[Response to Primary Biliary Cholangitis Treatment: Influencing Factors and the Role in Prognosis Prediction].

Objective: To examine the influencing factors and prognostic features of poor response to ursodeoxycholic acid (UDCA) treatment in primary biliary cholangitis (PBC) patients with dyslipidemia. Methods: A retrospective study was conducted, covering 512 patients who had a confirmed diagnosis of PBC, and who received treatment at West China Hospital, Sichuan University between January 2009 and March 2022. According to their actual response to UDCA treatment, patients were divided into two groups, UDCA full-response group ( n=305) and UDCA non-responding group ( n=207). The data from the two groups were compared to predict the adverse factors influencing patient response and the area under the curve ( AUC) of the receiver operating characteristic (ROC) curve, identify the cut-off value of total cholesterol (TC), and analyze the differences in baseline laboratory test findings and the rate of responses to treatment. According to the TC cut-off value, patients were divided into a group with TC≥5.415 mmol/L and another group with TC<5.415 mmol/L. In addition, differences in the prognosis of the two groups were assessed by comparing the UK-PBC and GLOBE scores. Results: The baseline data, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), triglycerides (TG), TC, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), were significantly increased in the UDCA non-responding group compared to those in the full-response group (all P<0.005), while the albumin level of the UDCA non-responding group was decreased compared to that of the full-response group ( P=0.012). Findings of multi-factor logistic regression analysis suggested that TC (odds ratio [ OR]=1.501, 95% confidence interval [ CI]: 1.275-1.767, P<0.01) and ALP ( OR=1.005, 95% CI: 1.003-1.006, P<0.01) were independent risk factors influencing patient response. The ROC curve analysis suggested worse prognosis for patients with TC≥5.415 mmol/L ( AUC: 0.727, 95% CI: 0.680-0.775, 63.8% sensitivity, 76.4% specificity). In addition, the UK-PBC risk score at 1 year of treatment was higher in the high-TC group (TC≥5.415 mmol/L) than that in the low-TC group (TC<5.415 mmol/L) ( P<0.05). Conclusions: Hypercholesterolemia is an independent risk factor for poor response to UDCA in PBC patients. When the baseline TC is equal to or higher than 5.415 mmol/L, PBC patients have a relatively poor response to UDCA and poor prognosis.

Worse Response to Ursodeoxycholic Acid in Primary Biliary Cholangitis Patients with Autoimmune Hepatitis Features.

BACKGROUND: There is limited evidence on the treatment response of primary biliary cholangitis (PBC) with autoimmune hepatitis (AIH) features but not meet the criteria of PBC-AIH syndromes. The aim of this study was to elucidate the clinical characteristics of PBC patients with features of AIH. METHODS: We included patients with diagnostic criteria of PBC. All patients were treated with ursodeoxycholic acid (UDCA) and without immunosuppressive agents for >1 year. The biochemical response was evaluated at 1 year after the treatment of UDCA. RESULTS: Among 432 patients with PBC, 166 (38.4%) patients did not achieve biochemical response within 1 year of UDCA treatment. Nonresponders had a lower albumin level and higher immunoglobulin G, alanine transaminase (ALT), alanine aminotransferase (AST), alkaline phosphatase, glutamyl transpeptidase and total bilirubin levels (p < 0.05). The response rates were significantly lower in patients with elevated level of IgG or ALT or AST. Moreover, the higher the IgG or AST level was, the lower the response rate was in patients with PBC, regardless of cirrhosis. For patients with cirrhosis, there was no differences among patients with different levels of ALT. Patients in the PBC with AIH features group had a significant lower response rate than patients in the PBC-only group. Among the 139 patients who underwent liver biopsy, 54 were nonresponsive to UDCA and 48 (88.9%) shown mild interface hepatitis. CONCLUSION: In conclusion, PBC patients with AIH features had a worse response to UDCA therapy.

Development and Validation of an Easy-to-Use Risk Scoring System for Screening High-Risk Varices in Patients with HBV-Related Compensated Advanced Chronic Liver Disease.

