Immunosuppression induces regression of fibrosis in primary biliary cholangitis with moderate-to-severe interface hepatitis.

BACKGROUND: In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy. METHODS: We conducted a multicenter study involving PBC patients with moderate-to-severe interface hepatitis who underwent paired liver biopsies. Firstly, we compared the efficacy of the combination therapy with UDCA monotherapy on improving biochemistry, histology, survival rates, and prognosis. Subsequently we investigated the predictors of a beneficial response. RESULTS: This retrospective cohort study with prospectively collected data was conducted in China from January 2009 to April 2023. Of the 198 enrolled patients, 32 underwent UDCA monotherapy, while 166 received combination therapy, consisting of UDCA combined with prednisolone, prednisolone plus mycophenolate mofetil (MMF), or prednisolone plus azathioprine (AZA). The monotherapy group was treated for a median duration of 37.6 months (IQR 27.5-58.1), and the combination therapy group had a median treatment duration of 39.3 months (IQR 34.5-48.8). The combination therapy showed a significantly greater efficacy in reducing fibrosis compared to UDCA monotherapy, with an 8.3-fold increase in the regression rate (from 6.3% to 52.4%, P < 0.001). Other parameters, including biochemistry, survival rates, and prognosis, supported its effectiveness. Baseline IgG >1.3 × ULN and ALP <2.4 × ULN were identified as predictors of regression following the combination therapy. A predictive score named FRS, combining these variables, accurately identified individuals achieving fibrosis regression with a cut-off point of ≥ -0.163. The predictive value was validated internally and externally. CONCLUSION: Combination therapy with IS improves outcomes in PBC patients with moderate-to-severe interface hepatitis compared to UDCA monotherapy. Baseline IgG and ALP are the most significant predictors of fibrosis regression. The new predictive score, FRS, incorporating baseline IgG and ALP, can effectively identify individuals who would benefit from the combination therapy.

Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1.

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∗35:01 (p = 8.17 × 10-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗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∗35:01, HLA-B∗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.

Effects of exposure to the explosive and environmental pollutant 2,4,6-trinitrotoluene on ovarian follicle development in rats.

Although 2,4,6-trinitrotoluene (TNT) is a dangerous carcinogen in environmental pollution, information on the reproductive effects of TNT explosive contamination is limited. To explore the possible ovarian effects, TNT explosive-exposed rat models were established, and Wistar female rats were exposed to low and high TNT (40 g and 80 g, air and internal) explosives. After a month of exposure, the estrous cycle, ovarian histopathology, and follicle counting were conducted. Serum hormones follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), progesterone, testosterone, and estradiol were detected, and the mRNA and protein expression of steroidogenic enzymes were measured. The results showed that the diestrus phase duration was significantly (P < 0.05) increased in the high TNT-exposed groups. In addition, the proportions of preantral follicles were significantly (P < 0.05) decreased in the high TNT-exposed groups, as well as the proportions of atretic follicles. The serum estradiol levels were significantly (P < 0.05) increased, and the follicle-stimulating hormone and luteinizing hormone levels were significantly (P < 0.05) decreased in the high TNT-exposed groups. The mRNA levels of steroidogenic acute regulatory protein (Star), cytochrome P450 cholesterol side chain cleavage (Cyp11a1, Cyp17a1 and Cyp19a1), hydroxysteroid dehydrogenase 3b (Hsd3b) and steroidogenic factor-1 (SF-1) were significantly (P < 0.05) increased in the TNT-exposed groups. The protein levels of Star, Cyp11a1 and Hsd3b were increased (P < 0.05) in the TNT-exposed groups. These results indicate that the exposure of rats to TNT explosive can subsequently affect ovarian follicle development, suggesting that the mechanism may involve disrupting steroidogenesis.

Primary hepatic angiosarcoma with noncirrhotic portal hypertension: A case report.

Background: Primary hepatic angiosarcoma (PHA) is a rare malignant tumor of mesothelial tissue origin in the liver. The diagnosis of PHA relies on pathology, and it is frequently misdiagnosed as multiple hepatic hemangioma. Noncirrhotic portal hypertension is a relatively rare pathological manifestation, and there are few reports of PHA as an uncommon cause of noncirrhotic portal hypertension. Case summary: A 36-year-old male was admitted with abnormal liver function and suspected drug-induced liver injury (DILI), initially manifesting as multifocal hepatic hemangioma. The liver biopsy revealed features of noncirrhotic portal hypertension (NCPH), and the patient was eventually diagnosed with multifocal hepatic angiosarcoma. Conclusion: Patients with PHA may present with NCPH in the liver due to injury to hepatic sinusoids; therefore, it is necessary to consider the possibility of unsampled vascular malignancy when hepatic masses are identified, and the histology is consistent with PHA.

