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Autoimmune hepatitis (AIH) is a chronic and progressive inflammatory process of the liver, with standard treatments including prednisone, azathioprine, and ultimately liver transplant. While there are many integrative and ayurvedic treatment options that have been shown to be helpful for other liver diseases, there are no studies that have been performed to evaluate these therapies particularly in AIH with cirrhosis. We detail the case of a 55-year-old female with cirrhosis in the setting of AIH placed on a liver transplant list after being treated with conventional therapies. She was started on various nutritional supplements and ayurvedic treatments which resulted in a significant decrease in her Model for End-Stage Liver Disease score, which was sustained at 7 months. This is the first case report to our knowledge detailing an integrative approach to cirrhosis in the setting of AIH showing such an improvement in liver function.

Background and aims Inflammatory bowel diseases (IBD) are chronic conditions that may be accompanied by autoimmune liver disease (AILD), most commonly primary sclerosing cholangitis (PSC). The objective of this study was to evaluate the behaviour of patients with IBD associated with AILD and compare a PSC group with a non-PSC group. Methods Medical records of patients with IBD associated with PSC, autoimmune cholangitis, primary biliary cholangitis, small-duct PSC, autoimmune hepatitis (AIH) and overlapping syndromes were assessed. Results Fifty-four patients were included: 48 (88.9%) had ulcerative colitis and six (11.1%) had Crohn's disease; 35 (64.8%) had PSC and 19 (35.2%) did not have PSC. There was no difference in outcomes (surgical treatment for IBD, liver transplantation or death) between the groups. Time since the diagnosis of IBD was associated with surgical treatment of IBD (p = 0.041; OR: 1.139, 95% CI: 1.006–1.255). Time since the diagnosis of AILD (p = 0.003; OR: 1.259, 95% CI: 1.1–1.396), as well as portal hypertension at diagnosis (p = 0.014; OR: 18.22, 95% CI: 1.815–182.96), were associated with liver transplantation. In addition, previous diagnosis of AIH was associated with de novo IBD (p = 0.012; OR: 7.1, 95% CI: 1.215–42.43). Conclusion Both groups had similar disease behaviour. A longer time since the diagnosis of IBD increased the risk for surgical treatment (13.9%/year). A 25.9%/year increase in liver transplantation was observed after the diagnosis of AILD, which was increased 18.22 times by the presence of portal hypertension. In addition, the diagnosis of AIH was associated with an increase in the number of diagnoses of de novo IBD (7.1).

The entry-inhibitor Bulevirtide (BLV) received conditional approval by EMA in July 2020 for the treatment of adult patients with compensated chronic hepatitis Delta. However, the effectiveness and safety of BLV administered as monotherapy beyond 48 weeks in difficult to treat HDV cirrhotic patients is presently unknown. Here we describe the first patients with HDV-related compensated cirrhosis who were treated with BLV (10 mg/day as a starting dose) for up to three years as compassionate use. Patients were also monitored for HBcrAg and HBV-RNA levels and HDV and HBV specific T-cells markers. In the patient who stopped BLV at week 48 after achieving a virological and biochemical response, the initial virological and biochemical rebound was followed by ALT normalization coupled with low HDV-RNA and HBsAg levels. In the two patients treated continuously for 3 years, virological and biochemical responses were maintained throughout the treatment period even after dose reduction. In a patient with advanced compensated cirrhosis, liver function tests significantly improved, esophageal varices disappeared, and histological/lab features of autoimmune hepatitis resolved. Overall, no safety issues were recorded, as bile salt increase was asymptomatic. While serum HBV-RNA levels remained undetectable in all patients, HBcrAg levels showed a progressive, yet modest decline during long-term BLV-treatment. No HDV-specific Interferon-γ producing T-cells were detected, neither after HDV reactivation (after BLV withdrawn in Patient 1) nor during 3 years of BLV treatment. In conclusion, this report shows that continuous administration of BLV monotherapy for three years provides excellent virological and clinical response in HDV cirrhotic patients who had contraindications to IFN-based therapies. LAY SUMMARY: HDV-RNA levels became undetectable, and ALT normalized in all three patients treated with Bulevirtide (BLV). Virological and biochemical responses were maintained even after dose reduction.- Improvement of liver function tests, regression of esophageal varices and recovery of HDV-related autoimmune disease were documented in the male cirrhotic patient long-term treated with BLV.- An asymptomatic increase of bile acids was the only drug-related clinical adverse event.

Background & Aims Infliximab has been associated with drug-induced liver injury (DILI), particularly drug-induced autoimmune hepatitis (DIAIH). DIAIH is commonly treated with corticosteroids, but there is limited data on the efficacy of corticosteroids in infliximab-induced DILI. Methods Patients were included for assessment if they had been treated with infliximab between 2009-2020 in Iceland and had developed elevated liver tests. Other specific etiologies of liver enzyme elevations were excluded. Patients treated with corticosteroids were compared to patients not receiving corticosteroids. Results A total of 36 patients with infliximab-induced DILI were identified: median age was 46 years (IQR 32-54) and 28 (78%) were female. Type of liver injury was predominantly hepatocellular (64%). Median peak liver enzymes were: alanine aminotransferase (ALT) 393 (328-695) U/L, aspartate aminotransferase 283 (158-564) U/L, alkaline phosphatase 116 (83-205) U/L, and bilirubin (10-20) 13 μmol/L. A total of 25 (69%) were positive for anti-nuclear antibody and/or had elevated IgG. Corticosteroids were initiated in 17 (47%). Median time from onset of liver injury to peak ALT value was longer in patients treated with corticosteroids, 22 (12-59) vs. 0 (0-3) days (p = 0.001). Time from peak ALT to normalization of liver enzymes was 45 days in the corticosteroid group vs. 77 days in others (p = 0.062). Corticosteroids were tapered in all patients, with no cases of relapse during the follow-up period of 1,245 (820-2,698) days. Overall 75% received another biologic, mostly adalimumab, without evidence of liver injury. Conclusion Approximately half of patients with infliximab-induced liver injury had slow improvement in ALT despite cessation of therapy and were treated with corticosteroids. Treatment response was good with prompt resolution of liver test abnormalities. Relapse of liver injury was not observed after tapering of corticosteroids despite prolonged follow-up and no patients developed DILI due to a second biologic. Lay summary A rare side effect of infliximab, a biologic medicine used to treat multiple inflammatory diseases, is liver injury and liver inflammation. Steroid treatment has been used in some patients with liver injury caused by infliximab, but there have been few studies supporting this treatment. In this study of 36 patients with infliximab-induced liver injury, approximately half of patients were treated with steroids and the results suggest that patients receiving steroids recover more quickly.

Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver characterized by parenchymal destruction, hypergammaglobulinemia, specific autoantibody production, and hepatic fibrosis and necrosis. Murine models of AIH have been described; however, little is known about the immunologic mechanisms of tissue destruction. In this study, a new murine model of type 2 AIH was developed using recombinant human cytochrome P450 (CYP) 2D6 emulsified with complete Freund's adjuvant (CFA). BALB/c mice were immunized with 2 μg/mL i.p. of CYP2D6 in CFA. The control group received CFA or phosphate-buffered saline alone. Alanine aminotransferase activity, autoantibody production, IgG concentrations, histologic damage, and specific T-cell response were evaluated. Persistent AIH, characterized by cellular infiltration, hepatic fibrosis, elevated alanine aminotransferase, and the production of anti-liver kidney microsomal antibody type 1 developed in CFA/CYP2D6-immunized mice. This group presented high levels of IgG and its subclasses IgG1, IgG2a, and IgG2b against liver self-proteins. Interestingly, IL-2+ and interferon γ-positive Cyp2d6-specific T cells were present in greater concentrations in mice immunized with CFA/CYP2D6 compared with controls. Immunization with CFA, in combination with a natural human autoantigen like CYP2D6, was demonstrated to break tolerance, resulting in a chronic form of autoimmune-related liver damage. This murine model of type 2 AIH is expected to be instrumental in understanding the immunologic mechanisms of the pathogenesis of this autoimmune liver disease.

BACKGROUND: Hyaline globules (HGs) in the cytoplasm of Kupffer cells (KCs) have been appraised for being a typical feature of autoimmune hepatitis (AIH). This study aimed to determine how useful Kupffer cell hyaline globules (KCHGs) are in diagnosing AIH vs. other causes of pediatric chronic liver diseases (PCLDs). MATERIALS AND METHODS: This retrospective study recruited 124 children; 58 with AIH, 50 with chronic hepatitis C virus (HCV) infection, and 16 with Wilson’s disease (WD). Two pathologists retrieved paraffin blocks of liver biopsies and prepared new cut sections for Periodic acid–Schiff–Diastase (PAS-D) stain. They independently examined liver biopsies before starting treatment. Two pediatricians reviewed medical records for demographic, clinical, laboratory, and serological findings. RESULTS: Females represented 48.6% of the studied children with a median age of 5.8 (4.9) years. Pathologists identified KCHGs in 67.24%, 12.5%, and 6.0% of AIH, WD, and HCV affected children respectively, P

In chronic hepatitis, a broad differential diagnosis should be considered to accurately identify the cause(s) of liver injury. Autoimmune liver diseases (autoimmune hepatitis, primary sclerosing cholangitis, overlap syndrome) can occur in the setting of limited symptoms; therefore, a high index of suspicion and appropriate diagnostic workup should be performed. Most children with autoimmune hepatitis achieve sustained remission with medical therapy; however, there are no equivalent therapies for primary sclerosing cholangitis that impact the progression of disease. Research should include biomarker studies to predict histologic remission in autoimmune hepatitis and mechanistic studies to define future treatment targets for primary sclerosing cholangitis.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis on histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to analyse AIH therapeutic interventions with reference to our knowledge of the pathogenesis of AIH. Standard treatment, based on steroids and azathioprine, leads to disease remission in 80-90% of patients. Alternative first-line treatment with budesonide is effective in adults, but less so in the juvenile form of AIH; first-line treatment with ciclosporin does not provide convincing advantages compared to standard treatment. Second-line treatments are needed for patients not responding or intolerant to first-line standard management. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but is teratogenic. Only few and heterogeneous data on calcineurin inhibitors and m-TOR inhibitors are available. Biologicals, including anti-tumour necrosis factor- α and anti-CD20 monoclonal antibodies, have given ambivalent results and may have severe side-effects. Clinical trials with new therapeutic options aiming at targeting B lymphocytes and proinflammatory cytokines, or expanding regulatory T cells to restore tolerance are ongoing.

Immune checkpoint inhibitors (ICI) improve the prognosis of patients with advanced non-small cell lung cancer. However, clinicians should be aware of potentially life-threatening immune-related adverse events (irAEs). We report a case of a 67-year-old man with lung adenocarcinoma who developed an acute ischemic stroke after the second administration of pembrolizumab. The patient benefited from thrombolysis and mechanical thrombectomy with improved neurological outcome. An anti-phospholipid syndrome (APS) was diagnosed. Simultaneously, he developed a grade IV autoimmune hepatitis. Both manifestations were considered irAEs and the ICI treatment was discontinued. Steroids were initiated resulting in irAEs resolution. Remarkably, the patient achieved a complete oncological response and persistent remission after one year follow-up despite early discontinuation of pembrolizumab. Of note, APS is rarely reported as irAE. To our knowledge, this is the first case reported in the context of lung cancer. A systematic review of the literature is provided., SCOPUS: re.j, info:eu-repo/semantics/published

Introduction and objectives It has been proposed that non-invasive methods may replace liver biopsy for the diagnosis of tissue damage in patients with autoimmune liver disease (ALD). The aim of this study was to determine diagnostic performance and degree of concordance between the APRI index and liver biopsy for diagnosing cirrhosis in these patients. Material and methods In a cohort of patients with ALD, the value of the APRI index and liver biopsy results were determined according to the METAVIR score. The AUC and the degree of concordance between an APRI value >2 and a METAVIR score of F4 were evaluated as markers of liver cirrhosis, through a kappa statistic. Results In total, 70 patients (age 51 ± 13 years) were included. The most common autoimmune liver diseases were primary biliary cirrhosis (PBC) (40%), autoimmune hepatitis (AIH) (24.3%) and AIH-PBC overlap syndrome (32.9%). Cirrhosis was confirmed by biopsy in 16 patients (22.9%). 15 patients (21.4%) had an APRI index >2 (Cirrhosis) and only six met both criteria. The AUC of the APRI was 0.77 (95% CI 0.65−0.88). The degree of concordance between the tests was low for an APRI cut-off point >2 (kappa 0.213; 95% CI 0.094−0.332), as well as for cut-off points >1.5, >1 and >0.5 (kappa 0.213, 0.255, 0.257, respectively) Conclusion Our results suggest that there is little concordance between APRI and liver biopsy for the diagnosis of cirrhosis in patients with ALD. It should therefore not be used as a single diagnostic method to determine cirrhosis.