BACKGROUND: A large portion of patients with compensated advanced chronic liver disease (cACLD) do not have varices or only have low risk varices. AIMS: To create and validate an easy-to-use risk scoring system to identify high-risk varices (HRV) and spare esophagogastroduodenoscopy (EGD) in patients with hepatitis B virus (HBV)-related cACLD. METHODS: In total, 334 patients with HBV-related cACLD who had undergone routine laboratory tests and ultrasound examination were enrolled. Multivariate logistic regression analysis was used to determine which variables were the independent risk factors for the presence of HRV, so as to establish the scoring system for screening HRV. The criteria were tested in a training cohort with 221 patients and validated in a validation cohort with 113 patients. RESULTS: In the training cohort, the prevalence of HRV was 29.5%. Albumin (ALB) [OR 0.83; 95% confidence index (CI) 0.77-0.90; P < 0.0001], platelet count (PLT) (OR 0.96, 95% CI 0.96-0.99; P < 0.0001) and portal vein diameter (OR 1.40; 95% CI 1.15-1.71; P = 0.001) were independent risk factors for the presence of HRV. The negative predictive value was > 95%, when albumin-platelet-portal vein diameter varices scores (APP score) were < 0.24. One hundred twenty-five of 221 (56.6%) patients met an APP score < 0.24 with a 4.8% HRV miss rate. In the validation cohort, 59 of 113 (51.3%) patients met the APP score < 0.24 with a 1.7% HRV miss rate. CONCLUSIONS: APP score is a potential model for safely screening HRV and sparing EGDs in patients with HBV-related cACLD.

Comparison of Concanavalin a-Induced Murine Autoimmune Hepatitis Models.

BACKGROUND/AIMS: Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver whose pathogenic mechanisms have not yet been elucidated. Moreover, the current treatment used for the vast majority of AIH patients is largely dependent on immunosuppressant administration and liver transplantation. However, research on the pathogenesis of AIH and effective new treatments for AIH have been hampered by a lack of animal models that accurately reproduce the human condition. METHODS: AIH models created by concanavalin A (ConA) injections at different times and doses. The levels of ALT, AST, LDH and inflammatory cytokines were examined at various times after 20 mg/kg ConA was administered by ELISA using commercially available kits. Moreover, liver pathological changes were observed by flow cytometry (FCM) and H&E staining. RESULTS: Our experiments demonstrated that the levels of ALT, AST, LDH and several inflammatory cytokines, including TNF-α, IFN-γ, and IL-6, were higher in the 20 mg/kg 12 h ConA group than in the other groups. Importantly, the numbers of activated CD4+ and CD8+ T lymphocytes in the blood, spleen and liver were calculated. These results showed that ConA (20 mg/kg for 12 h)-induced hepatitis was similar to that in clinical AIH patients. Furthermore, we found that the number of MDSCs in the blood was significantly increased in the ConA (20 mg/kg for 12 h) group compared with controls. Our findings indicated that ConA (20 mg/kg for 12 h)-induced hepatitis could be used as an experimental murine model that mirrors most of the pathogenic properties of human type I AIH. CONCLUSION: This model [ConA (20 mg/kg for 12 h)] provides a valuable tool for studying AIH immunopathogenesis and rapidly assessing novel therapeutic approaches.

Incorporating methylation genome information improves prediction accuracy for drug treatment responses.

BACKGROUND: An accumulation of evidence has revealed the important role of epigenetic factors in explaining the etiopathogenesis of human diseases. Several empirical studies have successfully incorporated methylation data into models for disease prediction. However, it is still a challenge to integrate different types of omics data into prediction models, and the contribution of methylation information to prediction remains to be fully clarified. RESULTS: A stratified drug-response prediction model was built based on an artificial neural network to predict the change in the circulating triglyceride level after fenofibrate intervention. Associated single-nucleotide polymorphisms (SNPs), methylation of selected cytosine-phosphate-guanine (CpG) sites, age, sex, and smoking status, were included as predictors. The model with selected SNPs achieved a mean 5-fold cross-validation prediction error rate of 43.65%. After adding methylation information into the model, the error rate dropped to 41.92%. The combination of significant SNPs, CpG sites, age, sex, and smoking status, achieved the lowest prediction error rate of 41.54%. CONCLUSIONS: Compared to using SNP data only, adding methylation data in prediction models slightly improved the error rate; further prediction error reduction is achieved by a combination of genome, methylation genome, and environmental factors.

