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Summary: Background and Aims: Diminished quality of life has been well characterized in patients with autoimmune hepatitis (AIH); however, the full spectrum of unmet needs is unclear. We hypothesized that there is a high burden of health‐related unmet needs in patients with AIH, and this burden differs by socioeconomic status (SES). Methods: Members of the Autoimmune Hepatitis Association were invited online and by email to complete a modified version of the Systemic Lupus Erythematosus Patient Needs Questionnaire. Demographic and clinical data were also captured. Low SES was defined as annual household income <30 k, education level below high school, or moderate–high concern for transportation, food or housing. Multivariable logistic regression assessed the association between unmet health‐related needs and SES. Results: There were 433 participants; 89.8% identified as women, 16.2% lived outside the US, and 25.6% were classified as low SES. Over 70% of respondents reported at least one moderate–high need in the health‐related unmet need domains. In multivariable logistic regression, patients in the low‐SES group reported significantly higher odds of unmet needs compared to the moderate–high‐SES group: for adequate information about side effects (OR 1.64, 95% CI 1.06–2.53, p = 0.026), opportunity to speak with others with AIH (OR 2.34, 95% CI 1.50–3.66, p < 0.001), healthcare professionals acknowledging patient emotions (OR 2.41, 95% CI 1.56–3.74, p < 0.001) and being taken seriously by medical providers (OR 2.09, 95% CI 1.34–3.28, p = 0.001). Conclusion: There is a high burden of health‐related unmet needs in all patients with AIH that is exacerbated by low SES. [ABSTRACT FROM AUTHOR]

AbstractAimMethodsResultsConclusionSweden has historically provided a fruitful arena for research in clinical medicine. We here share 40 years of experience of collaboration in the Swedish hepatology research group (SWEHEP) (https://www.swehep.se).We describe the way the Swedish hepatology pioneers started the group and how the network continuously developed over the years. Successful projects such as thorough studies of natural history and various clinical aspects of autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and steatosis are described.Over the years, more than 80 publications have been published by the group. A summary of new and ongoing research programs includes the randomized placebo-controlled trial of simvastatin in PSC (PiSCATIN), the prospective BIGMAP (Biochemical and genetic markers for the assessment and prognostication of liver cirrhosis) initiative in patients with liver cirrhosis, and the DETECT-HCC, a prospective multicenter cohort study comparing abbreviated MRI and ultrasound for surveillance of hepatocellular carcinoma every six months over two years. The group philosophy, success factors for the longstanding collaboration as well as experience of failures are shared.The success of hepatology research in Sweden is based on longstanding collaboration over generations of hepatologists, where everyone contributes, regular research meetings, mutual trust, and perseverance. [ABSTRACT FROM AUTHOR]

ABSTRACT 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. [ABSTRACT FROM AUTHOR]

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

Relapse after immunosuppression (IS) treatment withdrawal is frequent in patients with Autoimmune Hepatitis (AIH), and non-invasive biomarkers predictive of this risk are lacking. We assessed the frequency of circulating T cell subsets as potential biomarkers of disease activity and predictor of the risk of relapse after IS withdrawal. Serum levels of the cytokine B-cell Activating Factor (BAFF) were also investigated. Blood samples from 58 patients with active AIH, 56 AIH patients in remission, and 31 patients with NASH were analyzed. The frequency of activated CD4+ T peripheral helper (TPH) cells (CD4+CD45RA-CXCR5-PD1+CD38+) and of activated CD8+ T cells (CD8+CD45RA-PD1+CD38+) were assessed by flow cytometry. BAFF levels were determined by ELISA. Activated TPH and CD8+ T cell frequencies were significantly increased in patients with active AIH compared to remission AIH or NASH (TPH: 0.88% of total CD3+ vs. 0.42% and 0.39% respectively, p < 0.0001; CD8+ subset: 1.42% vs. 0.09% and 0.11% p < 0.0001). Among patients in remission undergoing treatment withdrawal (n = 18), those with increased frequencies of activated TPH (> 0.5% of total CD3+) and/or activated CD8+ T cells (> 0.18% total CD3+) had a higher risk of relapse (80% vs. 15% after 2 years, p = 0.0071). High BAFF serum concentration (> 213pg/ml) was also associated to a higher risk of relapse (57% vs. 11%, p = 0.0452). In conclusion, high frequency of activated TPH and of activated CD8+, as well as high levels of BAFF, before IS discontinuation, were significantly associated to a greater risk of relapse during the first two years. Thus, they represent promising biomarkers to provide personalized clinical follow-up for patients with AIH. [ABSTRACT FROM AUTHOR]

Background/Objectives: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease caused by an autoimmune attack on hepatocytes. The first-line treatment for AIH comprises two core components: glucocorticoids and thiopurine analog inhibitors and mycophenolate mofetil (MMF). Numerous studies have suggested an increased risk for lymphoma among patients with either rheumatoid arthritis or inflammatory bowel disease (IBD) who are treated with azathioprine/6-mercaptopurine (6-MP). The relative risk of non-Hodgkin lymphoma (NHL) among autoimmune hepatitis patients treated with these immunosuppressive drugs remains unclear. We aimed at investigating the risk of NHL across a large retrospective AIH cohort after a long-term follow-up. Methods: This retrospective, population-based study comprised approximately 2.7 million adults over two decades. It included adult patients aged 20 years or older at the time of autoimmune hepatitis diagnosis who had initiated treatment with azathioprine, 6-MP, or MMF. The primary outcome was the development of non-Hodgkin lymphoma. Results: The study initially included 834 patients diagnosed with AIH. A total of 685 patients remained in the research cohort after matching the data to the local cancer registry. Compared to the predicted NHL rate in the general population, NHL incidence was considerably higher in AIH patients (Standardized Incidence Ratio, SIR = 36.5). Subgroup studies showed that lymphoma mainly affected patients 45 years of age and over and was detected primarily during the first seven years following the AIH diagnosis. No correlation was found between the incidence of NHL and the treatment drug used. Conclusions: Patients with AIH exhibit a markedly higher risk of NHL compared to the general population. [ABSTRACT FROM AUTHOR]

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease treated by steroids and immunomodulator thiopurine drugs such as azathioprine (AZA). AZA is metabolized in the human body into bioactive forms such as 6-thioguanine (6-TG) and 6-methyl-mercaptopurine (6-MMP). Monitoring the levels of bioactive AZA metabolites is very important for proper treatment of patients. In this study, our aim was to develop and validate a fast and sensitive ultra-high performance liquid chromatography–mass spectrometry (UHPLC–MS) method for the analysis of 6-TG and 6-MMP from blood samples of patients with AIH to monitor the level of these bioactive metabolites. The detection and quantification of the analytes was carried out by Selected Reaction Monitoring (SRM)-based targeted mass spectrometry. The method was validated according to the EMA guidelines. Blood samples from patients with AIH treated with AZA were analysed with the developed method. The method was successfully validated with appropriate accuracy and precision for the target biomolecules and their concentration in the samples from patients with AIH was determined. The developed and validated UHPLC–MS method enables the fast and precise analysis of AZA metabolites. [ABSTRACT FROM AUTHOR]

