Emerging evidence suggests that the oral-gut-liver axis may play a role in the immunopathogenesis of autoimmune liver diseases (AILDs), particularly autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). Alterations in the oral microbiota may influence hepatic immune responses; however, this relationship remains poorly defined. This systematic review aimed to evaluate current evidence on the association between oral microbiota dysbiosis and AILDs, with a focus on microbial alterations, inflammatory profiles, and potential diagnostic implications. A systematic search of PubMed, Web of Science, and Scopus was conducted up to January 2026 in accordance with PRISMA guidelines. Eligible studies investigated oral microbiota composition in patients with AILDs compared with healthy controls. Data extraction was performed independently, and study quality was assessed using the Newcastle-Ottawa Scale (NOS). Six studies published between 2015 and 2021 met the inclusion criteria, comprising 252 patients with AILDs and 345 healthy controls. All included studies reported significant oral microbiota dysbiosis in AILD patients. The most consistent findings were an increased abundance of Veillonella in AILDs and Eubacterium in the PBC subgroup, along with a reduced presence of Streptococcus and Fusobacterium. These microbial alterations were associated with elevated salivary inflammatory markers, and showed correlations with disease activity. Some studies also suggested interactions between oral and gut microbiota, potentially mediated by increased intestinal permeability and bacterial translocation. Current evidence supports an association between oral microbiota dysbiosis and inflammatory mechanisms. Although causality cannot be established, the oral-gut-liver axis may represent a promising source of biomarkers and therapeutic targets.

A 62-year-old woman with Sjögren syndrome, rheumatoid arthritis, and autoimmune hepatitis presented with subacute confusion and generalized seizures. MRI revealed bilateral mesial temporal T2/FLAIR hyperintensity. Serology revealed anti-SSA and anti-SSB antibodies elevated at 5 times above the upper limit of normal. FDG-PET demonstrated marked relative mesial temporal hypermetabolism with widespread hypometabolism in the rest of the brain; z-score mapping confirmed focal mesial temporal hyperactivity. They received immunotherapy and antiseizure therapy. After 1 year, cognition improved, though memory deficits persisted. Follow-up FDG-PET showed a transition from mesial temporal hypermetabolism to relative hypometabolism, with recovery of cortical metabolism, highlighting FDG-PET's role in diagnosing and monitoring autoimmune limbic encephalitis in Sjögren syndrome.

In vivo CAR-Tfh cell reprogramming restores tolerance in a mouse model of autoimmune hepatitis.

Autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH), pose significant diagnostic and therapeutic challenges due to poorly understood mechanisms. While most studies focus on absolute protein levels, protein-protein ratios (PPRs), reflecting the relative abundance of paired plasma proteins, emerge as critical yet understudied biomarkers for decoding disease-specific network perturbations. To harness this potential, we integrated protein quantitative trait loci (pQTLs), ratio QTLs (rQTLs), and mediation Mendelian randomization (MR) to map causal proteomic networks, aiming to unravel pathogenic networks and identify therapeutic targets in AILDs. Using two-sample MR, we analyzed 2821 plasma PPRs and 2923 individual proteins from the UK Biobank Pharma Proteomics Project. The primary analysis employed the inverse-variance weighted (IVW) method, complemented by MR-Egger regression, weighted median, simple mode, and weighted mode methods, all within a random-effects model. Sensitivity analyses were performed to validate the findings, including Cochran's Q test, MR-Egger intercept analysis, MR-PRESSO, and Steiger filtering. Cross-trait linkage disequilibrium score regression (LDSC) quantified genetic correlations, while the MR approach based on Bayesian model averaging (MR-BMA) prioritized independent causal PPRs. Two-step mediation MR identified mechanistic pathways. Functional enrichment and protein-protein interaction (PPI) networks were constructed using STRING and the clusterProfiler package. Finally, we investigated the associations between the causal PPRs and AILD-related symptoms/complications, as well as the influence of modifiable lifestyle factors on these PPRs. CD74 exhibited dual roles in AILDs. Elevated plasma CD74 levels were associated with an increased risk of PSC (OR = 1.54, 95% CI 1.24-1.90), whereas CD74-PPRs exhibited robust protection. Specifically, CD74/JAM2 reduced risks of PSC (OR = 0.70, 95% CI 0.59-0.83) and AIH (OR = 0.53, 95% CI 0.39-0.71), while CD74/NPDC1 conferred protection against PSC (OR = 0.66, 95% CI 0.54-0.80). Mediation MR identified TRY3 as the dominant mediator of CD74/JAM2 in AIH (91.52% proportion mediated, P = 0.017), with GREM1 and TEK mediating CD74/NPDC1 effects in PSC. PPI networks implicated interactions among CD74, amyloid precursor protein (APP), and endoglin (ENG). Notably, CD74/JAM2 demonstrated cross-disease relevance, significantly lowering PSC-associated ulcerative colitis risk (OR = 0.35, 95% CI 0.22-0.54). This study pioneers the integration of pQTLs, rQTLs, and mediation MR to map dynamic proteomic interactions in AILDs. Our findings revealed the multifaceted impact of CD74 on AILDs: its direct elevation may promote disease, whereas its protein interactions appear to mitigate risk. These results advance understanding of AILD pathogenesis and pave the way for developing novel biomarkers and targeted therapies.

