Liver fibrosis is a life-threatening disease, with challenging morbidity and mortality for healthcare systems worldwide. It imparts an enormous economic burden to societies, making continuous research and informational updates about its pathogenesis and treatment crucial. This review′s focus is on the current knowledge about the Wnt signaling pathway, serving as an important pathway in liver fibrosis development and activation of hepatic stellate cells (HSCs). Two types of Wnt pathways are distinguished, namely the ß-catenin-dependent canonical and non-canonical Ca²⁺ or planar cell polarity (PCP)-dependent pathway. The dynamic balance of physiologically healthy liver and hepatocytes is disturbed by repeated liver injuries. Activation of the ß-catenin Wnt pathway prevents the regeneration of hepatocytes by the replacement of extracellular matrix (ECM), leading to the appearance of scar tissue and the formation of regenerated nodular hepatocytes, lacking the original function of healthy hepatocytes. Therefore, liver function is reduced due to the severely advanced disease. Selective inhibition of ß-catenin inhibits inflammatory processes (since chemokines and pro-inflammatory cytokines are produced during Wnt activation), reduces growth of activated HSCs and reduces collagen synthesis and angiogenesis, thereby reducing the progression of liver fibrosis in vivo. While the canonical Wnt pathway is usually inactive in a physiologically healthy liver, it shows activity during cell regeneration or renewal and in certain pathophysiological conditions, such as liver diseases and cancer. Targeted blocking of some of the basic components of the Wnt pathway is a therapeutic approach. These include the frizzled transmembrane receptor (Fz) receptors using the secreted frizzled-related protein family (sFRP), Fz-coreceptors low-density LRP 5/6 through dickkopf-related protein 1 (DKK1) or niclosamide, glycogen kinase-3 beta (GSK-3β) using SB-216763, cyclic-AMP response element-binding protein (CBP) using PRI-724 and ICG-001, the lymphoid enhancer binding factor (LEF)/T cell-specific transcription factor (TCF) system as well as Wnt inhibitory factor 1 (WIF1) and miR-17-5p using pinostilbene hydrate (PSH). Significant progress has been made in inhibiting Wnt and thus stopping the progression of liver fibrosis by diminishing key components for its action. Comprehending the role of the Wnt signaling pathway in liver fibrosis may lead to discovery of novel targets in liver fibrosis therapeutic strategies’ development. Full article

Timely and effective assessment scoring systems for predicting the mortality of patients with hepatitis E virus-related acute liver failure (HEV-ALF) are urgently needed. The present study aimed to establish an effective nomogram for predicting the mortality of HEV-ALF patients. The nomogram was based on a cross-sectional set of 404 HEV-ALF patients who were identified and enrolled from a cohort of 650 patients with liver failure. To compare the performance with that of the model for end-stage liver disease (MELD) scoring and CLIF-Consortium-acute-on-chronic liver failure score (CLIF-C-ACLFs) models, we assessed the predictive accuracy of the nomogram using the concordance index (C-index), and its discriminative ability using time-dependent receiver operating characteristics (td-ROC) analysis, respectively. Multivariate logistic regression analysis of the development set carried out to predict mortality revealed that γ-glutamyl transpeptidase, albumin, total bilirubin, urea nitrogen, creatinine, international normalized ratio, and neutrophil-to-lymphocyte ratio were independent factors, all of which were incorporated into the new nomogram to predict the mortality of HEV-ALF patients. The area under the curve of this nomogram for mortality prediction was 0.671 (95% confidence interval: 0.602–0.740), which was higher than that of the MELD and CLIF-C-ACLFs models. Moreover, the td-ROC and decision curves analysis showed that both discriminative ability and threshold probabilities of the nomogram were superior to those of the MELD and CLIF-C-ACLFs models. A similar trend was observed in the validation set. The novel nomogram is an accurate and efficient mortality prediction method for HEV-ALF patients. Full article