TLR8 agonist partially improves IFN-γ deficiency of NK cells in chronic hepatitis B through the synergy of monocytes.

BACKGROUND: Natural killer (NK) cells exhibit a selective deficiency of IFN-γ production in chronic hepatitis B (CHB). Toll-like receptor 8 (TLR8) agonists could induce IFN-γ production in immune cells, although their effects on the deficiency in NK cells remain unclear. AIMS: To investigate TLR8 expression in NK cells and the effect of TLR8 agonists in patients with CHB METHODS: We enrolled 32 patients with CHB and 19 healthy controls to assess TLR8 expression and IFN-γ production in NK cells. The sorted NK cells and monocytes were co-cultured to compare the extent of IFN-γ and IL-10 production after TLR8 agonist ssRNA40 stimulation. The synergic effect of NK cells and monocytes was assessed by blocking IL-12 and IL-18. We recruited another 22 patients with CHB undergoing nucleotide analogue (NA) therapy to explore the impact of antiviral treatment on the ssRNA40-mediated response of NK cells. RESULTS: In patients with CHB, TLR8 expression in NK cells was up-regulated, accompanied by insufficient IFN-γ production. The enhanced IFN-γ secretion by ssRNA40 in NK cells depended on monocyte-derived IL-12 and IL-18. NK cells displayed an imbalanced response to ssRNA40 in patients with CHB with a weak increase in IFN-γ despite a higher IL-10 production. The response was improved in patients with CHB undergoing NA therapy. CONCLUSIONS: In patients with CHB, targeting TLR8 partially rescues the IFN-γ insufficiency in NK cells. However, NK cells show an inhibitory response to TLR8 agonist stimulation. TLR8 agonist combined with NA may enhance the antiviral effect of NK cells.

Noninvasive diagnostic value of indocyanine green retention test in patients with esophagogastric varices in liver cirrhosis.

OBJECTIVE: This study aimed to evaluate the value of the indocyanine green retention test (ICG-R15) as a noninvasive predictor of gastroesophageal varices (GOV) in cirrhosis. METHODS: A total of 629 patients with cirrhosis who were admitted to Mengchao Hepatobiliary Hospital of Fujian Medical University between June 2016 and September 2020 (450 in the trial group and 179 in the validation group) were selected. The trial group was divided into a GOV group and a non-GOV group based on gastroscopic findings. The two group's ICG results, clinical hematological, biochemical, and ultrasound parameters were compared. A predictive model for the noninvasive diagnosis of GOV was developed by applying binary logistic regression analysis and compared with previous common noninvasive diagnostic methods, followed by model validation in a validation group. RESULTS: ICG-R15 is positively correlated with the degree of varicose veins. Univariate and multifactorial logistic regression analyses showed that PLT, PT, ICG-R15, splenic length, splenic vein diameter, and the presence of ascites were independent predictors of GOV. Predictive equation 1 for GOV was constructed based on the above factors: Logistic (Y1) = 1.327 × PLT + 0.691 × PT + 1.110 × ICG-R15 + 0.581 × SVD + 0.815 × SD + 1.130 × presence of ascites - 2.133, which predicted GOV in cirrhosis with an AUC of 0.861, sensitivity 84.5%, and specificity 74.1%. As the internal diameter of the splenic vein and the long diameter of the spleen are influenced by subjective factors and data are not easily available, we removed these two factors and constructed the prediction equation logistic (Y2) = 1.516 × PLT + 0.856 × PT + 1.135 × R15 + 1.297 × presence of ascites - 1.513. AUC for predicting GOV was also high at 0.850, with a sensitivity of 75.3% and a specificity of 83.2%. Similar results were obtained in the validation group. However, the previous GOV prediction models ARPI, AAR, FIB-4, Lok, FI, and King had AUCs of 0.731, 0.643, 0.781, 0.763, 0.735, and 0.730, respectively, in our trial group, with only low-to-moderate diagnostic efficacy. CONCLUSION: ICG-R15 correlates with the severity of GOV in cirrhosis, and the models based on it can further improve the noninvasive diagnostic efficacy of GOV.