Abstract Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) may coexist as an overlap syndrome, which can be challenging to diagnose and manage. In this case report, we describe a patient with AIH–PBC overlap syndrome refractory to conventional immunosuppressive therapy and with steroid-dependent disease. Rituximab was administered as rescue therapy, achieving biochemical normalization. This case supports the potential role of rituximab as a therapeutic option in patients refractory to standard immunosuppressive treatments.

Carbimazole, a widely used thionamide, is usually well tolerated but can rarely cause severe cholestatic hepatitis. We report a 43-year-old woman on carbimazole for newly diagnosed hyperthyroidism two months back, who presented with a history of fever for 12 days, associated with abdominal pain, pruritus, dark urine, and jaundice. Examination showed features of thyrotoxicosis with cholestatic jaundice. Investigations revealed marked hyperbilirubinaemia with raised alkaline phosphatase and gamma-glutamyl transferase, and persistently high free T4/T3 levels. Imaging excluded biliary obstruction. Screening for viral and autoimmune hepatitis was negative. Carbimazole was discontinued immediately. The patient received propranolol, ursodeoxycholic acid, lithium carbonate, intravenous hydrocortisone, and supportive care. Three therapeutic plasma-exchange sessions were performed, which led to clinical and biochemical improvement. She was commenced on levothyroxine following total thyroidectomy. Follow-up confirmed complete resolution of jaundice and normalisation of liver function. This case highlights that early recognition of carbimazole-induced liver injury is crucial, and plasma exchange can be an effective bridge to definitive treatment.

Gut microbiota dysbiosis plays a significant role in the pathogenesis of immune-mediated liver diseases (IMLDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), through multiple gut-liver axis mechanisms. Microbial metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids regulate hepatic immune homeostasis by activating G protein-coupled receptors (GPRs) and the farnesoid X receptor (FXR). Concurrently, disruption of the intestinal barrier integrity allows endotoxins (e.g., lipopolysaccharide) to activate hepatic macrophages via the TLR4/NF-κB pathway, triggering a pro-inflammatory cytokine cascade. Studies indicate an enrichment of Veillonella in AIH patients, while PBC patients display elevated Enterobacteriaceae and reduced Oscillospira spp. PSC is characterized by Klebsiella pneumoniae translocation and Candida albicans toxin-mediated injury. Therapeutic strategies such as fecal microbiota transplantation (FMT), probiotics, prebiotics, and bacteriophages therapy have shown efficacy in clinical settings, underscoring the potential of targeting the gut microbiota for managing IMLDs. Future research should integrate immune cell regulation by gut-derived factors and develop precision therapies based on the gut-liver axis.