Background & Aims Patients with autoimmune hepatitis (AIH) usually receive maintenance therapy with thiopurines, such as azathioprine (AZA) or mercaptopurine. Genetic polymorphisms in AZA metabolism can lead to variations in thioguanine nucleotide (TGN) and 6-methylmercaptopurine, both of which can cause adverse drug reactions (ADRs). In inflammatory bowel disease, a therapeutic TGN range (225–450 pmol/8x108 erythrocytes) has been identified to optimise effectiveness. We evaluated the benefits of a personalised medicine approach to thiopurine dosing, in comparison to standard weight-based dosing. Methods A retrospective matched cohort study of 214 patients with AIH who were seen at King’s College between 1999-2019 was performed. Metabolite levels were measured in 109 patients. The control group included 105 patients on weight-based thiopurine dosing with no metabolite monitoring. Results Biochemical response (BR) occurred more frequently at 6-month follow-up in patients with metabolite monitoring compared to those on a weight-based regimen (77% vs. 60%, p = 0.008). This remained true with data analysis based on clinicians who measure metabolites and those who do not (BR at 6 months: 84% vs. 64%, p = 0.016). Patients with BR had TGN levels within the therapeutic range of 225–450 pmol/8x108 erythrocytes significantly more often than those who failed to achieve or lost BR (40% vs. 13%, p Conclusion A strategy of personalised medicine using metabolite levels can optimise treatment regimens in AIH, resulting in fewer ADRs whilst maintaining BR. Lay summary This study looked to see if measuring the breakdown products of a medication used in autoimmune hepatitis increases the chances of gaining good control of the disease, when compared to a group of patients who were on a dose of this medication based on their weight. A group of 214 patients with autoimmune hepatitis were split into 2 groups: roughly half had their medication dose adjusted according to measurements of breakdown products in the blood, whilst the other half received their weight-based dose as normal. The results confirmed that using a personalised approach and checking drug breakdown products resulted in fewer side effects and potentially improved control of disease.

Background & Aims Chronic liver disease and liver transplantation (LT) can delay both timing and ability of women to conceive. With increased awareness and availability of in vitro fertilisation (IVF), the need for accurate counselling is paramount. To date, minimal data exist on outcomes of IVF in patients with chronic liver disease, cirrhosis, or post-LT. We report the largest experience of IVF in women with liver-related subfertility (LRSF). Methods A retrospective analysis was performed on 42 women with LRSF who had undergone 57 IVF cycles between 1990 and 2019. Results Forty-two women with LRSF received IVF; 9 cycles in 6 women with cirrhosis, 14 cycles in 11 women post-LT, and 34 cycles in 25 women without cirrhosis. The main aetiologies of liver disease included HBV, HCV, and autoimmune hepatitis (AIH). Of 57 IVF cycles evaluated, 43 (75%) resulted in successful implantation. Eight (2 post-LT, 3 with cirrhosis, 4 without cirrhosis) resulted in miscarriage. The live birth rate (LBR) was 74% (32/43). Two of 9 (22%) patients with cirrhosis, 4/14 (29%) patients who were post-LT, and 6/34 (18%) patients without cirrhosis had unsuccessful IVF attempts. Nine of 57 (16%) IVF cycles resulted in new liver enzyme derangement during therapy, which improved after treatment completion. Six pregnancies (2 in patients who were post-LT, 4 without cirrhosis) were complicated by obstetric cholestasis (OC). Ovarian hyperstimulation syndrome (OHSS) was rare (n = 3, 7%). One patient with AIH-related cirrhosis decompensated after initiating IVF, warranting discontinuation of therapy. There were no maternal deaths. Three women developed a hypertensive disorder of pregnancy. Half the pregnancies resulted in premature deliveries (range 27–36 weeks). Conclusions In selected cases, IVF in women with LRSF can be successful. However, patients should be counselled on the potential increased risks of OHSS, OC, and prematurity. Lay summary Women with liver disease or those who have had a liver transplant can experience difficulties getting pregnant. In this study, we look at whether alternative approaches to achieve pregnancy are harmful in these women. Overall, there were no significant issues with the use of in vitro fertilisation in women with liver disease, but they need to be aware of potential risks, such as early delivery of the baby.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of unknown origin that can lead to liver cirrhosis, hepatocellular carcinoma (HCC), liver transplantation or death. The diagnosis is performed upon a multifactorial score. Treatment is based on the combination of immunosuppressants and aims at clinical, laboratory and histological remission, the latter being the most difficult to be achieved and proven. The absence of liver inflammation, defined by biopsy, is the main determinant in remission or therapeutic modification. Imaging exams have a limited role in this clinical management and the main findings are those related to chronic liver disease. Imaging's relevance, therefore, lies mainly in helping to exclude overlapping syndromes and in assessing complications related to cirrhosis, such as in screening for HCC. In recent years, however, the radiological literature has been witnessing increasing advances with regard to imaging biomarkers in liver disease, leading some authors to consider a future of virtual liver biopsy performed by magnetic resonance imaging. The present study aims to review the role of imaging in the management of AIH in the light of recent advances in the current literature and to provide an illustrated guide with the main findings described in the disease.

Background & Aims In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated. Methods This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: i) Definite or probable AIH based on the simplified IAIHG score; ii) international normalized ratio (INR) ≥1.5 and/or bilirubin >200 μmol/L; iii) No previous history of AIH; iv) Histologically proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3 = (D3–D0)/D0. Results A total of 128 patients were included, with a median age of 52 (39–62) years; 72% were female. Overall survival reached 88%. One hundred and fifteen (90%) patients received corticosteroids, with a LT-free survival rate of 66% at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95% CI 2.23–21.06; p Conclusion In patients with AS-AIH, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort. Lay summary The management of patients with acute severe autoimmune hepatitis is highly challenging, particularly regarding their early referral for liver transplantation. We found that international normalized ratio at the initiation of corticosteroid therapy and the evolution of international normalized ratio and bilirubin values after 3 days of therapy were highly predictive of liver transplantation or death. We are thus proposing a score that combines these variables and identifies patients in whom liver transplantation is urgently required.

In their comprehensive and stimulating review, Moreau et al. report the distinctive features of “acute-on-chronic liver failure” (ACLF) based on different geographic definitions (European,North American, Chinese, Asian Pacific) and suggest that ACLF should be considered a unique clinical syndrome.1 However, in discussing hallmarks, causes and precipitating factors of ACLF, they do not consider the case of autoimmune hepatitis (AIH), which can initiate as acute hepatitis in more than 40% of cases.2 It is well recognized that AIH patients may develop ACLF either as hyperacute exacerbation of undiagnosed or misdiagnosed AIH, or in response to a second exogenous insult (viral, drug-induced, toxic) on typical AIH, possibly favored by long-term immunosuppression.