MELD score < 18 rule out 28-day ACLF development among inpatients with hepatitis B-related previous compensated liver disease.

The acute-on-chronic liver failure (ACLF) development is highly dynamic. Currently, no satisfactory algorithm identifies patients with HBV at risk of this complication. The aim of the study was to characterize ACLF development in hospitalized HBV-related patients without previous decompensation and to test the performance of traditional prognostic models in ruling out ACLF development within 28 days on admission we conducted a cohort study. Two multi-center cohorts with hospitalized HBV-related previous compensated patients were analyzed. Performances of MELD, MELD-Na, CLIF-C AD, and CLIF-C ACLF-D in ruling out ACLF development within 28 days were compared and further validated by ROC analyses. In the derivation cohort (n = 892), there were 102 patients developed ACLF within 28 days, with profound systemic inflammatory levels and higher 28-day mortality rate (31.4% vs. 1.0%) than those without ACLF development. The MELD score (cut-off = 18) achieved acceptable missing rate (missed/total ACLF development) at 2.9%. In the validation cohort (n = 1656), the MELD score (<18) was able to rule out ACLF development within 28 days with missing rate at 3.0%. ACLF development within 28 days were both lower than 1% (0.6%, derivation cohort; 0.5%, validation cohort) in patients with MELD < 18. While in patients with MELD ≥ 18, 26.6% (99/372, derivation cohort) and 17.8% (130/732, validation cohort) developed into ACLF within 28 days, respectively. While MELD-Na score cut-off at 20 and CLIF-AD score cut-off at 42 did not have consistent performance in our two cohorts. MELD < 18 was able to safely rule out patients with ACLF development within 28 days in HBV-related patients without previous decompensation, which had a high 28-day mortality.

Design for a Multicentre Prospective Cohort for the Assessment of Platelet Function in Patients with Hepatitis-B-Virus-Related Acute-on-Chronic Liver Failure.

Background: Acute-on-chronic liver failure (ACLF) has high short-term mortality and lacks sufficient medical therapy. Available algorithms are unable to precisely predict short-term outcomes or safely stratify patients with ACLF as emergent liver transplantation candidates. Therefore, a personalized prognostic tool is urgently needed. Purpose: Platelet function and its clinical significance in ACLF patients with chronic hepatitis B virus (HBV) infection have not been investigated. This study aimed to assess changes in platelet function using thromboelastography (TEG) and platelet mapping (TEG-PM) in HBV-related ACLF patients. Methods: Chronic liver disease patients with acute decompensation or acute hepatic injury were recruited. The derivation cohort enrolled HBV-related patients at Nanfang Hospital. HBV-related and non-HBV-related patients were both enrolled in internal and external validation cohorts at seven university hospitals. TEG and TEG-PM were performed at baseline in the derivation cohort and baseline, day 7, and day 14 in the validation cohorts. The primary outcome was all-cause 28-day mortality. Status check and new-onset complications were recorded during the 3-month follow-up, but status check will extend to 5 years. Conclusion and Future Plans: In this study, 586 participants were enrolled, including 100 in derivation cohort, 133 in internal validation cohort, and 353 in external validation cohort. Biomaterials, including plasma, serum, urine, and some explanted liver tissues, were collected from these patients. A 3-month follow-up with survival status was completed. The baseline characteristics indicated that 51% of the patients had adenosine diphosphate (ADP)-hyporesponsive circulating platelets. The prognostic potential of platelet function will be explored in the derivation cohort (HBV-related ACLF patients) and further substantiated in the validation cohorts (HBV-related and non-HBV-related ACLF patients). Biosamples are currently used to explore the underlying mechanisms related to ADP-hyporesponsive platelets. The ongoing proteomic and metabolic analyses will provide new insights into the pathogenesis of extrahepatic organ failures in ACLF patients.

Advantages of a Novel Model for Predicting Hepatic Fibrosis in Chronic Hepatitis B Virus Carriers Compared with APRI and FIB-4 Scores.

