Cancer cells frequently undergo energy metabolic stress induced by the increased dynamics of nutrient supply. Hepatocyte nuclear factor 4A (HNF4A) is a master transcription factor (TF) in hepatocytes that regulates metabolism and differentiation. However, the mechanism underlying how HNF4A functions in cancer progression remains unclear due to conflicting results observed in numerous studies. To address the roles of HNF4A in hepatocellular carcinoma (HCC), we investigated the regulatory functions of HNF4A in HCC cells under different glucose supply conditions. We found that HNF4A exhibited tumor-suppressive effects on the proliferation and migration of HCC cells in glucose-sufficient conditions and tumor-promotive effects on HCC cells in glucose-insufficient conditions. Further investigation revealed that this diverse function of HNF4A was dependent upon the AMPK pathway activity. Similarly, the prognosis predicted by HNF4A was also correlated with whether the AMPKa expression levels were low or high in clinical HCC patients. Multiomics approaches consisting of proteomics and ChIP-seq revealed that key HNF4A target genes, including NEDD4 and RPS6KA2, are involved in the diverse function of HNF4A in HCC in response to the AMPK activity status. Specifically, HNF4A could bind to the promoter region of NEDD4 and RPS6KA2, and upregulating their expression. Our study has demonstrated the relationship between and synergism of AMPK and HNF4A in the progression of HCC under diverse nutrient conditions.

The response to corticosteroids and optimal timing for liver transplantation (LT) in patients with autoimmune hepatitis (AIH) remain significant clinical challenges. This study aimed to assess short-term (90-day) mortality in patients with acute AIH (with or without underlying cirrhosis and chronic liver disease) treated with corticosteroids, and to identify factors that predict mortality in this population.

We conducted a prospective, single-center study between 2022 and 2024, involving patients with histologically confirmed AIH. All patients received corticosteroid treatment and were monitored for various clinical and laboratory parameters on days 3, 7, and 90 after initiating therapy.

A total of 104 patients were included in the study, with a mean age of 46.1 ± 14.3 years; 77% of the patients were female. The 90-day mortality rate following the initiation of corticosteroids was 13.47%. Univariate analysis identified several significant predictors of mortality, including older age, diabetes mellitus, cirrhosis, esophageal varices, hepatic encephalopathy, low serum albumin on day 3, model of end-stage liver disease (MELD) scores on days 3 and 7, and the survival and prognostic factors for acute severe autoimmune hepatitis (SURFASA) score (P < 0.05). Multivariate analysis revealed that MELD score on day 7 (odds ratio [OR] 1.25; 95% confidence interval [CI] {1.09-1.48}; P = 0.00) and SURFASA score (OR 7.46; 95% CI {1.05-53.06}; P = 0.04) were significant. Specifically, a MELD score ≥27.5 on day 7 (area under the receiver operating characteristic curve [AUC] = 0.998) with 100% sensitivity and 97.8% specificity, and a SURFASA score ≥ -2.95 (AUC = 0.969) with 100% sensitivity and 95.6% specificity were highly predictive of mortality.

Despite corticosteroid treatment, mortality rates remain high in the decompensated AIH and acute on chronic liver failure-AIH groups. The SURFASA score, along with MELD scores on days 3 and 7, are strong predictors of mortality and can assist clinicians in making timely decisions regarding referral for early liver transplantation.

The number of metabolic dysfunction-associated steatotic liver disease (MASLD) patients is increasing rapidly. More attention has been paid to the relationship between immunity and MASLD. This study explored the roles of serum autoantibodies, immunoglobulins, and complements in MASLD. A total of 182 MASLD patients were investigated and grouped by autoantibody or NAS scores. Correlation between immunology and clinical features was assessed. In addition, metabolic dysfunction-associated steatohepatitis (MASH) models were constructed to verify the findings. Neutrophils were isolated from mice and treated with complement C3 to investigate the association between C3 and neutrophil extracellular traps (NETs). IgG, IgM, and NAS scores in the autoantibody positive group were significantly higher than those in the autoantibody negative group. Antinuclear antibodies (ANA), IgA, IgE, IgG, C3, C4, ALT, and AST were related to MASH. Meanwhile, IgA and C3 correlated with the severity of MASLD. The ROC curve showed that IgA > 2.990 g/L or C3 > 1.115 g/L predicted the presence of MASH. More importantly, IgG, activated C3, and NETs were increased in MASH. C3 stimulation directly induced NET formation in the neutrophils. Immunity systems were activated in MASH and elevated IgG activated C3 to stimulate the production of NETs, thus exacerbating MASH.

Autoimmune Hepatitis (AIH) is a chronic inflammatory liver disease with significant morbidity and mortality if untreated. Current first-line treatment involves corticosteroids and azathioprine (AZA), which are effective but are associated with significant adverse effects and treatment intolerance. Mycophenolate mofetil (MMF), an immunosuppressive agent with a potentially better safety profile, has emerged as an alternative. This meta-analysis evaluated the efficacy and safety of MMF compared to AZA in treatment-naïve AIH patients.

We conducted a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Databases were searched for articles published up to May 2024. Statistical analysis was performed using RevMan, employing a random-effects model.

Five studies involving 621 patients were included. MMF showed significantly higher rates of complete biochemical response compared to AZA (odds ratio [OR] 3.64, 95% confidence interval [CI] 2.07-6.40, p < 0.00001) and lower non-response rates (OR 0.45, 95% CI 0.24-0.85, p = 0.01). Corticosteroid withdrawal rates were also higher in the MMF group (OR 2.89, 95% CI 1.69-4.94, p = 0.0001). Relapse rate and cumulative prednisolone dose were comparable between the two groups. MMF demonstrated a better safety profile, with significantly lower rates of gastrointestinal symptoms (OR 0.46, 95% CI 0.27-0.79, p = 0.005).

