The incidence of acute-onset autoimmune hepatitis (A-AIH) is increasing, yet diagnosis remains challenging, especially in patients with recent hepatotoxic drug exposure. The clinical presentations of A-AIH and drug-induced autoimmune-like hepatitis (DI-ALH) at onset are often indistinguishable, complicating timely diagnosis. We conducted a three-center retrospective study in China, screening patients with acute liver injury, hepatotoxic drug exposure, and autoimmune features. Patients were ultimately classified as DI-ALH if they achieved sustained remission after culprit drug cessation, or as A-AIH if they relapsed. We compared baseline demographics, laboratory indices, immunological profiles, liver histology, and established AIH diagnostic criteria. We developed and independently validated a multivariable logistic regression model to improve discrimination between A-AIH and DI-ALH. Of 458 patients screened, 238 met inclusion criteria and constituted the final cohort (94 A-AIH and 144 DI-ALH). Compared to DI-ALH, A-AIH showed significantly higher IgG levels, lower platelet counts, and higher autoantibody titers. Histologically, A-AIH exhibited more severe portal inflammation, interface hepatitis, fibrosis, and rosette formation. The discriminatory capacity of the 2022 and 2008 histological criteria was limited and comparable (AUC 0.62 vs. 0.59, p = 0.616). The Dx-AID score, incorporating platelet count, IgG, autoantibodies, and histological features, achieved high diagnostic accuracy in both the derivation cohort (AUC 0.84, 95

Background: Uncertainties persist regarding the optimal management of acute onset of autoimmune hepatitis, including the use of corticosteroids. This study aimed to compare the effectiveness and safety of rapid versus slow corticosteroid tapering in acute onset of AIH. Methods: A multicenter study involving patients with acute AIH was conducted. We defined acute AIH as an acute presentation (<30 days) with AIH and exhibiting no evidence of pre-existing liver diseases. Initially, corticosteroid treatment and overall outcomes were reported. Subsequently, the role of corticosteroid tapering rate in modifying outcomes across subgroups was investigated. For patients with an initial corticosteroid dose of 20 mg/ day or higher, we further classified patients into rapid tapering group (duration until dose of prednisone <20 mg/day <3 weeks) and slow tapering group (duration until dose of prednisone <20 mg/day >= 3 weeks). Adverse events were defined as any of the following events, progression (e.g., acute icteric AIH progression to AS-AIH or AIH-ALF, AS-AIH progression to AIH-ALF, non-cirrhotic progression to cirrhosis, compensated cirrhosis progression to decompensation), LT, and liver-related death. Results: This retrospective cohort study enrolled 237 patients, with 109 presenting acute icteric AIH, 97 with acute-severe AIH (AS-AIH), and 31 with AIH-acute liver failure (ALF). Among patients with acute icteric AIH, slow tapering significantly improved adverse outcome-free survival compared to rapid tapering (99 % vs. 71 %, P < 0.0001). Similarly, in AS-AIH patients, slow tapering resulted in notably higher adverse outcome-free survival rates compared to rapid tapering (92 % vs. 54 %, P < 0.001). Slow tapering independently predicted fewer adverse events (OR 0.144; 95 % CI 0.037-0.562; P = 0.005). However, in AIH-acute liver failure (ALF) patients, tapering rate did not significantly affect adverse outcome-free survival (38 % vs. 50 %, P = 0.590). Overall, there were no significant differences in osteoporosis or infection occurrence between tapering groups in the entire acute AIH cohort. Conclusion: A slow corticosteroid tapering reduced adverse outcomes in acute exacerbation of AIH patients, particularly in acute icteric AIH and AS-AIH.