The distinction of drug-induced liver injury (DILI), drug-induced autoimmune-like hepatitis (DI-ALH), and autoimmune hepatitis (AIH) can be challenging due to overlapping clinical characteristics. Recently, polyreactive immunoglobulin G (pIgG) was identified as a novel biomarker in AIH. This retrospective study aimed to evaluate the diagnostic accuracy of pIgG to distinguish between AIH, DI-ALH, and DILI and thus identify patients in need of immunosuppression. Samples from 120 patients (AIH = 81, DI-ALH = 16, DILI = 23) were compared to a control group (non-AIH-non-DILI-liver disease = 596 and healthy controls = 190). No patient in the DILI-group but 98% in the AIH- and 94% in the DI-ALH-group received immunosuppressive treatment. PIgG levels were significantly higher in the AIH-group 1.9 normalised arbitrary units (nAU) compared to DILI (1.1 nAU, p < 0.001), non-AIH-non-DILI-LD (1.0 nAU, p < 0.001) and healthy controls (0.27 nAU, p < 0.001). PIgG levels for DI-ALH (1.7nAU) were significantly higher compared to DILI (p = 0.044) and non-AIH-non-DILI-LD and healthy controls (both p < 0.001). Highest AUC was seen for pIgG (0.818) compared to conventional autoantibodies. The overall accuracy of pIgG to distinguish AIH from DILI (74%) and liver injuries with and without the need for immunosuppression (73%) was like that of ANA (71%/73%) and SMA (74%/69%) at cut-offs of ≥ 1/40. PIgG was positive in up to 79% of patients with AIH that were negative for a conventional autoantibody and was positive in 90% of DI-ALH cases compared to 25% in DILI that were caused by the same drugs. PIgG may complement current serologic tests to identify patients with liver injury in need of immunosuppressive treatment.

Can liver biopsy be spared for the diagnosis of autoimmune hepatitis in selected children? A multicenter retrospective study.

ABSTRACT Background Vancomycin‐resistant Enterococcus (VRE) infection is a life‐threatening complication after liver transplantation (LT). This study aimed to identify risk factors and develop a predictive score for post‐transplant VRE infection in LT recipients. Methods We conducted a single‐center, retrospective cohort study including all adult patients who underwent LT between 2010 and 2022. Patients were followed from 90 days before to 180 days after LT. The primary endpoint was time to the first VRE infection after LT, with death before infection treated as a competing event. We applied a stacked landmarking approach at weekly intervals during the first post‐transplant month, incorporating post‐LT VRE colonization as a time‐dependent covariate in Fine–Gray models. Random forests were used as machine‐learning comparators. Model discrimination was assessed by the AUC‐ROC, and sensitivity, specificity, and accuracy were calculated at thresholds determined by Youden's index. Results Among 1209 LT recipients, 76 (6.3%) developed VRE infection, most commonly intra‐abdominal (58.4%). Time‐updated post‐LT VRE colonization was the strongest predictor (HR 7.59). Additional risk factors included intraoperative bleeding (HR 4.06), early re‐transplantation (HR 3.85), pre‐LT VRE colonization (HR 3.20), renal replacement therapy (HR 2.01), and intensive care unit length of stay (HR 1.01/day). Viral hepatitis (HR 0.55), autoimmune hepatitis (HR 0.34), higher Charlson Comorbidity Index (HR 0.84), and deceased donors (HR 0.24) were associated with a lower risk of VRE infection. The final model showed good discrimination (AUROC = 0.76–0.85) with balanced sensitivity (75%–93%) and specificity (75%–86%).