MMF shows superior efficacy and tolerability compared to AZA in treatment-naïve AIH patients and may serve as a preferred first-line therapy, offering improved patient adherence and clinical outcomes. Further randomized controlled trials are warranted to confirm these findings.

Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.

Up now, several medications were proposed for the treatment of autoimmune hepatitis (AIH); however, because of the unclear pathophysiology of AIH, the most optimal treatment option needs to be elucidated. This systematic review sought to investigate the safety and efficacy of rituxiamb (RTX) in patients with AIH. A total of 27 studies were included in the present study. A total of 80 patients had the eligibility criteria, of which the majority of them were female (63 female and 17 male). Of the 80 patients, nine patients were pediatrics. The induction of remission and maintenance therapy were the most common indications for RTX in AIH. Of the 80 patients, we found complete remission in 55% of patients (n = 44) and partial remission in 11% of patients (n = 11). Of the nine pediatric patients, we found complete remission in 77% of patients (n = 7) and partial remission in 22% of patients (n = 2). Unclear response was also reported in 31% of patients (n = 25), which included four studies. 375 mg/m2 × 4 followed by 1000 mg × 2 was the most commonly applied RTX dosage used for treatment of AIH. RTX therapy was associated with infectious complications in six patients; however, one episode of cancer, death, mild conjunctivitis, and large bowel perforation were also reported. RTX is an anti-CD20 mAb and was shown to be effective for the treatment of AIH, but there is no consensus regarding the therapeutic role of RTX in AIH.

Although IgG4-related autoimmune hepatitis (IgG4-AIH) and IgG4-hepatopathy have been proposed as hepatic phenotypes of IgG4-related disease (IgG4-RD), their definitions and concepts remain insufficiently established. This study aims to conduct a clinicopathological investigation of cases reported as potential IgG4-AIH or IgG4-hepatopathy.

In previous nationwide epidemiological studies conducted in 2015 and 2018, we registered 1096 cases of IgG4-sclerosing cholangitis (IgG4-SC). Among these, 19 cases were identified as potential IgG4-AIH by the attending physicians, and other 20 cases as potential IgG4-hepatopathy with available liver histology were further evaluated using immunohistochemistry to assess the possibility of IgG4-AIH or IgG4-hepatopathy. For this purpose, we provisionally established diagnostic criteria for IgG4-AIH and IgG4-hepatopathy, primarily based on the comprehensive diagnostic criteria for IgG4-RD, which include IgG4 + cell count > 10/HPF and an IgG4 + /IgG ratio > 40%.

Of the 19 cases, 2 were diagnosed as IgG4-AIH, with IgG4 + cell counts/HPF of 25.3 and 18.7, and IgG4 + /IgG ratios of 310.2% and 53.4%, respectively. Neither storiform fibrosis nor obliterative phlebitis was observed in the liver of these cases, and both responded excellently to corticosteroid treatment. In addition, from other 20 cases, we diagnosed 8 cases as IgG4-hepatopathy, with IgG4-SC and autoimmune pancreatitis being present in 7 and 2 cases, respectively.

This study identified two cases of IgG4-AIH and eight cases of IgG4-hepatopathy. Further studies are necessary to explore the occurrence of IgG4-AIH using these diagnostic criteria in the AIH cohort. The presence of IgG4-hepatopathy may facilitate the diagnosis of IgG4-SC.

Anastrozole, an aromatase inhibitor (AI), has been used extensively for the treatment of estrogen receptor-positive breast cancer. Autoimmune hepatitis (AIH) is an extremely rare but serious complication of anastrozole treatment.

We present the case of an 81-year-old female who presented with significantly elevated liver function test (LFTs) results 8 months after the initiation of anastrozole for early-stage breast cancer. Serological and liver biopsy findings were consistent with AIH. Discontinuation of anastrozole, along with a short course of steroids, resulted in rapid clinical improvement and normalization of both LFTs and autoantibodies.

Clinicians should be aware of drug-induced AIH as a rare but life-threatening complication of anastrozole and potentially other aromatase inhibitors.

To evaluate the correlation between liver viscosity, as measured by shear wave dispersion (SWD), and fibrosis and inflammation in patients with autoimmune hepatitis (AIH). Additionally, to assess its potential as a non-invasive biomarker for hepatic fibrosis compared to shear wave elastography (SWE).

This prospective study included 25 AIH patients who underwent pre-biopsy SWD and SWE measurements using the SuperSonic Mach30 system. Liver biopsy samples were assessed for fibrosis using the Scheuer grading system and for inflammation using the modified Hepatic Activity Index (mHAI). Correlations between viscosity, elastography, fibrosis, and inflammation were analysed using Spearman's correlation coefficients.

Viscosity demonstrated a significant correlation with fibrosis stages (Spearman's coefficient: 0.58, p = 0.002), while SWE showed a weaker correlation (Spearman's coefficient: 0.50, p = 0.01). Viscosity measurements also correlated moderately with the mHAI score (Spearman's coefficient: 0.62, p = 0.001). Subgroup analyses revealed weak to moderate correlations between viscosity and mHAI components across fibrosis stages.