Introduction:Shenfu injection (SFI) is widely used in clinical severe conditions including sepsis due to its pharmacological effects of invigorating Qi and reviving Yang for resuscitation. SFI is known to alleviate sepsis-related intestinal injury. However, the underlying mechanism remains exclusive. This study aimed to investigate the regulatory role of SFI in the self-renewal of intestinal stem cells as well as gut microbiota during sepsis. Methods:Plasma of septic patients was collected for detecting intestinal dysfunction markers. Mechanistic investigations were performed using immunofluorescent co-staining, Western Blotting, hematoxylin-eosin(H&E) staining, immunohistochemical (IHC) staining, TUNEL staining, Enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription-PCR (RT-qPCR) and 16S rRNA gene sequencing. Results:Plasma levels of D-lactate and intestinal-type fatty acid-binding protein (I-FABP) in septic patients with intestinal dysfunction were significantly reduced following SFI administration. Compared to the control mice, sepsis induced severe mucosal damage in the intestine, including the decrease of the villus length and the number of crypts, which was significantly inhibited by SFI administration. In addition, SFI significantly reduced the levels of pro-inflammatory cytokines Interleukin 1β (IL-1β), Interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in septic mice. Cell proliferation and migration in the intestine were significantly increased in the intestine of septic mice upon SFI treatment. Mechanically, SFI facilitated the expression of activating transcription factor 4 (ATF4) to promote the transcription of SRY-Box Transcription Factor 9 (Sox9), thereby activating the stemness and proliferation of crypt stem cells. Moreover, the gut microbiota composition in septic mice was modulated by SFI administration. In particular, high dose of SFI (HSF) treatment was found to decrease the proportion of harmful bacteria including Proteobacteria and Escherichia-Shigella, while increase the abundance of beneficial bacteria such as Alloprevotella and Butyricimonas in septic mice. Discussion:Our findings revealed that SFI protects against sepsis-induced intestinal injury via promoting the self-renewal of crypt stem cells and regulating the gut microbiota composition, providing strong evidence for the potential of SFI in treating sepsis-related intestinal dysfunction.

Background & Aims: In this study, we aimed to evaluate the incidence, predictors, and prognostic significance of recompensation in autoimmune hepatitis (AIH)-related decompensated cirrhosis following immunosuppressive therapy (IST). Methods: We retrospectively analyzed patients with AIH at first decompensation. Recompensation, defined using modified Baveno VII criteria, required clinical resolution (≥12 months without ascites, variceal bleeding, or hepatic encephalopathy, with liver function restored to Child-Pugh A) along with aetiological suppression (complete biochemical response under IST). Predictors of recompensation were identified using multivariate regression, and survival outcomes were compared among compensated, recompensated, and non-recompensated groups. Results: A total of 258 patients with AIH-related decompensated cirrhosis were included (median follow-up: 47 months, IQR 28-75). Clinical resolution was achieved by 124 patients (48.1%), while 68 patients (30.9% of 220 treated with IST) met criteria for recompensation. Predictors of recompensation included ascites as the only complication (hazard ratio [HR] 14.40, 95% CI 4.17-49.64, p <0.001), lower IgG levels (HR 0.90, 95% CI 0.89-0.96, p <0.001), higher bilirubin levels (HR 1.04, 95% CI 1.00-1.08, p = 0.030), and higher platelet counts (HR 1.01, 95% CI 1.00-1.01, p = 0.039). Patients achieving recompensation experienced a significantly reduced risk of liver transplantation or death (HR 0.07, 95% CI 0.01-0.50, p = 0.009), with survival outcomes comparable to those of compensated patients. Conclusions: Recompensation was achieved in approximately one-third of patients with AIH-related decompensated cirrhosis undergoing IST, leading to markedly improved transplant-free survival. Predictors of recompensation included having ascites as the sole complication, lower IgG levels, higher bilirubin levels, and higher platelet counts. Impact and implications: The predictors and long-term prognostic implications of recompensation in patients with autoimmune hepatitis (AIH)-related decompensated cirrhosis remain unclear. This study demonstrates that recompensation is achievable in patients with AIH-related decompensated cirrhosis and is associated with significant long-term benefits, including improved survival and reduced transplantation needs. We identified ascites (as the sole decompensating event), lower IgG levels, higher bilirubin levels and higher platelet counts as independent predictors of recompensation. These findings can be used by clinicians to identify the patients most likely to benefit from immunosuppressive therapy.