Objective: Systemic lupus erythematosus (SLE) constitutes an autoimmune disorder with potential involvement of the gastrointestinal system (GIS). Our objective was to assess the gastrointestinal (GI) manifestations in patients diagnosed with childhood onset SLE. Methods: The study cohort consisted of 123 patients with childhood onset-SLE and GIS involvement from 16 referral departments of pediatric rheumatology. All participants met the Systemic Lupus International Collaborating Clinics criteria. Results: Out of 123 patients, 78 (63.4%) exhibited GIS involvement at the initial SLE diagnosis, whereas the remaining 45 (36.6%) developed GI symptoms after a median duration of 12 (3–140) months. Eighty-two (66.7%) individuals experienced symptoms related to the GI tract, whereas the remaining patients received a diagnosis of GI involvement through laboratory assessments. The predominant initial GIS involvement symptom was abdominal pain, observed in 77 (62.6%) patients, followed by elevated hepatic transaminases in 70 (56.9%), hepatomegaly in 40 (32.5%), diarrhea in 26 (21.1%), and jaundice in 11 (8.9%) patients. The GIS involvement was associated with SLE in 82 (78.6%), while it resulted from drug-related adverse events in 35 (28.5%) patients or comorbidities in 6 (0.5%) patients. Conclusion: GIS involvement should be considered in all childhood onset-SLE patients, especially in the presence of suggestive symptoms or elevated hepatic transaminases. It is also crucial to consider SLE in the differential diagnosis of GIS manifestations in children. Apart from GIS involvement directly associated with SLE, adverse events of drugs should be kept in mind. [ABSTRACT FROM AUTHOR]

Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute‐on‐chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first‐line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so‐called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug‐induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up‐to‐date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug‐induced, autoimmune‐like hepatitis (DI‐AIH). [ABSTRACT FROM AUTHOR]

Pro-inflammatory autoantigen-specific CD4+ T helper (auto-Th) cells are central orchestrators of autoimmune diseases (AIDs). We aimed to characterize these cells in human AIDs with defined autoantigens by combining human leukocyte antigen (HLA)-tetramer-based and activation-based multidimensional ex vivo analyses. In aquaporin4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) patients, auto-Th cells expressed CD154, but proliferative capacity and pro-inflammatory cytokines were strongly reduced. Instead, exhaustion-associated co-inhibitory receptors were expressed together with FOXP3, the canonical regulatory T cell (Treg) transcription factor. Auto-Th cells responded in vitro to checkpoint inhibition and provided potent B cell help. Cells with the same exhaustion-like (ThEx) phenotype were identified in soluble liver antigen (SLA)-antibody-autoimmune hepatitis and BP180-antibody-positive bullous pemphigoid, AIDs of the liver and skin, respectively. While originally described in cancer and chronic infection, our data point to T cell exhaustion as a common mechanism of adaptation to chronic (self-)stimulation across AID types and link exhausted CD4+ T cells to humoral autoimmune responses, with implications for therapeutic targeting. [Display omitted] • Auto-Th cells from AID patients have an exhausted-like (ThEx) phenotype • Auto-ThEx cell frequencies are stable for years despite successful therapy • ThEx cells respond to checkpoint inhibition and provide B cell help • ThEx phenotype development during chronic stimulation in vitro is regulated by FOXP3 CD4+ T cells are important contributors to autoimmune disease pathology. Saggau, Bacher et al. characterize autoantigen-specific CD4+ T helper cells in various human autoimmune diseases, revealing features of exhaustion. These findings provide insight into CD4+ T cell exhaustion in the context of chronic stimulation and suggest a role for exhausted autoantigen-specific CD4+ Th cells in promoting humoral autoimmunity. [ABSTRACT FROM AUTHOR]

Inflammasome is linked to many inflammatory diseases, including COVID-19 and autoimmune liver diseases. While severe COVID-19 was reported to exacerbate liver failure, we report a fatal acute-on-chronic liver failure (ACLF) in a stable primary biliary cholangitis-autoimmune hepatitis overlap syndrome patient triggered by a mild COVID-19 infection. Postmortem liver biopsy showed sparse SARS-CoV-2-infected macrophages with extensive ASC (apoptosis-associated speck-like protein containing a CARD) speck-positive hepatocytes, correlating with elevated circulating ASC specks and inflammatory cytokines, and depleted blood monocyte subsets, indicating widespread liver inflammasome activation. This first report of a fatal inflammatory cascade in an autoimmune liver disease triggered by a mild remote viral infection hopes to elucidate a less-described pathophysiology of ACLF that could prompt consideration of new diagnostic and therapeutic options. [ABSTRACT FROM AUTHOR]

Background/Objectives: Data regarding the outcomes of liver transplantation in disabled, highly dependent, and legally incapacitated adults are scarce, likely due to the infrequency of these procedures in such populations. Multicenter studies in adult transplant centers have shown that patients with coexisting intellectual and developmental disabilities (IDDs) may be denied transplantation because of their expected low longevity and the complexities associated with managing post-transplant care. We examined the long-term patient and graft outcomes in highly dependent, incapacitated patients with IDDs who underwent elective transplantation for chronic liver disease. Methods: Six adult patients who underwent liver transplantation for primary biliary cholangitis (n = 2), hepatitis C cirrhosis (n = 2), Wilson's disease (n = 1), and autoimmune hepatitis (n = 1) were included. The main causes of their disability were infantile cerebral palsy, myotonia, and Niemann–Pick disease. Results: Four of the six patients were women, with a median age of 26 (range: 23–36) years. Only one patient died during follow-up. Their 1- and 5-year survival rates were 100 and 75%, respectively, which were not statistically different from those of the general cohort of electively transplanted patients (95.8 and 90.1%, respectively) (p = 0.35). Conclusions: Adult patients who are highly dependent, disabled, or legally incapable should not be denied liver transplantation because of poor long-term survival rates. Physiological disorders and psychiatric comorbidities should not prevent patients from receiving life-saving surgeries due to poor postoperative compliance or low quality of life. [ABSTRACT FROM AUTHOR]

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

Background and Aim: There is no gold standard for making the diagnosis of autoimmune hepatitis (AIH), and the diagnosis of acute onset AIH (A‐AIH) is most challenging. A‐AIH sometimes develops into acute liver failure with poor prognosis if the diagnosis is delayed. Therefore, it is most important for the better prognosis to diagnose non‐severe A‐AIH early and treat appropriately. However, features in the early stage of A‐AIH are unclear. We examined initial characteristics of non‐severe A‐AIH in detail and tried to find novel clinical features for the early diagnosis. Methods: Clinical, biochemical, immunological, radiological, and histological features of 71 patients (54 women, mean age 57.9 ± 14.3 years) with non‐severe A‐AIH admitted to community hospitals between 2001 and 2022 were analyzed retrospectively. Result: Forty‐six had no symptom on onset and liver injuries were discovered by regular medical checkups. The mean duration from onset to consultation was 25.0 ± 29.3 days. Liver histology showed acute hepatitis in 59% and chronic hepatitis in 41%. Patients with symptoms revealed more male sex (P = 0.039), higher alanine aminotransferase (P < 0.001), higher total bilirubin (P < 0.001), and higher rate of histological acute hepatitis (P = 0.0013) than those without symptoms significantly. Male sex, presence of symptoms on onset, occurrence of jaundice in the course, and histological acute hepatitis were correlated. Conclusions: Sixty‐five percent of non‐severe A‐AIH patients were asymptomatic on onset, suggesting that A‐AIH would develop insidiously and present a longer clinical course than that reported. Male patients more often revealed true acute hepatitis clinically, biochemically, and histologically than female ones. [ABSTRACT FROM AUTHOR]