Our study suggests that viscosity may be better than SWE as a non-invasive marker for assessing hepatic fibrosis in AIH, particularly in the pre-treatment period when inflammation levels are elevated. However, we could not conclusively determine the relationship between viscosity and hepatic inflammation, as a small sample size limited our findings. Further research with a larger cohort of AIH patients is necessary to better understand the correlation between viscosity and inflammation in this rare condition.

Chitinase 3-like protein 1 (CHI3L1) is a marker of liver fibrosis produced mainly by hepatic macrophages. However, few studies have assessed the relationship between CHI3L1 and liver fibrosis in autoimmune liver diseases (AILDs). We aimed to explore the diagnostic value of CHI3L1 for liver fibrosis in AILDs and to compare its application differences between AILDs and chronic hepatitis B (CHB) patients.

The fibrotic group was defined as liver stiffness measurement (LSM) > 9.70kPa. Serum CHI3L1 levels were measured by ELISA in 78 AILDs patients, 65 chronic hepatitis B patients. The diagnostic accuracy was evaluated by the area under the receiver operating characteristic curve (AUROC).

Serum CHI3L1 levels in AILDs patients were positively correlated with LSM (r=0.750, p <0.001). The AUROC for serum CHI3L1 in identifying significant liver fibrosis was 0.939 (95% CI: 0.891 - 0.988), which was higher than that of other non - invasive fibrosis scores (APRI, FIB - 4, GPR, AAR, NLP, and PLR). At the optimal cutoff value of 86.84 ng/mL, the sensitivity and specificity were 92.9% and 83.3%, respectively. Furthermore, in patients with no significant difference in LSM, serum CHI3L1 levels were higher in the autoimmune liver disease group than in the CHB group.

Serum CHI3L1 is an effective non-invasive indicator for assessing liver fibrosis in AILDs patients and may vary in different etiologies.

Autoimmune hepatitis (AIH) is a rare immune-mediated chronic liver disease that is diagnosed based on a combination of biochemical, immunologic, and histologic features and the exclusion of other causes of liver disease. According to the new consensus criteria of the International Autoimmune Hepatitis Pathology Group (IAIHPG), the likely histologic features include a chronic hepatitis pattern of injury with a lymphoplasmacytic portal infiltrate, interface activity, and portal-based fibrosis. More than mild lobular hepatitis with any of the above features can also be diagnosed as likely AIH in the absence of features of another liver disease. Centrilobular injury with prominent hepatocellular necrosis and mononuclear inflammation may represent an acute-onset disease and indicate possible AIH in the absence of concurrent liver disease. Kupffer cell hyaline bodies and portal lymphocyte apoptosis are significantly associated with AIH, whereas emperipolesis and hepatocellular rosette formation are nonspecific features indicative of disease severity. Liver histology is an integral part of the clinical diagnostic scoring system and is required to confirm or support AIH diagnosis. Substitution of the histologic component of the simplified AIH scoring system with the consensus IAIHPG criteria has been proposed to optimize clinical diagnosis. This review explores the significant role of histopathology in AIH by analyzing its main features and current histologic diagnostic criteria, different AIH presentations, differential diagnosis, assessment of concurrent liver disease, and identification of AIH variants with primary cholangiopathy.

Management of patients with autoimmune hepatitis (AIH)-related decompensated cirrhosis is challenging because of the risk of treatment-related complications and lack of clinical recommendations. We investigated the predictive factors for treatment benefit in AIH-related decompensated cirrhosis at diagnosis and developed an algorithm to guide treatment decisions in clinical practice.

This retrospective, international, multicenter study included 232 patients with histologically confirmed AIH-related decompensated cirrhosis at diagnosis. The sub-hazard ratio (SHR) of mortality was determined by competing risk analysis, considering liver transplantation (LT) as competing event. A decision tree analysis was used to develop a treatment algorithm.

At diagnosis, 89% of patients had ascites, and 41% had overt hepatic encephalopathy (OHE). Treated patients (n = 214; 92%) had higher aminotransferases, bilirubin, and modified hepatic activity index. The SHR of mortality was lower in treated patients (0.438; 95% confidence interval [CI], 0.196-0.981; P = .045). Patients without OHE grade 3/4 and Model for End-Stage Liver Disease-Sodium (MELD-Na) ≤28 at diagnosis were more likely to benefit from treatment. In these patients, a decline in MELD-Na ≥11 after 4 weeks of treatment had a 100% negative predictive value for death/LT. Forty-nine percent of treated patients recompensated during follow-up. Twenty percent of patients had to discontinue treatment, 65% during the first 4 weeks, and only 4% due to infectious complications. OHE ≥grade 2 and MELD-Na at diagnosis predicted the need for treatment discontinuation.

Immunosuppression is beneficial in patients with AIH-related decompensated cirrhosis and active disease. OHE and MELD-Na at diagnosis, along with a decline in MELD-Na at 4 weeks of treatment, are the most important determinants of outcome and can guide treatment decisions.

The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.

