Chronic hepatitis B (CHB) is a global epidemic that can lead to severe liver diseases such as hepatic failure, liver cirrhosis, and hepatocellular carcinoma. Tenofovir alafenamide (TAF), a first-line antiviral drug for CHB, effectively suppresses viral replication but may cause dyslipidemia and alter gut microbiota with long-term use. This study aimed to investigate the effects of a probiotic consortium on the gut-liver axis in TAF-treated CHB patients. In a 12-week randomized double-blind trial, 84 CHB patients receiving TAF monotherapy were assigned to either probiotics (3 × 10¹⁰ CFU/day) or placebo. The primary outcomes were lipid profiles and gut microbiota composition, while secondary outcomes included liver function tests and gastrointestinal symptoms. Results showed that the probiotic group had stable atherogenic lipids compared to placebo. Microbiota analysis revealed specific modulation with increased Parabacteroides (2.1-fold, p = 0.018) and decreased Erysipelotrichaceae_UCG-003 (58

Background: Porto-sinusoidal vascular disorder (PSVD) is often misdiagnosed as liver cirrhosis due to overlapping clinical presentations and imaging features. This study conducted a blinded, independent imaging review to identify and compare the distinct imaging features between the two diseases, and to develop and validate a predictive model for differentiating PSVD from cirrhosis. Methods: Patients with histologically and clinically confirmed PSVD or cirrhosis and available contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans were retrospectively enrolled in the study. Imaging features were independently and systematically analyzed by two abdominal radiologists, who were blinded to the case grouping. Inter-reader discrepancies were resolved by consensus. The key features for analysis included liver surface nodularity (LSN), regenerative nodules (RNs), signs of portal hypertension (PH), and reticular delayed enhancement of the hepatic parenchyma. CT, MRI, and combined predictive models were developed to identify the top performing model, which was then selected and validated on an independent test cohort. Model performance was evaluated based on the area under the curve (AUC), sensitivity, and specificity. Results: In total, 106 patients with PSVD and 104 patients with cirrhosis were included for imaging evaluation and model development. The data of an additional 36 patients with PSVD and 51 patients with cirrhosis were collected for independent model testing. PSVD exhibited the same pronounced PH imaging features as cirrhosis, including grade 1-3 splenomegaly (77/106, 72.6% vs. 67/104, 64.4%; P>0.05), collateral vessels (103/106, 97.2% vs. 94/104, 90.4%; P>0.05), and ascites (35/106, 33.0% vs. 32/104, 30.8%; P>0.05). In addition, PSVD showed more increased small branches of intrahepatic blood vessels than cirrhosis (79/106, 74.5% vs. 41/104, 39.4%; P<0.001). Conversely, PSVD exhibited fewer cirrhosis-specific imaging features, such as reticular delayed enhancement of the hepatic parenchyma (10/48, 20.8% vs. 50/53, 94.3%; P<0.001), RNs (3/48, 6.3% vs. 29/53, 54.7%; P<0.001), and LSN (27/106, 25.5% vs. 75/104, 72.1%; P<0.001). In the validation set, the MRI model [AUC: 0.970, 95% confidence interval (CI): 0.912-1.0], which incorporated four imaging features (reticular delayed enhancement, RNs, LSN and increased small intrahepatic vascular branches), showed superior discriminatory performance compared to the CT model (AUC: 0.825, 95% CI: 0.646-1.0), with a sensitivity of 0.818 and a specificity of 0.889. While the combined model (AUC: 0.97, 95% CI: 0.912-1.0) did not improve upon the performance of the MRI model alone, with sensitivity of 0.821 and specificity of 0.889. Thus, we recommend the MRI model as the preferred modality for diagnosing PSVD. The MRI model also achieved optimal performance in the independent test set, with an AUC of 0.988 (95% CI: 0.967-1), sensitivity of 0.972, and specificity of 0.826. Conclusions: Patients presenting with severe PH imaging features but lacking typical cirrhosis imaging features should be thoroughly evaluated for PSVD. MRI is the preferred imaging modality. Our MRI-based predictive model reliably differentiates PSVD from cirrhosis, offering a non-invasive method for enhancing the suspicion of PSVD.