Purpose: To report an uncommon, isolated presentation of bilateral choroidal detachments in a patient diagnosed with P-ANCA-associated vasculitis and to highlight the importance of an inflammatory work-up in such cases. Methods: Case report. Results: A 70-year-old male with a past medical history of autoimmune hepatitis presented with a sudden decrease in vision in both eyes. Over the course of the previous decade, he had experienced recurrent attacks of episcleritis, which were successfully managed with topical corticosteroid eye drops. The patient was diagnosed with bilateral detachments without accompanying scleritis or intraocular inflammation. Inflammatory markers revealed high P-ANCA and anti-MPO levels, confirming the diagnosis of P-ANCA-associated vasculitis. Treatment with systemic rituximab and corticosteroids led to the resolution of the choroidal detachment in both eyes. A 40-month follow-up confirmed the sustained resolution of the detachments. Conclusion: Choroidal detachment without other extraocular/intraocular inflammation can be associated with P-ANCA-associated vasculitis, a previously under-reported link. It is important to consider an inflammatory work-up for patients presenting with choroidal detachment to rule out conditions like P-ANCA-associated vasculitis. [ABSTRACT FROM AUTHOR]

Rosacea and autoimmune liver diseases (AILDs) are diseases closely associated with immune system abnormalities. AILDs primarily includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Currently, research on the association between these two conditions is limited. Therefore, this study employed the bidirectional Mendelian randomization (MR) method to investigate potential causal relationships between rosacea and AILDs based on genetic predictions. Summary data related to Rosacea, AIH, PSC, and PBC were obtained from public genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was used as the primary analytical approach, supplemented by the MR-Egger, weighted mode method, weighted median, and simple mode. A series of sensitivity analyses were also conducted to identify heterogeneity and pleiotropy effects. The MR analysis results indicated a significant increase in the risk of rosacea being associated with PBC (OR = 1.09, 95% CI = 1.02–1.18, P = 0.014), but no such association was found with AIH or PSC. Furthermore, this study did not find a significant impact of rosacea on the risk of AILDs. This study represents the first in-depth exploration of the potential causal relationship between rosacea and AILDs using MR analysis. Thes findings suggest an increased risk of rosacea among PBC patients. [ABSTRACT FROM AUTHOR]

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

Indications for liver transplantation (LT) vary across age groups. We identified predictors of outcomes for teenage LT waitlisted candidates and recipients in the United States from 2008 to 2022. The Scientific Registry of Transplant Recipients 2008–2022 provided data (clinical, sociodemographic, indications for LT, outcomes) for all teenagers (13–19 years) waitlisted for LT in the United States. Sociodemographic and clinical characteristics, including primary listing diagnoses, were evaluated and compared by age group (13–16 vs. 17–19 years) among waitlisted teenage candidates. There were 2,813 teenage LT candidates listed between 2008 and 2022. The most common LT indication was acute liver disease (23.5%), followed by biliary atresia or hypoplasia (11.9%), autoimmune hepatitis (11.1%), and primary sclerosing cholangitis (9.7%). In contrast, chronic viral hepatitis, metabolic dysfunction-associated steatotic liver disease, and alcohol-related liver disease (the most common indications in adults) did not exceed 1% each; 2.8% had hepatocellular carcinoma. Excluding the two most recent years, 67.2% of candidates received a transplant; mean time to transplant was 217.0 days (standard deviation 371.6). Independent predictors of receiving a transplant were a more recent calendar year, younger age, higher model for end-stage liver disease score, and an acute liver disease diagnosis (all p <.05). Among the LT group, 3-year survival was 90%, with an improving survival trend. Higher post-transplant mortality was associated with earlier years of transplantation, older age, having Medicaid, being retransplanted, and having hepatocellular carcinoma (adjusted hazard ratios >1, all p <.05). Indications for LT among US teenagers are different from adults or younger children. There is a trend toward improved post-transplant outcomes. [ABSTRACT FROM AUTHOR]

To investigate the protective role of immune response gene 1 (IRG1) and exogenous itaconate in autoimmune hepatitis (AIH) and elucidate the underlying mechanisms. Wild-type and IRG1−/− AIH mouse models were established, and samples of liver tissue and ocular blood were collected from each group of mice to assess the effects of IRG1/itaconate on the expression of pro- and anti-inflammatory cytokines. The levels of liver enzymes and related inflammatory factors were determined using enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR). Liver histomorphology was detected through hematoxylin and eosin staining and then scored for liver injury, and the infiltration levels of tissue-resident memory T (TRM) cells and related molecules in the liver tissue were detected through immunofluorescence staining in vitro. RNA sequencing and gene enrichment analysis were conducted to identify the corresponding molecules and pathways, and lentiviral transfection was used to generate TRM cell lines with IRG1, Jak3, Stat3, and p53 knockdown. Real-time quantitative PCR and western blot were performed to detect the expression levels of relevant mRNAs and proteins in the liver tissue and cells. The percentage of apoptotic cells was determined using flow cytometry. IRG1/itaconate effectively reduced the release of pro-inflammatory cytokines and the pathological damage to liver tissue, thereby maintaining normal liver function. At the same time, IRG1/itaconate inhibited the JAK3/STAT3 signaling pathway, regulated the expression of related downstream proteins, and inhibited the proliferation and promoted the apoptosis of CD69+CD103+CD8+ TRM cells. For the first time, P53 was found to act as a downstream molecule of the JAK3/STAT3 pathway and was regulated by IRG1/itaconate to promote the apoptosis of CD8+ TRM cells. IRG1/itaconate can alleviate concanavalin A-induced autoimmune hepatitis in mice by inhibiting the proliferation and promoting the apoptosis of CD69+CD103+CD8+ TRM cells via the JAK3/STAT3/P53 pathway. [ABSTRACT FROM AUTHOR]

Purpose: There is an unmet clinical need for non-invasive imaging biomarkers that could replace liver biopsy in the management of patients with autoimmune hepatitis (AIH). In this study, we sought to evaluate the diagnostic accuracy of a simple uncorrected, non-contrast T1 mapping for detecting fibrosis and inflammation in AIH patients using histopathology as a reference standard. Material and methods: Over 3 years, 33 patients with AIH were prospectively studied using a multiparametric liver MRI protocol which included T1 mapping. Biopsies were performed up to 3 months before imaging, and a standardized histopathological score for fibrosis (F0–F4) and inflammatory activity (PPA0–4) was used as a reference. Statistical analysis included independent t test, Mann–Whitney U-test, and ROC (receiver operating characteristic) analysis. Results: T1 mapping values were significantly higher in patients with advanced fibrosis (F0–2 vs. F3–4; p < 0.015), significant fibrosis (F0–1 vs. F2–4; p < 0.005), and significant inflammatory activity (PPA 0–1 vs. PPA 2–4 p = 0.048). Moreover, the technique demonstrated a good diagnostic performance in detecting significant (AUC 0.856) and advanced fibrosis (AUC 0.835), as well as significant inflammatory activity (AUC 0.763). Conclusion: A rapid, simple, uncorrected, non-contrast T1 mapping sequence showed satisfactory diagnostic performance in comparison with histopathology for detecting significant tissue inflammation and fibrosis in AIH patients, being a potential non-invasive imaging biomarker for monitoring disease activity in such individuals. [ABSTRACT FROM AUTHOR]