Background and Aims: Aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) are widely used to assess liver fibrosis in chronic hepatitis B virus (HBV) infection. Currently, the definition of normal alanine aminotransferase (ALT) is controversial. We aimed to examine the diagnostic value of APRI and FIB-4 in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. Methods: 581 chronic HBV carriers were divided into the following four groups based on different ULNs for ALT: chronic HBV carriers I, II, III, and IV. Furthermore, 106 chronic HBV carriers formed an external validation group. Predictive values of APRI and FIB-4 were elucidated using the area under the curve (AUC). A liver fibrosis-predictive model-GPSA (named for its measure of gamma glutamyl transpeptidase, platelet count, HBsAg and albumin) was developed using multivariate logistic regression analysis. Results: In chronic HBV carriers I, the AUCs of APRI and FIB-4 were 0.680 and 0.609 for significant fibrosis and 0.678 and 0.661 for cirrhosis, respectively. The AUCs of GPSA for significant fibrosis in the training group, internal group, and external validation group were 0.877, 0.837, and 0.871, respectively. The diagnostic value of GPSA differed among chronic HBV carriers I, II, III, and IV, with AUCs for significant fibrosis being 0.857, 0.853, 0.868, and 0.905 and AUCs for cirrhosis being 0.901, 0.905, 0.886, and 0.913, respectively. GPSA showed a higher diagnostic value than APRI and FIB-4 for predicting significant fibrosis in the four groups. Conclusions: The GPSA model allows for accurate diagnosis of liver fibrosis in chronic HBV carriers with different ULN for ALT.

Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease. APPROACH AND RESULTS: We conducted a case-control association study of 1,622 Chinese patients with AIH type 1 and 10,466 population controls from two independent cohorts. A meta-analysis was performed to ascertain variants associated with AIH type 1. A single-nucleotide polymorphism within the human leukocyte antigen (HLA) region showed the strongest association with AIH (rs6932730: OR = 2.32; p = 9.21 × 10-73 ). The meta-analysis also identified two non-HLA loci significantly associated with AIH: CD28/CTLA4/ICOS on 2q33.3 (rs72929257: OR = 1.31; p = 2.92 × 10-9 ) and SYNPR on 3p14.2 (rs6809477: OR = 1.25; p = 5.48 × 10-9 ). In silico annotation, reporter gene assays, and CRISPR activation experiments identified a distal enhancer at 2q33.3 that regulated expression of CTLA4. In addition, variants near STAT1/STAT4 (rs11889341: OR = 1.24; p = 1.34 × 10-7 ), LINC00392 (rs9564997: OR = 0.81; p = 2.53 × 10-7 ), IRF8 (rs11117432: OR = 0.72; p = 6.10 × 10-6 ), and LILRA4/LILRA5 (rs11084330: OR = 0.65; p = 5.19 × 10-6 ) had suggestive association signals with AIH. CONCLUSIONS: Our study identifies two novel loci (CD28/CTLA4/ICOS and SYNPR) exceeding genome-wide significance and suggests four loci as potential risk factors. These findings highlight the importance of costimulatory signaling and neuro-immune interaction in the pathogenesis of AIH.

Sulfated Polysaccharides from Enteromorpha prolifera Attenuate Lipid Metabolism Disorders in Mice with Obesity Induced by a High-Fat Diet via a Pathway Dependent on AMP-Activated Protein Kinase.

