IntroductionAcute-on-chronic liver failure (ACLF) is a highly lethal clinical syndrome with limited effective therapeutic options. Urine-derived stem cells (USCs) represent a non-invasive and readily accessible cell source, but whether USCs obtained from patients with severe liver dysfunction retain therapeutic and immunomodulatory potential remains unclear.MethodsTo address this question, USCs derived from ACLF patients (LF-USCs) were evaluated in a Concanavalin A (Con A)-induced immune-mediated acute liver injury mouse model. Hydrogel-encapsulated LF-USCs were transplanted, and therapeutic efficacy was assessed by survival analysis, serum biochemical parameters, histological examination, and inflammatory cytokine profiling.ResultsTransplantation of hydrogel-encapsulated LF-USCs significantly improved mouse survival, reduced serum transaminase levels, and alleviated hepatocellular necrosis (p < 0.05). At the mechanistic level, LF-USC treatment was associated with decreased systemic inflammatory cytokine levels, attenuation of intrahepatic inflammatory injury, and dynamic modulation of macrophage-associated inflammatory signatures.DiscussionThese findings demonstrate that functionally competent USCs can be successfully obtained from ACLF patients and highlight their potential as a readily accessible autologous cell source for immune modulation and liver tissue repair in immune-mediated acute liver injury.

Aims and Background This study aimed to provide a preliminary clarification of the predictive factors for the development of cirrhosis within 1-year cirrhosis in non-cirrhotic HBV-associated acute-on-chronic liver failure (HBV-ACLF) patients and develop a risk stratification algorithm.Methods Non-cirrhotic HBV-ACLF patients who survived for at least 1 year and had complete clinical records were included from January 2016 to December 2023 at Beijing Youan Hospital, Capital Medical University. Multivariate logistic regression was performed to identify independent predictors of cirrhosis progression.Results Of the 329 HBV-ACLF patients initially screened, 109 were enrolled in the study, and a 1-year follow-up revealed that 21.1% of the non-cirrhotic patients developed cirrhosis. Multivariate logistic regression identified independent predictors of cirrhosis progression: non-resolution of total bilirubin (TB) levels within 28 days [5.64 (1.39-25.00)], failure to normalize the international normalized ratio (INR) within 28 days [6.34 (1.52-29.50)], and baseline platelet (PLT) count [0.98 (0.97-0.99)]. ROC analysis demonstrated strong predictive accuracy for cirrhosis with INR normalization (AUC = 0.82), TB resolution (AUC = 0.78), and baseline PLT count (AUC = 0.75). A risk stratification pathway incorporating INR normalization and baseline PLT effectively categorized patients into low, medium, and high-risk groups, with corresponding cirrhosis incidence rates of 5.4%, 29.4%, and 77.8%, respectively.Conclusion The findings underscore the importance of INR normalization, TB resolution, and baseline PLT count as independent predictors of cirrhosis and provide a useful framework for clinical decision-making and early intervention.

The heterogeneity in ACLF definitions proposed by different expert associations worldwide has led to variations in clinical phenotypes and prognosis. This study proposes a new approach for a unified definition based on the type of organ failure within the first week of disease onset.This prospective cohort study collected clinical data from hospitalized ACLF patients presenting with liver failure (total bilirubin ≥ 5 mg/dL, INR ≥ 1.5) across four liver centers in China. Patients with liver failure within the first week of onset were classified as Type I ACLF, while those with concurrent extrahepatic organ failure were categorized as Type II ACLF. We compared the clinical characteristics and prognosis of Type I and Type II ACLF patients, as well as the inclusivity of these classifications within existing mainstream ACLF definitions.A total of 846 patients were included in the analysis population. Type I ACLF occurred in 86.9% of cases, primarily in patients with non-cirrhotic chronic liver disease (34.3%) or compensated cirrhosis (48.6%), while Type II ACLF, observed in 13.1% of cases, predominantly developed in patients with cirrhosis (73%) (P < 0.001). Mortality rates at 28 and 90 days were significantly higher in Type II ACLF patients (43.2% and 52.3%) compared to those with Type I ACLF (15.8% and 24.9%) (P < 0.001). Patients with Type I ACLF met the APASL criteria more frequently (82.9%), whereas those with Type II ACLF more often met the EASL criteria (69.4%). For predicting the 90-day prognosis in Type I ACLF, the COSSH-ACLF II score achieved the highest AUROC at 0.788 (95% CI: 0.749-0.828). In Type II ACLF, the CLIF-C OF score provided the highest AUROC for predicting 90-day mortality, at 0.902 (95% CI: 0.840-0.964), outperforming the MELD, MELD-Na, and COSSH-ACLF II scores (P < 0.05) and showing no significant difference when compared to the CLIF-C ACLF score (0.872 [95% CI: 0.791-0.953], P = 0.426).This new clinical classification approach takes into account the characteristics defined by both Eastern and Western ACLF, and is expected to improve the comparability and interpretability of data in global studies, enhancing global understanding and management of ACLF.