Background: Seronegative autoimmune hepatitis in children is a rare but potentially severe disease, sometimes requiring liver transplantation. This type of hepatitis may be associated with various immunological and hematological disorders, ranging from isolated lymphopenia to aplastic anemia. Precise pathophysiological mechanisms are still unknown, but the role of viruses cannot be excluded, either as directly pathogenic or as triggers, responsible for an inappropriate immune stimulation. Having the impression of an increasing number of seronegative autoimmune hepatitis since the beginning of SARSCoV-2 pandemia period, we hypothesized that SARS-CoV-2 virus could be an infectious trigger. Methods: We conducted a retrospective, observational, descriptive study about children with seronegative autoimmune hepatitis, in a tertiary care center, between 2010 and 2022. Results: Thirty-two patients were included. The overall incidence of seronegative autoimmune hepatitis increased 3.3-fold in 2020-2022, during the SARS-CoV-2 pandemia period (16 patients in 2.8 years) compared with 2010-2019 the pre pandemia period (16 patients in 9 years). Patients' clinical and biochemical liver characteristics did not differ between the two periods. Hematological damages were less severe during the pandemia period. Immunological studies revealed a dysregulated immune response. The initiation of immunosuppressive therapy (corticosteroids ± cyclosporine) was earlier during the pandemia period than before. Conclusion: In cases of undetermined acute hepatitis, an immune-mediated origin should be considered, prompting a liver biopsy. If the histological aspect points to an immune origin, immunosuppressive treatment should be instituted even though autoimmune hepatitis antibodies are negative. Close hematological monitoring must be performed in all cases. The 3.3-fold increase of cases during the SARS-CoV-2 pandemia will need to be further analyzed to better understand the underlying immunological mechanisms, and to prove its potential involvement. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions The characteristics of autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and PBC‐AIH overlap syndrome (OS), have rarely been investigated and compared in Asia.At the Taiwan tertiary referral center, 330 PBC patients (87% treated with ursodeoxycholic acid [UDCA]), 143 AIH patients (94.4% treated with immunosuppressive therapy [IST]) and 21 PBC‐AIH OS patients (85.7% treated with UDCA and IST) were enrolled.Compared with AIH patients, PBC patients were older at baseline and had greater female‐to‐male sex ratios, alkaline phosphatase (ALP) and γ‐glutamyl transferase (γ‐GT) levels, and liver cirrhosis (LC), dyslipidemia, and hepatic and cardiometabolic complication rates. PBC patients had the lowest transaminase levels, whereas AIH patients had the highest transaminase levels. PBC patients had greater 22‐year all‐cause mortality and liver transplantation (ACMaLT) (43.5 vs 25.4%, P = 0.004), LC (75 vs 58.5%, P < 0.01), dyslipidemia (54.4 vs 45.9%, P = 0.001), and cerebrovascular accident (11.3 vs 0.8%, P = 0.019) cumulative incidences (CIs) than did AIH patients; PBC‐AIH OS patients had greater systemic lupus erythematosus (28.9 vs 8.9%, P = 0.009) CI than did PBC patients. Baseline ALP (hazard ratio: 1.001), albumin (0.514), platelet count (0.997), and LC (3.438) were associated with ACMaLT; age (1.110), albumin (0.350), cirrhosis (46.219), and hepatitis C virus antibody positivity (5.068) were associated with hepatocellular carcinoma (HCC); and female sex (2.183) and body mass index (1.054) were associated with autoimmune diseases.Compared with AIH patients, PBC patients had greater cardiometabolic CI, and ACMaLT CI, which was associated with cholestasis, liver functional reserve and LC. Older AILD patients with LC and females with obesity demand special caution for the development of HCC and extrahepatic autoimmune diseases, respectively. [ABSTRACT FROM AUTHOR]

Objective: To investigate the diagnostic value of ultrasound elastography combined with aspartate aminotransferase to platelet ratio index (APRI), international normalized ratio/platelet ratio (INPR), and four-factor-based liver fibrosis index (FIB-4) for liver fibrosis in patients with autoimmune hepatitis (AIH). Methods: 120 AIH patients who were admitted to our hospital from January 2021 to December 2022 underwent liver biopsy and the patients were divided into significant liver fibrosis group (F2-F4, n=74) and non-significant liver fibrosis group (F0-F1, n=46) according to the Metavir evaluation system, the baseline data, ultrasound elastography shear wave velocity (SWV), FIB-4, APRI and INPR were compared between the two groups. Logistic regression was used to analyze the influencing factors of significant liver fibrosis in AIH patients. The diagnostic value of SWV combined with APRI, INPR and FIB-4 for significant liver fibrosis in AIH patients were evaluated by receiver operating characteristic (ROC) curve. Results: The biopsy results of 120 AIH patients showed that: there were 15 cases (12.50%) in F0 stage, there were 31 cases (25.83%) in F1 stage, there were 35 cases (29.17%) in F2 stage, there were 27 cases (22.50%) in F3 stage, there were 12 cases (10.00%) in F4 stage. Compared with non-significant liver fibrosis group, the INR, SWV, APRI, INPR and FIB-4 values of the patients in the significant liver fibrosis group increased, and the PLT level decreased, with statistically significant differences (P<0.05). Logistic regression analysis showed that, elevated INPR, APRI, FIB-4 and SWV were risk factors for significant liver fibrosis in AIH (P<0.05). The results of ROC curve showed that, the AUC of APRI, INPR, FIB-4 and SWV in diagnosing the degree of liver fibrosis in AIH patients was>0.700, and the combination of the four items had the highest diagnostic efficiency. Conclusion: Ultrasound electrography parameters SWV combined with APRI, INPR and FIB-4 have high diagnostic value for significant liver fibrosis in AIH patients. [ABSTRACT FROM AUTHOR]

Background: In patients with cirrhosis, esophageal variceal hemorrhage (EVH) is a devastating consequence of portal hypertension (PH). Upper endoscopy is considered the gold standard for the detection and diagnosis of esophageal varices (EVs), despite being invasive and costly. This study was aimed at identifying and evaluating the diagnostic accuracy of noninvasive tools in predicting EVs in patients with compensated cirrhosis. Methods: This cross‐sectional study included 50 patients with compensated cirrhosis at the Tygerberg Hospital Gastroenterology Clinic in Cape Town between November 2022 and May 2023. We collected clinical, anthropometric, and laboratory data from patients' physical and electronic charts. All patients underwent an abdominal ultrasound, vibration‐controlled transient elastography (VCTE) to assess liver and splenic stiffness, and upper endoscopy. In this comparative study, we evaluated the diagnostic accuracy of different noninvasive tools in detecting EVs in patients with compensated cirrhosis. Results: Of the 50 patients included in the study, 30 (60%) were female and 20 (40%) were male. The patients' age ranged from 18 to 83, with a mean age of 46.6 years. Cirrhosis was mainly due to alcohol use (n = 11, 22%), hepatitis B virus (HBV) infection (n = 11, 22%), and autoimmune hepatitis (n = 10, 20%). The patients included in the study were divided into two subgroups: with (n = 34, 68%) or without (n = 16, 32%) EVs. Statistically significant differences were detected between groups in platelet count (PC), liver stiffness measurement (LSM), spleen stiffness measurement (SSM), portal vein diameter (PVD), bipolar spleen diameter (SBD), aspartate aminotransferase‐to‐platelet ratio index (APRI), fibrosis‐4 index (FIB‐4), platelet/bipolar spleen diameter ratio (PSR), liver stiffness‐spleen size‐platelet ratio (LSPS), liver stiffness‐spleen stiffness‐platelet ratio score (LS3PS), and spleen stiffness‐spleen size‐platelet ratio score (SSPS) (p < 0.001). The highest diagnostic precision was observed with SSM (96%), SSPS (96%), LS3PS (94%), LSPS (94%), PSR (94%), and PC (92%). SBD (88%), LSM (86%), APRI (82%), and FIB‐4 (82%) had the lowest diagnostic accuracy. Conclusion: SSM and SSPS have the highest diagnostic accuracy for predicting the presence of EVs in patients with compensated cirrhosis. LSPS, LS3PS, and PSR come second at 94%. We recommend SSM and SSPS in institutions with transient elastography equipped with the software necessary to measure splenic stiffness. We introduce and propose LS3PS as a novel composite score for predicting the presence of EVs in patients with compensated cirrhosis. Large‐sample‐size studies are needed to validate these prediction scores and to allow direct comparison with Baveno VII. These prediction tools can help clinicians avoid unnecessary endoscopic procedures in patients with compensated cirrhosis, especially in developing countries with limited resources such as South Africa. [ABSTRACT FROM AUTHOR]