Sequential Therapy or Standard Triple Therapy for Helicobacter pylori Infection: An Updated Systematic Review.

The effectiveness of standard triple therapy (STT) for the eradication of Helicobacter pylori has decreased recently. Sequential therapy (SQT) is a new regimen proposed to address this problem. The aim of this study was to compare the efficacy of SQT versus STT for H. pylori eradication. We searched The Cochrane Library, MEDLINE, Web of Science, and EMBASE databases up to July 2014. The risk ratios (RRs) of eradication rate were pooled, with a 95% confidence interval (CI). Thirty-six randomized clinical trials including a total of 10,316 patients met the inclusion criteria. The RR for eradication of H. pylori with SQT compared with STT was 1.14 (95% CI: 1.09-1.17), the eradication rates were 84.1% and 75.1%, respectively. There was significant heterogeneity between trial results (I = 73%; P < 0.00001). Subgroup analyses showed that SQT was superior to both 7- and 10-day STT, but not significantly better than 14-day STT. This superiority existed when patients were treated with either metronidazole or tinidazole. Patients with single clarithromycin-resistant strain showed a greater benefit of SQT over STT (eradication rates 80.9% vs. 40.7%), RR = 1.98 (95% CI: 1.33-2.94). There was no significant difference between groups in terms of the risk of adverse effects. In conclusion, SQT is more efficacious than STT (7 days and 10 days) in the eradication of HP, but the pooled rate seemed suboptimal. Further research is needed to develop more effective therapeutic approaches. Surveillance of resistance rates should be performed to guide treatment.

Nogo-B: A potential indicator for hepatic cirrhosis and regulator in hepatic stellate cell activation.

AIM: To evaluate plasma Nogo-B levels in liver cirrhotic patients and declare a novel molecular basis by which Nogo-B modulates hepatic stellate cell (HSC) activation. METHODS: Plasma Nogo-B levels from liver cirrhotic patients were detected by enzyme-linked immunosorbent assay. Rat primary HSC were culture activated or stimulated with transforming growth factor (TGF)-ß. Activated HSC were transfected for 48 h with Nogo-B shRNA to inhibit Nogo-B expression. Gene expressions of Nogo-B, α-smooth muscle actin (SMA), collagen type I, TGF-ß, endoplasmic reticulum (ER) stress key molecules, including C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), activating transcription factor (ATF)4, ATF6, X-box binding protein 1 (Xbp-1) and calnexin, and the marker of autophagy beclin 1, were detected by quantitative reverse transcription polymerase chain reaction. The protein expressions of Nogo-B, α-SMA, collagen type I, CHOP, GRP78 and the marker of autophagy LC3B were evaluated by western blot. RESULTS: Liver cirrhotic patients showed a much higher level of plasma Nogo-B compared with the healthy controls. Nogo-B expression and ER stress could be induced during the process of cultured HSC activation. TGF-ß treatment increased Nogo-B expression time- and dose-dependently. Knockdown of Nogo-B in HSC reduced the activation of HSC. After Nogo-B gene knockdown, there was a decline of expression of ER stress markers and autophagic markers. Agonist or antagonist of ER stress could regulate autophagy level. CONCLUSION: Circulating Nogo-B may be an effective indicator for liver cirrhosis. Nogo-B inhibition could diminish HSC activation, in which alleviating ER stress may be one of the mechanisms, suggesting a potential approach to interference Nogo-B in liver fibrosis.

[Effect of hypoxia on the activation and visfatin expression in rat hepatic stellate cells].