OBJECTIVE:To compare the efficacy and safety profile of arginine glutamate and L-ornithine-L-aspartate (LOLA) in treating mild hepatic encephalopathy (HE) and hyperammonemia in cirrhotic patients. METHODS:This single-center, open-label, non-inferiority, randomized controlled trial (RCT) enrolled patients aged 18-75 years with cirrhosis and mild HE. The patients were randomly allocated in the ratio of 1:1 using a randomization table to be treated with intravenous administration of arginine glutamate or LOLA for 7 days. The primary end-point was the clinical improvement of mild HE. Secondary end-points included post-treatment change in blood ammonia level and the time to complete the number connection test (NCT)-A. Adverse events and adverse drug reactions were documented. RESULTS:From July 2020 to June 2021, 108 cirrhotic patients with mild HE were included and randomized to receive either arginine glutamate or LOLA for 7 days. Clinical improvement was observed in 88.9% of the patients receiving arginine glutamate and 90.7% of those having LOLA (between-group difference -1.9%, 95% confidence interval -13.3% to 9.6%), indicating non-inferiority of arginine glutamate to LOLA. The two groups showed comparable reductions in blood ammonia levels and improvements in time to complete NCT-A. The rate of adverse events was similar between the two groups, with only four cases reported adverse drug reactions. CONCLUSIONS:Both regimens effectively alleviated mild HE symptoms and reduced ammonia levels. Arginine glutamate showed non-inferiority to LOLA in terms of clinical improvement, ammonia reduction, and time to complete NCT-A, with no significant adverse events.

Published studies on tenofovir alafenamide (TAF) therapy for preventing vertical transmission of hepatitis B virus (HBV) have primarily enrolled mothers with viremic levels of approximately 7 log10 IU/mL. This study aimed to evaluate the efficacy and safety of TAF therapy in preventing mother-to-child transmission (MTCT) in mothers with exceptionally high viral loads, defined as HBV DNA levels > 2,000,000 IU/mL. Hepatitis B e antigen (HBeAg)-positive mothers with HBV DNA levels > 2,000,000 IU/mL were prospectively enrolled from four hospitals and initiated on TAF therapy between gestational weeks 26 and 28, continuing until delivery. All infants received immunoprophylaxis and were followed up to 28 weeks postpartum. The primary endpoints were the MTCT rate and the occurrence of congenital abnormalities in infants. Secondary outcomes included maternal HBV suppression at delivery and the safety of both mothers and infants. Among 137 mothers screened, 120 were enrolled in TAF therapy, and 121 infants completed the study. At delivery, 93.3% (112/120) of mothers achieved HBV DNA levels < 200,000 IU/mL. At birth, 0.8% (1/121) of infants had a congenital malformation, and 9.9% (12/121) tested positive for HBsAg. The vertical transmission rate was 2% (2/121, intention-to-treat) at 28 weeks of age. No severe adverse effects were reported in mothers or infants. On-treatment and postpartum alanine aminotransferase (ALT) flares after TAF cessation occurred in 7.5% (9/120) and 41.1% (46/112) of mothers, respectively, alongside viral rebound after cessation. Infant physical development remained within normal ranges based on national reference standards. In summary, approximately 2% of mothers on TAF therapy during late pregnancy experienced MTCT, despite proper immunoprophylaxis for their infants. Extending the treatment duration beyond 12 weeks for mothers with extremely high viral loads is recommended to improve MTCT prevention. No safety concerns were observed for either mothers or infants.