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

Background and Aims: Pre-liver transplant (LT) functional status is an important determinant of prognosis post LT. There is insufficient data on how functional status affects outcomes of transplant recipients based on the specific etiology of liver disease. We stratified LT recipients by etiology of liver disease to evaluate the effects of functional status on post-LT prognosis in each subgroup. Methods: 2005–2019 United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) was used to select patients with liver transplant. A total of 14,290 patients were included in the analysis. These patients were stratified by functional status according to Karnofsky Performance Scale (KPS) score: no assistance, some assistance, or total assistance. They were then further divided into six diagnosis categories: metabolic dysfunction-associated steatotic liver disease (MASLD), hereditary disorders, hepatitis C, hepatitis B, autoimmune disease (AID), and alcoholic liver disease (ALD). Primary endpoints included all-cause mortality and graft failure, while secondary endpoints included organ-specific causes of death. Those under the age of 18 and those with non-whole liver or prior liver transplantation were excluded. Results: Patients with MASLD requiring some assistance (aHR: 1.57, 95% CI 1.03–2.39, p = 0.04) and those requiring total assistance (aHR: 2.32, 95% CI 1.48–3.64, p < 0.001) had higher incidences of graft failure compared to those requiring no assistance. Those with MASLD requiring total assistance had a higher all-cause mortality rate than those needing no assistance (aHR: 1.62, 95% CI 1.38–1.89, p < 0.001). Patients with hereditary causes of liver disease showed a lower incidence of all-cause mortality in recipients needing some assistance compared with those needing no assistance (aHR: 0.52, 95% CI 0.34–0.80, p = 0.003). LT recipients with hepatitis C, AID, and ALD all showed higher incidences of all-cause mortality in the total assistance cohort when compared to the no assistance cohort. For the secondary endpoints of specific cause of death, transplant recipients with MASLD needing total assistance had higher rates of death due to general cardiac causes, graft rejection, general infectious causes, sepsis, general renal causes, and general respiratory causes. Conclusion: Patients with MASLD cirrhosis demonstrated the worst overall outcomes, suggesting that this population may be particularly vulnerable. Poor functional status in patients with end-stage liver disease from hepatitis B or hereditary disease was not associated with a significantly increased rate of adverse outcomes, suggesting that the KPS score may not be broadly applicable to all patients awaiting LT. [ABSTRACT FROM AUTHOR]

Autoimmune diseases of the liver and biliary tract require timely and accurate diagnosis. This study evaluates the D-tek panel (D-Tek, Mons, Belgium) of 10 immunodot antigens for its effectiveness in diagnosing autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). We retrospectively analysed serum samples from 111 patients who had undergone routine testing, including indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assays (ELISA), to confirm or exclude autoimmune liver or biliary tract disease. The panel tested for M2/nPDC, M2/OGDC-E2, M2/BCOADC-E2, M2/PDC-E2, gp210, sp100, LKM1, LC1, SLA, and F-actin antigens. Results showed that all positive IIF+ELISA results were confirmed by the immunodot panel, except for two samples from patients who had never been diagnosed with AIH. The immunodot test identified over 20 additional autoantibodies in samples initially negative by IIF, corroborated by laboratory imaging and medical history. The immunodot technique proved to be a quick, sensitive, and specific method with high overall accuracy. This study suggests that the immunodot technique may be an effective screening and confirmatory method for autoimmune liver diseases, potentially improving diagnostic efficiency and accuracy in clinical practice. [ABSTRACT FROM AUTHOR]

Smooth muscle antibodies (SMA) with anti-microfilament actin (MF-SMA) specificity are regarded as highly specific markers of type 1 autoimmune hepatitis (AIH-1) but their recognition relying on immunofluorescence of vessel, glomeruli, and tubules (SMA-VGT pattern) in rodent kidney tissue, is restricted by operator-dependent interpretation. A gold standard method for their identification is not available. We assessed and compared the diagnostic accuracy for AIH-1 of an embryonal aorta vascular smooth muscle (VSM) cell line-based assay with those of the rodent tissue-based assay for the detection of MF-SMA pattern in AIH-1 patients and controls. Sera from 138 AIH-1 patients and 295 controls (105 primary biliary cholangitis, 40 primary sclerosing cholangitis, 50 chronic viral hepatitis, 20 alcohol-related liver disease, 40 steatotic liver disease, and 40 healthy controls) were assayed for MF-SMA and SMA-VGT using VSM-based and rodent tissue-based assays, respectively. MF-SMA and SMA-VGT were found in 96 (70%) and 87 (63%) AIH-1 patients, and 2 controls (P < 0.0001). Compared with SMA-VGT, MF-SMA showed similar specificity (99%), higher sensitivity (70% vs 63%, P = ns) and likelihood ratio for a positive test (70 vs 65). Nine (7%) AIH-1 patients were MF-SMA positive despite being SMA-VGT negative. Overall agreement between SMA-VGT and MF-SMA was 87% (kappa coefficient 0.870, [0.789–0.952]). MF-SMA were associated with higher serum γ‐globulin [26 (12–55) vs 20 g/l (13–34), P < 0.005] and immunoglobulin G (IgG) levels [3155 (1296–7344) vs 2050 mg/dl (1377–3357), P < 0.002]. The easily recognizable IFL MF-SMA pattern on VSM cells strongly correlated with SMA-VGT and has an equally high specificity for AIH-1. Confirmation of these results in other laboratories would support the clinical application of the VSM cell-based assay for reliable detection of AIH-specific SMA. (i) The search for smooth muscle antibodies (SMA) is a cornerstone of hepatic autoimmune serology, being one of the diagnostic criteria of autoimmune hepatitis (AIH). (ii) SMA are directed against structures of the cytoskeleton such as microfilaments, intermediate filaments, and microtubules. Although they may be detected in sera of patients with viral hepatitis, drug-induced hepatitis, and alcohol-related and non-alcohol-related fatty liver disease, SMA directed against actin microfilaments (MF-SMA) are highly AIH-specific. (iii) The recommended rodent tissue-based IFL for detecting MF-SMA is somewhat complicated, and the interpretation of the results depends on the operator's experience. The use of an embryonal aorta vascular smooth muscle cell line-based IFL assay provides high accuracy and easy detection of MF-SMA, the most AIH-specific SMA. Graphical Abstract [ABSTRACT FROM AUTHOR]

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of lives, leading to significant morbidity and mortality. With >772 million cases and nearly seven million deaths reported worldwide to date, the development of vaccines has been a critical step in mitigating the impact of COVID-19. However, concerns have arisen regarding the potential for SARS-CoV-2 mRNA vaccination to trigger autoimmune diseases, including autoimmune hepatitis (AIH). The present single-center, retrospective study aimed to compare the clinical and pathological features of AIH in patients with or without a history of SARS-CoV-2 mRNA vaccination. A total of 72 patients with AIH were examined. Among them, 10 had received the SARS-CoV-2 mRNA vaccination prior to AIH onset. These patients exhibited more pronounced CD4+ T cell infiltration into the liver tissue compared with those who were unvaccinated. No significant differences in the levels of other liver enzymes, autoimmune antibodies, or CD8+ T cell infiltration were observed between the groups. Moreover, the AIH patients with a history of SARS-CoV-2 mRNA vaccination had more extensive CD4+ T cell infiltration in their liver tissues than the unvaccinated patients. These findings suggested that the immune response to SARS-CoV-2 mRNA vaccination may influence the pathogenesis of AIH, highlighting the need for further research into the relationship between SARS-CoV-2 mRNA vaccination and autoimmune liver diseases. Such studies will also help clarify the distinction between vaccine-induced liver injury and traditional AIH. [ABSTRACT FROM AUTHOR]