OBJECTIVE: To investigate the effect of hypoxia on the visfatin and the expression of smooth muscle-actin (alpha-SMA) and hypoxia-inducible factor-1alpha (HIF-1alpha) in rat hepatic stellate cells (HSCs). METHODS: Rat primary HSCs were isolated from SD rats by in situ perfusion of collagenase and pronase and single-step Nycodenz density gradient centrifugation, and then cultured and activated. Completely activated primary HSCs were exposed to hypoxic conditions (37 degrees C, 5% CO2, 1% O2, 94% N2), or normoxic conditions (37 degrees C, 5% CO2, 21% O2, 74% N2), for 3, 6, 12 or 24 h respectively. The expression of alpha-SMA, the marker of HSC activation, and visfatin were assessed by Real time-PCR and Western blot. The Expression of HIF-1alpha was detected by Real time-PCR. RESULTS: HIF-1alpha mRNA in rat HSCs was induced after exposed to hypoxia for 3 h, and maintained elevated status up to 24 h. HSCs exposed to 1% O2 hypoxic conditions for 6 h increased alpha-SMA mRNA and protein expression. Visfatin mRNA expression was up-regulated after subjected to hypoxia for 12 h, and protein level was elevated after 6 h hypoxia. A positive linear correlation existed between alpha-SMA and visfatin expression in responsible to hypoxia (r = 0.991 (genes) and r = 0.968 (proteins), P < 0.05). CONCLUSION: Microcirculation impairment could significantly induce alpha-SMA and visfatin expression in rat HSCs, which might potentate the activation process of HSCs.

[Construction of shRNA expressing plasmid targeted rat NogoB and observation of the effection about NogoB on hepatic stellate cells].

OBJECTIVE: To construct shRNA expressing plasmid inhibiting rat NogoB and to observe its possible effect on rat primary hepatic stellate cells (HSCs) contraction. METHODS: Three pairs of shRNAs targeting different sequence of rat NogoB were designed and constructed into pSuper plasmid by DNA recombination technique. Culture-activated HSCs were transfected with NogoB-shRNA plasmids to scan the effective plasmid which could inhibit NogoB gene expression by Real-time PCR. And this depressant effect was also confirmed with Western blot. After NogoB was knocked-down effectively, ETA and ETB mRNA expression were assessed by Real-time PCR. RESULTS: Among the three pairs of recombinant plasmids, NogoB-shRNA2 plasmid could inhibit NogoB expression specifically. In HSCs, NogoB knockdown decreased the ratio of ETA and ETB. CONCLUSION: We constructed specific NogoB-shRNA expression plasmid successfully which might be involved in contraction of HSCs.

[Comparison of clinical features between gastroesophageal reflux diseases with atypical and typical symptoms].

OBJECTIVE: To study the differences between gastroesophageal reflux disease (GERD) with atypical symptoms (a-GERD) and typical symptoms (t-GERD). METHODS: 30 patients of suspected a-GERD were recruited and examined with upper gastrointestinal endoscopy, high-resolution manometry (HRM), 24 h esophageal multichannel intra-luminal impedance monitoring with pH sensor (MII-pH) and proton pump inhibitor (PPI) trials. The results were compared with those of 33 cases of GERD with typical symptoms. RESULTS: Among the 30 patients of suspected GERD, 24 were confirmed with a-GERD. One third of those patients were over sixty-years old, significantly higher than those with typical GERD (P < 0.05). No significant differences in prevalence of esophageal mucosa breakage and esophageal manometry readings were found between the two groups (P > 0.05). The a-GERD patients had higher data readings in 24 h esophageal MCII-pH monitoring than the t-GERD patients (P < 0.05). Supine type of GER and mixed reflux were predominately seen in the a-GERD patients, while upright type of GER was predominate seen in the t-GERD patients. The response rate of PPI in the a-GERD patients was significantly lower than that in the t-GERD patients when a course of standard dosage of PPI was given (45.8% vs. 78.8%, P < 0.01). But there was no significant difference in PPI response between these two groups when a second course with double standard dosage of PPI combined with pro-motility agents were given (72.7% vs. 88.0%, P < 0.05). CONCLUSION: Compared with patients of t-GERD, older onset age, more severe degree of acid reflux are presented in patients of a-GERD. a-GERD should be considered when it is hard to explain the symptoms of upper part of the chest in clinical practice. 24 h esophageal MII-pH monitoring and/or diagnostic therapy with double standard dosage of PPI helps make a correct diagnosis.