Aims Differential diagnosis of autoimmune hepatitis (AIH) incorporates various liver diseases, including alcoholic liver disease (ALD). We report on clinical, laboratory and outcome characteristics of AIH patients who were initially referred as ALD based on increased alcohol consumption (AIH/ALD). Methods From 2000-2019, we retrospectively identified 12 AIH/ALD patients [9 males, age: 61 (30-73) years] in our prospective data base of 317 AIH patients. Results AIH diagnosis was based on aminotransferases elevation in 10 patients, high IgG in 8, compatible autoantibody profile in all and typical/compatible histology in all 9 with available biopsy. There were no significant differences of baseline demographics, presentation, cirrhosis at diagnosis, response to treatment and simplified score compared to 45 age- and sex-matched AIH patients without alcohol consumption and 44 age- and sex-matched ALD patients. However, the AIH/ALD cohort was characterized by more frequent progression to cirrhosis, higher liver-related deaths and overall mortality compared to AIH, though similar to the ALD group. AST/ALT ratio>1 seems to bear a good positive (0.84) and negative predictive value (0.88) for ALD and AIH diagnosis, respectively, but cannot help in discriminating the AIH/ALD variant. Conclusions AIH should not be forgotten in patients with alcohol use when clinical and laboratory features hint towards the diagnosis of AIH/ALD variant as this group seems to have worse outcome compared to those with AIH alone suggesting the need for closer follow-up and surveillance. Reliable autoantibody testing and cautious interpretation of liver histology appear mandatory for AIH diagnosis in these difficult to diagnose cases.

BACKGROUND AND AIMS: Autoimmune hepatitis presenting as acute on chronic liver failure (AIH-ACLF) is a novel entity with limited data on clinical course and management. We assessed outcomes in patients of AIH-ACLF with no extrahepatic organ dysfunction/failure when administered steroids. METHODS: In this retrospective analysis, clinical data, laboratory parameters, liver biopsy indices and prognostic scores such as model for end-stage liver disease (MELD) and Child–Turcotte–Pugh (CTP) scores at baseline were computed for patients with AIH-ACLF and compared across strata of incident infections and transplant-free survival. The primary outcome was 90-day transplant-free survival. Biochemical remission was assessed, and predictors of end points were identified. RESULTS: Twenty-nine patients of AIH-ACLF were included with a median follow-up of 4 months. The 90- and 180-day transplant-free survival rates of 55.2 [95% confidence interval (CI): 39.7–76.6]% and 30.2(95% CI: 16.7–54.6)%, respectively, were attained on steroids. Three patients (10.3%) underwent liver transplant while 16 (55.2%) deaths occurred. Infections developed in 12 patients (41.3%), leading to worsening prognostic scores, new onset organ dysfunction/failure and 11 deaths. Seven of ten patients (70%) in the transplant-free survivor group attained biochemical remission on follow-up. The MELD score

ObjectivesWe aimed to identify pre- and perinatal risk factors for developing pediatric-onset immune-mediated inflammatory (pIMID).MethodsThis nation-wide, cohort study included all children born in Denmark from 1994 to 2014 identified from the Danish Medical Birth registry. Individuals were followed through 2014 and cross-linked to the continuously updated national socioeconomic and healthcare registers to obtain data on pre- and perinatal exposures (maternal age, educational level, smoking, maternal IMID, parity, mode of conception and delivery, plurality, child's sex, and birth season). The primary outcome was a pIMID diagnosis (inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, juvenile idiopathic arthritis, or systemic lupus erythematosus) before 18 years of age. Risk estimates were calculated using Cox proportional hazards model and presented by hazard ratios (HR) with 95% confidence intervals (95%CI).ResultsWe included 1,350,353 children with a follow-up time of 14,158,433 person-years. Among these, 2,728 were diagnosed with a pIMID. We found a higher risk of pIMID in children born to women with a preconception IMID diagnosis (HR: 3.5 [95%CI: 2.7–4.6]), children born by Caesarean section (HR: 1.2 [95%CI: 1.0–1.3]), and among females (1.5 [95%CI: 1.4–1.6]) than among children without these characteristics. Plural pregnancies were associated with a lower risk of pIMID than single pregnancies (HR: 0.7 [95%CI: 0.6–0.9]).ConclusionsOur results indicate a high genetic burden in pIMID but also identifies intervenable risk factors, such as Cesarean section. Physicians should, keep this in mind when caring for high-risk populations and pregnant women previously diagnosed with an IMID. Objectives: We aimed to identify pre- and perinatal risk factors for developing pediatric-onset immune-mediated inflammatory (pIMID). Methods: This nation-wide, cohort study included all children born in Denmark from 1994 to 2014 identified from the Danish Medical Birth registry. Individuals were followed through 2014 and cross-linked to the continuously updated national socioeconomic and healthcare registers to obtain data on pre- and perinatal exposures (maternal age, educational level, smoking, maternal IMID, parity, mode of conception and delivery, plurality, child's sex, and birth season). The primary outcome was a pIMID diagnosis (inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, juvenile idiopathic arthritis, or systemic lupus erythematosus) before 18 years of age. Risk estimates were calculated using Cox proportional hazards model and presented by hazard ratios (HR) with 95% confidence intervals (95%CI). Results: We included 1,350,353 children with a follow-up time of 14,158,433 person-years. Among these, 2,728 were diagnosed with a pIMID. We found a higher risk of pIMID in children born to women with a preconception IMID diagnosis (HR: 3.5 [95%CI: 2.7–4.6]), children born by Caesarean section (HR: 1.2 [95%CI: 1.0–1.3]), and among females (1.5 [95%CI: 1.4–1.6]) than among children without these characteristics. Plural pregnancies were associated with a lower risk of pIMID than single pregnancies (HR: 0.7 [95%CI: 0.6–0.9]). Conclusions: Our results indicate a high genetic burden in pIMID but also identifies intervenable risk factors, such as Cesarean section. Physicians should, keep this in mind when caring for high-risk populations and pregnant women previously diagnosed with an IMID.

