Primary biliary cholangitis.

Primary biliary cholangitis is a chronic, autoimmune, cholestatic disease that mainly affects women aged 40-70 years. Recent epidemiological studies have shown an increasing incidence worldwide despite geographical heterogeneity and a decrease in the female-to-male ratio of those the disease affects. Similar to other autoimmune diseases, primary biliary cholangitis occurs in genetically predisposed individuals upon exposure to environmental triggers, specifically xenobiotics, smoking, and the gut microbiome. Notably, the diversity of the intestinal microbiome is diminished in individuals with primary biliary cholangitis. The intricate interplay among immune cells, cytokines, chemokines, and biliary epithelial cells is postulated as the underlying pathogenic mechanism involved in the development and progression of primary biliary cholangitis, and extensive research has been dedicated to comprehending these complex interactions. Following the official approval of obeticholic acid as second-line treatment for patients with an incomplete response or intolerance to ursodeoxycholic acid, clinical trials have indicated that peroxisome proliferator activator receptor agonists are promising additional second-line drugs. Future dual or triple drug regimens might reach a new treatment goal of normalisation of alkaline phosphatase levels, rather than a decrease to less than 1·67 times the upper limit of normal levels, and potentially improve long-term outcomes. Improvement of health-related quality of life with better recognition and care of subjective symptoms, such as pruritus and fatigue, is also an important treatment goal. Promising clinical investigations are underway to alleviate these symptoms. Efforts to facilitate better access to medical care and dissemination of current knowledge should enable diagnosis at an earlier stage of primary biliary cholangitis and ensure access to treatments based on risk stratification for all patients.

Exploring predictive markers for liver failure post-hepatectomy in hepatocellular carcinoma patients.

This letter to the editor addresses the study titled "Predictive value of NLR, Fib4, and APRI in the occurrence of liver failure after hepatectomy in patients with hepatocellular carcinoma" by Kuang et al in the World Journal of Gastrointestinal Surgery. The study acknowledges the comprehensive patient data analysis while suggesting that there is a need for further discussion on the clinical applicability of these markers across diverse patient populations. This letter recommends prospective studies for validation and considers the influence of confounding factors. This finding underscores the significance of this study in improving hepatocellular carcinoma management.

FGF4 protects the liver from immune-mediated injury by activating CaMKKß-PINK1 signal pathway to inhibit hepatocellular apoptosis.

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine; however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca2+/calmodulin-dependent protein kinasekinase 2 (CaMKKß) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

Interaction between systemic iron parameters and left ventricular structure and function in the preserved ejection fraction population: a two-sample bidirectional Mendelian randomization study.

BACKGROUND: Left ventricular (LV) remodeling and diastolic function in people with heart failure (HF) are correlated with iron status; however, the causality is uncertain. This Mendelian randomization (MR) study investigated the bidirectional causal relationship between systemic iron parameters and LV structure and function in a preserved ejection fraction population. METHODS: Transferrin saturation (TSAT), total iron binding capacity (TIBC), and serum iron and ferritin levels were extracted as instrumental variables for iron parameters from meta-analyses of public genome-wide association studies. Individuals without myocardial infarction history, HF, or LV ejection fraction (LVEF) < 50% (n = 16,923) in the UK Biobank Cardiovascular Magnetic Resonance Imaging Study constituted the outcome dataset. The dataset included LV end-diastolic volume, LV end-systolic volume, LV mass (LVM), and LVM-to-end-diastolic volume ratio (LVMVR). We used a two-sample bidirectional MR study with inverse variance weighting (IVW) as the primary analysis method and estimation methods using different algorithms to improve the robustness of the results. RESULTS: In the IVW analysis, one standard deviation (SD) increased in TSAT significantly correlated with decreased LVMVR (ß = -0.1365; 95% confidence interval [CI]: -0.2092 to -0.0638; P = 0.0002) after Bonferroni adjustment. Conversely, no significant relationships were observed between other iron and LV parameters. After Bonferroni correction, reverse MR analysis showed that one SD increase in LVEF significantly correlated with decreased TSAT (ß = -0.0699; 95% CI: -0.1087 to -0.0311; P = 0.0004). No heterogeneity or pleiotropic effects evidence was observed in the analysis. CONCLUSIONS: We demonstrated a causal relationship between TSAT and LV remodeling and function in a preserved ejection fraction population.