ABSTRACT Chronic hepatitis B (CHB) remains incurable due to the immune system's tolerance toward the hepatitis B virus (HBV) surface antigen (HBsAg). This study aimed to achieve a functional cure by breaking HBV tolerance through immunotherapy. CHB patients were treated with either standard nucleotide analog (NA) therapy (Adefovir Dipivoxil, ADV) (Cohort 1) or ADV combined with interferon‐alpha (IFN‐α) (Cohort 2). Additionally, a third cohort received the THRIL‐GM‐Vac regimen: three low‐dose GM‐CSF injections followed by one dose of the HBV vaccine, alongside standard treatment. THRIL‐GM‐Vac treatment (Cohort 3) achieved a significant 2log10 reduction in HBsAg levels in 21.7% of participants, and 8.7% HBsAg clearance in Cohort 3 compared to 0% and 4.17% in Cohorts 1 and 2, respectively. Furthermore, THRIL‐GM‐Vac significantly reduced HBV‐specific tolerogenic T cells (Tregs), explaining the sustained HBsAg decrease. Upregulation of anti‐HBV T cell responses confirmed THRIL‐GM‐Vac's ability to disrupt HBV tolerance and enhance HBsAg‐specific cellular immunity. This suggests its potential effectiveness in treating individuals with moderate to low HBsAg levels. THRIL‐GM‐Vac treatment in Cohort 3 resulted in 8.7% HBsAg clearance alongside Treg depletion and enhanced anti‐viral T cell responses. These findings present a promising strategy to overcome immunotolerance and potentially combat chronic HBV infection.

Background & Aims: Nucleo(s)tide analogue (NUC) cessation can lead to hepatitis B surface antigen (HBsAg) clearance but also a high rate of virological relapse. However, the effect of pegylated interferon alpha-2a (PegIFN-alpha-2a) on virological relapse after NUC cessation is unknown. Therefore, this study aimed to evaluate the effect of switching from NUC to PegIFN-alpha-2a treatment for 48 weeks on virological relapse up to week 96. Methods: In this multicenter randomized-controlled clinical trial, 180 non-cirrhotic patients with HBeAg-negative chronic hepatitis B on continuous NUC therapy for >=-2.5 years, with HBV DNA levels <60 IU/ml, were randomized to discontinue NUC therapy (n = 90) or receive 48 weeks of PegIFN-alpha-2a treatment (n = 90). Patients were followed up for up to 96 weeks. The primary endpoint was the virological relapse rate up to week 96. Results: Intention-to-treat analysis revealed patients in the interferon monotherapy group had significantly lower cumulative virological relapse rates than the NUC cessation group until week 96 (20.8% vs. 53.6%, p <0.0001). Consistently, a significantly lower proportion of patients in the interferon monotherapy group had virological relapse than those in the NUC cessation group at 48 weeks off treatment (17.8% vs. 36.7%, p = 0.007). The virological relapse rate positively correlated with HBsAg levels in the NUC cessation group. The interferon monotherapy group had a lower cumulative clinical relapse rate (7.8% vs. 20.9%, p = 0.008) and a higher HBsAg loss rate (21.5% vs. 9.0%, p = 0.03) than the NUC cessation group. Conclusions: Switching from NUC to PegIFN-alpha-2a treatment for 48 weeks significantly reduces virological relapse rates and leads to higher HBsAg loss rates than NUC treatment cessation alone in patients with HBeAg-negative chronic hepatitis B. (c) 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

BACKGROUND:Porto-Sinusoidal Vascular Disorder (PSVD) is a non-cirrhotic vascular liver disease associated with or without signs of portal hypertension (PH). Chronic hepatitis B virus (HBV) infection frequently coexists with PSVD, but its clinical impact remains unclear. This study investigates the clinical and histopathological features of PSVD with and without chronic HBV infection. METHODS:Liver biopsy records of 2007 patients from Huashan Hospital, Shanghai, China (2017-2024), were reviewed, identifying 73 cases of PSVD, of which 31 had concurrent chronic HBV infection. Clinical, histological, and imaging data were analyzed from diagnosis to follow-up. A matched analysis by age and gender compared PSVD patients with and without HBV infection. RESULTS:HBV prevalence among PSVD patients (43.1%) was significantly higher than in the general population (6.1%, < 0.0001). HBV-positive patients had lower nodular regenerative hyperplasia (p = 0.008) and higher nonzonal sinusoidal dilation (p = 0.068). The HBV-negative group had higher BMI and more severe PH manifestations, including varices and portosystemic collaterals (p < 0.0001). Liver enzyme levels differed significantly between groups (p < 0.05). CONCLUSION:HBV-infected PSVD patients exhibit milder PH and distinct histopathological features. Routine PSVD screening is recommended in long-term HBV management.