Background: Pediatric liver diseases encompass a broad spectrum of disorders with diverse etiologies, clinical presentations, and outcomes. Histopathological examination of liver biopsy specimens plays a crucial role in establishing the diagnosis, determining disease severity, and guiding clinical management. The present study was undertaken to evaluate the morphological spectrum of pediatric liver diseases encountered in a tertiary care institution. Material and Methods: This retrospective descriptive study was conducted in the Department of Pathology of a tertiary care teaching hospital. A total of 112 liver biopsy specimens obtained from pediatric patients aged ≤18 years were included in the study. Relevant clinical details and laboratory data were collected from medical records. Biopsy specimens were fixed in 10% neutral buffered formalin, processed routinely, and stained with hematoxylin and eosin. Special stains were applied when indicated. Histopathological evaluation was performed to determine the morphological diagnosis and to assess the degree of hepatic fibrosis. Data were analyzed using descriptive statistics and presented as frequencies and percentages. Results: Among the 112 cases, the majority of patients were in the 1–5 years age group (32.1%), followed by children younger than 1 year (25.0%). Males constituted 57.1% of the study population. The most common clinical indication for liver biopsy was persistent jaundice (33.9%), followed by hepatomegaly or hepatosplenomegaly (25.0%). Histopathological evaluation revealed neonatal hepatitis (23.2%) as the most frequent diagnosis, followed by biliary atresia (16.1%) and glycogen storage disease (12.5%). Non-alcoholic fatty liver disease (10.7%), autoimmune hepatitis (8.9%), and chronic hepatitis (8.9%) were also observed. When categorized broadly, cholestatic disorders accounted for 39.3%, followed by metabolic liver diseases (25.0%) and inflammatory liver diseases (17.9%). Evaluation of fibrosis demonstrated no fibrosis in 35.7%, mild fibrosis in 28.6%, moderate fibrosis in 21.4%, and advanced fibrosis or cirrhosis in 14.3% of cases. Conclusion: Pediatric liver diseases show considerable histopathological diversity, with cholestatic and metabolic disorders being the most prevalent. Liver biopsy remains an essential diagnostic modality for accurate disease characterization and assessment of hepatic fibrosis in pediatric patients.

Autoimmune hepatitis (AIH) is a severe, chronic disease where IgG elevation and autoantibody profile are defining features. However, linking autoantibodies to AIH pathogenesis remains elusive. We employed phage-display immunoprecipitation sequencing and uncovered a novel humoral signature specific to AIH. Embedded within this signature were antibodies against the known AIH autoantigen SLA/LP and novel reactivities to disco-interacting protein 2 homolog A (DIP2A), and the relaxin family peptide receptor 1 (RXFP1). Fine mapping of the DIP2A epitope revealed preferential enrichment for a nearly identical 9-amino acid sequence derived from the U27 protein of human herpesvirus 6 (HHV6). Preincubation with the HHV6 epitope blocked DIP2A binding, consistent with cross-reactivity. AIH patients positive for anti-DIP2A had higher titers of HHV6 IgG, suggestive of reactivation. AIH patients had antibodies against the antifibrotic receptor, RXFP1, which inhibited relaxin-2 signaling in an IgG-dependent manner. These data provide evidence for a novel serological profile in AIH, linking HHV6 reactivation anti-RXFP1 antibodies to disease pathogenesis.

Background/Objectives: Autoimmune hepatitis (AIH) often coexists with extrahepatic autoimmune diseases (EADs); however, the clinical significance of EAD comorbidity and its subtypes remains incompletely understood. In addition, an increasing proportion of AIH without EAD (NEAD-AIH) has been suggested but not systematically evaluated. Methods: We retrospectively analyzed 46 patients diagnosed with AIH between 2014 and 2023. Clinical features were compared between EAD-associated AIH (EAD-AIH) and NEAD-AIH. Analyses were performed focusing on major EAD subtypes, including Sjögren’s syndrome (SS), autoimmune thyroid disease (AITD), and systemic sclerosis (SSc). Steroid-treated cases were further evaluated for treatment response and renal outcomes. Results: Among the 46 patients (median age, 63 years; 89% female), 61% had concomitant EADs. Compared with EAD-AIH, NEAD-AIH showed significantly higher AST, ALT, IgG, and bilirubin levels, together with lower albumin and prothrombin activity. Acute-onset hepatitis and corticosteroid use were more frequent in NEAD-AIH, and all cases of liver failure occurred in this group. The proportion of NEAD-AIH increased over time (from 21% to 54%). A small number of recent NEAD-AIH cases occurred after COVID-19 vaccination or immune checkpoint inhibitor therapy, although causality could not be established. Among EAD subtypes, SSc-AIH was characterized by relatively low IgG levels, whereas SS-AIH showed favorable biochemical profiles with low relapse rates. No excess renal deterioration was observed in SSc-AIH after steroid therapy. Conclusions: AIH exhibits substantial clinical heterogeneity according to EAD status and subtype. NEAD-AIH tends to present with a more acute and severe phenotype and appears to be increasing, whereas EAD-AIH shows distinct immunologic characteristics. These findings underscore the importance of considering autoimmune background in the clinical evaluation of AIH.