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

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

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

Interleukin‐41 (IL‐41) is a newly discovered cytokine, named Cometin, Subfatin, meteorin‐like transcription (Metrnl), and so forth. It is widely expressed in animals and can exert its biological roles through autocrine and paracrine forms. It has functions such as anti‐inflammatory, improving body metabolism, regulating immunity, regulating fat metabolism and participates in the process of autoimmune disease or inflammatory injury. It plays an important role in psoriasis, diabetes, Crohn's disease (CD), osteoarthritis, Kawasaki disease (KD), Graves' disease, autoimmune hepatitis, infertility, obesity, sepsis, cardiovascular diseases and respiratory diseases. This paper reviews the biological functions of IL‐41, the relationship between IL‐41 and diseases, the effects of IL‐41 in the cytokine network and the possible signalling pathways. In order to explore the same target or the same drug for the treatment of different diseases from the perspective of homotherapy for heteropathy, cytokine strategies based on IL‐41 have been put forward for the precise treatment of immune diseases and inflammatory diseases. It is worth noting that IL‐41 related preparations for lung protection and smoking cessation are interesting research fields. [ABSTRACT FROM AUTHOR]

Purpose of Review: The purpose of the article is to review treatment options for patients with AIH for whom first-line therapy is not successful. We outline recommended approaches for providers and new therapies on the horizon. Recent Findings: Budesonide, while advantageous in some respects, may not be as effective as predniso(lo)ne. Mycophenolate mofetil is most effective in the setting of azathioprine intolerance and less effective when the response to azathioprine has been inadequate. Infliximab is the biologic agent with the most evidence for use in AIH. Clinical trials studying interleukin 2, regulatory T cells, inhibitors of BAFF signaling, and immunoproteasome inhibitors have been initiated but more research is needed, particularly in Black people, Indigenous people, and People of Color. Summary: While multiple agents have been reported as second- or third-line therapies, the evidence is limited. Future research will require multicenter collaboration and should explore therapeutics supported by molecular studies. [ABSTRACT FROM AUTHOR]

Abstract Background The pathogenesis of chronic active Epstein–Barr virus (EBV) disease (CAEBV) is complex, involving infection, inflammation, and in some cases malignancy. EBV reactivates in some patients, who develop a chronic disease with infectious mononucleosis-like symptoms. On occasion, it might be confused with autoimmune hepatitis (AIH), based on the similar symptoms and elevated liver enzymes. We aimed to describe a similar case to remind reader of this disease. Case Presentation : A 14-year-old girl was diagnosed with AIH based on biopsy and biomarker findings 1 year prior to admission and initially presented with elevated liver enzymes, portal hypertension, and parenchymal liver disease. Despite steroid administration, her condition fluctuated, and she was admitted to the hospital several times. She underwent a renal biopsy because of massive ascites, hypoalbuminemia, and increased renal echogenicity. An evaluation for impaired liver function showed positivity for EBV IgM, IgG, and early antigen (EBEA) antibodies. A PCR-based assay showed 5265 copies/mL of EBV DNA in peripheral blood. Epstein–Barr encoding region (EBER) in situ hybridization revealed abundant positive cells. Immunohistochemistry for CD56 also showed abundant positive cells, and CAEBV was diagnosed on this basis. Chemotherapy, hematopoietic stem cell transplantation (HSCT), and liver transplantation were proposed but her family refused. Conclusions CAEBV should be considered when diagnosing AIH or in cases of treatment-refractory AIH.

The aim of the publication. The case of abnormal elevation of alpha-fetoprotein (AFP) in a patient with autoimmune hepatitis (AIH) of the 1-st type is submitted.Features of clinical case. At a 17 years old female patient AIH of 1-st type debuted by jaundice, severe rise of transaminase activity and level of gamma-globulins. Manifestations of AIH, at first glance were typical, accompanied by over 200-fold elevation of serum concentration of AFP that required differential diagnostics with hepatocellular carcinoma. Achievement of immunosuppressor-induced remission resulted in normalization of AFP level.Conclusion. Derepression of respective gene may serve as the mechanism of serum AFP concentration increase at active hepatitis which, however, in absence of neoplastic proliferation is under control of certain regulatory factors. Over 200-fold elevation of AFP level in presented case, that rapidly decreased up to normal level under the influence of successful immune suppressive treatment, can be hard to explain from traditional point of view. Apparently, it is necessary to take into account specific features of AFP synthesis regulation, manifested at vast destruction of hepatic parenchyma.

Abstract Autoimmune hepatitis(AIH) is a chronic progressive inflammatory liver disease induced by loss of immune tolerance. The role of circulating metabolites in disease pathogenesis is unclear. This study aimed to investigate potential causal links between plasma metabolites and AIH risk by employing a two-sample Mendelian randomization approach. A comprehensive bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide significant variant-metabolite and variant-AIH associations in European ancestry individuals. Various methods assessed causal relationships among 1400 metabolites and AIH, incorporating sensitivity analyses to evaluate pleiotropy and heterogeneity. Fifty-eight metabolites displayed possible associations, including increased AIH risk with genetically predicted higher kynurenine (p = 2.79 × 10− 5, OR: 1.64, 95% CI 1.30–2.07) and a protective effect for the dopamine sulfate ratio (p = 1.06 × 10− 5,OR: 0.62, 95% CI 0.49–0.79). Reciprocal analysis revealed a causal effect of AIH on kynurenine( p = 2.79 × 10− 5, OR: 1.64, 95% CI 1.30–2.07), but not on the dopamine sulfate ratio(p = 0.691, OR: 1.05, 95% CI 0.67–1.64). Our genetics-based approach provides evidence supporting a causal role for specific metabolite levels in AIH risk. The results deliver evidence supporting a causal effect of a specific metabolite ratio(dopamine 4-sulfate/dopamine 3-O-sulfate) on AIH risk. Experimental validation and mechanistic examinations are warranted to confirm findings.

Posterior reversible encephalopathy syndrome (PRES) is a neurological disease characterized by a variety of neurological findings, in accordance with radiological characteristics. PRES is commonly secondary to elevated BP and/or conditions such as autoimmune patients receiving immunosuppressive drugs. Our case involves a 36-year-old female with a history of autoimmune hepatitis (AIH), who presented with sudden onset headaches from 3 weeks prior, and a single episode of seizure attack the morning before admission. In the initial examination she had highly elevated blood pressure (BP) (190/116). Her neurological examination revealed decline in force of limbs in addition to mild paresthesia. After primary stabilization, she underwent brain magnetic resonance imaging. Due to the clinical and radiological findings, the patient was diagnosed with PRES. In the following work-up of BP elevation, abdominopelvic sonography and subsequent computed tomography scan, multiple lesions were observed in spleen and both kidneys consistent with infarction. In further evaluation, Lupus-like anticoagulants were found to be elevated, which, in conjunction with the confirmed antiphospholipid syndrome (APS), suggested a possible role for APS-nephropathy as the missing link between PRES and APS. However, despite the role of an autoimmune disease in increasing the risk of developing other autoimmune conditions, APS and AIH have been rarely observed together. Our study indicates that developing APS in the context of AIH is a rare occurrence. However, APS could serve as a critical intermediary, potentially facilitating the onset of PRES despite lower BP.