BACKGROUND: Obesity-related metabolic diseases have recently evoked worldwide attention. Studies have demonstrated that Enteromorpha polysaccharide (EP) exerts lipid-lowering effects, but the underlying mechanism remains unclear. OBJECTIVES: We investigated whether EP regulates lipid metabolism disorders in mice with high-fat diet (HFD)-induced obesity via an AMP-activated protein kinase (AMPK)-dependent pathway. METHODS: Six-week-old male C57BL/6J mice (18 ± 2 g) were fed a normal diet (ND; 10% energy from fats) or an HFD (60% energy from fats) for 6 weeks to induce obesity and treated intragastrically with EP (200 mg/kg body weight) or distilled water (10 mL/kg body weight) for 8 weeks. Biochemical indicators, AMPK-dependent pathways, and lipid metabolism-related genes were evaluated to assess the effects of EP on HFD-induced lipid metabolism disorders. The essential role of AMPK in the EP-mediated regulation of lipid metabolism was confirmed using HFD-fed male Ampka2-knockout mice (aged 6 weeks; 17 ± 2 g) treated or not treated with the above-mentioned dose of EP. The data were analyzed by t-tests, 2-factor and 1-way ANOVAs. RESULTS: Compared to the ND, the HFD resulted in a greater body weight (24.3%), perirenal fat index (2.2-fold), and serum total cholesterol (24.66%) and LDL cholesterol (1.25-fold) concentrations (P < 0.05) and dysregulated the AMPK-dependent pathway and the expression of most lipid metabolism-related genes (P < 0.05). Compared to the HFD, EP treatment resulted in a lower perirenal fat index (31.22%) and LDL cholesterol concentration (23.98%) and partly reversed the dysregulation of the AMPK-dependent pathway and the altered expression of lipid metabolism-related genes (P < 0.05). Ampka2 knockout abolished the above-mentioned effects of EP in obese mice and the EP-mediated effects on the expression of lipid metabolism-related genes (P > 0.05). CONCLUSIONS: These findings suggest that EP can ameliorate lipid metabolism disorders in mice with HFD-induced obesity via an AMPK-dependent pathway.

Sulfated Polysaccharides from Enteromorpha prolifera Attenuate Lipid Metabolism Disorders in Mice with Obesity Induced by a High-Fat Diet via a Pathway Dependent on AMP-Activated Protein Kinase.

BACKGROUND: Obesity-related metabolic diseases have recently evoked worldwide attention. Studies have demonstrated that Enteromorpha polysaccharide (EP) exerts lipid-lowering effects, but the underlying mechanism remains unclear. OBJECTIVES: We investigated whether EP regulates lipid metabolism disorders in mice with high-fat diet (HFD)-induced obesity via an AMP-activated protein kinase (AMPK)-dependent pathway. METHODS: Six-week-old male C57BL/6J mice (18 ± 2 g) were fed a normal diet (ND; 10% energy from fats) or an HFD (60% energy from fats) for 6 weeks to induce obesity and treated intragastrically with EP (200 mg/kg body weight) or distilled water (10 mL/kg body weight) for 8 weeks. Biochemical indicators, AMPK-dependent pathways, and lipid metabolism-related genes were evaluated to assess the effects of EP on HFD-induced lipid metabolism disorders. The essential role of AMPK in the EP-mediated regulation of lipid metabolism was confirmed using HFD-fed male Ampka2-knockout mice (aged 6 weeks; 17 ± 2 g) treated or not treated with the above-mentioned dose of EP. The data were analyzed by t-tests, 2-factor and 1-way ANOVAs. RESULTS: Compared to the ND, the HFD resulted in a greater body weight (24.3%), perirenal fat index (2.2-fold), and serum total cholesterol (24.66%) and LDL cholesterol (1.25-fold) concentrations (P < 0.05) and dysregulated the AMPK-dependent pathway and the expression of most lipid metabolism-related genes (P < 0.05). Compared to the HFD, EP treatment resulted in a lower perirenal fat index (31.22%) and LDL cholesterol concentration (23.98%) and partly reversed the dysregulation of the AMPK-dependent pathway and the altered expression of lipid metabolism-related genes (P < 0.05). Ampka2 knockout abolished the above-mentioned effects of EP in obese mice and the EP-mediated effects on the expression of lipid metabolism-related genes (P > 0.05). CONCLUSIONS: These findings suggest that EP can ameliorate lipid metabolism disorders in mice with HFD-induced obesity via an AMPK-dependent pathway.

A novel HBsAg-based model for predicting significant liver fibrosis among Chinese patients with immune-tolerant phase chronic hepatitis B: a multicenter retrospective study.