[Role of macrophage migration inhibitory factor in hepatic stellate cells activation].

OBJECTIVE: To investigate the role of macrophage migration inhibitory factor (MIF) in activation of primary hepatic stellate cells (HSC), and to explore the blocking effect of specific antisense oligonucleotides (ASONs) targeting MIF on the activation of primary HSCs. METHODS: Rat primary HSC were isolated from SD rats by in situ perfusion of collagenase and pronase and single-step Nycodenz density gradient centrifugation, and then cultured and activated. The expression of alpha-smooth muscle actin (alpha-SMA), the marker of HSC activation, was assessed by RT-PCR and immunocytochemistry (ICC). The expression of MIF was detected by RT-PCR, enzyme-linked immuno sorbent assay (ELISA), immunofluorescence (IF) or ICC. Completely activated primary HSC were transfected with MIF-specific antisense oligonucleotide (MIF-ASONs), mis-sense oligonucleotides of MIF, or blank liposome (negative-control). RESULTS: Quiescent HSC expressed very low level of MIF, while MIF gene and protein expression increased significantly during the process of HSC activation. Positive correlation was found between the expression of alpha-SMA and MIF (r = 0.944, P < 0.01). Compared with the control, activated primary Gen HSC transfected with MIF-ASONs showed lower MIF and alpha-SMA expressions at gene and protein profiles (P < 0.05). CONCLUSION: The expression of MIF was up-regulated in the process of HSC activation. Activation in culture of primarily isolated rat HSC could be inhibited by MIF-ASONs, suggesting at least in part that, MIF might be a novel and important factor involved in HSC activation and hepatic fibrosis.

Myeloid-derived suppressor cells ameliorate liver mitochondrial damage to protect against autoimmune hepatitis by releasing small extracellular vesicles.

BACKGROUND: Autoimmune hepatitis (AIH) is an inflammatory liver disease that is associated with impaired self-tolerance. Myeloid-derived supprfessor cells (MDSCs) have been considered to exert counterregulatory effects on AIH. However, the specific mechanism underlying these effects is unclear. Herein, we investigated the efficacy and safety of MDSCs in protecting against AIH and explored the underlying mechanism. METHODS: Circulating and liver MDSC expression levels in 71 AIH patients and 47 healthy control (HC) individuals were detected by flow cytometry and immunohistochemistry. The adoptive transfer of induced bone marrow-derived MDSCs (BM MDSCs) to AIH mice was used to explore the function of MDSCs. Hepatic injury and mitochondrial damage were evaluated by transaminase levels, histopathology, immunohistochemistry, transmission electron microscopy and western blotting. MDSCs were pretreated with the small extracellular vesicle (sEV) generation inhibitor GW4869 to explore the mechanism. Importantly, sEVs derived from MDSCs and MDSCs-GW4869 were injected into model mice to monitor mitochondrial function and biogenesis. RESULTS: Circulating and liver MDSCs were expanded in AIH patients and mouse model. Furthermore, the follow-up data of AIH patients showed that immunosuppressive therapy further promoted the expansion of MDSCs. More importantly, the adoptive transfer of BM MDSCs to AIH mice effectively ameliorated liver injury and regulated the imbalance of the immune microenvironment. Additionally, BM MDSCs reduced liver mitochondrial damage and improved mitochondrial biogenesis. Mechanistically, sEVs derived from BM MDSCs showed the same biological effects as cells, and blocking sEV production weakened the function of BM MDSCs. Finally, multiple long-term administrations of BM MDSCs were proven to be safe in general. CONCLUSION: In conclusion, MDSCs ameliorate liver mitochondrial damage to protect against autoimmune hepatitis by releasing small extracellular vesicles.