ImportanceStandard care for preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) in highly viremic mothers consists of maternal antiviral prophylaxis beginning at gestational week 28 combined with an HBV vaccine series and HBV immune globulin (HBIG) at birth. However, HBIG is unavailable in some resource-limited areas.ObjectiveTo determine whether initiating tenofovir disoproxil fumarate (TDF) at gestational week 16 combined with HBV vaccinations for infants is noninferior to the standard care of TDF at gestational week 28 combined with HBV vaccinations and HBIG for infants in preventing MTCT in mothers with HBV and high levels of viremia.Design, Setting, and ParticipantsAn unblinded, 2-group, randomized, noninferiority clinical trial was conducted in 7 tertiary care hospitals in China. A total of 280 pregnant individuals (who all identified as women) with HBV DNA levels greater than 200 000 IU/mL were enrolled between June 4, 2018, and February 8, 2021. The final follow-up occurred on March 1, 2022.InterventionsPregnant individuals were randomly assigned to receive either TDF starting at gestational week 16 with HBV vaccinations for the infant or TDF starting at gestational week 28 with HBV vaccinations and HBIG administered to the infant.Main Outcomes and MeasuresThe primary outcome was the MTCT rate, defined as detectable HBV DNA greater than 20 IU/mL or hepatitis B surface antigen positivity in infants at age 28 weeks. Noninferiority was established if the MTCT rate in the experimental group did not increase by more than an absolute difference of 3% compared with the standard care group, as measured by the upper limit of the 2-sided 90% CI.ResultsAmong 280 pregnant individuals who enrolled in the trial (mean age, 28 years; mean gestational age at enrollment, 16 weeks), 265 (95%) completed the study. Among all live-born infants, using the last observation carried forward, the MTCT rate was 0.76% (1/131) in the experimental group and 0% (0/142) in the standard care group. In the per-protocol analysis, the MTCT rate was 0% (0/124) in the experimental group and 0% (0/141) in the standard care group. The between-group difference was 0.76% (upper limit of the 2-sided 90% CI, 1.74%) in all live-born infants and 0% (upper limit of the 2-sided 90% CI, 1.43%) in the per-protocol analysis. Both comparisons met the criterion for noninferiority. Rates of congenital defects and malformations were 2.3% (3/131) in the experimental group and 6.3% (9/142) in the standard care group (difference, 4% [2-sided 95% CI, −8.8% to 0.7%]).Conclusions and RelevanceAmong pregnant women with HBV and high levels of viremia, TDF beginning at gestational week 16 combined with HBV vaccination for infants was noninferior to the standard care of TDF beginning at gestational week 28 combined with HBIG and HBV vaccination for infants. These results support beginning TDF at gestational week 16 combined with infant HBV vaccine to prevent MTCT of HBV in geographic areas where HBIG is not available.Trial RegistrationClinicalTrials.gov Identifier: NCT03476083

To compare the efficacy and safety profile of arginine glutamate and L-ornithine-L-aspartate (LOLA) in treating mild hepatic encephalopathy (HE) and hyperammonemia in cirrhotic patients. This single-center, open-label, non-inferiority, randomized controlled trial (RCT) enrolled patients aged 18–75 years with cirrhosis and mild HE. The patients were randomly allocated in the ratio of 1:1 using a randomization table to be treated with intravenous administration of arginine glutamate or LOLA for 7 days. The primary end-point was the clinical improvement of mild HE. Secondary end-points included post-treatment change in blood ammonia level and the time to complete the number connection test (NCT)-A. Adverse events and adverse drug reactions were documented. From July 2020 to June 2021, 108 cirrhotic patients with mild HE were included and randomized to receive either arginine glutamate or LOLA for 7 days. Clinical improvement was observed in 88.9% of the patients receiving arginine glutamate and 90.7% of those having LOLA (between-group difference −1.9%, 95% confidence interval −13.3% to 9.6%), indicating non-inferiority of arginine glutamate to LOLA. The two groups showed comparable reductions in blood ammonia levels and improvements in time to complete NCT-A. The rate of adverse events was similar between the two groups, with only four cases reported adverse drug reactions. Both regimens effectively alleviated mild HE symptoms and reduced ammonia levels. Arginine glutamate showed non-inferiority to LOLA in terms of clinical improvement, ammonia reduction, and time to complete NCT-A, with no significant adverse events.