Mast cells (MCs) are multifunctional innate immune cells that regulate inflammation, tissue repair, and immune responses, and they are increasingly recognized as contributors to chronic liver disease. In parallel, the aryl hydrocarbon receptor (AhR) has emerged as a key environmental sensor activated by gut-derived tryptophan metabolites such as kynurenine and microbial indoles. The current literature separately describes the role of AhR in MC signaling, as well as the contributions of MCs to liver pathology and the disrupted gut-liver axis, which drives immune dysfunction in chronic liver disease. However, these aspects have been rarely considered together. This review aims to bridge these fragmented areas, providing an integrated framework where AhR-driven MC responses are examined within the gut-liver axis along with their impacts on liver inflammation and fibrosis. We discuss how this microbial-immune dialogue shapes autoimmune and cholestatic liver diseases, including autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cholangitis. Finally, we highlight translational perspectives, from microbiota modulation to AhR-targeting approaches, as potential strategies to control MC-driven hepatic inflammation. By integrating these currently separate concepts, this review offers a novel perspective on the role of MCs as important mediators at the interface of gut-derived signals and liver pathology via AhR signaling, while highlighting innovative therapeutic avenues through the modulation of the microbiota, targeting of AhR, and regulation of MC responses.

Autoimmune hepatitis (AIH) involves chronic liver injury from abnormal immune responses, leading to hepatocyte death and inflammation. Currently, the role of pyroptosis in AIH has not been fully elucidated. Emerging evidence indicates that Nlrp12, a cytosolic sensor of damage-associated molecular patterns (DAMPs), participates in inflammasome assembly and pyroptotic signalling. Therefore, this study aims to investigate the role of Nlrp12 in AIH. Using a concanavalin A (ConA)-induced AIH mouse model, we observed that ConA challenge significantly upregulated Nlrp12 expression in liver tissues. Genetic ablation of Nlrp12 improved survival rates, lowered serum aminotransferase levels, reduced pro-inflammatory cytokine production, and ameliorated histological liver damage. Further studies revealed that Nlrp12 drives the assembly of PANoptosomes (including ASC, RIPK3, and Caspase-8), promoting the release of PANoptosis-related proteins and inflammatory factors. The RIPK3 inhibitor GSK-872 blocked PANoptosome formation, mitigating liver injury and inflammation. These findings unveil a previously unrecognized role for Nlrp12 in aggravating immune-mediated liver injury via PANoptosis activation, highlighting the Nlrp12-PANoptosis axis as a promising therapeutic target for AIH.

Autoimmune hepatitis (AIH) is a long-lasting liver ailment. It causes hepatocellular necrosis and inflammation, leading to fibrosis. It can develop into cirrhosis and liver failure. The disease predominantly affects young to middle-aged women more than men. AIH flares up during gestation and is linked with a high rate of embryonic and maternal problems. With maternal and antenatal care becoming advanced, this disorder should be identified and managed for successful maternal and embryonic outcomes. We present a case report of a primigravida diagnosed with AIH at 14 weeks antenatally. Our main aim in reporting this case is to create general awareness for healthcare professionals and thereby for patients and caregivers about this condition in pregnancy.

The incidence of pancreatic cancer (PC) and autoimmune diseases (ADs) has been increasing worldwide. While certain associations between specific ADs, such as pancreatitis, and PC have long been well confirmed, population-focused research investigating the broader spectrum of ADs and their relationship with PC risk remains limited. We implemented a cohort study based on population data to analyze the relationships between ADs and PC susceptibility. Diagnostic information on 43 ADs was obtained from the Swedish Inpatient Register (1964-2018), while cancer incidence and mortality data were sourced from the National Cancer Registry and Cause of Death Register starting in 1997. Relative cancer risks were quantified using standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs). Within the study's total population of 16.4 million, 1.1 million cases of ADs were identified, and 3257 patients were later diagnosed with PC accounting for 5.42% of all cancer cases in the cohort. The SIRs for PC in patients with ADs were 1.24 (men) and 1.19 (women); 12 ADs were positively correlated with the incidence of PC. The SMRs for PC in patients with ADs were 1.28 (men) and 1.22 (women); 15 ADs were positively correlated with PC mortality. When the follow-up time was less than 1 year, the overall risk of PC in patients with ADs was 3.88; over 10 years, the risk reached 1.12. We have newly discovered the relationship between several ADs and the risk of PC incidence and mortality, including discoid lupus erythematosus, lupoid hepatitis, giant-cell arteritis, and rheumatic fever. The results of this study back the notion that ADs may have a role in promoting the onset of PC.