A+T rich interaction domain protein 3a (Arid3a) impairs Mertk-mediated efferocytosis in cholestasis.

BACKGROUND & AIMS: Macrophages are key elements in the pathogenesis of cholestatic liver diseases. Arid3a plays a prominent role in the biologic properties of hematopoietic stem cells, B lymphocytes and tumor cells, but its ability to modulate macrophage function during cholestasis remains unknown. METHODS: Gene and protein expression and cellular localization were assessed by q-PCR, immunohistochemistry, immunofluorescence staining and flow cytometry. We generated myeloid-specific Arid3a knockout mice and established three cholestatic murine models. The transcriptome was analyzed by RNA-seq. A specific inhibitor of the Mertk receptor was used in vitro and in vivo. Promoter activity was determined by chromatin immunoprecipitation-seq against Arid3a and a luciferase reporter assay. RESULTS: In cholestatic murine models, myeloid-specific deletion of Arid3a alleviated cholestatic liver injury (accompanied by decreased accumulation of macrophages). Arid3a-deficient macrophages manifested a more reparative phenotype, which was eliminated by in vitro treatment with UNC2025, a specific inhibitor of the efferocytosis receptor Mertk. Efferocytosis of apoptotic cholangiocytes was enhanced in Arid3a-deficient macrophages via upregulation of Mertk. Arid3a negatively regulated Mertk transcription by directly binding to its promoter. Targeting Mertk in vivo effectively reversed the protective phenotype of Arid3a deficiency in macrophages. Arid3a was upregulated in hepatic macrophages and circulating monocytes in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Mertk was correspondingly upregulated and negatively correlated with Arid3a expression in PBC and PSC. Mertk+ cells were located in close proximity to cholangiocytes, while Arid3a+ cells were scattered among immune cells with greater spatial distances to hyperplastic cholangiocytes in PBC and PSC. CONCLUSIONS: Arid3a promotes cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes by macrophages during cholestasis. The Arid3a-Mertk axis is a promising novel therapeutic target for cholestatic liver diseases. IMPACT AND IMPLICATIONS: Macrophages play an important role in the pathogenesis of cholestatic liver diseases. This study reveals that macrophages with Arid3a upregulation manifest a pro-inflammatory phenotype and promote cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes during cholestasis. Although we now offer a new paradigm to explain how efferocytosis is regulated in a myeloid cell autonomous manner, the regulatory effects of Arid3a on chronic liver diseases remain to be further elucidated.

ARID3a from the ARID family: structure, role in autoimmune diseases and drug discovery.

The AT-rich interaction domain (ARID) family of DNA-binding proteins is a group of transcription factors and chromatin regulators with a highly conserved ARID domain that recognizes specific AT-rich DNA sequences. Dysfunction of ARID family members has been implicated in various human diseases including cancers and intellectual disability. Among them, ARID3a has gained increasing attention due to its potential involvement in autoimmunity. In this article we provide an overview of the ARID family, focusing on the structure and biological functions of ARID3a. It explores the role of ARID3a in autoreactive B cells and its contribution to autoimmune diseases such as systemic lupus erythematosus and primary biliary cholangitis. Furthermore, we also discuss the potential for drug discovery targeting ARID3a and present a plan for future research in this field.

IL-26 modulates T cell function in autoimmune hepatitis.