Immunoglobulin G4-related disease (IgG4-RD) is a distinct immunoinflammatory disorder of unknown aetiology that may involve one or more organs, either synchronously or metachronously. Nonetheless, the pathophysiological mechanism is complex and poorly understood. The hepatobiliary manifestations of IgG4-RD [IgG4-hepatobiliary (IgG4-HB)], per se, have been sporadically reported in the literature. We describe the clinicoradiological, histomorphological, serological, and therapeutic data of 16 cases of IgG4-HB diagnosed on needle core liver biopsies applying 2021 Japanese guidelines. These included 11 cases of IgG4-sclerosing cholangitis (IgG4-SC), two with IgG4-sinusoidal dilatation and congestion (IgG4-SDC) in the absence of increased IgG4+ plasma cells in tissue but raised in serum, and three cases of IgG4-autoimmune hepatitis (IgG4-AIH). There was a male preponderance (M/F=11/5), with a median age at diagnosis of 49.5 years (13-73). On imaging, mass lesions mimicking a pseudotumour (n=6) or even cholangiocarcinoma (n=3) and biliary stricture (n=9) were common in the IgG4-SC subgroup. There was a positive but insignificant correlation between serum and tissue IgG4 levels (Spearman r=0.24, p=0.37), although increasing serum IgG4 levels were associated with biliary stricture (p=0.653). There was a satisfactory response to steroid therapy among 12 of 14 cases (median duration of follow-up 16.5 months). To the best of our knowledge, this represents the largest histomorphological series of IgG4-HB on needle biopsy from a single tertiary care centre in India. A larger prospective study with longer follow-up data is needed to validate our observations.

There is limited evidence that hepatitis A virus (HAV) infection can trigger hepatic autoimmunity, but this area remains largely unexplored. This study was thus planned with the aim to compare HAV-induced autoimmune-like hepatitis (HAV-ALH) with HAV-related liver dysfunction (HAV-acute viral hepatitis or HAV-AVH) and classical autoimmune hepatitis (AIH). This was a retrospective review of 46 patients with HAV infection who underwent liver biopsy (including 17 cases of HAV-ALH: diagnosis based on histopathology), and they were compared to 46 cases of age- and gender-matched classical AIH. Overall, HAV cohort (n = 46) had higher prevalence of pruritus, higher bilirubin levels, higher proportion of cholestasis, lower IgG levels, higher seronegativity and lack of disease recurrence, while the classical AIH group had higher proportion/severity of interface hepatitis, fibrosis, necrosis and pseudorosetting (p < 0.05). In comparison to the classical HAV-AVH group, HAV-ALH group had higher AST levels, higher presence of autoantibodies, and higher prevalence of severe zone 3 perivenulitis and marked pseudorosetting on histology (p < 0.05). Also, HAV-ALH group, in comparison to the AIH group, had more pruritus (OR 7.29, p < 0.004) and more seronegativity (41% vs. 13%, p < 0.031), while duration of illness (p < 0.003), IgG (p < 0.001) levels and liver stiffness measurement (p < 0.006) were significantly higher in AIH group (versus the HAV-ALH and HAV-AVH groups). Histologically, in comparison to AIH, HAV-ALH group had significantly less interface hepatitis (OR 0.03, p < 0.001) and fibrosis (OR 0.08, p < 0.001) and significantly more cholestasis (OR 4.5, p < 0.021). HAV infection can act as a potential trigger for immune-mediated hepatic damage, akin to drug-induced autoimmune-like hepatitis. Larger multicentric studies are needed to further explore this aspect.

Autoimmune hepatitis (AIH) is a relatively infrequent and complex liver disease characterized by acute or chronic inflammation, interface hepatitis in histology examination, elevation of immunoglobulin G (IgG), production of autoantibodies, and is often responsive to immunosuppression. The incidence of AIH has been increasing worldwide, affecting people of all ages and sexes. AIH represents a diagnostic challenge because of its heterogeneous presentation and the lack of pathognomonic findings. Even when treated, AIH can remain a progressive disease. In this review, we present recent data on the natural history of AIH and the developing evidence on the management of patients with AIH.

This review outlines the clinical presentation, risk factors linked to poorer clinical outcomes, the diagnostic algorithm, and the current management strategies for individuals living with AIH.

AIH remains a clinical challenge, and new tools for better diagnosis and stratification of risk are needed. In addition, better treatments are needed as a complete response is achieved in less than 60% of cases, and intolerance to first-line treatment is frequent. The use of biological treatment in AIH seems to improve the response rate and minimize the risk of side effects of current medication in this increasingly prevalent disease.

Autoimmune hepatitis (AIH) is a rare, heterogeneous liver disease marked by autoantibodies, hypergammaglobulinemia, and distinct histological features. Predominantly affecting women, its incidence and prevalence show significant regional variability globally. Therefore, our aim is to examine the trends of AIH and to assess its demographics, management, and disease progression using an extensive population-based database.

This retrospective, population-based study analyzed data from 2.7 million adults in Clalit Health Services, focusing on autoimmune hepatitis (AIH) diagnoses between 2009 and 2023. Data reordered included demographics, clinical details, and treatment regimens. Key outcomes tracked were the development of cirrhosis and its complications.

This study included 992 AIH patients with a median age of 51.5 years, 80.4 % female, and a median follow-up of 6.1 years. Obesity was present in 23.2 %, and 10.9 % had thyroid disease. At diagnosis, 22.9 % had cirrhosis, and an additional 137 patients developed cirrhosis during follow-up, leading to a total prevalence of 36.5 %. Among cirrhotic patients, 29.9 % experienced decompensation, 25.3 % developed ascites, 9.3 % had variceal bleeding, and 10.4 % developed hepatic encephalopathy. Hepatocellular carcinoma (HCC) occurred in 5.24 % of cirrhotic patients, with an incidence rate of 6.32 cases per 1000 patient-years. Overall, 11.2 % of cirrhotic patients underwent liver transplantation. The proportion of AIH patients diagnosed with cirrhosis at the time of diagnosis significantly decreased over the study period (p = 0.0028).

This study demonstrates a decreasing trend in AIH patients diagnosed with cirrhosis, suggesting earlier detection and improved management, alongside a lower documented incidence of HCC.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.

