TAF and TDF attenuate liver fibrosis through NS5ATP9, TGFβ1/Smad3, and NF-κB/NLRP3 inflammasome signaling pathways Abstract Background This study aimed to investigate the roles and mechanisms of tenofovir alafenamide fumarate (TAF)/tenofovir disoproxil fumarate (TDF) in treating liver fibrosis. Methods The effects of TAF/TDF on carbon tetrachloride (CCl4)-induced liver fibrosis in C57BL/6 wild-type or nonstructural protein 5A transactivated protein 9 (NS5ATP9) knockout mice were studied. The differentiation, activation, and proliferation of LX-2 cells after TAF/TDF treatment were tested in vitro. The expression of NS5ATP9 and activities of transforming growth factor-β1 (TGFβ1)/Sekelsky mothers against decapentaplegic homolog 3 (Smad3) and NF-κB/NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome signaling pathways were detected in TAF/TDF-treated mice and LX-2 cells. The genes related to extracellular matrix accumulation were detected in vivo and in vitro after NS5ATP9 silencing or knockout. Results TAF/TDF significantly inhibited CCl4-induced liver fibrosis in mice, and regulated the differentiation, activation, and proliferation of hepatic stellate cells (HSCs). Furthermore, TAF/TDF suppressed the activities of TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways in vivo and in vitro. NS5ATP9 inhibited liver fibrosis through TGFβ1/Smad3 and NF-κB signaling pathways. TAF/TDF upregulated the expression of NS5ATP9 in vivo and in vitro. Finally, TAF/TDF could only show marginal therapeutic effects when NS5ATP9 was silenced and knocked out in vivo and in vitro. Conclusions TAF/TDF prevented progression and promoted reversion of liver fibrosis through assembling TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways via upregulating the expression of NS5ATP9. TAF/TDF also regulated the differentiation, activation, and proliferation of HSCs. The findings provided strong evidence for the role of TAF/TDF as a new promising therapeutic strategy in liver fibrosis.

Sarcopenia: an emerging risk factor for non-alcoholic fatty liver disease

Change in antibiotic regimen for emerging multidrug resistance in nosocomial ascitic fluid infection Graphic abstract

Use of HBsAg quantification in the natural history and treatment of chronic hepatitis B Abstract In patients with chronic hepatitis B (CHB) infection, it is important to monitor the natural history, assess treatment response, and predict the risk of liver-related complications. Quantification of serum hepatitis B surface antigen (HBsAg) has gained wide interests since the last decade. It is secreted from hepatocytes in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative phases of the disease, and can be transcribed and translated from different sources of viral genome [ccc DNA or integrated hepatitis B virus (HBV) DNA]. In untreated patients, it declines slowly through the natural course and remains stable for a long time after HBeAg seroconversion. In patients treated with nucleos(t)ide analogues (NA), it also declines very slowly, even though serum hepatitis B DNA has been rendered negative. Low serum HBsAg may predict either spontaneous or treatment-induced HBsAg seroclearance, and potentially selects out HBeAg-negative patients who can safely stop NA. High serum HBsAg is associated with high risk of hepatocellular carcinoma in untreated population, and predicts treatment failure in patients receiving pegylated interferon. These potential roles of HBsAg quantification are applicable to selected populations only. There is also a need for novel markers to study the effect of emerging antiviral therapies targeting various parts of the HBV cycle to reflect their distinct mechanistic effects. Several agents measuring HBsAg levels have shown rapid and significant decline. Ongoing studies are required to demonstrate the sustainability of HBsAg suppression by these novel agents.

Correction to: Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update The article Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update, written by [Shiv Sarin], was originally published electronically on the publisher’s internet portal (currently SpringerLink) on June 06, 2019 without open access.

Refining the role of epicardial adipose tissue in non-alcoholic fatty liver disease

Sarcopenia and fatty liver disease Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease which may progress to non-alcoholic steatohepatitis. The prevalence of sarcopenia, which is the loss of muscle mass and strength, is increasing in the aging society. Recent studies reported the relationship between NAFLD and sarcopenia. The skeletal muscle is the primary organ for glucose disposal. Loss of muscle mass can cause insulin resistance, which is an important risk factor for NAFLD. Moreover, obesity, chronic low-grade inflammation, vitamin D deficiency, physical inactivity, hepatokines, and myokines might be involved in the pathophysiologic mechanism of sarcopenia and NAFLD. Although most of the previous studies have demonstrated the positive correlation between sarcopenia and NAFLD, the difference in diagnostic methods of sarcopenia and NAFLD leads to difficulties in interpretation and application. This review discusses the concept and diagnosis of sarcopenia and NAFLD, common pathophysiology, and clinical studies linking sarcopenia to NAFLD. The presentation of the association between sarcopenia and NAFLD may provide an opportunity to prevent the deterioration of fatty liver disease. Graphic abstract