To date, monthly oral bisphosphonates have not been available in China. In this randomized, double blind, positive-controlled, multicenter phase III clinical trial, we compared the efficacy and safety of monthly minodronate versus weekly alendronate in the treatment of Chinese postmenopausal women with osteoporosis. A total of 548 participants were screened across 31 study centers, of which 330 participants were randomized into two groups: the experimental group (n = 165) received oral minodronate (50 mg/tablet once every four weeks) and alendronate placebo (once weekly), while the positive control group (n = 165) received oral alendronate (70 mg/tablet once weekly) and minodronate placebo (once every four weeks) for a duration of 48 weeks. The bone mineral density (BMD) of the lumbar spine, femoral neck and total hip were measured using dual-energy X-ray absorptiometry (DXA) at baseline and at 24 and 48 weeks. At the end of treatments, the experimental group exhibited a mean increase (SD) in BMD above the baseline at the lumbar spine, femoral neck and total hip of 4.61% (4.613%), 3.04% (4.034%) and 3.40% (3.569%), respectively, compared with those of 4.55% (3.753%), 1.86% (3.592%) and 2.30% (4.838%) in the control group. All improvements from the baseline in the two groups were statistically significant. The monthly minodronate did not cause new safety risks compared with alendronate. This study demonstrates that monthly minodronate administration is non-inferior to weekly alendronate in terms of therapeutic efficacy, while maintaining a comparable safety profile. Furthermore, the monthly dosing schedule of minodronate may significantly enhance medication adherence among osteoporosis patients, potentially improving long-term treatment outcomes.

BACKGROUND:Osteoporosis is a chronic disease of bone metabolism with high incidence rates. Recently, exosome therapy has emerged as a promising avenue for the treatment of osteoporosis. However, the role of autophagy-induced osteoblast-derived exosomes (Auto-exo) in osteoporosis has yet to be elucidated. METHODS:The effect of Auto-exo on bone formation was assessed in vivo. The composition of gut microbiota was determined through 16S rDNA sequencing, and metabolite profiles were analyzed using liquid chromatography-mass spectrometry (LC-MS). Cell experiments were conducted to explore the role of bilirubin in bone formation. RESULTS:Auto-exo were successfully isolated and identified. Auto-exo promoted bone formation and alleviated osteoporosis progression in a mouse model of osteoporosis. 16S rDNA sequencing revealed that Auto-exo changed diversity and composition of gut microbiota in osteoporotic mice, with a notable increase in Lactobacillus and a decrease in Dubosiella and Faecalibaculum. LC-MS analysis indicated that Auto-exo treatment reduced the elevated levels of bilirubin in osteoporotic mice. Cell experiments uncovered that bilirubin remarkably inhibited osteoblast differentiation. Furthermore, Auto-exo promoted osteoblast differentiation via inhibiting bilirubin production. CONCLUSIONS:Our findings demonstrated that Auto-exo promoted bone formation by modulating the gut microbiota-metabolite bilirubin axis, thereby alleviating osteoporosis progression. This discovery provides a novel perspective on the mechanism underlying the therapeutic effects of Auto-exo on osteoporosis.

Patients with primary biliary cholangitis (PBC) commonly experience extrahepatic rheumatic diseases. However, the epidemiologic and genetic associations as well as causal relationship between PBC and these extrahepatic conditions remain undetermined. In this study, we first conducted systematic review and meta-analyses by analyzing 73 studies comprising 334,963 participants across 17 countries and found strong phenotypic associations between PBC and rheumatic diseases. Next, we utilized large-scale genome-wide association study summary data to define the shared genetic architecture between PBC and rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Sjögren's syndrome (SS). We observed significant genetic correlations between PBC and each of the four rheumatic diseases. Pleiotropy and heritability enrichment analysis suggested the involvement of humoral immunity and interferon-associated processes for the comorbidity. Of note, we identified four variants shared between PBC and RA (rs80200208), SLE (rs9843053), and SSc (rs27524, rs3873182) using cross-trait meta-analysis. Additionally, several pleotropic loci for PBC and rheumatic diseases were found to share causal variants with gut microbes possessing immunoregulatory functions. Finally, Mendelian randomization revealed consistent evidence for a causal effect of PBC on RA, SLE, SSc, and SS, but no or inconsistent evidence for a causal effect of extrahepatic rheumatic diseases on PBC. Our study reveals a profound genetic overlap and causal relationships between PBC and extrahepatic rheumatic diseases, thus providing insights into shared biological mechanisms and novel therapeutic interventions.