Pharmacokinetics, Safety, and Tolerability of Vonoprazan- or Esomeprazole-Based Bismuth-Containing Quadruple Therapy: A Phase 1, Double-Blind, Parallel-Group Study in Adults with Helicobacter pylori Infection in China.

Quadruple therapy comprising 2 antibiotics, a proton pump inhibitor, and bismuth, is recommended for Helicobacter pylori eradication in China. This Phase 1, double-blind, parallel-group study aimed to evaluate the pharmacokinetics, safety, and tolerability of bismuth-containing vonoprazan- or esomeprazole-based quadruple therapy in H. pylori-positive healthy subjects at a single site in China. Quadruple therapy comprising vonoprazan 20 mg or esomeprazole 20 mg with bismuth potassium citrate 600 mg (equivalent to bismuth 220 mg), clarithromycin 500 mg, and amoxicillin 1000 mg was administered twice daily for 2 weeks. Forty-four subjects were enrolled, 22 each in the vonoprazan (mean age, 34.5 years; men, 63.6%) and esomeprazole (mean age, 31.6 years; men, 59.1%) groups. Day 14 bismuth plasma pharmacokinetic parameters area under the plasma concentration-time curve during a dosing interval (geometric mean ratio, 1.07 [90% confidence interval, 0.82-1.40]) and maximum observed plasma concentration (geometric mean ratio, 1.30 [90% confidence interval, 0.94-1.81]) were similar between the treatment groups. At Day 42 follow-up, 100% and 94.4% of subjects were H. pylori negative in the vonoprazan and esomeprazole groups, respectively. The incidence of treatment-emergent adverse events was similar between the groups, with no serious adverse events. No new safety concerns were identified. In conclusion, vonoprazan had no significant effect on plasma bismuth exposure compared with esomeprazole.

Metabolic heterogeneity caused by HLA-DRB1*04:05 and protective effect of inosine on autoimmune hepatitis.

Autoimmune hepatitis (AIH) is an autoimmune disease caused by disruption of liver immune homeostasis. Genetic studies have revealed the predisposition of AIH with the human leukocyte antigen (HLA) region. Recently, metabolomics integrated with genomics has identified many genetic loci of biomedical interest. However, there is no related report in AIH. In the present study, we found that HLA-DRB1*04:05 was linked to the clinical features and prognosis of AIH in Chinese patients. Furthermore, our patients were divided into DRB1*04:05 positive and DRB1*04:05 negative groups and the metabolic profiling was done by HPLC/MS. We chose inosine, one of the highly altered metabolites, to explore the effect on an acute severe hepatitis murine model. The results showed that inosine treatment attenuated hepatocyte apoptosis, enhanced antioxidant ability and inhibited the activation and glycolysis of CD4+ T cell. We propose that inosine participates in the regulation of AIH through its protective effect on hepatocytes and inhibition of overactivated immune cells, which might provide a potential novel approach in treating acute form of AIH.

Glucose Metabolism Reprogramming of Regulatory T Cells in Concanavalin A-Induced Hepatitis.