Background Concurrent extrahepatic autoimmune disorders (CEHAID) are frequently observed in autoimmune hepatitis (AIH). It is not clear whether there is any prognostic significance of CEHAID on AIH. The aim of this study was to examine the prognostic impact of CEHAID and the correlation with the disease severity of AIH. Methods This study included 65 hospitalized subjects who fulfilled the accepted criteria for AIH during an 8-year period (2009–2016). All records were manually screened for presence of associated autoimmune diseases. Disease severity of AIH was assessed by liver laboratory tests including the ratio of aspartate aminotransferase to alanine aminotransferase (AST/ALT) and liver histology. Results Among the enrolled patients, 52 (80%) were female (median age 61 years, IQR 45–75). Fifty-six (86.2%) were classified as type-1 AIH. In 26 (40%) patients at least one additional extrahepatic autoimmune disease was diagnosed. Thirty-four subjects were referred to our hospital because of acute presentation of AIH (supposed by an acute elevation of hepatic enzymes) for subsequent liver biopsy resulting in initial diagnosis of AIH. This group was stratified into 3 subgroups: (A) AIH alone (n = 14); (B) overlap with primary biliary cirrhosis (PBC) / primary sclerosing cholangitis (PSC) (n = 11); and (C) with CEHAID (n = 9). AST/ALT ratio was the lowest in subgroup C (median 0.64, IQR 0.51–0.94; P = 0.023), compared to subgroup A (median 0.91, IQR 0.66–1.10) and subgroup B (median 1.10, IQR 0.89–1.36). Patients with AIH alone showed a trend to the highest grade of fibrosis (mean 2.3; 95% CI: 1.5–3.0) with no statistical significance compared to subjects with CEHAID (lowest grade of fibrosis; mean 1.5; 95% CI: 0.2–2.8; P = 0.380) whereas the ongoing inflammation was comparable. Conclusions AST/ALT ratio and extent of fibrosis were lower in subjects with AIH and CEHAID, compared to subjects with only AIH. Therefore, the occurrence of CEHAID might be a predictor for lower disease severity of newly diagnosed acute onset AIH, possibly caused by an earlier diagnosis or different modes of damage.

Background & Aims In autoimmune hepatitis (AIH), the imbalance between regulatory T cells (Tregs) and T-helper type 17 (Th17) cells has been linked to low levels of CD39, an ectoenzyme that hydrolyses ATP, ultimately generating immunosuppressive adenosine. Upregulation of CD39 results from activation of aryl hydrocarbon receptor (AHR), which mediates toxin responses to modulate T-cell immunity. In this study, we investigated whether altered AHR signalling underlies defective CD39 expression and function in AIH Tregs and Th17 cells, therefore contributing to regulatory/effector cell imbalance. Methods Tregs and Th17 cells, obtained from the peripheral blood of 49 patients with AIH and 21 healthy individuals (HI), were tested for response to endogenous and exogenous AHR ligands. Results When compared to those of HI, AIH-derived Tregs and Th17 cells displayed impaired responses to AHR activation, reflected by impaired upregulation of CD39, delayed increase in ectoenzymatic activity, and defective Treg suppressive function. These impairments resulted, at least in part, from heightened levels of AHRR and Erα in Tregs and high HIF-1α in Th17 cells, and were reverted upon molecular blockade. Importantly, in AIH-derived Tregs, the binding affinity of AHR was higher for Erα than ARNT. Conclusions In AIH, high levels of AHRR and HIF-1α inhibit AHR signalling in Tregs and Th17 cells. AHR non-canonical binding to Erα further amplifies the lack of effective CD39 upregulation. Blockade of these inhibitory and/or non-canonical activation pathways represents a potential therapeutic approach to restore CD39 and immunohomeostasis in AIH. Lay summary In patients with autoimmune hepatitis, the imbalance between regulatory T cells and T helper type-17 cells is linked to dysfunction of the aryl hydrocarbon receptor pathway, resulting from aberrant inhibition or non-canonical activation. These alterations impair Treg- and Th17 cell-induced upregulation of CD39, an ectoenzyme key to immunoregulation. Blockade of excessive inhibition or non-canonical activation of the aryl hydrocarbon receptor pathway might represent a novel therapeutic strategy to control inflammation while restoring immune balance in autoimmune hepatitis.

Complications of cirrhosis are the main cause of hospital admissions in liver units. In areas where HCV is prevalent, most of these admissions are attributable to HCV-related cirrhosis (HCV-cirrhosis). This study assessed the impact of direct-acting antivirals (DAA) in the profile of patients with liver disease admitted to a referral liver unit from a university hospital.We registered hospital admissions resulting from cirrhosis to the Liver Unit of the Hospital Clinic of Barcelona, from 2011 to 2014 (pre-DAA period) and from 2015 to 2019 (post-DAA period).From a total of 14,865 hospital admissions, 10,053 resulted from cirrhosis (corresponding to 6,272 patients). The number and proportion of hospital admissions because of HCV-cirrhosis remained stable during the period 2011-2014 (525 per year, 48.8% of the total), but decreased progressively after 2015 (p0.001), reaching300 (27.1%) admissions in 2019. Similarly, HCV-cirrhosis accounted for 3,885 inpatient days per year (44.9%) during the pre-DAA period and decreased steadily after 2015 (p0.001), reaching only 1,909 inpatient days (22%) in 2019. The figures for intensive care unit admissions followed a similar pattern. By means of a slope analysis (binomial regression model), we predicted that HCV-cirrhosis hospital admissions will be residual by 2025 (2.3%, 95% CI 0-10.9%). By contrast, we observed a significant increase in hospital admissions because of metabolic-associated fatty liver disease (5-fold) and autoimmune hepatitis (4-fold) during the study period.In summary, our data showed a profound reduction in HCV-cirrhosis hospitalisation burden since 2015, coincident with the wide use of DAAs in Spain. Our predictions suggest that, by 2025, HCV-cirrhosis will be a marginal cause of hospital admissions for patients with liver disease.Over the past few years, the wide use of antiviral drugs that cure HCV has had a significant effect on patients being admitted to hospital. Most patients with HCV and cirrhosis are treated (and often cured) in the community and, thus, the number of hospital admissions because of severe forms of HCV has decreased drastically. HCV is no longer the first cause of admission into liver units and, in only a few years from now, it is likely to be only a residual cause of hospitalisation.

The extraction process of Paeoniae radix alba polysaccharides (PRAP) was optimized as the liquid-solid ratio of 10.65 mL/g, the extraction time of 2.10 h, and the 2 extraction repetitions through a response surface methodology. The chemical profiles of the obtained PRAP were characterized by measuring the contents of total carbohydrates, total phenolics, uronic acid and protein, and by analyzing the FT-IR spectrum and monosaccharide composition. To determine the therapeutic effects of PRAP on experimental autoimmune hepatitis (EAH), we established an EAH mice model. After treated with PRAP, liver and spleen injuries were reduced, and hepatocyte regeneration and liver function were improved. Further study of the mechanism by which PRAP treats EAH showed that PRAP significantly inhibited oxidative stress in the livers of EAH model mice. More importantly, PRAP inhibited immune inflammatory reactions in EAH model mice, including the hepatic infiltration of inflammatory CD4+ and CD8+ T cells, as well as overexpression of inflammatory cytokines IL-2, IL-6 and IL-10, via inhibition of the NF-κB signaling pathway.