Uncertainty remains about many aspects of first-line treatment of autoimmune hepatitis (AIH).

Systemic review with meta-analysis (MA).

Bespoke AIH Endnote Library, updated to 30 June 2024.

Randomised controlled trials (RCTs) and comparative cohort studies including adult patients with AIH, reporting death/transplantation, biochemical response (BR) and/or adverse effects (AEs).

Data pooled in MA as relative risk (RR) under random effects. Risk of bias (ROB) assessed using Cochrane ROB-2 and ROBINS-1 tools.

From seven RCTs (five with low and two with some ROB) and 18 cohort studies (12 moderate ROB, six high for death/transplant), we found lower death/transplantation rates in (a) patients receiving pred+/-aza (vs no pred): overall (RR 0.38 (95% CI 0.20 to 0.74)), in patients without symptoms (0.38 (0.19-0.75)), without cirrhosis (0.30 (0.14-0.65)), and with decompensated cirrhosis (RR 0.38 (0.23-0.61)), and (b) patients receiving pred+aza (vs pred alone) (0.38 (0.22-0.65)). Patients receiving higher (vs lower) initial pred doses had similar BR rates (RR 1.07 (0.92-1.24)) and mortality (0.71 (0.25-2.05)) but more AEs (1.73 (1.17-2.55)). Patients receiving bud (vs pred) had similar BR rates (RR 0.99 (0.71-1.39)), with fewer cosmetic AEs (0.46 (0.34-0.62)). Patients receiving mycophenolate mofetil (MMF) (vs aza) had similar BR rates (RR 1.32 (0.73-2.38)) and fewer AEs requiring drug cessation (0.20 (0.09-0.43)).

Mortality is lower in pred-treated (vs untreated) patients, overall and in several subgroups, and in those receiving pred+aza (vs pred). Higher initial pred doses confer no clear benefit and cause more AEs. Bud (vs pred) achieves similar BR rates, with fewer cosmetic AEs. MMF (vs aza) achieves similar BR rates, with fewer serious AEs.

The diagnostic value of primary biliary cholangitis (PBC)-specific antibodies in patients with elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) levels, and other identifiable causes, was unclear. Our study aimed to determine whether etiological treatments in PBC-specific antibody-positive patients could improve liver biochemical tests, thereby distinguishing them from individuals with PBC.

We enrolled patients who were positive for PBC-specific antibodies and elevated ALP and/or GGT levels but with other identifiable etiologies. Changes in liver biochemistry following non-ursodeoxycholic acid etiological treatments were monitored.

A total of 155 patients with positive PBC-specific antibodies and elevated ALP and/or GGT levels due to non-PBC diseases were enrolled. Among them, 100 patients were diagnosed with non-PBC liver diseases, mainly metabolic-associated fatty liver disease, drug-induced liver injury, and autoimmune hepatitis. Additionally, 55 patients had non-liver diseases, predominantly connective tissue diseases. The median follow-up duration was 15.9 (4.7-25.6) months. Among 141 patients who completed follow-up after receiving etiological treatments, 85.1% (120/141) showed improvement in ALP and/or GGT levels, with 51.8% (73/141) achieving normalization of both ALP and GGT. However, 68 patients continued to exhibit elevated ALP and/or GGT, with 55 patients displaying isolated GGT elevation and 11 patients showing liver histological changes not consistent with PBC.

PBC-specific antibodies, along with elevated ALP and GGT levels, may occur in various non-PBC diseases. Etiological treatments may improve or even resolve cholestatic biochemistry. For these patients, initiating etiological treatment rather than immediately starting ursodeoxycholic acid therapy would be justified.

The present study aimed at comparing simplified and modified histologic criteria alone and along with other indicators in the diagnosis of chronic autoimmune hepatitis (AIH).

In this cross-sectional study, 48 cases were selected from slides and paraffin blocks of patients suspected of chronic AIH according to clinical and laboratory data, including serology and autoantibody findings and viral hepatitis test results. Then, scores equal to 1 (compatible hepatitis), 2 (typical hepatitis), ≤6 (probable hepatitis), and ≥7 (definite hepatitis) were calculated based on the simplified histologic criteria, modified histologic criteria, and these two criteria, along with other indicators including antinuclear antibodies (Ab), smooth muscle Ab or liver-kidney microsomal Ab or soluble liver antigen (Ag) and serum immunoglobulin G (IgG) and absence of viral hepatitis.

The results of this study revealed that based on the simplified histologic criteria, 43.8% and 56.3% of these cases were assigned a score of 1 and 2 points, respectively. However, calculating the total score using the simplified criteria along with other indicators showed that 60.4% and 39.6% of cases were assigned a score ≤6 and ≥7 points, respectively. Moreover, the modified histologic criteria indicated that 25% and 75% of cases were assigned a score of 1 and 2 points, respectively.

According to the findings of the present study, the modified histologic criteria compared to the simplified histologic criteria identified a higher percentage of patients assigned a score of 2 points. Moreover, modified histologic criteria, along with other indicators, were more accurate in detecting definite AIH (score ≥7 points).

Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis, but their validation is limited because of insufficient data.

To investigate the diagnostic performance of three fibrosis noninvasive tests [FibroTest, vibration-controlled transient elastography (VCTE), and the fibrosis-4 index (FIB-4) and two activity biomarkers (alanine aminotransferase (ALT) and ActiTest].

This study enrolled 103 patients for whom liver biopsy, hepatic elastography results, and laboratory markers were available. Diagnostic performance was assessed with receiver operating characteristic (ROC) curves, the Obuchowski measure (OM), and the Bayesian latent class model.