OBJECTIVES: Autoimmune hepatitis (AIH) is an aberrant autoimmune condition mediated by T cell abnormality, which may cause fulminant liver failure and persistent liver injury. This study aimed to disclose the histopathological and functional engagement of interleukin (IL)-26, a potent inflammation mediator, in AIH disease progression. METHODS: We conducted immunohistochemical staining on liver biopsy samples to evaluate intrahepatic expression of IL-26. Cellular sources of hepatic IL-26 were detected by confocal microscopy. Flow cytometry was employed to determine the immunological alterations of CD4+ and CD8+ T cells following in vitro IL-26 treatment on primary peripheral blood mononuclear cells from healthy controls. RESULTS: Statistically significant increase in IL-26 level was observed in AIH (n = 48) liver samples in comparison with patients having chronic hepatitis B (n = 25), nonalcoholic fatty liver disease (n = 18), and healthy donors for living donor liver transplantation (n = 10). The number of intrahepatic IL-26+ cells was positively correlated with histological and serological severity. An immunofluorescence staining indicated that liver-infiltrating CD4+ T cells, CD8+ T cells, and CD68+ macrophages orchestrated IL-26 secretion in AIH. Both CD4+ and CD8+ T cells demonstrated effective activation, lytic, and proinflammatory functions upon IL-26 stimulation. CONCLUSION: We observed elevated IL-26 in AIH liver which promoted T cell activation and cytotoxic capacity, indicating a therapeutic potential of IL-26 intervention in AIH.

Repair of proximal hypospadias with single-stage (Duckett's method) or Bracka two-stage: a retrospective comparative cohort study.

Background: Surgical correction of proximal hypospadias is challenging. The complication rate of proximal hypospadias is still high, and the debate over its optimal treatment is ongoing. Duckett's method is a classic non-staging operation, and two-stage Bracka repair is an attractive alternative procedure. Herein, we retrospectively analyzed the effects of two surgical techniques on proximal hypospadias in order to reduce the complication rates of proximal hypospadias, and analyzed the various risk factors that cause complications. Methods: This study retrospectively evaluated 94 consecutive patients who underwent repair of penoscrotal or proximal defects between 2015 and 2019. Patients were assigned to two groups: 46 patients were treated with Bracka and 48 with Duckett. Patient age at surgery, urethral meatus location, and postoperative complications were recorded. One-way analysis of variance (ANOVA) was used to analyze the length and curvature of the penis and the length of the urethral defect. Results: There was no significant difference between the two groups in terms of age and type of hypospadias. In the Bracka group, there was 1 case (2.2%) of meatal stenosis after the first stage, which was restored with ureteral dilatation. After second-stage repair, a urethral fistula was noted in 4 cases (8.7%) and strictures in 2 cases (4.3%). In the Duckett group, urethral fistulas were noted in 8 cases (16.7%), strictures in 4 cases (8.3%), partial glans dehiscence in 4 cases (8.3%), and diverticulum in 1 case (2.1%) postoperatively. Compared with the Duckett group, the overall complication rate for Bracka repair was lower (35.4% vs. 13%, P=0.016). In addition, compared with the Duckett group, children with perineal hypospadias who were treated with the Bracka operation had fewer postoperative complications (100% vs. 13%, P=0.015). Risk factor analysis showed that the initial curvature of the penis, initial urethral defect, and degree of penile curvature after skin degloving were not correlated with complications. There was a significant correlation between urethral defects after correction of the chordee and urethral fistulas (P=0.019). Conclusions: Compared with the Duckett procedure, the Bracka two-stage repair may be a safer and more reliable approach for proximal hypospadias in children. The Bracka two-stage repair should be used for perineal hypospadias. The larger the urethral defect after chordee correction, the greater the possibility of a postoperative urethral fistula.

Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers.

Stem cell-independent reprogramming of differentiated cells has recently been identified as an important paradigm for repairing injured tissues. Following periportal injury, mature hepatocytes re-activate reprogramming/progenitor-related genes (RRGs) and dedifferentiate into liver progenitor-like cells (LPLCs) in both mice and humans, which contribute remarkably to regeneration. However, it remains unknown which and how external factors trigger hepatocyte reprogramming. Here, by employing single-cell transcriptional profiling and lineage-specific deletion tools, we uncovered that periportal-specific LPLC formation was initiated by regionally activated Kupffer cells but not peripheral monocyte-derived macrophages. Unexpectedly, using in vivo screening, the proinflammatory factor IL-6 was identified as the niche signal repurposed for RRG induction via STAT3 activation, which drove RRG expression through binding to their pre-accessible enhancers. Notably, RRGs were activated through injury-specific rather than liver embryogenesis-related enhancers. Collectively, these findings depict an injury-specific niche signal and the inflammation-mediated transcription in driving the conversion of hepatocytes into a progenitor phenotype.