BACKGROUND: Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) in the immune-tolerant (IT) phase is significantly associated with high risk for hepatocellular carcinoma, suggesting requirement for antiviral therapy, particularly for those with histological liver injury. This study aimed to establish a non-invasive panel to assess significant liver fibrosis in IT chronic hepatitis B. PATIENTS AND METHODS: One hundred and thirteen IT-phase CHB patients were retrospectively recruited and divided into two histopathological groups according to their histological profiles: necroinflammatory score <4 (N <4)/fibrosis score ⩽1 (F0-1), and necroinflammatory score ⩾4 (N ⩾4)/fibrosis score ⩾2 (F2-4). Multivariate analysis was conducted to assess the predictive value of the non-invasive model for significant liver fibrosis. RESULTS: IT-phase CHB patients with N <4/F0-1 had significantly higher HBsAg levels than those with N ⩾4/F2-4. The optimal HBsAg level of log 4.44 IU/mL for significant liver fibrosis (F ⩾2) gave an area under the curve (AUC) of 0.83, sensitivity of 81.1%, specificity of 81.6%, positive predictive value (PPV) of 68.2%, and negative predictive value (NPV) of 89.9%. An IT model with HBsAg and gamma glutamyl transpeptidase (GGT) in combination was established, and it had an AUC of 0.86, sensitivity of 86.5%, specificity of 81.6%, PPV of 69.6, NPV of 92.5, and accuracy of 83.2% to predict F ⩾2 in the IT-phase CHB patients. Notably, the IT model exhibited higher predictive value than the existing aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 score, and GGT to platelet ratio. CONCLUSION: The established IT model combining HBsAg and GGT has good performance in predicting significant liver fibrosis in IT-phase CHB patients.

Tri-typing of hepatitis B-related acute-on-chronic liver failure defined by the World Gastroenterology Organization.

BACKGROUND AND AIM: Tri-typing of acute-on-chronic liver failure (ACLF), as proposed by the World Gastroenterology Organization (WGO), has not been validated in patients infected with hepatitis B virus (HBV). We aim to compare the three types of ACLF patients in clinic characteristics. METHODS: Hospitalized ACLF patients with chronic hepatitis B from five hepatology centers were retrospectively selected and grouped according to the WGO classification. For each group, we investigated laboratory tests, precipitating events, organ failure, and clinical outcome. RESULTS: Compared with type-B (n = 262, compensated cirrhosis) and type-C (n = 129, decompensated cirrhosis) ACLF, type-A patients (n = 195, non-cirrhosis) were associated with a younger age, the highest platelet counts, the highest aminotransferase levels, and the most active HBV replications. HBV reactivation were more predominant in type-A, while bacterial infections in type-B and type-C ACLF cases. Liver failure (97.4%) and coagulation failure (86.7%) were most common in type-A compared with type-B or type-C ACLF patients. Kidney failure was predominantly identified in type-C subjects (41.9%) and was highest (23/38, 60.5%) in grade 1 ACLF patients. Furthermore, type-C ACLF showed the highest 28-day (65.2%) and 90-day (75.3%) mortalities, compared with type-A (48.7% and 54.4%, respectively) and type-B (48.4% and 62.8%, respectively) ACLF cases. Compared with type-A (11.7%) ACLF patients, the increased mortality from 28 to 90 days was higher in type-B (31.6%) and type-C (37.5%). CONCLUSION: Tri-typing of HBV-related ACLF in accordance with the WGO definition was able to distinguish clinical characteristics, including precipitating events, organ failure, and short-term prognosis in ACLF patients.

Serum ceruloplasmin can predict liver fibrosis in hepatitis B virus-infected patients.

BACKGROUND: The presence of significant liver fibrosis in hepatitis B virus (HBV)-infected individuals with persistently normal serum alanine aminotransferase (PNALT) levels is a strong indicator for initiating antiviral therapy. Serum ceruloplasmin (CP) is negatively correlated with liver fibrosis in HBV-infected individuals. AIM: To examine the potential value of serum CP and develop a noninvasive index including CP to assess significant fibrosis among HBV-infected individuals with PNALT. METHODS: Two hundred and seventy-five HBV-infected individuals with PNALT were retrospectively evaluated. The association between CP and fibrotic stages was statistically analyzed. A predictive index including CP [Ceruloplasmin hepatitis B virus (CPHBV)] was constructed to predict significant fibrosis and compared to previously reported models. RESULTS: Serum CP had an inverse correlation with liver fibrosis (r = -0.600). Using CP, the areas under the curves (AUCs) to predict significant fibrosis, advanced fibrosis, and cirrhosis were 0.774, 0.812, and 0.853, respectively. The CPHBV model was developed using CP, platelets (PLT), and HBsAg levels to predict significant fibrosis. The AUCs of this model to predict significant fibrosis, advanced fibrosis, and cirrhosis were 0.842, 0.920, and 0.904, respectively. CPHBV was superior to previous models like the aspartate aminotransferase (AST)-to-PLT ratio index, Fibrosis-4 score, gamma-glutamyl transpeptidase-to-PLT ratio, Forn's score, and S-index in predicting significant fibrosis in HBV-infected individuals with PNALT. CONCLUSION: CPHBV could accurately predict liver fibrosis in HBV-infected individuals with PNALT. Therefore, CPHBV can be a valuable tool for antiviral treatment decisions.