FibroTest and VCTE outperformed FIB-4 in cases of significant fibrosis (≥ F2), with areas under the ROC curve of 0.83 [95% confidence interval (CI): 0.73-0.90], 0.86 (95%CI: 0.77-0.92), and 0.71 (95%CI: 0.60-0.80), respectively. The mean (standard error) OM values were 0.92 (0.01), 0.93 (0.01), and 0.88 (0.02) for FibroTest, VCTE, and FIB-4, respectively; FibroTest and VCTE performed comparably, and both were superior to FIB-4 (P = 0.03 and P = 0.005). The areas under the ROC curve values for activity biomarkers were 0.86 (95%CI: 0.76-0.92) for ActiTest and 0.84 (95%CI: 0.73-0.90) for ALT (P = 0.06). The OM values for ActiTest and ALT were 0.92 (0.02) and 0.90 (0.02), respectively (P = 0.005).

FibroTest and VCTE outperformed FIB-4 according to the OM. FibroTest-ActiTest facilitated the evaluation of both fibrosis and activity.

Intravenous methylprednisolone (IVMP) pulses, widely used for managing multiple sclerosis (MS) exacerbations, can lead to acute liver injury, presenting a diagnostic challenge in distinguishing between drug-induced autoimmune-like hepatitis (DI-ALH) and idiopathic autoimmune hepatitis (AIH). This study aimed to delineate the clinical and biochemical features of IVMP-induced liver injury, discern its etiology, and evaluate the efficacy of glucocorticoid (GC) therapy in treatment. A retrospective analysis of 13 relapsing MS patients with IVMP-induced liver injury was conducted. Liver injury was classified as hepatocellular, cholestatic, or mixed, with severity assessment guiding liver biopsy in selected cases. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) and the Simplified Diagnostic Criteria for AIH. All patients were initially monitored for a minimum of six months, with a mean follow-up period of 4.30 years. The median onset of liver injury was 37.46 days post-IVMP, with a mean peak alanine transaminase (ALT) level of 618.46 U/L. antinuclear antibody (ANA) positivity was observed in 61.53% of cases, with elevated serum immunoglobulin G (IgG) at 15.38%. Hepatocellular injury was universal among patients, and causality assessment predominantly supported DI-ALH. GC therapy was administered in six cases, achieving favorable outcomes in all but one, which necessitated rituximab. Biochemical normalization occurred within a mean of 55.41 days, with GC-treated patients recovering faster (48 days). These findings support the hypothesis that IVMP can induce hepatocellular injury, likely DI-ALH, during MS exacerbations. A tapering GC regimen proved effective in promoting recovery, particularly in severe cases. Additionally, this study introduced a diagnostic and therapeutic algorithm for managing IVMP-induced liver injury, offering a practical framework for clinical application.

Rheumatoid arthritis (RA) and Sjögren's syndrome (SS) are systemic autoimmune conditions. SS frequently occurs associated with RA. In patients with RA, those with SS exhibit a higher disease burden, increased disease activity, and more complex comorbidities compared with those without SS.

We report a 54-year-old female patient who was previously diagnosed with early-stage RA less than 1 year ago. She was subsequently confirmed to have SS associated with RA. Additionally, she developed multiple autoimmune comorbidities, including autoimmune hepatitis and type 1 renal tubular acidosis. The patient resisted various treatments, including immunosuppressive drugs, disease-modifying antirheumatic drugs, and anti-inflammatory small-molecule drugs. This was evidenced by poor DA28 responses, persistent laboratory abnormalities, and ongoing symptoms and signs. Finally, she responded well to Telitacicept, a BLyS/APRIL dual inhibitor.

Even in the early stage, multiple autoimmune comorbidities can exhibit high levels of disease activity and may not respond to conventional therapies. Telitacicept, the first dual inhibitor of BLyS/APRIL, has the potential to provide significant efficacy and safety for RA patients who also have overlapping SS and other autoimmune diseases that do not respond to standard treatments. The limitations included the absence of a liver biopsy and the short follow-up period.

Background/Objectives: This article presents the case of a 31-year-old primigravida who experienced acute liver failure in the 23rd week of pregnancy, along with a review of the literature on this rare condition during pregnancy. The purpose of this publication is to highlight the diagnostic and therapeutic challenges associated with acute liver failure in pregnant women. Methods: The patient presented with jaundice, pruritus, and dark-colored urine. Laboratory tests revealed a significant increase in aminotransferase, bilirubin, and bile acid levels, suggesting liver problems; however, due to the patient's rapidly deteriorating condition and test results, autoimmune hepatitis was considered. Viral infections and other causes of liver damage were excluded. No clear diagnosis was established. The patient was administered ursodeoxycholic acid and due to her worsening condition, a cesarean section was performed at 23 weeks of gestation. After delivery, the patient's condition improved, although she did experience cardiac arrest during hospitalization. The patient was discharged with a diagnosis of acute liver failure in the course of an overlap syndrome of autoimmune hepatitis and primary cholangitis or intrahepatic cholestasis of pregnancy. No abnormalities were noted during a follow-up visit 6 weeks after delivery. Despite a detailed case analysis, a final diagnosis was not established, which complicates planning for future pregnancies. Discussion: Several liver conditions can occur during pregnancy, including intrahepatic cholestasis of pregnancy, primary biliary cholangitis, and autoimmune hepatitis. Diagnosing these conditions can be challenging due to overlapping symptoms and metabolic and immunological adaptations during pregnancy that can affect the course of liver diseases. Rapid intervention is crucial to protect the health of both the mother and the fetus. Conclusions: In summary, this article aims to increase awareness of the complexities surrounding acute liver failure during pregnancy, highlighting the diagnostic challenges and importance of prompt medical intervention for the well-being of both the mother and the child. This paper aims to provide a comprehensive overview of the complexities surrounding acute liver failure during pregnancy, aiming to improve the understanding, diagnosis, and management of this condition.