IMPORTANCE Standard care for preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) in highly viremic mothers consists of maternal antiviral prophylaxis beginning at gestational week 28 combined with an HBV vaccine series and HBV immune globulin (HBIG) at birth. However, HBIG is unavailable in some resource-limited areas. OBJECTIVE To determine whether initiating tenofovir disoproxil fumarate (TDF) at gestational week 16 combined with HBV vaccinations for infants is noninferior to the standard care of TDF at gestational week 28 combined with HBV vaccinations and HBIG for infants in preventing MTCT in mothers with HBV and high levels of viremia. DESIGN, SETTING, AND PARTICIPANTS An unblinded, 2-group, randomized, noninferiority clinical trial was conducted in 7 tertiary care hospitals in China. A total of 280 pregnant individuals (who all identified as women) with HBV DNA levels greater than 200 000 IU/mL were enrolled between June 4, 2018, and February 8, 2021. The final follow-up occurred on March 1, 2022. INTERVENTIONS Pregnant individuals were randomly assigned to receive either TDF starting at gestational week 16 with HBV vaccinations for the infant or TDF starting at gestational week 28 with HBV vaccinations and HBIG administered to the infant. MAIN OUTCOMES AND MEASURES The primary outcome was the MTCT rate, defined as detectable HBV DNA greater than 20 IU/mL or hepatitis B surface antigen positivity in infants at age 28 weeks. Noninferiority was established if the MTCT rate in the experimental group did not increase by more than an absolute difference of 3% compared with the standard care group, as measured by the upper limit of the 2-sided 90% CI. RESULTS Among 280 pregnant individuals who enrolled in the trial (mean age, 28 years; mean gestational age at enrollment, 16 weeks), 265 (95%) completed the study. Among all live-born infants, using the last observation carried forward, the MTCT rate was 0.76% (1/131) in the experimental group and 0% (0/142) in the standard care group. In the per-protocol analysis, the MTCT rate was 0% (0/124) in the experimental group and 0% (0/141) in the standard care group. The between-group difference was 0.76% (upper limit of the 2-sided 90% CI, 1.74%) in all live-born infants and 0% (upper limit of the 2-sided 90% CI, 1.43%) in the per-protocol analysis. Both comparisons met the criterion for noninferiority. Rates of congenital defects and malformations were 2.3% (3/131) in the experimental group and 6.3% (9/142) in the standard care group (difference, 4% [2-sided 95% CI, -8.8% to 0.7%]). CONCLUSIONS AND RELEVANCE Among pregnant women with HBV and high levels of viremia, TDF beginning at gestational week 16 combined with HBV vaccination for infants was noninferior to the standard care of TDF beginning at gestational week 28 combined with HBIG and HBV vaccination for infants. These results support beginning TDF at gestational week 16 combined with infant HBV vaccine to prevent MTCT of HBV in geographic areas where HBIG is not available.

Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.

Objective To investigate the characteristics of intrahepatic and extrahepatic organ failure at the onset of acute－on-chronic liver failure（ACLF），to explore the features of a new clinical classification system of ACLF，and to provide a basis for the diagnosis，treatment，prognostic analysis of the disease. Methods A retrospective analysis was performed for the clinical data of the patients who were hospitalized Beijing YouAn Hospital，Capital Medical University，from January 2015 to October 2022 and were diagnosed with ACLF for the first time. According to the conditions of intrahepatic and extrahepatic organ failure at disease onset，they were classified into type Ⅰ ACLF and type Ⅱ ACLF. Type Ⅰ ACLF referred to liver failure on the basis of chronic liverdiseases，and type Ⅱ ACLF referred to acute decompensation of chronic liver diseases combined with multiple organ failure. The clinical features of patients with type Ⅰ or type Ⅱ ACLF were analyzed，and the receiver operating characteristic（ROC）curve was used to assess the value of MELD，MELD－Na，and CLIF－C ACLF scoring system in predicting the 90－day prognosis of ACLF patients with type Ⅰ or type Ⅱ ACLF. The independent－samples t test was used for comparison of normally distributed continuous data between two groups，and the Wilcoxon rank－sum test was used for comparison of non－normally distributed continuous data between two groups；the chi－square test or the Fisher’s exact test was used for comparison of categorical data between two groups. Results A total of 582 patients with ACLF were enrolled， among whom there were 535 patients with type Ⅰ ACLF and 47 patients with type Ⅱ ACLF. Hepatitis B and alcoholic liver disease were the main causes in both groups，with no significant difference between the two groups（P>0.05）. Chronic non－cirrhotic liver disease（28.2%）and compensated liver cirrhosis（56.8%） were the main underlying liver diseases in type Ⅰ ACLF，while compensated liver cirrhosis（34.0%）and decompensated liver cirrhosis（61.7%）were the main underlying liver diseases in type Ⅱ ACLF，and there was no significant difference inunderlying liver diseases between the patients with type Ⅰ ACLF and those with type Ⅱ ACLF（P<0.001）. The patients with type Ⅱ ACLF had significantly higher median MELD score，MELD－Na score，and CLIF－C ACLF score than those with type Ⅰ ACLF（all P<0.001）. The patients with type Ⅱ ACLF had significantly higher 28－and 90－day mortality rates than those with type Ⅰ ACLF（38.3%/53.2% vs 15.5%/27.5%，P<0.001）. For the patients with type Ⅰ ACLF who did not progress to multiple organ failure，the patients with an increase in MELD score accounted for 63.7% in the death group and 10.1% in the survival group（P<0.001），while for the patients with type Ⅰ ACLF who progressed to multiple organ failure， there was no significant difference in the change in MELD score between the survival group and the death group（P>0.05）. In the patients with type Ⅰ ACLF，MELD score，MELD－Na score，and CLIF－C ACLF score had an area under the ROC curve（AUC）of 0.735，0.737，and 0.740，respectively，with no significant difference between any two scores（all P>0.05）. In the patients with type Ⅱ ACLF，CLIF－C ACLF score had a significantly higher AUC than MELD score（0.880 vs 0.560， P<0.01）and MELD－Na score（0.880 vs 0.513，P<0.01）. Conclusion There are differences in underlying liver diseases， clinical features，and prognosis between type Ⅰ and type Ⅱ ACLF，and different prognosis scoring systems have different emphases，which provide a basis for the new clinical classification system of ACLF from the perspective of evidence－based medicine.