Autoimmune hepatitis (AIH) is an inflammatory liver disease caused by a dysregulated immune response. Although the pathogenesis of AIH remains unclear, impaired regulatory T cells (Tregs) have been considered a driver of AIH development. Unlike autoreactive T cells, Tregs mainly utilize oxidative phosphorylation (OXPHOS) as their energy supply. Elevated glycolysis has been reported to limit the suppressive functions of Tregs. However, whether glucose metabolism reprogramming in Tregs is involved in AIH etiology remains unknown. The aim of this study was to examine alternations in Treg numbers and functions in AIH patients and concanavalin A (Con A)-induced hepatitis, while exploring associations between impaired Tregs and glucose metabolism. The frequency of Tregs was decreased in the peripheral blood but increased in liver biopsies of AIH patients. Moreover, immunosuppressive therapy rescued circulating Tregs in AIH. In Con A-induced immune hepatitis, enhanced intrahepatic Treg accumulation was observed over time, accompanied by reduced splenic Treg numbers. To investigate whether functional impairment of Tregs occurs in AIH, Tregs were isolated from experimental AIH (EAH) model mice and normal controls and the former displayed downregulated mRNA levels of FOXP3, CTLA4, CD103, TIGIT, CD39, and CD73. EAH model-derived Tregs also produced fewer anti-inflammatory mediators (TGF-ß and IL-35) than control Tregs. Moreover, enhanced glycolysis and reduced OXPHOS were found in Tregs from EAH model mice, as reflected by elevated levels of key glycolytic enzymes (HK2, PK-M2, and LDH-A) and a decreased ATP concentration. This study revealed a decreased peripheral Treg frequency and abnormal intrahepatic Treg infiltration in AIH. It is first reported that glucose metabolism reprogramming is associated with decreases and functional impairments in the Treg population, promoting AIH development. Targeting glucose metabolism may provide novel insights for the treatment of AIH.

Two-dimensional shear wave elastography for screening varices in Asian patients with primary biliary cholangitis.

Objectives: The presence of varices affects the survival of patients with primary biliary cholangitis (PBC). The aim of this study is to assess the criteria based on liver stiffness (LS) measured by two-dimensional shear wave elastography (2D-SWE) and platelet count (PLT), and recently published noninvasive models for triaging PBC patients.Methods: 231 patients with PBC who underwent EGD and 2D-SWE examination were enrolled. Areas under the receiver-operating characteristic curve (AUROC) were used to assess the performance of 2D-SWE for predicting all-size varices and high-risk varices. All-size varices and high-risk varices miss rate < 10% and <5%, respectively, were acceptable for screening varices.Results: The AUROCs of LS for predicting all-size varices and high-risk varices were 0.87 (95%CI: 0.82-0.91) and 0.84 (95%CI: 0.74-0.86), respectively. LS <25 kPa and PLT >110 × 109/L spared 46.3% EGD screening, with 3.7% high-risk varices miss rate and 8.4% all-size varices miss rate. One hundred and sixteen (50.2%) patients met the Newcastle varices in PBC score (cutoff, 0.5), with 4.3% high-risk varices miss rate and 11.2% all-size varices miss rate.Conclusion: The criteria based on LS and PLT are useful for triaging PBC patients. LS <25 kPa and PLT >110 × 109/L could be the optimal criteria for screening varices.

Long Noncoding RNA and Circular RNA Expression Profiles of Monocyte-Derived Dendritic Cells in Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a chronic liver disease caused by disruption of liver immune homeostasis. The effect of dendritic cells (DCs) on the pathogenesis of AIH is not fully understood. Long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) have been shown to play critical roles in the regulation of cell function. In this study, we analyzed the immunophenotypic characteristics of DCs in the peripheral blood. The percentage of mature DCs was higher in AIH patients than in healthy controls (HCs), and the proportion of mature DCs decreased after treatment. We isolated monocyte-derived DCs (moDCs) from the peripheral blood, obtained whole RNA-sequencing (RNA-seq) data for the moDCs from the two groups, and identified differentially expressed (DE) lncRNAs, circRNAs, miRNAs and mRNAs. In addition, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for the DE mRNAs and constructed competing endogenous RNA (ceRNA) networks. ENST00000543334, hsa_circ_0000279, and hsa_circ_0005076 were selected and validated by RT-qPCR. These results provide a possible molecular mechanism of DCs in the pathogenesis of AIH and identify some potential therapeutic targets.

Roles of Macrophages and Exosomes in Liver Diseases.