Background Autoimmune hepatitis (AIH) is a chronic inflammatory condition that can progress to liver cirrhosis. Genetics, immune system dysfunctions, and environmental factors influence the global prevalence of AIH. AIH exhibits variable clinical outcomes across ethnic groups, with Hispanic patients having a higher prevalence of cirrhosis, whereas African American patients are noted to have higher hospitalization and mortality rates. Aim The purpose of our study is to assess the clinical course of autoimmune hepatitis, specifically in Hispanic and African American patients. Methodology We performed a retrospective chart review of patients diagnosed with AIH and managed by the Gastroenterology Service from July 2006 to June 2023. The study population comprised individuals who were either Hispanic or African American and aged 18 years or older. Patients who were hospitalized and did not continue with outpatient follow-up were excluded from the analysis. Results Out of the 30 patients in our study, 27 (90%) were female and 3 (10%) were male. About 21 (70%) of the patients were Hispanic, while 9 (30%) were African American. The mean age at the time of AIH diagnosis was 45 years. Liver cirrhosis was confirmed with liver biopsy in 21 (70%) of the patients, and by imaging or clinical findings alone in an additional 3 (10%). Concomitant autoimmune diseases were present in 7 (23%) of the patients. Approximately 11 (36%) of the patients required hospitalization due to decompensated liver cirrhosis. About 19 (63%) were initially referred to the gastroenterology service due to abnormal liver function tests and were asymptomatic at the time of the first visit. About 6 (20%) of the patients presented with abdominal pain as their initial symptom. One patient had nausea and vomiting, two presented with jaundice, and one presented with altered mental status. Notably, none of the patients died during the study period. Conclusion Our study indicates that AIH is more prevalent among female and Hispanic patients as compared to male and African American patients. A significant proportion of our patients developed cirrhosis. Further studies are necessary to improve outcomes of autoimmune hepatitis in African American and Hispanic populations.

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.

Drug-induced liver injury (DILI) due to metamizole has gained increasing attention. Causality assessment remains a challenge, especially in patients with co-medications. We therefore aimed to further characterise metamizole DILI cases.

The data of patients with metamizole intake from our prospective study on acute liver injury with potential drug-related causes were analysed. Diagnosis and causality assessment were based on a thorough work-up and long-term follow-up.

DILI was associated with metamizole in 61 of 324 DILI patients (prevalence 18.8%). A highly characteristic clinical pattern was observed in 43 of the 61 patients, characterised by marked elevation of transaminases peaking at the time of DILI recognition and a more pronounced increase of bilirubin within the first 3 days of clinical presentation. Patients fitting this picture had higher rates of jaundice, coagulopathy, and acute liver failure, however outcomes did not differ significantly when compared to non-metamizole DILI and autoimmune hepatitis (AIH) patients. Overall, fatal adverse outcomes defined by death or liver transplantation were observed in 13.1% of metamizole DILI patients. On multivariate analysis, only aspartate aminotransferase (AST) and INR were independently associated with a fatal adverse outcome. INR, in particular, performed better than Hy's law, bilirubin, transaminases, and the model for end-stage liver disease (MELD), with a c-statistic of 0.85 (95% CI: 0.70-1.0). At a cut-off of ≥ 2.1, sensitivity and specificity for a fatal adverse outcome were 75% and 96%, respectively.

Metamizole DILI can present with a characteristic pattern that can help clinicians to identify metamizole as the causative agent. Outcome, however, is not associated with this clinical picture and should rather be predicted by INR at onset.

ClinicalTrials.gov identifier: NCT02353455.

The identification of autoantibodies associated with autoimmune liver disease (ALD) is crucial for diagnosis and management. Various laboratory methods have been introduced to detect autoantibody profiles. However, the variable performance of these assays may create challenges for clinicians and patients.

To investigate the concordance rates and diagnostic performance of 2 commercially available assays, line immunoassay (LIA) and digital liquid chip method (DLCM), in patients with ALD.

A total of 291 serum samples were collected, consisting of 180 sera from patients with ALD and 111 sera from controls. The samples were detected through LIA and DLCM. The agreement and diagnostic performance of each assay were analyzed.

There was substantial to almost perfect agreement among prevalent autoantibodies (anti-mitochondrial antibody M2; antibodies against gp210, Sp100, and Ro52). Nevertheless, the Cohen κ coefficient of some uncommon autoantibodies (anti-LKM-1, anti-LC-1, and anti-SLA/LP) between the 2 methods was not ideal. LIA showed slightly better sensitivity, accuracy, and negative predictive value, while DLCM exhibited slightly higher specificity and positive predictive value.

LIA and DLCM demonstrated comparable performance for the detection of common ALD-related autoantibodies. LIA seemed to be more sensitive, while DLCM displayed more specificity. However, standardization of ALD autoantibody detection still faces challenges between these diverse detection systems. Comprehensive interlaboratory validation is essential to mitigate potential misunderstanding and confusion among patients and clinicians.