Objective We aimed to explore the relationship between the withdrawal of antiviral therapy after delivery and the risk for abnormal liver function (ALF) after delivery in pregnant women with high hepatitis B virus (HBV) DNA load by meta-analysis, in order to provide the corresponding theoretical basis for further guiding the clinical use of antiviral drugs in such pregnant women. Methods We searched multiple databases for controlled studies that enrolled pregnant women with chronic HBV infection treated with antiviral therapy from January 1, 2010 to November 1, 2020. Study selection and data extraction were performed by pairs of independent reviewers. The main index was the percentage of ALF higher than the upper limit of normal at 0 to 12 and 12 to 24 weeks after delivery. Meta-analysis was used to compare the risk for ALF after stopping antiviral drugs at different time points following delivery, and subgroup analysis was conducted according to the types of drugs used. Results We included 10 studies that enrolled 1080 pregnant women. There were 749 pregnant women in the treatment group and 331 pregnant women in the control group (who were not treated with antiviral therapy). The risk ratio (RR) for ALF in the 2 groups at 0 to 12 weeks after delivery: RR = 0.88; 95% CI, 0.71-1.09; at 12-24 weeks: RR = 0.46; 95% CI, 0.29-0.73, were compared. According to the different types of medication, subgroup analysis showed that the lamivudine treatment group compared with the control group at 0-12 weeks: RR = 0.67; 95% CI, 0.26-1.75; at 12-24 weeks, RR = 0.27; 95% CI, 0.11-0.67. The telbivudine treatment group was compared with the control group: at 0-12 weeks: RR = 0.77; 95% CI, 0.43-1.39; at 12-24 weeks: RR = 0.62, 95% CI, 0.23-1.64. The tenofovir treatment group was compared with the control group: at 0-12 weeks RR = 1.02; 95% CI, 0.67-1.55; at 12-24 weeks RR = 0.5; 95% CI, 0.25, 0.99. The lamivudine antiviral treatment group was further analyzed according to different treatment withdrawal time points. Compared with the control group, the immediate withdrawal of lamivudine in labor group at 0-12 weeks RR = 0.29; 95% CI, 0.11-0.77; at 12-24 weeks RR = 0.22; 95% CI, 0.05-0.88; the results were significantly different. There was no significant difference between the 4-week group and the 4-12 week group and the control group. Conclusion In pregnant women with a high HBV DNA load, immediate withdrawal after antiviral treatment in the second or third trimester of pregnancy did not increase the risk for ALF after delivery.

Background and Aims:Occult HBV infection (OBI) in children has proven to be associated with their immune response to hepatitis B vaccine (HepB). This study aimed to investigate the effect of a booster HepB on OBI, which is rarely investigated.Methods:This study enrolled 236 maternal HBsAg-positive children who were followed up annually until 8 years of age and were hepatitis B surface antigen (HBsAg) negative. Of those 100 received a booster HepB between 1 and 3 years of age (booster group), and 136 were never boosted (non-booster group). Serial follow-up data of children and baseline data of their mothers were collected and between-group differences were analyzed.Results:The incidence of OBI varied dynamically during follow-up, with 37.14% (78/210), 19.09% (42/220), 20.85% (44/211), 31.61% (61/193), 8.65% (18/208) and 12.71% (30/236) at 7 months, 1, 2, 3, 4, and 8 years of age. At 8 years of age, the negative conversion rate of HBV DNA in the booster group was significantly higher than that in non-booster group [57.89% (11/19) vs. 30.51% (18/59), p=0.032]. For children without OBI at 7 months old, the incidence of OBI in booster group was significantly lower than that in non-booster group [25.64% (10/39) vs. 67.74% (63/93), p<0.001].Conclusions:The incidence of OBI in maternal HBsAg-positive children was high, serum HBV DNA in children with OBI was intermittently positive at low levels, and a booster HepB in infancy reduced the incidence of OBI in children with HBsAg-positive mothers.