Exosomes are small discoid extracellular vesicles (EVs) originating from endosomes that are 30-150 nm in diameter and have a double lipid layer. They participate in the immune response, cell migration, cell differentiation, and tumor invasion and mediate intercellular communication, regulating the biological activity of receptor cells through the proteins, nucleic acids, and lipids that they carry. Exosomes also play vital roles in the diagnosis and treatment of liver diseases. Macrophages, which show unique phenotypes and functions in complex microenvironments, can be divided into M1 and M2 subtypes. M1 macrophages function in immune surveillance, and M2 macrophages downregulate the immune response. Recent studies have shown that macrophages are involved in non-alcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Moreover, several studies have demonstrated that liver diseases are associated with exosomes derived from or transferred to macrophages. This review focuses on the participation of macrophages and exosomes in liver diseases.

MicroRNAs in autoimmune liver diseases: from diagnosis to potential therapeutic targets.

Autoimmune liver diseases (AILDs) are a group of liver disorders composed of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) characterized by chronic hepatic and biliary inflammation. Although several genetic factors, such as HLA alleles, TNFA, and CTLA-4, have been reported in the pathogenesis of AILDs, many details remain unknown. In recent years, microRNAs (miRNAs) have emerged as crucial components in the diagnosis and therapeutic applications of various autoimmune diseases, including systemic lupus erythematosus (SLE), glomerulonephritis, and AILDs. MiRNAs comprise a class of small, noncoding molecules of 19--25 nucleotides that modulate multiple genes by suppressing or degrading target mRNAs. Altered miRNA profiles have been identified in serum, immune cells, and live tissues from AILD patients. Elevated serum miR-21 and miR-122 levels in AIH patients as well as decreased miR-200c levels in PSC patients indicate their diagnostic utility. Highly expressed miR-122 and miR-378f as well as downregulated miR-4311 and miR-4714-3p in serum samples from refractory PBC patients suggest their potential to evaluate treatment efficacy. Moreover, miRNAs have been reported to participate in AILD development. Increased miR-506 levels may impair bile secretion in PBC by inhibiting Cl-/HCO3-anion exchanger 2 (AE2) and type III inositol 1,4,5-trisphosphate receptor-3 (InsP3R3). Additionally, different miRNA mimics or antagonists, such as atagomiR-155 and miR-223 mimics, have been widely applied in experimental AILD murine models with great efficacy. Here, we provide an overview of miRNAs in AILDs, aiming to summarize their potential roles in diagnosis and therapeutic interventions, and we discuss the challenges and future applications of miRNAs in clinical practice.

Concomitant systemic lupus erythematosus might have a negative impact on the biochemical responses to treatment in patients with primary biliary cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is often overlapping with other autoimmune conditions, including systemic lupus erythematosus (SLE). Since the concomitant PBC and SLE are rare, the impacts of SLE on the response and prognosis in ursodeoxycholic acid (UDCA)-treated patients with PBC remain unclear. METHODS: A PBC database of 769 patients at West China hospital was used to identify 26 patients with concomitant PBC and SLE. The clinical and biochemical characteristics of these patients were collected and analyzed. Propensity score matching was used to compensate for the differences in age, total bilirubin, and alkaline phosphatase. The biochemical responses and prognoses were compared between the patients with and without concomitant SLE. RESULTS: The female-to-male ratio was 25:1 in the PBC patients with concomitant SLE. Compared with the group with PBC alone, the median hemoglobin and albumin values in the PBC-SLE group at the time of diagnosis of PBC were lower (both P < 0.05). After treatment, the group with PBC alone showed lower alanine aminotransferase and glutamyltransferase values and aspartate aminotransferase/platelet ratio indices at the final visit (all P < 0.05). The Kaplan-Meier estimate showed that the adverse event-free survival did not differ between the patients with and without concomitant SLE (P = 0.564). CONCLUSION: The results of this retrospective, single-center study suggested that the concomitant SLE status might have a negative impact on the biochemical responses to the treatment, while the effect of concomitant SLE on PBC progression remains to be further defined.Key Points• The prevalence of SLE in the PBC population being in a large PBC cohort was as low as 3.4%.• Compared with PBC-SLE group, the group with PBC alone showed lower alanine aminotransferase and glutamyltransferase values and aspartate aminotransferase/platelet ratio indices at the final visit, indicating that the concomitant SLE may have a negative impact on the biochemical responses to the treatment of PBC.