Transmission dynamics of SARS-COV-2 in China: impact of public health interventions

COVID-19 has become a global pandemic. However, the impact of the public health interventions in China needs to be evaluated. We established a SEIRD model to simulate the transmission trend of China. In addition, the reduction of the reproductive number was estimated under the current forty public health interventions policies. Furthermore, the infection curve, daily transmission replication curve, and the trend of cumulative confirmed cases were used to evaluate the effects of the public health interventions. Our results showed that the SEIRD curve model we established had a good fit and the basic reproductive number is 3.38 (95% CI, 3.25-3.48). The SEIRD curve show a small difference between the simulated number of cases and the actual number; the correlation index (H2) is 0.934, and the reproductive number (R) has been reduced from 3.38 to 0.5 under the current forty public health interventions policies of China. The actual growth curve of new cases, the virus infection curve, and the daily transmission replication curve were significantly going down under the current public health interventions. Our results suggest that the current public health interventions of China are effective and should be maintained until COVID-19 is no longer considered a global threat.

Activation of the Toll­like receptor 2 signaling pathway inhibits the proliferation of HCC cells in vitro.

Toll­like receptor 2 (TLR2), is an important pattern recognition receptor which serves a role in chronic inflammation of the liver. However, the role of TLR2 in the progression of human hepatocellular carcinoma (HCC) remains unknown. The aim of the present study was to examine the effects of the activation of the TLR2 signaling pathway on biological functions, such as proliferation and apoptosis. TLR2 expression in HCC tissues was assayed by quantitative polymerase chain reaction, flow cytometry and western blotting. B76/Huh7 cells were transfected with overexpression plasmids, and cell proliferation was detected using a Cell Counting Kit­8 assay and the secreted cytokines in the supernatant of transfected cells were measured by ELISA. The findings revealed that TLR2 expression was increased in the peritumoral groups compared with inner­tumoral groups. Activation of the TLR2 signaling pathway through overexpression of pathway molecules inhibited the growth of B76/Huh7 cells and the secretion of interleukin­6 and tumor necrosis factor­α were reduced. Inhibition of the TLR2 signaling pathway resulted in a significant increase in the downstream signaling cascade, thus potentially increasing hepatocarcinogenesis and tumor progression. Activation of the TLR2 signaling pathway may be a potential target for therapeutic intervention in patients with HCC and downstream secreted cytokines are required for the functional biological effect. Therefore, modulation of the TLR2 signaling pathway may provide important insight into designing effective therapeutic regimens for treating patients with HCC.

Increased Serum Soluble Urokinase Plasminogen Activator Receptor Predicts Short-Term Outcome in Patients with Hepatitis B-Related Acute-on-Chronic Liver Failure.

AIMS: Soluble urokinase plasminogen activator receptor (suPAR) reflects the immune activation in circumstances of inflammation and infection. It has been considered as a risk biomarker associated with poor outcome in various low-grade inflammation and infectious diseases. The study is aimed at investigating whether suPAR has a predictive value with short-term survival in patients with hepatitis B-related acute-on-chronic liver failure (HB-ACLF). METHODS: Serum suPAR expression was compared among patients with different states of chronic hepatitis B virus infection. Sixty HB-ACLF patients were recruited as the training cohort and followed up for 90 days. Serum suPAR level and the clinical relevance with short-term outcome were investigated. The temporal dynamics of suPAR were evaluated in 50 HB-ACLF patients with available serum sequentially at baseline, week 2 and week 4. Another 167 HB-ACLF patients were enrolled to validate the predictive value of suPAR with respect to the prognosis. RESULTS: Serum suPAR level was significantly increased in HB-ACLF patients compared to non-ACLF patients. In the training set of HB-ACLF, we observed higher suPAR level, INR, MELD score, and more complications in nonsurvivors than survivors. Longitudinal analysis revealed an increased trend of suPAR level in nonsurvivors during week 0 to week 4 and the modest decline in survivors. It showed that the synchronous suPAR level was higher in nonsurvivors at all indicated time points. Elevated suPAR level at baseline was identified as a strong predictor of a 90-day mortality of HB-ACLF patients. It was confirmed suPAR > 16.26 ng/ml had a positive predictive value of 72.22% and a negative predictive value of 77.88% for poor outcome in the validation cohort. CONCLUSIONS: Serum suPAR level increases significantly in HB-ACLF patients and associated with a 90-day mortality. It suggests that suPAR might be a potential biomarker to predict the prognosis of HB-ACLF patients.

