%; P =.724). In treated patients, the age ≥70 y was only associated with the overall mortality (HR 8.3 [95% CI: 2.1‐36.4], P =.003), but not with the liver‐related mortality (HR 3.4 [95% CI: 0.4‐30.0], P =.268). Conclusion: AIH should be seriously considered in patients ≥70 y with unexplained impaired liver function tests as the disease is not infrequent in this group and seems to bear an increased risk for advanced disease stage at diagnosis. However, if immunosuppression is started promptly, it seems as safe and effective as in younger patients. [ABSTRACT FROM AUTHOR]

Currently, the management of patients with DILI is mainly symptomatic and there is no evidence-based pharmacological treatment that has been shown to be able to change the natural course of the liver injury in DILI patients in general, other than withdrawing the suspected offending agent and providing supportive care.[[10], [12]] Therefore, there is a medical need to identify an effective therapy for DILI in patients who otherwise might develop acute liver failure and/or have prolonged jaundice and itching. Drug-induced liver injury registries are important Abbreviations DILI drug-induced liver injury MARS molecular adsorbent recirculating system Pro-Euro-DILI prospective European DILI study DATA AVAILABILITY STATEMENT Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. [Extracted from the article]

AIH is considered "likely" when there is a predominantly portal lymphoplasmacytic hepatitis with more than mild interface activity and/or more than mild lobular hepatitis and in the absence of histological features suggesting other liver diseases. Criteria for lobular hepatitis may be less stringent than those for portal hepatitis, as the differential diagnosis for severe lobular hepatitis besides acute AIH would include DILI and idiopathic hepatitis, for example, seronegative acute liver failure, conditions that often have lymphoplasmacytic infiltration at least focally and may easily meet the criteria of likely AIH. For the "portal hepatitis pattern", they include the degree of interface hepatitis, the degree of lobular hepatitis and the presence of histological features suggestive of other liver diseases; for the "lobular hepatitis pattern", they include lymphoplasmacytic infiltrates, interface hepatitis, portal-based fibrosis and histological features suggestive of other liver diseases. Autoimmune hepatitis (AIH) is a progressive inflammatory disease characterised by a female preponderance, elevated transaminase and immunoglobulin G (IgG) levels, non-organ-specific autoantibodies, inflammatory histology and a dramatic response to corticosteroids. [Extracted from the article]

Background and Aims: Liver stiffness measurements (LSM), commonly performed by transient elastography (TE) or two‐dimensional shear wave elastography (2D‐SWE), are used to quantify liver fibrosis. Active hepatitis, a hallmark of autoimmune hepatitis (AIH), could bias LSM. This bias might be overcome by measurement spleen 2D‐SWE. Here, we compare liver and spleen 2D‐SWE to TE and liver biopsy (LB) in prospectively recruited patients with AIH. Methods: We analysed liver and spleen 2D‐SWE in relation to liver TE in 90 patients treated ≥ 6 months for AIH. Liver and spleen 2D‐SWE were also compared to LB in 63 individuals with AIH. Finally, we evaluated these tools in 220 patients with AIH and during 18 months follow‐up. Results: Liver 2D‐SWE correlated with surrogate markers of active hepatitis (ALT and IgG, both P <.001) but there was no link between spleen 2D‐SWE and ALT. Liver 2D‐SWE, but not spleen 2D‐SWE, was associated with histopathological inflammatory score (P <.01). When compared to LB, the optimal cut‐offs for detecting cirrhosis by liver and spleen 2D‐SWE were 16.1 kPa (AUROC 0.93) and 29.8 kPa (AUROC 0.95), respectively. In patients with active hepatitis the combined diagnostic approach including liver and spleen 2D‐SWE had significantly better AUROC for detecting cirrhosis than liver 2D‐SWE alone. Conclusions: Liver and spleen 2D‐SWE are reliable complementary methods for the diagnosis of advanced fibrosis in AIH. Spleen 2D‐SWE seems to be less biased by inflammation and could facilitate fibrosis assessment in therapy‐naïve patients or in the presence of active hepatitis. [ABSTRACT FROM AUTHOR]

Is immunosuppression truly associated with worse outcomes in autoimmune hepatitis patients with COVID-19? In addition, at least one-quarter of patients is cirrhotic, making AIH peculiar when investigating the COVID-19 outcomes, due to the high risk of adverse COVID-19 course linked to cirrhosis. The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a highly transmissible and pathogenic virus leading to coronavirus disease 2019 (COVID-19), is continuing to have a devastating global impact. [Extracted from the article]