Overall mortality among U.S. adults has been stable in past years; however, racial disparity influenced 10 leading causes of death or age-specific mortality in Blacks or African Americans. Unfortunately, the trends in sex- and race-adjusted age-standardized cause-specific mortality are poorly understood. We here aimed to identify the underlying causes of death (UCD) with sex- and race-adjusted, and age-standardized mortality that has changed in recent years. We extracted the data of UCD from the Multiple Cause of Death database of the Centers for Disease Control and Prevention (CDC). Multivariable log-linear regression models were used to estimate trends in sex- and race-adjusted, and age-standardized mortality of UCD during 2013–2017. A total of 31,029,133 deaths were identified. Among the list of 113 UCDs compiled by the CDC, there were 29 UCDs exhibiting an upward trend, 33 UCDs exhibiting a downward trend and 56 UCDs with no significant trends. The 2 UCDs with the largest annual percent change were both nutrition related (annual percent change [APC] = 17.73, 95% CI [15.13–20.33] for malnutrition, and APC = 17.49, 95% CI [14.94–20.04] for Nutritional deficiencies), followed by accidental poisoning and exposure to noxious substances. The 4 UCDs with the largest decreasing APC were viral hepatitis (APC = −11.71), chronic and unspecified bronchitis (APC = −8.26), emphysema (APC = −7.11) and human immunodeficiency virus disease (APC = −7.10). This study thus reports UCDs with changing mortality in recent years after sex- and race-adjustments and age-standardizations. More effort and resources should focus on understanding, preventing and controling the mortality linked to these UCDs. Continuous monitoring of mortality trends is recommended. Full article

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (2019 coronavirus disease, COVID-19) since December 2019, from Wuhan, China, has been posing a significant threat to global human health. The clinical features and outcomes of Chinese patients with COVID-19 have been widely reported. Increasing evidence has witnessed the frequent incident liver injury in COVID-19 patients, and it is often manifested as transient elevation of serum aminotransferases; however, the patients seldom have liver failure and obvious intrahepatic cholestasis, unless pre-existing advanced liver disease was present. The underlying mechanisms of liver injury in cases of COVID-19 might include psychological stress, systemic inflammation response, drug toxicity, and progression of pre-existing liver diseases. However, there is insufficient evidence for SARS-CoV-2 infected hepatocytes or virus-related liver injury in COVID-19 at present. The clinical, pathological and laboratory characteristics as well as underlying pathophysiology and etiology of liver injury in COVID-19 remain largely unclear. In this review, we highlight these important issues based on the recent developments in the field, for optimizing the management and treatment of liver injury in Chinese patients with COVID-19. Full article

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has attracted increasing worldwide attention. Cases of liver damage or dysfunction (mainly characterized by moderately elevated serum aspartate aminotransferase levels) have been reported among patients with COVID-19. However, it is currently uncertain whether the COVID-19-related liver damage/dysfunction is due mainly to the viral infection per se or other coexisting conditions, such as the use of potentially hepatotoxic drugs and the coexistence of systemic inflammatory response, respiratory distress syndrome-induced hypoxia, and multiple organ dysfunction. Based on the current evidence from case reports and case series, this review article focuses on the demographic and clinical characteristics, potential mechanisms, and treatment options for COVID-19-related liver dysfunction. This review also describes the geographical and demographic distribution of COVID-19-related liver dysfunction, as well as possible underlying mechanisms linking COVID-19 to liver dysfunction, in order to facilitate future drug development, prevention, and control measures for COVID-19. Full article

Nonalcoholic fatty liver disease (NAFLD) is a systemic disorder with a complex multifactorial pathogenesis and heterogenous clinical manifestations. NAFLD, once believed to be an innocuous condition, has now become the most common cause of chronic liver disease in many countries worldwide. NAFLD is already highly prevalent in the general population, and owing to a rising incidence of obesity and diabetes mellitus, the incidence of NAFLD and its impact on global healthcare are expected to increase in the future. A subset of patients with NAFLD develops progressive liver disease leading to cirrhosis, hepatocellular carcinoma, and liver failure. NAFLD has emerged as one of the leading causes of cirrhosis and hepatocellular carcinoma in recent years. Moreover, HCC can occur in NAFLD even in absence of cirrhosis. Compared with the general population, NAFLD increases the risk of liver-related, cardiovascular and all-cause mortality. NAFLD is bidirectionally associated with metabolic syndrome. NAFLD increases the risk and contributes to aggravation of the pathophysiology of atherosclerosis, cardiovascular diseases, diabetes mellitus, and chronic kidney disease. In addition, NAFLD is linked to colorectal polyps, polycystic ovarian syndrome, osteoporosis, obstructive sleep apnea, stroke, and various extrahepatic malignancies. Extended resection of steatotic liver is associated with increased risk of liver failure and mortality. There is an increasing trend of NAFLD-related cirrhosis requiring liver transplantation, and the recurrence of NAFLD in such patients is almost universal. This review discusses the growing burden of NAFLD, its outcomes, and adverse associations with various diseases. Full article