Lower Expression of MicroRNA-155 Contributes to Dysfunction of Natural Killer Cells in Patients with Chronic Hepatitis B.

MicroRNAs have been reported to be regulated in different ways in a variety of liver diseases. As a key modulator of cellular function in both innate and adaptive immunity, the role of miR-155 in chronic hepatitis B virus infection remains largely unknown. Here, we investigated the expression and function of miR-155 in chronic hepatitis B (CHB) patients. It was found that miR-155 expression in peripheral blood mononuclear cells (PBMCs) was lower in CHB patients than healthy controls (HC). Among CHB infection, immune-active (IA) patients with abnormal alanine aminotransferase (ALT) levels had relatively higher miR-155 expression in PBMCs and serum than immune-tolerant carriers, but were comparable to inactive carriers. Moreover, there was a positive correlation between miR-155 expression and ALT levels in CHB patients. Particularly, miR-155 expression in natural killer (NK) cells was significantly downregulated in IA patients compared with HC. Inversely, suppressor of cytokine signaling 1 (SOCS1), a target of miR-155, was upregulated in NK cells of IA patients. Overexpression of miR-155 in NK cells from IA patients led to a decrease in SOCS1 expression and an increase of IFN-γ production. Finally, accompanied by the normalization of ALT, miR-155 expression in PBMCs gradually decreased during telbivudine or peg-IFN-α-2a therapy. Interestingly, higher miR-155 expression at baseline was associated with better response to telbivudine therapy, but not peg-IFN-α-2a. In conclusion, our data suggested that miR-155 downregulation in NK cells of IA patients impaired IFN-γ production by targeting SOCS1, which may contribute to immune dysfunction during CHB infection. Additionally, baseline miR-155 expression could predict the treatment response to telbivudine therapy.

Interleukin-1 receptor antagonist expression is inversely associated with outcomes of hepatitis B-related acute-on-chronic liver failure.

Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring anti-inflammatory antagonist of the proinflammatory cytokine IL-1, a critical factor in many inflammatory diseases. The aim of the present study was to investigate the role of IL-1ra in hepatitis B-related acute-on-chronic liver failure (HB-ACLF). Serum cytokine concentrations were measured using a Q-Plex array in 31 patients with HB-ACLF, 28 patients with acute hepatitis B (AHB), 31 patients with chronic hepatitis B (CHB) and 15 healthy control patients (HCs). Additionally, peripheral blood mononuclear cells (PBMCs) from patients with HB-ACLF were incubated with PBS or lipopolysaccharide and/or different concentrations of recombinant human IL-1ra (rhIL-1ra) in vitro. Cytokines in the supernatant were measured using a Q-Plex array. The median serum IL-1ra level in patients with HB-ACLF was 186.46 (350.22) pg/ml, which was significantly higher than all other groups (AHB, P=0.012; CHB, P<0.001; HCs, P<0.001). However, the ratio of IL-1ra/IL-1ß was significantly lower in the HB-ACLF group compared with the AHB group (P=0.048). Median serum IL-1ra levels in patients with AHB were also significantly increased compared with those in the CHB (P<0.001) and HC (P<0.001) groups. Patients who succumbed to mortality within 3 months of the study were found to have significantly lower IL-1ra concentrations (P=0.02) and IL-1ra/IL-1ß ratios (P=0.007) compared with surviving patients with HB-ACLF. Furthermore, serum IL-1ra concentrations were negatively associated with the Model for End-stage Liver Disease score (r=-0.870; P<0.001). Cytokine secretion by PBMCs in vitro was significantly inhibited in a dose-dependent manner by rhIL-1ra (125-500 ng/ml; all P<0.05). These results suggest that IL-1ra is associated with the development of liver inflammation, which is reduced in patients with HB-ACLF and inversely associated with disease severity.