Background: Guidelines regarding treatment for autoimmune hepatitis (AIH) favour two strategies for azathioprine (AZA) introduction: concurrent with steroids at induction or delayed by 2‐4 weeks. The safety and efficacy of both strategies have been unexplored. Methods: We established a cohort of 900 AIH patients from 12 centres in 7 European countries. There were 631 patients who used AZA as part of the therapeutic regimen. We distinguished two groups: patients with early AZA (<2 weeks) or delayed AZA initiation (≥2 weeks). Primary outcome was discontinuation of AZA in the first year of treatment. Cox regression and propensity score matching was performed to determine difference in outcomes between groups. Results: Patients with early AZA initiation had significantly lower transaminases and bilirubin at baseline. Discontinuation rates of AZA did not differ between early and delayed starters (16.6% vs 14.2%), which did not reach statistical significance (hazard ratio 0.97, 95% confidence interval 0.61‐1.55, P =.90). Stratification according to baseline disease activity or propensity score matching did not alter the results. Main reason for AZA discontinuation was intolerance to treatment (14.0% vs 13.2%, P =.78) with nausea and vomiting as main side effects. AIH remission rates were comparable among groups. Conclusion: The discontinuation rate of AZA in AIH treatment is ~15% in the first year of treatment. Early or delayed AZA initiation does not differ in remission and discontinuation rates in AIH induction therapy. Our data suggest that either strategy may be used as part of AIH treatment. [ABSTRACT FROM AUTHOR]

Background & Aims: Check point inhibitors (CPI) have improved survival of oncology patients but adverse effects that mimic autoimmune disorders have been reported. Our aim was describe the characteristics of immune‐related hepatitis (irH) and prognosis, and compared them to those of patients with autoimmune hepatitis (AIH). Methods: This is a retrospective study including all grade ≥ 3 (severe) irH diagnosed among 414 patients treated with CPI from 2016 to 2018. Results: Twenty‐eight cases of severe irH were recorded: 10 on anti‐CTLA‐4 ± anti‐PD1/PD‐L1 and 18 on anti‐PD1/PD‐L1. Half were female, age 63 years, median time on CPI three cycles. Four (14.3%) presented acute liver injury or failure and one (3.6%) died as consequence. 94% presented normal immunoglobulin G (IgG). Six (21.4%) patients were retreated with CPI and none presented relapse or new immune‐related adverse events after a median cycles of 11 (range 6‐36). Subjects with irH were older and had lower IgG values than a cohort of AIH (N = 38). Presentation tended to be more severe in AIH. Twenty‐five percent of irH and 84% AIH presented ANAs ≥ 1:80 (P =.001). In irH Initial dose of corticosteroids was higher (60 vs 30 mg, P <.001) but duration shorter (2.3 vs 7 months, P <.001) and frequently in monotherapy (41.7% vs 91.3%, P <.001). Conclusions: Immune‐related hepatitis can lead to acute liver failure, with absence of increased values of IgG and ANAs. In contrast to autoimmune hepatitis, initial corticosteroids dose were higher, duration shorter with few requiring additional immunosuppression. Retreatment with CPI was not associated with recurrence. [ABSTRACT FROM AUTHOR]

Autoimmune liver diseases (AILD), namely autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are rare diseases. These days, patients with PBC almost never require liver transplantation. When treated early with ursodeoxycholic acid patients have a normal life expectancy if the disease is diagnosed at an early stage and the patients respond to treatment. Patients with AIH often go into remission with first‐line therapy including corticosteroids alone or in combination with azathioprine. Nevertheless, about one quarter of patients already developed cirrhosis at diagnosis. Those who do not respond to first line standard of care (SOC) have significant liver‐related morbidity and mortality. No approved second‐ or third‐line treatments are available and the drugs are selected based on limited case series and personal experience. Larger trials are needed to develop efficient therapies for difficult‐to‐treat AIH patients. No treatment has been found to alter the natural course of disease in patients with PSC except for liver transplantation. Identifying PSC patients at risk of developing cholangiocarcinoma (CCA) is another unmet need. Current research in all AILD including AIH, PBC and PSC, focuses on improving our understanding of the underlying disease process and identifying new therapeutic targets to decrease morbidity and mortality. [ABSTRACT FROM AUTHOR]

The priming of T cells in the liver is widely accepted. Nonetheless, it is controversial whether immune activation in autoimmune hepatitis (AIH) occurs in the liver or in the spleen. To address this issue, we splenectomized mice and induced experimental murine AIH (emAIH) with an adenovirus (Ad)‐expressing formiminotransferase cyclodeaminase (FTCD). Post‐splenectomy, the experimental mice developed emAIH to a higher extent than the control mice. In addition, splenectomized mice harboured more intrahepatic B cells and a disproportionately small number of regulatory T cells (Tregs) within a reduced T cell population at the site of inflammation. These results imply that the spleen is not the site of AIH induction. In contrast, the spleen seems to have a protective function since the pathological score was more severe in splenectomized animals. These findings have important implications for the aetiology of AIH. [ABSTRACT FROM AUTHOR]