BACKGROUND AND AIM: Adipocytokines, especially leptin is involved in a wide spectrum of proinflammatory functions, in various tissues. This study was carried out to assess the role of serum leptin in autoimmune hepatitis. METHODS: Serum leptin was analyzed in treatment naïve autoimmune hepatitis (AIH, n = 48) patients and compared with the primary biliary cholangitis (PBC, n = 16), chronic hepatitis C (CHC, n = 16) and healthy controls (n = 15). Serum leptin correlation was assessed on liver function tests, disease activity, T regulatory cells (Tregs), and Th17 cells in the liver biopsies and on steroid treatment response in AIH. RESULTS: Serum leptin was higher in AIH than in PBC, CHC, and HC {AIH: 335 (106.2–580), PBC: 126 (52–381.2), CH: 67 (3.7–133.5) and HC: 66 (40–157.5) ng/ml; P = 0.001}. In AIH cases; serum leptin correlated with hepatic activity index (r = 0.896; P < 0.001); serum transaminases (aspartate aminotransferases (AST) = 0.615, P < 0.001, alanine aminotransferases (ALT) = 0.551, P < 0.001). It had inverse correlation with Treg cells (P = −0.711, P < 0.001) and positively correlated with Th17 cells (r = 0.650, P < 0.001) in the liver biopsy tissue. High serum leptin was found to be associated with steroid partial or nonresponsiveness at 4 weeks (P = 0.002). CONCLUSION: Serum leptin is indicative of higher AIH activity and a reduced number of Tregs cells in liver biopsy tissue. Leptin negative cases have more chances of steroid responsiveness and could help in the selection of AIH cases for appropriate therapy.

Autoimmune hepatitis (AIH) is a rare liver disease of autoimmune aetiology that classically affects women at reproductive age. Diagnosis of AIH is not always straightforward, and other causes of chronic liver disease must be excluded. Pregnancy in patients with AIH is associated with an increased risk of adverse maternal and foetal outcomes. In older studies, the incidence of adverse outcomes was high, with a large number of flare-ups, maternal deaths, and perinatal complications. In the most recent series, improved care based on multidisciplinary surveillance, a larger number of patients treated before and during pregnancy, and reduced incidence of cirrhosis at conception have led to better maternal outcomes and a live-birth rate similar to that in the general population. Nonetheless, AIH is still associated with preterm birth, foetal growth restriction, and unpredictable liver flares, and it represents a group of patients who need close evaluation during pregnancy.

BACKGROUND/OBJECTIVES: Acute liver failure (ALF) is rare and associated with poor outcomes. The outcomes of ALF and predictors of outcome may vary as per the etiology. There are limited data on the predictors of spontaneous survival among patients with ALF of non–A-E hepatitis or cryptogenic etiology. We aimed to assess clinical course, complications, and outcome of non–A-E etiology ALF. METHODS: In this prospective analysis, all consecutive ALF patients (n = 1555; January 1986–June 2018) were analyzed. Non–A-E-ALF was defined as ALF that could not be attributed to known etiologies such as drugs, viral hepatitis, autoimmune hepatitis, and Wilson's disease. Clinical course, complications, and outcomes of non–A-E-ALF patients who did not undergo liver transplantation were analyzed. Unadjusted and adjusted odds ratios (ORs) were calculated. RESULTS: Non–A-E-ALF constituted 34.6% (n = 538) of all ALF patients, whereas hepatitis E virus (HEV), hepatitis B virus (HBV), and anti-tuberculosis therapy (ATT) accounted for 29.5% (n = 459), 8.6% (n = 134), and 7.4% (n = 115), respectively. Among non–A-E-ALF patients, mean age was 28.8 ± 12.0 years, 50.9% females, majority (63.1%) had hyperacute presentation, and 79.2% had advanced encephalopathy at presentation. The frequency of cerebral edema in non–A-E-ALF (53.3%) was higher than that in HEV-ALF (41.2%) and ATT-ALF (44.2%), P < 0.001. The survival rate in non–A-E-ALF (37.5%) was poorer than HEV-ALF (54.9%) and was comparable to that in HBV (35.8%) and ATT (29.6%) induced ALF. The baseline prothrombin time prolongation (odds ratio [OR] 1.041; 95% confidence intervals [CI], 1.017–1.065) and infection (OR 2.366; 95%CI, 1.107–5.055) were independent predictors of outcome in non–A-E-ALF. The 3-days acute liver failure early dynamic model had the best value in predicting the outcome. CONCLUSIONS: Non–A-E-ALF accounts for one-third of all cases of ALF and is associated with poor spontaneous survival.

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. COVID-19 affected close to 2 million persons worldwide in fewer than 4 months, after the report of the first cases in China in December 2019. The relation of the disease caused by SARS-Cov-2 to immunosuppressive treatment used in different gastrointestinal disorders is uncertain, resulting in debate with regard to suspending immunosuppressive therapy to improve infection outcome. Said suspension implies the inherent risk for graft rejection or autoimmune disease exacerbation that can potentially worsen the course of the infection. Based on the presently available evidence, a treatment stance has been established for patients with gastrointestinal diseases that require immunosuppressive therapy. Resumen: La enfermedad por coronavirus 2019 (COVID-19) es causada por el virus de Síndrome Respiratorio Agudo Grave - Coronavirus 2 (SARS-CoV-2). COVID 19 afectó cerca de 2 millones de personas en todo el mundo en menos de 4 meses posterior al reporte de los primeros casos en China en diciembre 2019. La relación que guarda la enfermedad por SARS-Cov-2 con el tratamiento inmunosupresor utilizado en diversos trastornos gastrointestinales es incierta, esto genera el debate sobre suspender el tratamiento inmunosupresor para mejorar el pronóstico de la infección, lo cual incluye el riesgo inherente de rechazo de injerto o agudización de enfermedades autoinmunes que potencialmente pudieran agravar el curso de la infección. En base a la evidencia disponible se logra establecer una postura de tratamiento en pacientes con enfermedades gastrointestinales que requieren terapia inmunosupresora.

Background There is limited evidence linking achievement of biochemical response with outcomes in Autoimmune Hepatitis (AIH), and it is unclear whether normalization of serum immunoglobulin G (IgG) levels influences prognosis. Aims We aimed to investigate factors associated with death or liver transplantation in patients affected by AIH. Methods We undertook a retrospective analysis of all AIH patients attending a tertiary liver unit since 1980. Patients not meeting established diagnostic criteria for AIH or with a follow-up shorter than 18 months were excluded. Results 107 patients meeting inclusion criteria were included in the study. Mean age at diagnosis was 44 years, 29 patients (27.1%) had cirrhosis at baseline. Median follow-up was 79 months, and 70 patients (79.5%) reached biochemical response. Biochemical response was associated with reduced hazard of liver transplant or death (HR 0.07, 95% CI 0.01–0.46), whereas cirrhosis at diagnosis was an independent predictor of liver transplantation or death (Hazard ratio (HR) 11.8, 95%, confidence interval (CI) 1.18–117.4). Lack of normalization of serum IgG levels was associated with reduced 5-year transplant-free survival (95% in patients normalizing, compared to 86%, p = 0.02). Conclusion Normalization of serum IgG levels alone translates in better transplant-free survival in patients with AIH and should be a treatment target along with transaminases.