This review compiles the mechanisms of acute liver failure (ALF) as well as the current and potential therapeutic approaches, including aetiology-specific treatment, and the issues encountered with such approaches. On a cellular level, ALF is characterized by massive hepatocyte death due to different types of cellular demise. Compensatory hyperplasia and functional recovery are possible when the regenerative capacity is sufficient to sustain hepatic function. ALF has a high mortality of about 30% and can lead to death in a very short time despite maximum therapeutic intervention. Besides aetiology-specific therapy and intensive care, the therapeutic option of emergency liver transplantation has significantly improved the prognosis of patients with ALF. However, due to limiting factors such as organ shortage, many patients die on the waiting list. In addition to graft assessment, machine perfusion may have the potential to recondition marginal organs and thus expand the organ donor pool.

Background/Objectives:Catha edulis, also known as Khat, is a stimulant with hepatotoxic properties. Studies reporting laboratory patterns are scarce. The aim was to assess the patterns associated with hepatic dysfunction due to Khat usage. Methods: Patients with liver injury and self-reported Khat consumption presenting to the gastroenterology department at the King Fahad Central Hospital in Jazan between January 2017-May 2024 were retrospectively included in the study. Patients with any signs of cirrhosis or viral hepatitis were excluded to have a more homogenous inclusion. Normal distribution was not assumed; data were presented as the median (IQR or %). Results: Sixty-three patients (of which 62 (98.4%) were male) aged 35 (29-41) years were included in the study. An IgG > 20 g/L was present in 41 (61.5%) patients, and the majority (n = 48, 76.2%) had a hepatocellular injury pattern based on an R-factor > 5. Over half of the patients had at least one positive autoantibody(ANA 47.6%; SMA 55.6% and AMA 4.8%), while 57 (90.5%) patients received immunosuppressive therapy. Conclusions: Khat-induced liver injury seems to be predominantly AIH-like in nature, given the IgG elevation, hepatocellular injury pattern, and relatively high rate of autoantibody positivity.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) stand as distinct diseases, yet occasionally intertwine with overlapping features, posing diagnostic and management challenges. This recognition traces back to the 1970s, with initial case reports highlighting this complexity. Diagnostic scoring systems like IAIHG and simplified criteria for AIH were introduced but are inherently limited in diagnosing variant syndromes. The so-called Paris criteria offer a diagnostic framework with high sensitivity and specificity for variant syndromes, although disagreements among international guidelines persist. Histological findings in AIH and PBC may exhibit overlapping features, rendering histology alone inadequate for a definitive diagnosis. Autoantibody profiles could be helpful, but similarly cannot be considered alone to reach a solid and consistent evaluation. Treatment strategies vary based on the predominant features observed. Individuals with overlapping characteristics favoring AIH ideally benefit from corticosteroids, while patients primarily manifesting PBC features should initially receive treatment with choleretic drugs like ursodeoxycholic acid (UDCA).

Autoimmune hepatitis (AIH) is a rare chronic liver disease with an increasing incidence in many countries. Chronic autoimmune responses against the liver can cause hepatic and extrahepatic symptoms, decreased quality of life and reduced liver transplant-free survival if inadequately treated. Although standard treatment with corticosteroids and thiopurines improves the life expectancy of patients with AIH, remission rates and tolerability are generally overestimated and the development of alternative first-line and salvage therapies has been disappointingly slow compared to in rheumatological diseases or inflammatory bowel disease. Other gaps include the lack of disease-specific diagnostic markers for AIH. Similarly, the new entity of drug-induced autoimmune-like hepatitis underscores the need to re-evaluate previous diagnostic criteria. The International AIH Group (IAIHG) has initiated a series of research workshops over the last decade to promote the identification of research gaps and subsequently improve the pace of scientific progress by stimulating collaboration between expert centres. This review reports on the results of the 5th Research Workshop, held in Hannover, Germany in June 2024, and summarises the progress made since the 4th Workshop in 2022. Patient representatives from the European Reference Network (ERN) Rare Liver Youth Panel participated in the workshop. The specific objectives of this year's 5th Workshop were: (1) To further improve diagnostics. (2) Initiate clinical trials including knowledge transfer on drugs from extrahepatic immune-mediated diseases, including B cell-depleting CAR T cells. (3) Utilisation of multi-omics approaches to improve the understanding of disease pathogenesis. (4) Application of machine learning-based approaches established in oncology or transplantation medicine to improve diagnosis and outcome prediction in AIH.

Objective Metabolic-associated fatty liver disease (MAFLD) has only recently been proposed; therefore, the characteristics of patients with autoimmune hepatitis (AIH) and MAFLD remain unclear. This study evaluated the effect of MAFLD on AIH patients with AIH. Methods We reevaluated the Japanese Nationwide Survey of AIH in 2018, which involved a survey of patients diagnosed with AIH between 2014 and 2017. We categorized patients with AIH according to the presence or absence of MAFLD and compared the clinical characteristics between the two groups. Results A total of 427 patients (77 men and 350 women) were included in this study. The overall prevalence of MAFLD was 10.5%. Compared to AIH patients without MAFLD, AIH patients with MAFLD had the following characteristics at the time of the AIH diagnosis: (1) a higher body mass index, (2) a higher prevalence of hypertension, (3) mild elevation of hepatobiliary enzymes and total bilirubin, and (4) histologically progressive fibrosis. However, the levels of hepatobiliary enzymes and total bilirubin after treatment were significantly higher in AIH patients with MAFLD than in those without MAFLD. Conclusion AIH patients with MAFLD had characteristics different from those of AIH patients without MAFLD. These findings could help increase our understanding of patients with AIH with MAFLD.