Background and Aim Drug development for non-alcoholic fatty liver disease (NAFLD) is frequently hampered by the poor translation of preclinical findings into clinical efficacy. To address this critical challenge, we developed a quantitative cross-species model designed to predict human clinical outcomes from efficacy data in mouse models. Methods We performed a model-based meta-analysis (MBMA) of 18 NAFLD drugs, integrating data from published clinical trials with corresponding preclinical mouse studies identified through a systematic search of the Embase and PubMed databases. Using the change in alanine aminotransferase (ΔALT) as the primary biomarker, we constructed an exponential model to define the relationship between ALT reduction in mice and the placebo-corrected response in humans (ΔΔALT). The model's predictive performance was then externally validated using an independent dataset from a study of Linggui Zhugan Tang (LGZGT). Results The analysis yielded a robust exponential model, which revealed that a reduction in mouse ΔALT of at least 53.3 U/L is required for a drug to show superiority over placebo in human trials. A more substantial decrease of 128.3 U/L in mice predicted a clinical efficacy exceeding that of Resmetirom, the first FDA-approved therapy for this condition. The model's predictive power was successfully confirmed through external validation with the LGZGT data. Conclusions This study developed a cross-species efficacy model from NAFLD clinical and mouse data, revealing an exponential relationship between human and mouse ALT levels. This provides quantitative thresholds for preclinical screening to improve drug development success rates.

B- and T-lymphocyte attenuator (BTLA) levels are increased in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This condition is characterized by susceptibility to infection and T-cell immune exhaustion. However, whether BTLA can induce T-cell immune exhaustion and increase the risk of infection remains unclear. Here, we report that BTLA levels are significantly increased in the circulating and intrahepatic CD4 + T cells from patients with HBV-ACLF, and are positively correlated with disease severity, prognosis, and infection complications. BTLA levels were upregulated by the IL-6 and TNF signaling pathways. Antibody crosslinking of BTLA activated the PI3K-Akt pathway to inhibit the activation, proliferation, and cytokine production of CD4 + T cells while promoting their apoptosis. In contrast, BTLA knockdown promoted their activation and proliferation. BTLA -/- ACLF mice exhibited increased cytokine secretion, and reduced mortality and bacterial burden. The administration of a neutralizing anti-BTLA antibody reduced Klebsiella pneumoniae load and mortality in mice with ACLF. These data may help elucidate HBV-ACLF pathogenesis and aid in identifying novel drug targets.

We evaluated the diagnostic accuracy of various international guideline criteria for identifying HBeAg-positive chronic HBV infection patients with no significant liver disease. A total of 1108 HBeAg-positive CHB patients were retrospectively enrolled. The guidelines assessed included those from the European Association for the Study of the Liver (EASL) 2017, the American Association for the Study of the Liver Disease (AASLD) 2018, the Asian Pacific Association for the Study of the Liver (APASL) 2015 and the Chinese Society of Hepatology (CSH) 2022. The CSH criteria demonstrated a higher proportion of patients with G0-1 and S0-1 (82.9%) compared to the EASL (75.9%), AASLD (75.3%) and APASL groups (58.8%). Additionally, the CSH criteria exhibited a significantly higher predictive value (AUC 0.782, 95% CI 0.754-0.809) than the EASL (AUC 0.765, 95% CI 0.737-0.793), AASLD (AUC 0.749, 95% CI 0.720-0.778) and APASL (AUC 0.720, 95% CI 0.690-0.750) criteria for identifying G0-1 and S0-1. Adding quantitative HBsAg levels (> 104 IU/mL) to the EASL, AASLD and APASL criteria improved diagnostic performance. Consequently, the CSH guideline thresholds showed higher accuracy in identifying Chinese HBeAg-positive patients with no significant liver disease compared to EASL, AASLD and APASL criteria, emphasising the importance of considering quantitative HBsAg in the evaluation of HBeAg-positive chronic HBV infection.

RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4+ T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient’s T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOHC82Y, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.