Hepatocytes are the targets in autoimmune hepatitis (AIH) that results in T cell-dependent liver injury. However, hepatocytes may also affect the hepatic T cells in AIH, but the underlying mechanisms are not fully understood. Here we report that hepatocytes could secrete galectin-9 (Gal-9) to suppress the intrahepatic production of Th1 cytokine IFN-γ and restrict AIH development, but hepatocyte damage resulted in opposite effects due to release of TLR2/4 ligands that promoted the intrahepatic production of IL-1β, IL-6, and IL-12. Through Tim-3, Gal-9 could efficiently suppress the intrahepatic T cell activation despite presence of TLR2/4 ligands, thus attenuating Th1 response in AIH. Intriguingly, intrahepatic IL-6/IL-12 suppressed the effect of TGF-β on Treg cells. Therefore, in AIH, Gal-9 promoted Foxp3 expression and function of hepatic Treg cells through TL1A signaling, although Treg function was still impaired, compared with that in naive state. Due to its promoting effect on Treg function, together with its effect on T effector cells in a Tim-3-independent way, Gal-9 could attenuate intrahepatic IFN-γ production by hindering the increase of hepatic CD4+CD43+ T cells resulting from extrahepatic T cell activation. TLR2/4 ligands attenuated the effects of Gal-9 on Treg cells and CD4+CD43+ T cells by increasing intrahepatic IL-6 and IL-12. Blocking TLR2/4 ligands could efficiently suppress intrahepatic IFN-γ production, liver injury, and hepatic fibrosis. These findings suggest that hepatocytes paradoxically affect Th1 response in AIH due to Gal-9 expression and TLR2/4 ligands release, and that targeting TLR2/4 signaling may provide an important approach in the therapeutic strategy for AIH.

Previously we have shown that in autoimmune hepatitis CD4 positive lymphocytes form an immunologic synapse with hepatocytes, leading to gradual diminishing and elimination of the hepatocyte. We wondered whether a similar mechanism may occur in alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH). We conducted immunofluorescence studies of expression of MHCII, the binding partner of CD4, on patient liver biopsies of AH, NASH, and normal controls. In cases of alcoholic hepatitis, there was prominent sinusoidal expression of MHC II; In NASH biopsies there was comparatively lower expression of MHC II, but still more than control tissue. Immunohistochemical stain for CD4 showed CD4 positive lymphocytes closely associated with hepatocytes in AH biopsies. Furthermore, expression levels of the multifunctional cytokine IL-1α was higher in AH compared to NASH and control biopsies. These results underlie the more severe nature of alcoholic hepatitis and underscore the autoimmune mechanisms involved in the liver damage found in alcoholic hepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease (almost 25% of the general population). Autoimmune hepatitis (AIH) is a relatively rare liver disease of unknown aetiology characterized by female predominance and large heterogeneity regarding epidemiology, clinical manifestations, genetics, serology and liver pathology. The potential NAFLD/AIH coincidence or an AIH diagnosis alone instead of NAFLD represent a challenge for clinicians, both in making a correct and timely diagnosis but also in the management of these diseases. The diagnosis of both diseases can be challenging as: (a) reliable laboratory tests to confidently diagnose or exclude NAFLD or AIH are missing; (b) physicians and pathologists are much more familiar with a very common disease like NAFLD so, they do not consider an alternative or additional diagnosis; (c) most NAFLD studies do not investigate the patients for all autoantibodies involved in AIH diagnosis, apply the diagnostic scoring systems for AIH or address the possibility of AIH features on liver histology and (d) the recent European and American practice guidelines for NAFLD do not mention clearly the importance of IgG determination and liver autoimmune serology according to the AIH guidelines. Patients with NAFLD/AIH coincidence have significantly more frequently hypertension, diabetes, obesity, older age, lower transaminases, bilirubin and simplified score for AIH diagnosis but no female predominance compared to AIH patients only. The true outcome of NAFLD/AIH patients is practically unknown while their management is quite problematic because official clinical practice guidelines for this condition are missing.

Background Autoimmune hepatitis (AIH) is a rare progressive liver disease, which manifests as acute hepatitis in 40%-50% of pediatric cases. This refers predominantly to spontaneous exacerbations of previously unrecognized subclinical AIH with laboratory and histological signs of chronic hepatitis, or to acute exacerbations of known chronic disease. Only a few of these patients fulfill criteria for acute liver failure (ALF). Methods Forty children diagnosed with AIH in our center between 2000 and 2018 were included in this study. All of them fulfilled revised diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) for probable or confirmed AIH, and other etiologies of liver diseases were excluded. Patients were divided into two groups: acute AIH (A-AIH) or chronic AIH (C-AIH). Results Acute onset of AIH occurred in 19/40 children (48%). Six of them fulfilled the criteria of ALF with coagulopathy and encephalopathy. Five of 6 children with ALF suffered from exacerbation of previously undiagnosed chronic AIH, among which 4 children were histologically confirmed as micronodular cirrhosis. The remaining one patient had fulminant AIH with centrilobular necrosis, but no histological signs of previous chronic liver damage. We observed significantly lower levels of albumin, higher levels of aminotransferases, bilirubin, INR, IgG, higher IAIHG score and more severe histological findings in A-AIH than in C-AIH. No differences in patient age and presence of autoantibodies were observed between A-AIH and C-AIH. All children, including those with ALF and cirrhosis, were treated with corticosteroids, and are alive and achieved AIH remission. Liver transplant was not indicated in any patient. Conclusion Rapid and accurate diagnosis of A-AIH may be difficult. However, timely start of immunosuppressive therapy improves prognosis and decreases number of indicated liver transplantations in children with AIH.