Implications of gut microbiota in autoimmune liver diseases.

Autoimmune liver diseases (AILD) are a group of immune-mediated liver inflammatory diseases with three major forms including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Interaction of both genetic and environmental factors leads to the breakdown of self-tolerance, hence resulting in hyper-responsive of autoantibodies and aggressive autoreactive immune cells. Genetic studies have identified dozens of risk loci associated with initiation and development of AILD. However, the role of exogenous factors remains unclear. Recently, both infectious and inflammatory diseases have been associated with microbiota, which colonizes multiple mucosal surfaces and participates in human physiological process and function in immune system, particularly influencing liver, and biliary system via gut-liver axis. Emerging evidence on the role of gut microbiota has expanded our knowledge of AILD in both pathogenesis and potential therapeutic targets, along with putative diagnosis biomarkers. Herein we review the relationship between host and gut microbiota, discuss their potential roles in disease onset and progression, and summarize the compositional and functional alterations of the microbiota in AILD. We also highlighted the microbiota-based therapeutics such as antibiotics and fecal microbiota transplantation (FMT).

Evaluation of tunica vaginalis flap-covering combined with modified Glenn-Anderson in one-stage repair of proximal hypospadias with incomplete penoscrotal transposition.

Objective: To explore a novel repair method for proximal hypospadias with incomplete penoscrotal transposition in children and evaluate its safety and outcomes. Methods: A retrospective analysis of clinical data was conducted for 86 children with severe proximal hypospadias with incomplete penoscrotal transposition who were hospitalized in our department between June 2018 and February 2021. In total, 42 patients (Group A) underwent repair following a one-stage method in which tunica vaginalis flap-covering was combined with a modified Glenn-Anderson procedure, while 44 patients (Group B) underwent a two-step repair consisting of tunica vaginalis flap-covering using the Duplay technique and the modified Glenn-Anderson procedure. The two groups were compared on operation time, length of postoperative hospital stay, postoperative complications, and associated costs. Results: All operations were successful in both groups. No statistical difference was observed between the two groups in incidence of stenosis of the urinary meatus (2.38% vs. 4.54%, P = 0.279), urethral stricture (2.38% vs. 2.27%, P = 0.948), urinary fistula (7.14% vs. 6.82%, P = 0.907), or urinary infection (7.14% vs. 4.55%, P = 0.309). Additionally, there was no statistical difference between the groups in operation time (63.21 ± 5.20 vs. 62.07 ± 4.47 min, P = 0.059), postoperative off-bed time (7.02 ± 1.32 vs. 6.84 ± 1.20 days, P = 0.456), or duration of hospitalization (10.55 ± 1.15 vs. 10.15 ± 1.45 days, P = 0.092). However, Group B patients underwent an additional second-stage operation, incurring extra costs. Three months after surgery, Group A were judged more positively on the PPPS (specifically receiving higher scores on shaft skin and general appearance) by both the parents (shaft skin: 2.10 ± 0.82 vs. 1.93 ± 0.62, P = 0.024; general appearance: 2.16 ± 0.91 vs. 1.93 ± 0.72, P = 0.042) and the surgeon (shaft skin: 2.42 ± 0.70 vs. 2.25 ± 0.58, P = 0.025; general appearance: 2.38 ± 0.69 vs. 2.29 ± 0.51, P = 0.041). In most cases, the parents and surgeon were satisfied with the appearance of the genitals after one-stage repair. Conclusion: The advantages of the novel repair technique include use of a single-stage operation, producing a better appearance at a lower cost. The tunica vaginalis flap-covering method is not only demonstrated to be safe and effective, but it is also a simpler method than the conventional operation.

Intestinal homeostasis in autoimmune liver diseases.