It has been reported that high-altitude adaptation (HAA) and susceptibility to multiple liver diseases/traits differ between individuals at higher altitudes compared to those at lower altitudes. To investigate this association, we conducted a Mendelian randomization study. To investigate the association between HAA and liver diseases/traits, we utilized genome-wide association studies focusing on East Asian ancestry. Our study included six liver disease-related phenotypes: autoimmune hepatitis, chronic hepatitis B, chronic hepatitis C, acute hepatitis by hepatitis A virus, hepatic cancer, and hepatic bile duct cancer, as well as five liver traits: alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase (GGT), and total bilirubin. A Bonferroni-corrected significance was set at p < 4.55 × 10-3. Our study identified a significant genetically predicted causal impact of HAA on GGT (odds ratio [OR] = 1.601; 95% confidence interval [CI] = 1.204-2.129; p = 0.0012). Interestingly, the association remained statistically significant even when the causal direction was reversed, with GGT predicting HAA (OR = 1.01; 95% CI = 1.003-1.011; p = 0.0013). Both findings surpassed the Bonferroni-corrected threshold. In conclusion, our study provides suggestive evidence for a potentially causal bidirectional association between HAA and GGT. These novel insights may inform the development of targeted preventive measures and therapeutic interventions for liver diseases and high-altitude adaptation.

Actin-specific smooth muscle antibodies bridge adult and juvenile autoimmune hepatitis diagnosis

The gut-liver axis is believed to be crucial in the pathogenesis of primary sclerosing cholangitis (PSC). However, the impact of colectomy on liver disease progression is unclear. Our study estimated the effect of colectomy on PSC progression with correction for time dependency and established risk factors by pooling data from several cohorts across different countries. We analysed data from the International PSC Registry (IPSCR), comprising patients from Finland, The Netherlands, Norway, and Sweden. Primary endpoint was defined as liver transplantation (LT) or PSC-related death. Cox proportional hazards regression onto time-dependent colectomy status, with specification for extent, was performed with adjustment for sex, age at diagnosis, large or small duct PSC, features of autoimmune hepatitis, time-dependent inflammatory bowel disease (IBD) status, centre of inclusion, and country of residence. A total of 3,110 participants were included, of whom 470 (15%) had undergone colectomy. During a total follow-up of 32,236 patient-years, 395 deaths and 653 LTs were observed. Compared with patients with PSC with intact colon, the hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy with permanent ileostomy (HR 0.41; 95% CI 0.24-0.71). This effect was less pronounced in case of hemi- or subtotal colectomy (HR 0.81; 95% CI: 0.58-1.12) and not observed for proctocolectomy with pouch (HR 1.00; 95% CI: 0.73-1.38). The reduced risk was mainly associated with a lower rate of LT or death resulting from liver failure (HR 0.24; 0.10-0.53). Proctocolectomy with permanent ileostomy was associated with decreased risk for LT and PSC-related death. These findings support the role of the gut-liver axis in the pathophysiology of PSC and call for consideration in counselling patients who face impending colorectal surgery. The impact of the gut-liver axis in the pathophysiology of primary sclerosing cholangitis (PSC) has remained uncertain. In this study, proctocolectomy with ileostomy was associated with improved transplant-free survival, defined as a reduced risk of liver transplantation or PSC-related death, indicating that intestinal factors may influence disease progression. These findings are important for clinicians, researchers, and patients as they suggest that surgical management of colonic disease may have prognostic implications in PSC, and for further studies to clarify mechanisms and guide clinical decision-making.