Non-obese histologically confirmed NASH patients with abnormal liver biochemistry have more advanced fibrosis Abstract Background and aims Non-alcoholic fatty liver disease (NAFLD) commonly affects subjects with obesity, yet non-obese NAFLD is increasingly being recognized. We aimed to investigate the clinicopathological and genetic characteristics of non-obese NAFLD patients. Methods The clinical, histological and genetic data of 84 NAFLD patients with biopsy for abnormal liver function test were reviewed. Both NAS-CRN and SAF scoring systems were applied for histopathological evaluation. PNPLA3 and TMS6F2 genotyping were also performed. Results All of the 84 patients were histologically diagnosed with non-alcoholic steatohepatitis (NASH), with 36 of them (42.9%) being non-obese (BMI < 25 kg/m2). Compared with the obese group, non-obese group were predominantly females (88.9% vs 52.1%, p < 0.001), tended to have higher prevalence of diabetes (p = 0.068). More importantly non-obese patients had a significant higher prevalence of advanced fibrosis (F ≥ 3) (58.3% vs 29.2%, p = 0.013), and a trend of higher degree of ballooning (p = 0.061). In addition, values of liver stiffness measurement were also significantly higher in non-obese group (12.1 kPa vs 8.1 kPa, p = 0.032). There was also a trend of higher prevalence of TM6SF2 T allele in non-obese group (p = 0.085), while the prevalence of PNPLA3 risk allele did not differ between two groups. Multivariate analysis showed that higher fasting glucose (p = 0.038) and lower serum platelets (p = 0.040) were two independent predictors for advanced fibrosis in non-obese patients. Conclusions Non-obese NASH patients have a female predominance and more advanced fibrosis. Liver biopsy is crucial to evaluate the severity of disease in non-obese patients especially those with abnormal liver biochemistry. Clinical trial number NCT03386890.

Significant decrease in Faecalibacterium among gut microbiota in nonalcoholic fatty liver disease: a large BMI- and sex-matched population study Abstract Background Compositional changes of the gut microbiota are known to occur in patients with nonalcoholic fatty liver disease (NAFLD); however, the changes did not corroborate between the studies. We evaluated the gut microbiota between NAFLD and non-NAFLD participants, excluding the influence of obesity and sex in this study involving a large number of participants. Methods In total, 1148 adults participated in the health survey. NAFLD was defined as fatty liver by ultrasonography in the absence of other causes of steatosis. To exclude the influence of obesity and sex, NAFLD participants were matched to non-NAFLD participants based on BMI and sex. The relative abundance of each bacterial taxa in fecal samples was calculated using 16S ribosomal RNA amplification and was compared between NAFLD and non-NAFLD participants. Results There were 205 (23.5%) participants defined as having NAFLD. Before matching, there were significant differences in the relative abundance of more than 1% in two classes, two orders, three families, and three genera including Faecalibacterium between NAFLD and non-NAFLD participants. After matching, 153 matched pairs were obtained. In terms of the relative abundance of more than 1%, the relative abundance of two taxa, including the family Ruminococcaceae and the genus Faecalibacterium, was significantly lower in NAFLD participants than in non-NAFLD participants (p = 0.016 and p = 0.018). Conclusions The significant decrease in Faecalibacterium is a remarkable characteristic on BMI- and sex-matched analysis in NAFLD participants in a large study population. The decrease in Faecalibacterium is related to the pathogenesis of NAFLD.

Circulating tumor cells are associated with poor outcomes in early-stage hepatocellular carcinoma: a prospective study Abstract Background Previous studies evaluating association between circulating tumor cells (CTCs) and clinical outcomes in hepatocellular carcinoma (HCC) have shown inconsistent results due to suboptimal detection methods and patient heterogeneity. Methods Patients undergoing surgery for early-stage HCC were prospectively enrolled. The CTC numbers were determined using a tapered slit platform, which detects CTCs based on the cell size and morphology. Survival and recurrence were evaluated, and Cox proportional hazards models were used to demonstrate the prognostic significance of CTC. Results Of 105 patients, 25 had increased CTC numbers after surgery (ΔCTC > 0, defined as positive) and a significantly higher level of recurrence (p = 0.042). A positive ΔCTC was seen to be an independent predictor of recurrence (hazard ratio 2.28), along with hepatitis B virus infection, alanine aminotransferase level, and the presence of satellite nodules (all p < 0.05). Subgroup analyses showed that a positive ΔCTC was associated with lower survival and higher recurrence among patients with low alpha-fetoprotein levels and cirrhosis (all p < 0.05). Conclusion Calculation of ΔCTC based on the physical properties of the cells is predictive of recurrence in patients with early HCC undergoing surgery.