ABSTRACT: Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system. Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease (AILD). Autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related sclerosing cholangitis have been linked to gut dysbiosis. Diverse mechanisms contribute to disturbances in intestinal homeostasis in AILD. Bacterial translocation and molecular mimicry can lead to hepatic inflammation and immune activation. Additionally, the gut and liver are continuously exposed to microbial metabolic products, mediating variable effects on liver immune pathologies. Importantly, microbiota-specific or associated immune responses, either hepatic or systemic, are abnormal in AILD. Comprehensive knowledge about host-microbiota interactions, included but not limited to this review, facilitates novel clinical practice from a microbiome-based perspective. However, many challenges and controversies remain in the microbiota field of AILD, and there is an urgent need for future investigations.

Tissue-resident memory T cells in chronic liver diseases: Phenotype, development and function.

Tissue-resident memory (TRM) T cells are a unique subset of memory T cells that are critical for the first line of defense against pathogens or antigens in peripheral non-lymphoid tissues such as liver, gut, and skin. Generally, TRM cells are well adapted to the local environment in a tissue-specific manner and typically do not circulate but persist in tissues, distinguishing them from other memory T cell lineages. There is strong evidence that liver TRM cells provide a robust adaptive immune response to potential threats. Indeed, the potent effector function of hepatic TRM cells makes it essential for chronic liver diseases, including viral and parasite infection, autoimmune liver diseases (AILD), nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC) and liver transplantation. Manipulation of hepatic TRM cells might provide novel promising strategies for precision immunotherapy of chronic liver diseases. Here, we provide insights into the phenotype of hepatic TRM cells through surface markers, transcriptional profiles and effector functions, discuss the development of hepatic TRM cells in terms of cellular origin and factors affecting their development, analyze the role of hepatic TRM cells in chronic liver diseases, as well as share our perspectives on the current status of hepatic TRM cell research.

Prevalence and clinical characteristics of autoimmune liver disease in hospitalized patients with cirrhosis and acute decompensation in China.

BACKGROUND: Autoimmune liver disease (AILD) has been considered a relatively uncommon disease in China, epidemiological data for AILD in patients with cirrhosis and acute decompensation (AD) is sparse. AIM: To investigate the prevalence, outcome and risk factors for AILD in cirrhotic patients complicated with AD in China. METHODS: We collected data from patients with cirrhosis and AD from two prospective, multicenter cohorts in hepatitis B virus endemic areas. Patients were regularly followed up at the end of 28-d, 90-d and 365-d, or until death or liver transplantation (LT). The primary outcome in this study was 90-d LT-free mortality. Acute-on-chronic liver failure (ACLF) was assessed on admission and during 28-d hospitalization, according to the diagnostic criteria of the European Association for the Study of the Liver (EASL). Risk factors for death were analyzed with logistic regression model. RESULTS: In patients with cirrhosis and AD, the overall prevalence of AILD was 9.3% (242/2597). Prevalence of ACLF was significantly lower in AILD cases (14%) than those with all etiology groups with cirrhosis and AD (22.8%) (P < 0.001). Among 242 enrolled AILD patients, the prevalence rates of primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and PBC-AIH overlap syndrome (PBC/AIH) were 50.8%, 28.5% and 12.0%, respectively. In ACLF patients, the proportions of PBC, AIH and PBC/AIH were 41.2%, 29.4% and 20.6%. 28-d and 90-d mortality were 43.8% and 80.0% in AILD-related ACLF. The etiology of AILD had no significant impact on 28-d, 90-d or 365-d LT-free mortality in patients with cirrhosis and AD in both univariate and multivariate analysis. Total bilirubin (TB), hepatic encephalopathy (HE) and blood urea nitrogen (BUN) were independent risk factors for 90-d LT-free mortality in multivariate analysis. The development of ACLF during hospitalization only independently correlated to TB and international normalized ratio. CONCLUSION: AILD was not rare in hospitalized patients with cirrhosis and AD in China, among which PBC was the most common etiology. 90-d LT-free mortality were independently associated with TB, HE and BUN.

Serum Biomarkers for Autoimmune Hepatitis Type 1: the Case for CD48 and a Review of the Literature.