Background Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease. An inadequate response to ursodeoxycholic acid (UDCA) poses a high risk of progression toward end-stage liver disease. Gut dysbiosis has been implicated in PBC. Here, we aimed to investigate microbial signatures that permit risk stratification and provide mechanistic insights into novel therapies for PBC. Methods We prospectively recruited UDCA treatment-naive patients with PBC and performed metagenomic sequencing and metabolomic profiling using stool and serum samples obtained before (n = 132) and after (n = 59) treatment. PBC microbiome subtypes were identified using unsupervised machine learning methods and validated in two independent cohorts. Findings PBC baseline metagenomes clustered into two community subtypes characterized by varying abundances of Clostridia taxa. Compared with Clostridialow microbiomes, Clostridiahigh microbiomes were more similar to healthy controls. Notably, patients in the Clostridialow subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridiahigh subtype (41% vs. 20%, p = 0.015). Integrative analysis of metagenomic and metabolomic data revealed divergent functional modules and metabolic activities between the two metacommunities. In particular, anaerobic fermentation and the production of bioactive metabolites, including tryptophan derivatives and secondary bile acids, crucial for immune regulation and gut barrier maintenance, were markedly diminished in the Clostridialow subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridiahigh group. Importantly, the microbiome subtypes and their associations with UDCA response were reproducible in two independent treatment-naive PBC cohorts. Conclusions Characterizing baseline microbiota patterns may enable the prediction of treatment outcomes in PBC and facilitate personalized treatment strategies. Funding This research was mainly supported by the National Natural Science Foundation of China.

Background & aims: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients.Methods: We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls.Results: A total of 588 HLA variants were significantly associated with AIH, with HLA-B & lowast;35:01 (p = 8.17 x 10(-304); odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B & lowast;08:01 (p = 1.35 x 10(-33); OR = 4.26) and rs7765379 (p = 5.08 x 10(-18); OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B & lowast;35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels.Conclusions: Our study reveals three novel and independent variants at HLA-B & lowast;35:01, HLA-B & lowast;08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH.Impact and implications: This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.(c) 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Primary biliary cholangitis (PBC) is a chronic immune-mediated liver disease. Previous genome-wide meta-analysis has identified the association between variants in TMEM163 with PBC. Here we aimed to evaluate the association between variants near the reported risk loci of TMEM163 at 2q21.3 and prognosis of PBC patients. We performed a retrospective analysis of 347 PBC patients treated with ursodeoxycholic acid (UDCA) for at least 1 year. We collected clinical data at diagnosis and 1 year after UDCA treatment. SNPs within 200 kb upstream and downstream of the lead variant were genotyped and screened. We identified that rs661899 near MGAT5 and TMEM163 showed the strongest association with prognosis in PBC patients. Patients carrying the rs661899 T allele tended to respond incompletely to UDCA treatment and had worse performances in laboratory values including aspartate aminotransferase (53.5 vs 32 vs 28.5 U/L, p = 0.001), alkaline phosphate (157.25 vs 125 vs 113 U/L, p = 0.001), albumin (41.5 vs 42.3 vs 43.7 g/L, p = 0.008) and bilirubin (19.2 vs 14.9 vs 12.85 μmol/L, p = 0.001). GLOBE scores (p = 4.8 × 10–5) and UK-PBC risk scores (p = 4.6 × 10–4) were strongly correlated with rs661899 genotype. Patients with TT genotype had a higher risk for adverse events compared with CC genotype (p = 0.039) during the 1-year follow-up. Results were also verified in an independent cohort. PBC patients carrying the rs661899 T allele are associated with poor prognosis and adverse outcomes after 1-year UDCA therapy.

Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

The biliary epithelial cells release CC chemokine receptor 6 (CCR6) ligand 20 (CCL20), leading to recruitment of CCR6+ T cells and subsequent infiltration into the biliary epithelium in primary biliary cholangitis patients. Previous genome-wide multi-national meta-analysis, including our Han Chinese cohort, showed significant association of CCR6 and CCL20 single nucleotide polymorphisms (SNP) with PBC. We report here that significantly associated SNPs, identified in the CCR6 locus based on our Han Chinese genome-wide association study, can be separated into “protective” and “risk” groups, but only “risk” SNPs were confirmed using a separate Han Chinese PBC cohort. Only weak association of CCL20 SNPs was observed in Han Chinese PBC cohorts. Fine-mapping and logistical analysis identified a previously defined functional variant that, leads to increased CCR6 expression, which contributed to increased genetic susceptibility to PBC in Han Chinese cohort.

