NTCP Deficiency Affects the Levels of Circulating Bile Acids and Induces Osteoporosis

BackgroundThe p.Ser267Phe mutation in the SLC10A1 gene can cause NTCP deficiency. However, the full clinical presentation of p.Ser267Phe homozygous individuals and its long-term consequences remain unclear. Hence, in the present study, we characterized the phenotypic characteristics of NTCP deficiency and evaluated its long-term prognosis.MethodsTen NTCP p.Ser267Phe homozygous individuals were recruited and a comprehensive medical evaluation with a 5-year follow-up observation was performed. The phenotypic characteristics of NTCP deficiency were also demonstrated using an NTCP-global knockout mouse model.ResultsDuring the 5-year follow-up observation of 10 NTCP p.Ser267Phe homozygous adults, we found that the most common phenotypic features of NTCP deficiency in adults were hypercholanemia, vitamin D deficiency, bone loss, and gallbladder abnormalities. The profile of bile acids (BAs) in the serum was significantly altered in these individuals and marked by both elevated proportion and concentration of primary and conjugated BAs. Moreover, the NTCP deficiency led to increased levels of serum BAs, decreased levels of vitamin D, and aggravated the osteoporotic phenotype induced by estrogen withdrawal in mice.ConclusionsBoth mice and humans with NTCP deficiency presented hypercholanemia and were more prone to vitamin D deficiency and aggravated osteoporotic phenotype. Therefore, we recommend monitoring the levels of BAs and vitamin D, bone density, and abdominal ultrasounds in individuals with NTCP deficiency

Pan-cancer analysis reveals that G6PD is a prognostic biomarker and therapeutic target for a variety of cancers

BackgroundDespite accumulating evidence revealing that Glucose-6-phosphate dehydrogenase (G6PD) is highly expressed in many tumor tissues and plays a remarkable role in cancer tumorigenesis and progression, there is still a lack of G6PD pan-cancer analysis. This study was designed to analyze the expression status and prognostic significance of G6PD in pan-cancer.MethodsG6PD expression data were obtained from multiple data resources including the Genotype-Tissue Expression, the Cancer Genome Atlas, and the Tumor Immunity Estimation Resource. These data were used to assess the G6PD expression, prognostic value, and clinical characteristics. The ESTIMATE algorithms were used to analyze the association between G6PD expression and immune-infiltrating cells and the tumor microenvironment. The functional enrichment analysis was also performed across pan-cancer. In addition, the GDSC1 database containing 403 drugs was utilized to explore the relationship between drug sensitivity and G6PD expression levels. Furthermore, we also performed clinical validation and in vitro experiments to further validate the role of G6PD in hepatocellular carcinoma (HCC) cells and its correlation with prognosis. The R software was used for statistical analysis and data visualization.ResultsG6PD expression was upregulated in most cancers compared to their normal counterparts. The study also revealed that G6PD expression was a prognostic indicator and high levels of G6PD expression were correlated with worse clinical prognosis including overall survival, disease-specific survival, and progression-free interval in multiple cancers. Furthermore, the G6PD level was also related to cancer immunity infiltration in most of the cancers, especially in KIRC, LGG, and LIHC. In addition to this, G6PD expression was positively related to pathological stages of KIRP, BRCA, KIRC, and LIHC. Functional analysis and protein-protein interactions network results revealed that G6PD was involved in metabolism-related activities, immune responses, proliferation, and apoptosis. Drug sensitivity analysis showed that IC50 values of most identified anti-cancer drugs were positively correlated with the G6PD expression. Notably, in vitro functional validation showed that G6PD knockdown attenuated the phenotypes of proliferation in HCC.ConclusionG6PD may serve as a potential prognostic biomarker for cancers and may be a potential therapeutic target gene for tumor therapy

Effects of Hepatitis B Surface Antigen on Virus-specific and Global T Cells in Patients With Chronic HBV infection

10.1053/j.gastro.2020.04.019Gastroenterolog

Progress on clinical prognosis assessment in liver failure

Liver failure is a group of clinical syndromes with a mortality rate of >50%. The accurate evaluation of severity in patients with liver failure has been a meaningful and hot topic in clinical research and an important guide for liver transplantation. Numerous prognosis studies have emerged in recent years with high accuracy and adequate validity. Nonetheless, different models utilize distinct parameters and have unequal efficiencies, leading to a specific value and unique application situations for each model. This review focused on the progress in recent prognostic studies including the model for end-stage liver disease, sequential organ failure assessment and its derivative models, the Chinese Group on the Study of Severe Hepatitis B Acute-on-Chronic Liver Failure, the Tongji prognostic predictor model, and other emerging prognostic models and predictors. This review aims to assist clinicians understand the framework of recent models and choose the appropriate model and treatment