In autoimmune hepatitis (AIH), the persisting inflammation contributes to fibrosis progression, for which conventional biochemical markers manifest relatively unsatisfactory prediction. Herein, we assessed the value of serum CD48 (sCD48) as an indicator for inflammation and fibrosis in AIH type 1. The levels of sCD48 were detected first in an exploratory cohort using ELISA. In this cohort, compared with healthy controls (4.90 ng/mL, P < 0.0001), primary biliary cholangitis (7.32 ng/mL, P < 0.0001), and non-alcoholic fatty liver disease (7.76 ng/mL, P < 0.0001), sCD48 levels were elevated in AIH (12.81 ng/mL) and correlated with histological inflammation and fibrosis. Further using multivariate logistic regression analysis, sCD48 was identified as an independent predictor for both significant inflammation (G3-4) and advanced fibrosis (S3-4). Two predictive scores, based on sCD48, were constructed for diagnosing significant inflammation and advanced fibrosis (sCD48-AIH-SI and sCD48-AIH-AF, respectively). Using these data as a premise, predictive abilities were subsequently evaluated and verified in a validation cohort. In the exploratory cohort, the area under the receiver operating characteristic curve of sCD48 and sCD48-AIH-SI, for significant inflammation, were 0.748 and 0.813, respectively. Besides, during treatment follow-up, sCD48 levels gradually decreased from immunosuppression initiation to re-evaluation biopsy, in parallel with aspartate transaminase, total sera IgG, and fibrosis-4 score. For AIH patients in a re-evaluation biopsy cohort, sCD48 could predict significant fibrosis (S2-4). Further using immunohistochemistry, hepatic CD48 expression was elevated in AIH patients and decreased after treatment. In conclusion, sCD48 and sCD48-based predictive scores predict histological inflammation and fibrosis in AIH-1. Detecting sCD48 might help in the clinical management of AIH.

Association of novel TMEM67 variants with mild phenotypes of high gamma-glutamyl transpeptidase cholestasis and congenital hepatic fibrosis.

TMEM67 (mecklin or MKS3) locates in the transition zone of cilia. Dysfunction of TMEM67 disrupts cilia-related signaling and leads to developmental defects of multiple organs in humans. Typical autosomal recessive TMEM67 defects cause partial overlapping phenotypes, including abnormalities in the brain, eyes, liver, kidneys, bones, and so forth. However, emerging reports of isolated nephronophthisis suggest the possibility of a broader phenotype spectrum. In this study, we analyzed the genetic data of cholestasis patients with no obvious extrahepatic involvement but with an unexplained high level of gamma-glutamyl transpeptidase (GGT). We identified five Han Chinese patients from three unrelated families with biallelic nonnull low-frequency TMEM67 variants. All variants were predicted pathogenic in silico, of which p. Arg820Ile and p. Leu144del were previously unreported. In vitro studies revealed that the protein levels of the TMEM67 variants were significantly decreased; however, their interaction with MKS1 remained unaffected. All the patients, aged 7-39 years old, had silently progressive cholestasis with elevated GGT but had normal bilirubin levels. Histological studies of liver biopsy of patients 1, 3, and 5 showed the presence of congenital hepatic fibrosis. We conclude that variants in TMEM67 are associated with a mild phenotype of unexplained, persistent, anicteric, and high GGT cholestasis without typical symptoms of TMEM67 defects; this possibility should be considered by physicians in gastroenterology and hepatology.

Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial.

BACKGROUND: Treatment of chronic drug-induced liver injury (DILI) or herb-induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications for corticosteroids for chronic DILI/HILI. AIMS: To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI. METHODS: This was a randomised open-label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48-week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48-week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety. RESULTS: Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40 years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p = 0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)-like DILI and non-AIH-like subgroups, showed comparable responses. No severe adverse events were observed during the trial. CONCLUSION: This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH-like features can achieve both biochemical response and histological improvements with good safety. (ClinicalTrials.gov, NCT02651350).

Myeloid-Derived Suppressive Cells Deficient in Liver X Receptor α Protected From Autoimmune Hepatitis.