In recent decades, there has been an increase in the incidence of autoimmune diseases (AID) among adults and children. The immunopathogenesis of AID is based on an imbalance between autoaggressive and regulatory cells (Tregs), which is regulated by metabolic signaling pathways and the cytokine microenvironment. Understanding the mechanisms of immunometabolism opens up new possibilities for the treatment of patients with AID. The aim was to evaluate the activity of lymphocyte dehydrogenases associated with OXPHOS and glycolysis, depending on the level of proinflammatory and anti-inflammatory cytokines in children with AID.324 children with AID were examined: 80 – Crohn’s disease (CD), 53 – ulcerative colitis (UC), 89 – psoriasis (PS), 66 – multiple sclerosis (MS), 36 – autoimmune hepatitis (AIH). Activity of mitochondrial dehydrogenases (succinate dehydrogenase (SDH) and glycerol-3-phosphate dehydrogenase (GFDH)) were evaluated by immunocytochemical method using flow cytometry. The level of cytokines (CС) in blood sera was determined by multiplex analysis.In each studied group of children, CС with the highest values in exacerbation and remission of the disease were identified. The maximum values of CС were in patients with exacerbation: CD, UC, PS, MS – IL-23; AIH – IL-27. Evaluation of cytokine complexes associated with cells showed significant differences between patients in exacerbation/remission: CD, UC and PS – M1(IL-1+IL-6+TNFα), cTh1(IFNγ+IL-12p70+TNFβ+IL-2), cTh2 (IL-4+IL-5+IL-10+IL-13+IL-17E/IL-25+IL-33), cTh17 (IL-1β+IL-6+IL-17A+IL-17F+IL-21+IL-22+IL-23); MS – M1, cTh1, cTh2; AIH – cTh2. SDH activity in AID remission differed between pathologies in CD4+ cells, Th17 and Tregs. In exacerbation of AID, there were differences in Tregs between patients with UC and PS. The highest GPDH activity in exacerbation was observed in CD4+ lymphocytes, Th17 and Tregs in CD. The ratio of SDH/GPDH in T-lymphocytes in children with CD in exacerbation and remission was lowest and significantly lower than in UC, PS, MS, AIH and apparently healthy children. In the group of children with a low SDH/GPDH ratio, the levels of CCL20/MIP3α, IFNγ, IL-12p70, IL-13, IL-17A, IL-1β, and TNFα were significantly increased. Conclusions. Informative cytokine complexes were identified in children with AID. The relationship between the metabolic activity of lymphocytes and the level of circulating cytokines is shown.

Mengyi Shen,1,&ast; Leyu Zhou,1,&ast; Xiaoli Fan,1 Ruiqi Wu,1 Shuyun Liu,2 Qiaoyu Deng,1 Yanyi Zheng,1 Jingping Liu,2 Li Yang1 1Department of Gastroenterology and Hepatology and Laboratory of Gastrointestinal Cancer and Liver Disease, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2NHC Key Laboratory of Transplant Engineering and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Yang; Jingping Liu, Email yangli_hx@scu.edu.cn; liujingping@scu.edu.cnBackground: Autoimmune hepatitis (AIH) is a serious liver disease characterized by immune disorders, particularly effector T-cell overactivation. This study aimed to explore the therapeutic effect and underlying mechanism of mesenchymal stem cell-derived extracellular vesicle (MSC-EV) treatment on CD4+ T-cell overactivation and liver injury in AIH.Methods: The metabolic changes of CD4+ T cells were assayed in human AIH and mouse hepatitis models. The liver protective effect of MSC-EVs was evaluated by transaminase levels, liver histopathology and inflammation. The effect of MSC-EVs on the metabolic state of CD4+ T cells was also explored.Results: Enhanced glycolysis (eg, ~1.5-fold increase in hexokinase 2 levels) was detected in the CD4+ T cells of AIH patient samples and mouse hepatitis models, whereas the inhibition of glycolysis decreased CD4+ T-cell activation (~1.8-fold decrease in CD69 levels) and AIH liver injury (~6-fold decrease in aminotransferase levels). MSC-EV treatment reduced CD4+ T-cell activation (~1.5-fold decrease in CD69 levels) and cytokine release (~5-fold decrease in IFN-γ levels) by reducing glycolysis (~3-fold decrease) while enhancing mitochondrial oxidative phosphorylation (~2-fold increase in maximal respiration) in such cells. The degree of liver damage in AIH mice was ameliorated after MSC-EV treatment (~5-fold decrease in aminotransferase levels). MSC-EVs carried abundant mitochondrial proteins and might transfer them to metabolically reprogram CD4+ T cells, whereas disrupting mitochondrial transfer impaired the therapeutic potency of MSC-EVs in activated CD4+ T cells.Conclusion: Disordered glucose metabolism promotes CD4+ T-cell activation and associated inflammatory liver injury in AIH models, which can be reversed by MSC-EV therapy, and this effect is at least partially dependent on EV-mediated mitochondrial protein transfer between cells. This study highlights that MSC-EV therapy may represent a new avenue for treating autoimmune diseases such as AIH.Keywords: autoimmune hepatitis, extracellular vesicles, metabolic reprogramming, mitochondria, inflammation

Autoimmune Hepatitis (AIH) is a rare autoimmune disease that damages the liver over time and, if left untreated, can progress to liver cirrhosis. Clinical manifestations range from asymptomatic patients to those with acute hepatitis or chronic liver failure. Chronic autoimmune liver disease causes persistent liver injury, which results in unresolved inflammation, proliferation of cells, and the formation of extracellular matrix proteins by stellate cells of the liver and portal myofibroblasts. Cirrhosis of the liver and the resulting loss of normal liver function are unavoidable. Cirrhotic patients have a higher risk of morbidity and mortality, and problems of portal hypertension and/or liver dysfunction result in substantial deterioration in the decompensated phase. The theory suggests that among idiopathic or cryptogenic chronic hepatitis, most of them are autoimmune in origin. It is considered one of the rare liver diseases, especially in the Indian population. Portal hypertension is a dangerous complication caused by an obstruction in portal blood flow, such as cirrhosis or portal vein thrombosis. Hepatic Haemangiomas (HH) are benign liver tumours that are made up of groups of blood-filled cavities lined by endothelial cells and fed by the hepatic artery. The vast majority of HH are asymptomatic and are discovered by chance during imaging studies for unrelated pathologies. Hereby, the authors present a case of 53-year-old female with chronic liver disease with ascites, fatty change, and nodular hepatocellular hyperplasia, which was later found to be cirrhosis of autoimmune origin.

Autoimmune hepatitis (AIH) is a chronic, inflammatory liver disease of unknown aetiology which requires lifelong immunosuppression. Most therapeutic and outcome studies of aih have been conducted predominantly in caucasian (European Ancestry, EA) cohorts, with the exclusion of African American (AA) patients due to inadequate sample size. It is known that aa patients have a severe phenotype of autoimmune diseases and demonstrate a poor response to conventional medical therapy. Understanding cellular and molecular pathways which determine AIH severity and progression in aa patients is likely to lead to the discovery of novel, personalised and better tolerated therapies. the aim of the study is to determine the distinct effector B cell phenotypes which contribute to disease severity and progression of aih in AA children as compared to their ea cohorts. PBMcs were isolated from blood samples collected from patients visiting children's healthcare of atlanta (CHOA) and were grouped into AA, (n = 12), EA, (n = 11) and controls (n = 12) and were processed for flow cytometry. Markers of B cell development, maturation and activation were assessed namely CD19, CD21, IgD, CD27, CD38, CD11C, CD24, CD138. aa children with AIH demonstrated an expansion of CD19+ ve, activated Naïve (aN), (CD19+ IgD-/CD27-Double Negative (DN2) ([CD19+/IgD-/CD27++CD38++) cells. Plasmablasts were significantly higher along with signalling lymphocytic activation molecule F7 (SLAMF7). Unswitched memory [CD19+] IgD+CD27+ (USM) B cells were significantly contracted in AA patients with AIH. B cell phenotyping reveals a distinct profile in AA AIH patients with a major skewing towards the expansion of effector pathways which have been previously characterised in severe sle in aa patients. these results suggest that the quantification and therapeutic target of B cell pathway could contribute substantially to the clinical approach to AIH especially in the AA population. [ABSTRACT FROM AUTHOR]