RESEARCH Open Access Liver myofibroblasts up-regulate monocyte CD163

Background: Although patients with liver failure exhibit a generalized inflammatory-imbalance status, substantial evidence indicates that this immunosuppressive or anti-inflammatory state may be deleterious. Increased expression of CD163 (known to be involved in several anti-inflammatory functions of the immune system) in patients with liver failure is significantly correlated with a fatal outcome. However, little is known of the regulatory mechanisms that influence the expression of CD163. Methods: We assessed the expression of CD163 on monocytes from both circulating cells and the liver tissues of patients with hepatitis B induced liver failure using flow cytometry and isolated the myofibroblasts from diseased livers. The ability of human liver myofibroblasts to regulate CD163 expression on monocytes was studied in vitro. Results: We showed that CD163 + monocytes were enriched primarily in diseased livers and that they were associated with liver myofibroblasts in the same area. Accordingly, liver myofibroblasts were significantly superior to normal skin fibroblasts in inducing the expression of CD163 on monocytes in vitro. Moreover, we found that liver myofibroblasts triggered the activation of monocytes by secreting PGE2. Inhibition of PGE2 production in liver myofibroblasts using NS-398 markedly reduced CD163 expression in vitro. Conclusion: These results suggest that liver myofibroblasts play a direct role in regulating the expression of CD163 on monocytes in human liver tissues and thereby may regulate monocyte function during hepatitis B induced liver failure

Efficacy Comparison of Tenofovir and Entecavir in HBeAg-Positive Chronic Hepatitis B Patients with High HBV DNA

Objectives. To compare entecavir (ETV) and tenofovir disoproxil fumarate (TDF) effects in chronic hepatitis B (CHB) patients with high HBV DNA. Method. 96 patients treated initially with tenofovir (TDF group) or entecavir (ETV group) were included in this retrospective study. The following parameters were assessed: HBeAg and hepatitis B e antibody (anti-HBe) status, serum alanine aminotransferase (ALT), and HBV-DNA levels at weeks 4, 12, 24, 36, 48, 60, 72, and 96; time to ALT normalization, undetectable HBV-DNA levels, and HBeAg seroconversion; total duration of follow-up and adverse reactions. Results. The patients included 66 (69%) and 30 (31%) individuals administered ETV and TDF, respectively, comprising 75% males. They were 35.1±4.5 and 33.7±4.6 years old in ETV and TDF groups, respectively. At 36 weeks, the response rate was significantly higher in the TDF group than in ETV treated patients (90% versus 69.7%, p=0.03). At 48 weeks, less patients administered ETV showed undetectable HBV-DNA levels compared with the TDF group (86.4% versus 96.7%), a non-statistically significant difference (p=0.13). Only 1 ETV treated patient developed virological breakthrough at 48–96 w. No adverse reactions were found. Conclusion. ETV and TDF are comparable in efficacy and safety to suppress HBV-DNA replication in HBeAg-positive CHB patients with high HBV DNA

Inappropriate cessation of nucleos(t)ide analog associated with reduced liver transplant-free survival in patients with HBV-related acute on chronic liver failure

The inappropriate cessation of nucleos(t)ide analog (NA) therapy may lead to acute exacerbations of chronic hepatitis B virus (HBV) infection, acute-on-chronic liver failure (ACLF), and even death. This study aims to elucidate the association between inappropriate NA cessation and prognosis in patients with HBV-ACLF. A total of 901 patients with ACLF were enrolled and stratified into inappropriate NA cessation and non-NA cessation group. Clinical characteristics and prognosis between the two groups were compared. The association between inappropriate NA cessation and the prognosis of patients with HBV-ACLF was evaluated using Cox proportional hazard models after propensity score matching (PSM). NA cessation was identified in 132 patients (NA cessation group), while 769 patients were triggered by other factors (non-NA cessation group). The 28- and 90-day liver transplant-free survival rates were higher in patients with non-NA cessation than in those with NAs cessation (78.3 % vs. 62.1 %, P < 0.001; 62.8 % vs. 44.7 %, P < 0.001). The need for liver transplantation was significantly higher in the NA cessation group compared with the non-NAs cessation group (21.2 % vs. 7.0 %, P < 0.001). The Kaplan-Meier curve showed that inappropriate NA therapy discontinuation had reduced 28- and 90-day live transplant-free survival compared with other precipitating events prior to PSM (all P < 0.001). After matching, the 28- and 90-day transplantation-free survival was also significantly lower in the NA cessation group vs. the non-NA cessation group (P = 0.012 and P = 0.022). In conclusion, the inappropriate cessation of NA therapy is associated with reduced liver transplant-free survival in patients with HBV-related ACLF