Background and aims Immunosuppressed patients are at risk of severe infections with vaccination preventable diseases. We evaluated vaccination rate and immunity of children and adolescents with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). Methods Immunization rate of 329 children with IBD (n = 300) and AIH (n = 29) was assessed in seven German centres using vaccination certificates, history of chicken pox and by determining anti-varicella zoster virus (VZV) and anti-measles IgG antibodies. Results Of the total cohort 86% received long-term immunosuppression. Four doses of a hexavalent vaccine were documented in 89%, at least one dose of measles, mumps, and rubella (MMR) vaccination was documented in 325 (99%), with 300 (92%) receiving two doses. Anti-measles IgG concentrations were insufficient in 11% of the immunized patients. VZV vaccination was officially recommended in Germany since 2004, and implemented in 88% born from 2005 onwards. In patients born earlier VZV catch up vaccination only reached 25% (n = 67). Of 118 patients with documented VZV vaccination 25 (21%) did not display sufficient anti-VZV IgG. Of 198 patients with a history of chicken pox, six had undetectable anti-VZV IgG. Of 29 patients having neither had chicken pox nor VZV vaccination, 20 were found to have sufficient anti-VZV IgG. Conclusions In our cohort vaccination coverage for hexavalent and MMR vaccinations was good, but insufficient for VZV vaccination in patients born before 2005. Neither the vaccination certificate nor the history of chicken pox is reliable to predict VZV immunity indicating a need for serologic investigations and if needed vaccination before initiating immunosuppressive therapy.

Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. A recent population-based study found a crude incidence of approximately 19 cases per 100,000 a year. Amoxicillin-clavulanate continues to be the most commonly implicated agent in most Western countries, reported to occur in approximately 1 of 2300 users. In patients with drug-induced autoimmune hepatitis, liver tests often do not normalize with cessation of the drugs and require corticosteroids. DILI associated with jaundice can lead to death from liver failure or require liver transplantation in at least 10% of cases.

The major histocompatibility complex class II (MHC II)-CD4 immunologic synapse is classically described between the T-cell receptor of CD4-positive lymphocytes and MHC II on antigen-presenting cells. This interaction and others between surrounding costimulatory and checkpoint molecules promote differentiation of naive CD4 T lymphocytes into helper T cells subtypes, including types 1, 2, and 17 helper T cells, that have more tailored immunologic responses. Although MHC II is mainly produced by professional antigen-presenting cells, it can be aberrantly produced by other cell types, including hepatocytes in various liver pathologies, such as autoimmune hepatitis and alcoholic hepatitis. This can lead to direct targeting of hepatocytes by CD4-positive lymphocytes, which form an immunologic synapse with the hepatocyte. The lymphocytes internalize the MHC II-CD4 complexes in a phagocytosis-like mechanism and in the process eat the hepatocyte piece by piece. We review the evidence for this mechanism and the role of these autoimmune responses in various liver diseases, including alcoholic hepatitis, autoimmune hepatitis, and primary biliary cirrhosis. The role of aberrant MHC II in malignancy, including hepatocellular carcinoma, is also reviewed. Further understanding of this mechanism can lead to better understanding of the immune mechanisms involved in these liver pathologies, with potential diagnostic and therapeutic applications.

Background and aims: Autoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment. Methods: a systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis. Results: the consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term 'complete biochemical response' defined as 'normalization of serum transaminases and IgG below the upper limit of normal' be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as ', YAEL Foundation

Autoimmune hepatitis (AIH) is an acute or chronic liver disease that causes significant inflammation at a cellular level and leads to cirrhosis if left untreated. The basis of diagnosis is increased liver enzymes and immunoglobulins with positive autoantibodies and necroinflammatory changes on liver biopsy. Clinical presentations can vary. Asymptomatic patients may only have raised liver enzymes detected on routine testing, the other extreme of presentation being represented by fatigue, jaundice and liver failure. Other autoimmune liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis can evolve during the clinical course. AIH typically responds well to immunosuppressant therapy. Patients should be monitored closely for adverse effects of drugs and, more importantly, to detect possible non-response or partial response to therapy to avoid disease progression and initiation of early second-line therapy. Monitoring for adverse effects should also cover bone health, diabetes and skin-related issues.

We present the case of a patient with acute transaminitis, with positive anti-smooth muscle antibody and hepatitis E antibodies. The remainder of the non-invasive liver screen was unremarkable. A liver core revealed moderately active acute hepatitis with portal and parenchymal inflammation, including apoptotic bodies and focal confluent necrosis. The features were in keeping with an acute hepatitis, with a differential of either drug, viral or autoimmune aetiology. Hepatitis E RNA was subsequently detected by PCR. This case illustrates the importance of considering hepatitis E as a differential for acute hepatitis, in a patient with autoantibodies. Review of the literature revealed several similar reports, studies suggesting increased hepatitis E seroprevalence in patients with autoimmune hepatitis, and studies finding autoantibody positivity in up to 50% of patients with acute hepatitis E. Together, these findings indicate a not-uncommon association, and so emphasize the importance of considering hepatitis E as a differential for acute autoimmune hepatitis.

Within the spectrum of autoimmune liver diseases, there are patients who manifest features of more than one disease, which was previously identified as having overlap syndrome1,2 and is now referred to as variant syndromes. The most common variant syndrome is between primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). Typically, AIH presents with elevated serum immunoglobulin (Ig) G, whereas PBC is associated with elevated serum IgM.3,4 Previous studies have suggested that plasma cells in liver biopsies of AIH patients are predominantly IgG+, whereas in PBC, there is an abundance of IgM+ cells.5,6 We wanted to determine the immunostaining pattern for IgG and IgM of liver plasma cells among Hispanic patients in Los Angeles with features of both PBC-AIH compared with those with PBC or AIH alone.

Timely diagnosis and management of severe acute-onset autoimmune hepatitis (SA-AIH), a potential cause of acute liver failure (ALF), are challenging. An initial trial of corticosteroids (CS) followed by an assessment of clinical responses over 1-2 weeks is advocated by the latest international practice guidelines1,2 and expert reviews.3,4 Consideration of a second-line drug while evaluating for liver transplantation (LT) is also recommended.2 Established predictors of "CS responsiveness" to guide decision-making are nonexistent. Herein, we determined the diagnostic abilities of early dynamics to define CS responsiveness in SA-AIH using the model for end-stage liver disease (MELD) scores.

There are rare instances where patients with acute hepatitis A virus infection subsequently developed autoimmune hepatitis. The diagnosis of autoimmune hepatitis in this setting is challenging. Furthermore, information on treatment with steroids or other immune suppressants, duration of therapy and possibility of treatment discontinuation is currently unclear. Here we report a case series of four patients with histology proven autoimmune hepatitis after hepatitis A virus infection. We describe the presenting features, diagnosis, treatment and long-term outcomes of these cases. This case series provides a insight into the clinical presentation and treatment of autoimmune hepatitis after hepatitis A infection with interesting take home points for clinical hepatologists.

Autoimmune hepatitis (AIH) frequently affects women of childbearing age in whom the desire to have a family raises the question regarding the potential risks for the fetus and the mother. The information on AIH in pregnant patients is scarce.1 The aims of this study were (1) to identify the risk factors associated with flares in pregnant patients diagnosed with AIH, (2) to determine the course of AIH in patients with pregnancy-related flares, and (3) to describe the outcome of AIH diagnosed in the postpartum period.