Yinchenhao Decoction (YCHD) is a classic prescription in traditional chinese medicine (TCM). It appears to play an important role in anti-inflammation and autoimmunity protection. As one of the key active ingredients in YCHD, quercetin is a novel anti-inflammatory metabolite that exerts protective effects in many autoimmune diseases. However, its role in autoimmune hepatitis (AIH)-related hepatic injury has not been studied. the aim of this study was to reveal the hepatocyte protective mechanism of quercetin. in this study, we used concanavalin a (Con A) to establish an in vitro hepatocyte injury-associated aih model. Brl3a hepatocyte injury was induced by the supernatant of J774a.1 cells treated with Con A. We found that quercetin mitigated con a-induced via macrophage-mediated Brl3a hepatocyte injury. Quercetin administration reduced the levels of alanine transaminase (ALT) and aspartate transaminase (AST) in the supernatant of Con A-treated Brl3a cells and attenuated the infiltration of J774A.1 macrophages induced by Con A. Moreover, quercetin effectively inhibited the expression of proinflammatory cytokines including interleukin-1β (IL-1β) by Con A. Furthermore, quercetin decreased hepatocyte apoptosis and ferroptosis levels in the macrophage-induced hepatocyte injury model. in conclusion, our study indicates that quercetin alleviates macrophage-induced hepatocyte damage by reducing the inflammatory response, apoptosis and ferroptosis. Our work suggests that quercetin might be a potential therapeutic strategy for AIH. [ABSTRACT FROM AUTHOR]

Autoimmune liver diseases are rare serious diseases causing chronic inflammation and fibrosis in the liver parenchyma and bile ducts. Yet, the prevalence and burden of autoimmune liver diseases are largely unexplored in Arctic native populations. We investigated the prevalence and management of autoimmune liver diseases in Greenland using nationwide cross-sectional register data and subsequent medical chart reviews validating diagnoses and extracting liver histology examinations and medical treatments. The overall prevalence of autoimmune liver diseases in Greenland was 24.6 per 100,000 (95% CI: 14.7-41.3). This was based on 7 patients with autoimmune hepatitis (AIH) (12.3 per 100,000), 3 patients with primary biliary cholangitis (PBC) (5.3 per 100,000), 4 patients with AIH/PBC overlap disease (7.0 per 100,000), and no patients with primary sclerosing cholangitis. All diagnoses were confirmed by liver histology examinations. Medical treatments adhered to internal recommendations and induced complete remission in most patients with AIH, and complete or partial remission in 1 patient with PBC and 3 patients with AIH/PBC overlap disease. One patient had established cirrhosis at the time of diagnosis, while 2 patients progressed to cirrhosis. In conclusion, the prevalence of autoimmune liver diseases was lower in Greenland than in Scandinavia and among Alaska Inuit. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect any organ system in the body. It may also be complicated by other autoimmune diseases. This case report describes a patient who presented with massive splenomegaly on a background of clinical features of SLE. Splenomegaly in SLE however, is not common. The patient was evaluated further for haematological complications and liver involvement. She was diagnosed to have SLE-Autoimmune hepatitis overlap. SLE-AIH overlap syndrome is rare, but specific diagnosis is important because it influences the choice of immune-suppressants as well as long-term outcome. Liver biopsy helps clinch the diagnosis and should be encourage early in the diagnostic plan. It is also important to differentiate between the various causes of liver involvement in SLE.

The IgG4-associated autoimmune hepatitis (IgG4-AIH) is a newly proposed disease entity characterised by the accumulation of the IgG4-expressing plasma cells in the liver. Its pathophysiology and clinical significance remain unclear and have poor evidence in the paediatric population. Thus, our study aims at comparing the group of paediatric patients with classical AIH and the IgG4-AIH. We carried out a retrospective analysis of 23 children (median age 8.5 years) diagnosed with AIH, who were compared according to the presence of IgG4-positive plasma cells in the liver biopsy. IgG4-AIH was defined if 10 or more IgG4 positive plasma cells/high-power field were found in the biopsy. The presence of the IgG4 component seems to be clinically insignificant. That is why, the conventional immunosuppressive protocol should be considered the standard treatment in the case of the IgG4-associated AIH.

Background and Objectives: Juvenile autoimmune hepatitis (AIH) is an inflammatory, immune-mediated liver disease that affects individuals from infancy to adolescence. The clinical presentation of AIH can mimic other hepatic disorders, such as viral hepatitis, toxic hepatitis, and Wilson's disease, often manifesting with symptoms like fatigue, nausea, vomiting, jaundice, fever, and pruritus.Case Presentation: A 16-year-old male with a history of congenital ichthyosis, xerosis cutis, mild intermittent asthma, and environmental allergic rhinitis presented to the clinic with upper respiratory symptoms. Upon examination, the patient was found to be jaundiced, prompting an urgent referral for further evaluation. This led to a diagnosis of autoimmune hepatitis and inflammatory bowel disease.Discussion: Juvenile autoimmune hepatitis is a rare but serious inflammatory liver disorder that primarily affects infants and adolescents. Due to its similarities with various other liver diseases, differential diagnosis can be quite challenging. Overall, the prognosis for our patient appears to be positive.

Abstract Aims Although useful for distinguishing drug‐induced liver injury (DILI) from autoimmune hepatitis (AIH), liver biopsy is an invasive examination, and the presence of antinuclear antibody (ANA) positivity in patients with DILI could lead to excessive use of biopsy. Hence, we aimed to identify screening markers for histological features of AIH in patients with ANA‐positive DILI and verify their clinical outcomes after 1 year. Methods This retrospective study included patients with ANA‐positive DILI, who underwent liver biopsy between January 2017 and April 2022. Two pathologists identified histological features of AIH. We detected the independent indicators associated with histological features of AIH using logistic regression. We evaluated their diagnostic ability for histological features of AIH using the receiver operating characteristic curve. The follow‐up period to determine clinical outcomes was 1 year after DILI onset. The χ2 test or Fisher's exact test was used to compare categorical data and the Wilcoxon rank‐sum test was used to compare continuous variables. Two‐sided p

Post-transplantation primary central nervous system lymphoma (PT-PCNSL) is a rare neoplasm that occurs in immunocompromised patients. It can manifest months or years after transplantation, presenting with various neurological symptoms. A 64-year-old woman, who had received a liver transplant due to autoimmune hepatitis, presented with generalized weakness, headache, and confusion. Further investigation revealed multiple ring-enhancing lesions in the right frontal and temporoparietal regions on brain MRI. A brain biopsy confirmed the diagnosis of PT-PCNSL. This case underscores the importance of considering PT-PCNSL in the differential diagnosis of contrast-enhancing brain lesions in post-transplant patients. Timely recognition of PT-PCNSL is crucial for appropriate management and improved outcomes. To the best of our knowledge, this report describes the first instance of isolated CNS lymphoma in a liver transplant recipient, due to autoimmune hepatitis, successfully brought to complete remission with a rituximab-methotrexate regimen. [ABSTRACT FROM AUTHOR]