Background and aims: Antibodies against soluble liver antigen/liver pancreas (anti‐SLA/LP) are highly specific for autoimmune hepatitis (AIH) and have been linked with a more severe clinical course of the disease, frequent relapses after treatment withdrawal and worse outcome. To address definitely the clinical significance of anti‐SLA/LP, we investigated a large number of anti‐SLA/LP‐positive and ‐negative patients followed in three referral centres. Methods: Prospectively collected data from 89 anti‐SLA/LP‐positive AIH patients (29 from Hamburg‐Germany, 20 from Bologna‐Italy and 40 from Larissa‐Greece) were analysed retrospectively. Age‐ and sex‐matched anti‐SLA/LP‐negative patients served as disease controls (n = 230; 1:2.5 ratio). Results: In respect to baseline characteristics, anti‐SLA/LP‐positive patients were more frequently asymptomatic compared to anti‐SLA/LP‐negative (P <.05). However, anti‐SLA/LP‐positive patients did not differ from anti‐SLA/LP‐negative in terms of the overall response to treatment, disease progression and survival even though, they were less likely to achieve corticosteroid withdrawal (P <.05), needed longer treatment duration to achieve first complete response (P <.001) and relapsed more frequently after treatment withdrawal compared to anti‐SLA/LP‐negative patients (P = <.001). Conclusions: We showed that anti‐SLA/LP antibodies do not characterize a group of AIH patients with distinct features and cannot identify patients with a more severe form of the disease or worse survival. Most importantly, however, anti‐SLA/LP‐positive patients appear to require lifelong immunosuppression as they are less likely to achieve the cessation of corticosteroids and present higher relapse rates after treatment withdrawal. Therefore, close long‐term monitoring should be advised in all anti‐SLA/LP‐positive patients after withdrawal of immunosuppressive treatment. [ABSTRACT FROM AUTHOR]

Background & aims: Population‐based studies on the epidemiology of autoimmune hepatitis (AIH) are scarce. Drug‐induced AIH (DIAIH) is increasingly recognized in association with immunomodulatory therapy. We aimed to determine the incidence, prevalence and natural history of AIH in a population‐based setting. Methods: We collected data of new diagnosis of AIH in Iceland from 2006 to 2015. Cases were identified through search of diagnostic codes and text search for AIH within electronical medical records of all hospitals in Iceland and through records of smooth muscle antibodies (SMA) test results by the only laboratory in the country analyzing SMA. Patients were included in the final analysis if they received the clinical diagnosis of AIH or were started on immunosuppressive therapy. Results: The mean annual incidence of AIH in Iceland was 2.2 cases per 100 000 inhabitants. Point prevalence on 31 December 2015 was 27/100 000. The median age at diagnosis was 56 years and 86% of patients were of female gender. DIAIH was suspected in 13 of 71 patients (18%) of which eight cases were related to infliximab. Immunosuppressive treatment was started in all but two patients. At the end of follow‐up (median 4.8 years) 66 of 71 (93%) patients were alive. Conclusion: The incidence and prevalence rates of AIH in Iceland are the highest reported so far in a population‐based setting. Higher incidence can partly be explained by the increasing use of biological drugs. Immunosuppressive therapy was very effective in achieving remission and prognosis was favorable. [ABSTRACT FROM AUTHOR]

Background & Aims: Four major autoimmune diseases target the liver. They develop because of bile duct destruction, leading to chronic cholestasis or result from hepatocyte damage like autoimmune hepatitis (AIH). Interestingly, some patients simultaneously show features of both cholangitis and AIH. Our goal was to mimic such concurrent characteristics in a mouse model that would help deciphering mechanisms possibly involved in an inflammatory crosstalk between cholestatic disease and hepatitis. Methods: Mdr2−/− mice, which spontaneously develop sclerosing cholangitis because of accumulation of toxic bile salts, were infected with adenovirus (Ad) encoding human Cytochrome P4502D6 (hCYP2D6), the major target autoantigen in type‐2 AIH, to trigger hepatocyte injury. Wild type FVB mice were controls. Results: Resulting Ad‐Mdr2−/− mice presented with cholangitis, fibrosis and cellular infiltrations that were higher than in Mdr2−/− or Ad‐FVB mice. Increased levels of anti‐neutrophil cytoplasmic antibodies but similar anti‐hCYP2D6 antibody titres were detected in Ad‐Mdr2−/− compared to Mdr2−/− and Ad‐FVB mice respectively. IFNγ‐expressing hCYP2D6‐specific CD4 T cells declined, whereas hCYP2D6‐specific CD8 T cells increased in Ad‐Mdr2−/− compared to Ad‐FVB mice. The overall T cell balance in Ad‐Mdr2−/− mice was a combination of a type 17 T cell response typically found in Mdr2−/− mice with a type 1 dominated T cell response characteristic for Ad‐FVB mice. Simultaneously, the type 2 T cell compartment was markedly reduced. Conclusions: Experimental hepatitis induction in a mouse with sclerosing cholangitis results in a disorder which represents not simply the sum of the individual characteristics but depicts a more complex entity which urges on further analysis. [ABSTRACT FROM AUTHOR]

Acute-onset AIH patients, male patients and patients who had complicated conditions (such as cholestasis, DILI, alcohol consumption and so on) were more suitable for using the simplified score, and the simplified score is easy to use for physicians in primary hospital. It is well known that, drug-induced liver injury (DILI) could have similar presentation to acute AIH, and some DILI eventually develop into AIH or they just belong to a special type of AIH performed like DILI.8 In our centre, a few AIH patients also had history of high alcohol consumption. As for the revised score, it is appropriate for patients - acute-on-chronic AIH patients and chronic patients - who have typical features of AIH. [Extracted from the article]