Background: Oral lichen planus (OLP) is a common chronic oral mucosal disease with 1.4 % malignant transformation rate, and its etiology especially immune pathogenesis remains unclear. This study was aimed at investigating the immune cells related molecular underlying the pathophysiology of OLP through bioinformatics analysis. Methods: The dataset GSE52130 obtained from the Gene Expression Omnibus (GEO) database was conducted a comprehensive analysis in this study. The CIBERSORTx was used for investigating immune cells infiltration. The gene set enrichment analysis (GSEA) and gene ontology (GO) enrichment were performed for exploring the biological functions and gene annotation. The protein-protein interactions (PPI) were constructed by STRING database and visualized by Cytoscape software. The cytohubba plugin was utilized for screening hub genes. The receiver operating characteristic (ROC) was performed for evaluating diagnostic value of hub genes. The miRNAs, lncRNAs and drugs were respectively predicted by NetworkAnalyst, miRTarbase, ENCORI, and DGIdb database. Results: This study identified 595 differentially expressed genes (DEGs). The GSEA indicated keratinization, innate immune system and biological oxidation were involved in OLP. GO analysis showed extracellular matrix and keratinocyte were mainly enriched. And we found the activated memory CD4+ T cells were lowly infiltrated in OLP. We identified 101 activated memory CD4+ Tcells-related DEGs. Three hub genes (APP, IL1B, TF) were selected. APP and IL1B were significantly up-regulated, whereas TF was down-regulated in OLP. The three hub genes show high diagnostic value in OLP. Additionally, they were involved in MAPK signal, NF-kappaB signal and iron metabolism in OLP. What's more, NEAT1/XIST - miR - 15a - 5p/miR - 155-5p - APP/IL1B signal axis was focused in competing endogenous RNA (ceRNA) network. In addition, 35 drugs were predicted for OLP. Conclusion: Three activated memory CD4+ T-cells-related DEGs were identified by integrative analysis. It may provide novel insight into the pathogenesis of OLP and suggest potential therapeutic targets for OLP.

OBJECTIVE:This study aimed to analyze the correlation between bone mineral density (BMD) and bone resorption markers in postmenopausal women with osteoporosis fractures and identify risk factors for second fractures.METHODS:This retrospective analysis of 1,239 older women with fractures with a median age of 70 years who attended Shanghai General Hospital from January 2007 to December 2016, included a first fracture group (1,008 cases) and a second fractures group (231 cases). The risk factors for fractures were analyzed by comparing these groups on clinical characteristics, BMD, and bone metabolism markers stratified by quartiles of serum C-terminal telopeptide of type 1 collagen (CTX). Binary logistic regression analysis was used to identify risk factors for second fractures.RESULTS:In the whole sample, BMD was negatively correlated with age and serum osteocalcin and positively correlated with body mass index (BMI). In women with first fractures, those in the highest quartile of serum CTX had the lowest spine and hip BMD. Second fractures were significantly associated with BMI, lower spine and hip BMD, and higher serum osteocalcin but not CTX. Binary logistic regression analysis showed that high BMI (odds ratio [OR], 1.08 [95% CI, 1.03-1.14]; P = 0.001), low lumbar BMD (OR, 0.24 [95% CI, 0.07-0.82]; P = 0.023), low total hip BMD (OR, 0.05 [95% CI, 0.00-0.88]; P = 0.041), and lack of antiosteoporosis treatment (OR, 2.71 [95% CI, 2.71-4.08]; P < 0.001) were independent risk factors for second fractures.CONCLUSIONS:In older women with fractures, BMD was significantly lower in women with second fractures than in those with first fractures. Higher levels of serum CTX and osteocalcin, which indicates increased bone resorption, were negatively correlated with BMD. In women with a first fracture, serum CTX higher than 605 pg/mL was negatively correlated with BMD, whereas no correlation was found between different CTX and BMD in women with second fractures. High BMI and low BMD as well as not receiving antiosteoporosis treatment were independent risk factors for second fractures.

Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.3 locus variant(s) contributes to the pathogenesis of PBC. A genome-wide meta-analysis of 1931 PBC subjects and 7852 controls in two Han Chinese cohorts confirms the strong association between 19p13.3 locus and PBC. By integrating functional annotations, luciferase reporter assay and allele-specific chromatin immunoprecipitation, we prioritize rs2238574, an AT-Rich Interaction Domain 3A (ARID3A) intronic variant, as a potential causal variant at 19p13.3 locus. The risk allele of rs2238574 shows higher binding affinity of transcription factors, leading to an increased enhancer activity in myeloid cells. Genome-editing demonstrates the regulatory effect of rs2238574 on ARID3A expression through allele-specific enhancer activity. Furthermore, knock-down of ARID3A inhibits myeloid differentiation and activation pathway, and overexpression of the gene has the opposite effect. Finally, we find ARID3A expression and rs2238574 genotypes linked to disease severity in PBC. Our work provides several lines of evidence that a non-coding variant regulates ARID3A expression, presenting a mechanistic basis for association of 19p13.3 locus with the susceptibility to PBC.

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.(c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Backgrounds: Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases. Methods: We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2-/- mice injured by DDC, and P4HA2-/-/MDR2-/- double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation. Results: The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2-/- mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2-/-/MDR2-/- mice compared with MDR2-/- mice. Cholangiocytes isolated from P4HA2-/-/MDR2-/- mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP. Conclusions: P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC.

目的 了解骨转换指标(bone turnover markers,BTMs)以及其他骨代谢指标水平与女性原发性骨质疏松症(primary osteoporosis,POP)患者初次脆性骨折发生的相关性.方法 2005年7月至2016年12月在上海市第一人民医院骨质疏松症专病门诊初次就诊且已确诊POP、资料齐全并符合骨折史由初诊时患者自述及影像学检查显示为初次新发骨折,为主要部位脆性骨折等纳入标准的女性患者,共117例,按骨折后1年内就诊患者及未发生骨折患者分为骨折组和未骨折组,记录所有研究对象的一般资料、血清生化及BTMs、骨密度(bone mineral density,BMD)检测结果、骨折史等临床资料进行回顾性分析研究.结果 与未骨折组相比,骨折组血清Ca显著下降,差异有统计学意义(P<0.05);且骨折组BMD L1-4显著降低,差异有统计学意义(P<0.05).按年龄进行亚组分析发现:骨折组血清Ca均低于未骨折组,其中≤70岁两组差异有统计学意义(P<0.05);骨折组BMD较未骨折组均下降,>70岁组BMD L1-4差异有统计学意义(P<0.05).Spearman相关分析显示:BMD L1-4(r=-0.188,P=0.043)、血清骨钙素(bone Gla protein,BGP)(r=-0.217,P=0.019)、血清Ca(r=-0.302,P=0.001)、血清25羟维生素D(25 hydroxyvitamin D,25OHD)(r=-0.189,P=0.041)与骨折发生呈负相关;二元Logistic回归分析表明:BMDL1-4(OR=0.042,P=0.039)、血清BGP(OR=0.948,P=0.049)、Ca(OR=0.042,P=0.039)、25OHD(OR=0.975,P=0.015)均为骨折的保护因素.结论 腰椎BMD、血清BGP、Ca、25OHD与脆性骨折发生相关.

We read with great interest the manuscript by Pape et al. entitled ???Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group (IAIHG) presents a statement on 5 agreed response criteria and endpoints for autoimmune hepatitis (AIH).1 Herein, we want to validate the new IAIHG response criteria and endpoints in Chinese patients with AIH. We performed a retrospective analysis of patients with AIH recruited from Renji tails of this cohort have been previously described.2 Adult patients with AIH and a simplified IAIHG score >???6 were included, whilst patients with variant syndromes or competing liver diseases were excluded.3,4 A total of 650 patients were eligible for the analysis. The mean age was 50.0 ?? 12.7 years and 82.9% were female. Patients were initially treated with prednisolone and the prednisolone dose was gradually tapered after remission. Maintenance therapy consisted of prednisolone