Myeloid-derived suppressor cells (MDSCs) emerge as a promising candidate for the immunotherapy of autoimmune hepatitis (AIH). However, targets for modulating MDSC in AIH are still being searched. Liver X receptors (LXRs) are important nuclear receptors linking lipid metabolism and immune responses. Despite the extensive studies of LXR in myeloid compartment, its role in MDSCs is currently less understood. Herein, expression of LXRα was found to be upregulated in AIH patients and colocalized with hepatic MDSCs. In ConA-induced hepatitis, deletion of LXRα led to increased expansion of MDSCs in the liver and alleviated the hepatic injury. MDSCs in LXRα-/- mice exhibited enhanced proliferation and survival comparing with WT mice. T-cell proliferation assay and adoptive cell transfer experiment validated the potent immunoregulatory role of MDSCs in vitro and in vivo. Mechanistically, MDSCs from LXRα-/- mice possessed significantly lower expression of interferon regulatory factor 8 (IRF-8), a key negative regulator of MDSC differentiation. Transcriptional activation of IRF-8 by LXRα was further demonstrated. Conclusion: We reported that abrogation of LXRα facilitated the expansion of MDSCs via downregulating IRF-8, and thereby ameliorated hepatic immune injury profoundly. Our work highlights the therapeutic potential of targeting LXRα in AIH.

The Clinical Significance of Hepatic CD69+ CD103+ CD8+ Resident-Memory T Cells in Autoimmune Hepatitis.

BACKGROUND AND AIMS: The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic. APPROACH AND RESULTS: We report herein that CD69+ CD103+ CD8+ tissue-resident memory T cells (TRM ) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8+ TRM cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8+ TRM cells decreased significantly. CD69+ CD8+ and CD69+ CD103+ CD8+ T cells, also known as CD8+ TRM cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL-15 and TGF-ß on inflammatory cells, and extensive hepatic expression of E-cadherin; these factors likely contribute to the development and localization of CD8+ TRM cells. Based on these data and, in particular, the relationships between disease severity and CD8+ TRM cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8+ TRM cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8+ TRM cells induced by IL-15 and TGF-ß and with direct down-regulation of the nuclear factor Blimp1 of CD8+ TRM cells. CONCLUSIONS: Our data suggest that CD8+ TRM cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8+ TRM cell expansion.

Evaluation of controlled attenuation parameter in assessing hepatic steatosis in patients with autoimmune liver diseases.

BACKGROUND: Hepatic steatosis commonly occurs in some chronic liver diseases and may affect disease progression. AIM: To investigate the performance of controlled attenuation parameter (CAP) for the diagnosis of hepatic steatosis in patients with autoimmune liver diseases (AILDs). METHODS: Patients who were suspected of having AILDs and underwent liver biopsy were consistently enrolled. Liver stiffness measurement (LSM) and CAP were performed by transient elastography. The area under the receiver operating characteristic (AUROC) curve was used to evaluate the performance of CAP for diagnosing hepatic steatosis compared with biopsy. RESULTS: Among 190 patients with biopsy-proven hepatic steatosis, 69 were diagnosed with autoimmune hepatitis (AIH), 18 with primary biliary cholangitis (PBC), and 27 with AIH-PBC overlap syndrome. The AUROCs of CAP for the diagnosis of steatosis in AILDS were 0.878 (0.791-0.965) for S1, 0.764 (0.676-0.853) for S2, and 0.821 (0.716-0.926) for S3. The CAP value was significantly related to hepatic steatosis grade (P < 0.001). Among 69 patients with AIH, the median CAP score was 205.63 ± 47.36 dB/m for S0, 258.41 ± 42.83 dB/m for S1, 293.00 ± 37.18 dB/m for S2, and 313.60 ± 27.89 dB/m for S3. Compared with patients with nonalcoholic fatty liver disease (NAFLD) presenting with autoimmune markers, patients with AIH concomitant with NAFLD were much older and had higher serum IgG levels and LSM values. CONCLUSION: CAP can be used as a noninvasive diagnostic method to evaluate hepatic steatosis in patients with AILDs. Determination of LSM combined with CAP may help to identify patients with AIH concomitant with NAFLD from those with NAFLD with autoimmune phenomena.