A Novel Prediction Model for Significant Liver Fibrosis in Patients with Chronic Hepatitis B

Background. Preventing liver fibrosis from progressing to cirrhosis and even liver cancer is a key step in the treatment of chronic hepatitis B (CHB). This study is aimed at constructing and validating a new nomogram for predicting significant liver fibrosis (S≥2) in CHB patients. Methods. The nomogram was based on a retrospective study of 252 CHB patients. The predictive accuracy and discriminative ability of the nomogram were evaluated by the area under receiver operating characteristic curve (AUROC), decision curves, and calibration curve compared with the fibrosis 4 score (FIB-4) and aspartate aminotransferase-to-platelet ratio index (APRI). The results were validated using bootstrap resampling and an external set of 168 CHB patients. Results. A total of 420 CHB patients were enrolled based on liver biopsy results. Independent factors predicting significant liver fibrosis were laminin (LN), procollagen type III N-terminal peptide (PIIINP), and blood platelet count (PLT) in a multivariate analysis, and these factors were selected to construct the nomogram. The calibration curve for the probability of significant liver fibrosis showed optimal agreement between the prediction from the nomogram and actual observation. The prediction from the nomogram was more consistent with the results of liver biopsy than FIB-4 and APRI. The AUROC of the nomogram was higher than that of FIB-4 and APRI for predicting significant liver fibrosis. These results were confirmed in the validation set. Furthermore, the decision curve analysis suggested that the most net benefits were provided by the nomogram. Conclusions. We found the proposed nomogram resulted in a more accurate prediction of significant liver fibrosis in CHB patients and could provide the most net benefits. We recommend this noninvasive assessment for patients with liver fibrosis to avoid the risk of liver biopsy and earlier intervention to prevent the development of cirrhosis or liver cancer

TDF Monotherapy Is Effective Regardless of Prior Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Patients in China

Background/Aims. Many patients had to transfer to tenofovir disoproxil fumarate (TDF) if there is other nucleos(t)ide analogue (NA) resistance. We aimed to investigate antiviral effects of TDF monotherapy between NA-naive and NA-experienced chronic hepatitis B (CHB) patients in China. Methods. A total of 102 NA-naive and NA-experienced CHB patients with TDF monotherapy (300 mg/day) were retrospectively analyzed for useful parameters up to 72 weeks. Results. There were 36 and 66 patients with matched HBV DNA baseline level in NA-naïve and NA-experienced group, respectively. There were no significant differences between NA-naïve and NA-experienced groups in HBV DNA levels (all P>0.05) and HBV DNA undetectable rates (all P>0.05) at all time points. At the end of follow-up, HBV DNA undetectable rates in NA-naïve and NA-experienced group were 96.2% (25/26) and 91.8% (45/49), respectively (P=0.476). Baseline HBV DNA level was the only independent predictor for HBV DNA negative time (P=0.018). In addition, 27.8% (5/18) and 11.4% (4/35) achieved HBeAg seroconversion at the end of the follow-up, respectively (P=0.133). Conclusions. TDF monotherapy was effective regardless of prior NA experienced. Baseline HBV DNA was a key predictive factor for HBV DNA negative time in TDF monotherapy

Low Platelet to White Blood Cell Ratio Indicates Poor Prognosis for Acute-On-Chronic Liver Failure

Background. Platelet to white blood cell ratio (PWR) was an independent prognostic predictor for outcomes in some diseases. However, the prognostic role of PWR is still unclear in patients with hepatitis B related acute-on-chronic liver failure (ACLF). In this study, we evaluated the clinical performances of PWR in predicting prognosis in HBV-related ACLF. Methods. A total of 530 subjects were recruited, including 97 healthy controls and 433 with HBV-related ACLF. Liver function, prothrombin time activity (PTA), international normalized ratio (INR), HBV DNA measurement, and routine hematological testing were performed at admission. Results. At baseline, PWR in patients with HBV-related ACLF (14.03 ± 7.17) was significantly decreased compared to those in healthy controls (39.16 ± 9.80). Reduced PWR values were clinically associated with the severity of liver disease and the increased mortality rate. Furthermore, PWR may be an inexpensive, easily accessible, and significant independent prognostic index for mortality on multivariate analysis (HR = 0.660, 95% CI: 0.438–0.996, p=0.048) as well as model for end-stage liver disease (MELD) score. Conclusions. The PWR values were markedly decreased in ACLF patients compared with healthy controls and associated with severe liver disease. Moreover, PWR was an independent prognostic indicator for the mortality rate in patients with ACLF. This investigation highlights that PWR comprised a useful biomarker for prediction of liver severity