To facilitate the achieving of the goal of “eliminating viral hepatitis as a major public health threat by 2030” set by the World Health Organization, the Chinese Society of Hepatology together with the Chinese Society of Infectious Diseases (both are branches of the Chinese Medical Association) organized a panel of experts and updated the guidelines for prevention and treatment of chronic hepatitis B in China (version 2022). With the support of available evidence, this revision of the guidelines focuses on active prevention, large scale testing, and expansion of therapeutic indication of chronic hepatitis B with the aim of reducing the hepatitis B related disease burden. Full article

Overexpression of IGF2BP3 is associated with the prognosis of hepatocellular carcinoma (HCC). However, its role in regulating tumor immune microenvironment (TME) is not well characterized. Here, we investigated the effects of IGF2BP3 on macrophages and CD8⁺ T cells within the TME of HCC. The relationship between IGF2BP3 and immune cell infiltration was analyzed using online bioinformatics tools. Knockout of IGF2BP3 in mouse hepatoma cell line Hepa1-6 was established using CRISPR/Cas9 technology. In vitro cell coculture and subcutaneously implanted hepatoma mice model were used to explore the effects of IGF2BP3 on immune cells. Expression of CCL5 or transforming growth factor beta 1 (TGF-β1) was detected with quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The binding of IGF2BP3 and its target RNA was verified by trimolecular fluorescence complementation system and RNA immunoprecipitation followed by quantitative or semiquantitative polymerase chain reaction. IGF2BP3 expression was elevated in HCC and was positively correlated with macrophage infiltration. Patients with higher IGF2BP3 expression and lower macrophage infiltration had a better survival rate. We found that IGF2BP3 could bind to the mRNA of CCL5 or TGF-β1, increasing their expression, and inducing macrophage infiltration and M2 polarization while inhibiting the activation of CD8⁺ T cells. Furthermore, inhibition of IGF2BP3 combined with anti-CD47 antibody treatment significantly suppressed the growth of hepatoma in Hepa1-6 xenograft tumor mice. IGF2BP3 promoted the infiltration and M2-polarization of macrophages and suppressed CD8⁺ T activation by enhancing CCL5 and TGF-β1 expression, which facilitated the progression of Hepa1-6 xenograft tumor. Full article

Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer for which effective therapeutic agents are lacking. Fibroblast growth factor receptor 2 (FGFR2) has become a promising therapeutic target in ICC; however, its incidence and optimum testing method have not been fully assessed. This study investigated the rearrangement of FGFR2 in intrahepatic cholangiocarcinoma using multiple molecular detection methods. The samples and clinical data of 167 patients who underwent surgical resection of intrahepatic cholangiocarcinoma in Zhongshan hospital, Fudan university were collected. The presence of FGFR2 gene rearrangement was confirmed using fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS). FGFR2 protein expression was determined using immunohistochemistry (IHC). The concordance between the methods was statistically compared. PD-L1 expression was also assessed in this cohort. The clinicopathological characteristics and genomic profile related to FGFR2 rearrangements were also analyzed to assist candidate-screening for targeted therapies. FGFR2 rearrangement was detected in 21 of the 167 ICC cases (12.5%) using FISH. NGS analysis revealed that FGFR2 rearrangement was present in 16 of the 20 FISH-positive cases, which was consistent with the FISH results (kappa value=0.696, p<0.01). IHC showed that 80 of the 167 cases (48%) were positive for FGFR2 expression, which was discordant with both FISH and NGS results. By comparison, FGFR2-positivity tended to correlate with unique clinicopathological subgroups, featuring early clinical stage, histologically small duct subtype, and reduced mucus production (P<0.05), with improved overall survival (p<0.05). FGFR2-positivity was not associated with PD-L1 expression in ICCs. In genome research, we identified eight partner genes fused with FGFR2, among which FGFR2-BICC1 was the most common fusion type. BAP1, CDKN2A, and CDKN2B were the most common concomitant genetic alterations of FGFR2, whereas KRAS and IDH1 mutations were mutually exclusive to FGFR2 rearrangements. FISH achieved satisfactory concordance with NGS, has potential value for FGFR2 screening for targeted therapies. FGFR2 detection should be prioritized for unique clinical subgroups in ICC, which features a histological small duct subtype, early clinical stage, and reduced mucus production. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new concept, proposed in 2020; however, its applicability in Asia populations has yet to be evaluated. Therefore, we aimed to compare the difference in epidemiological and clinical characteristics between MAFLD and non-alcoholic fatty liver disease (NAFLD) among Asian populations. Based on the Jinchang cohort, 30,633 participants were collected. The prevalence and incidence of MAFLD and NAFLD were used to analyze the epidemic characteristics and its overlapping effects. In addition, the corresponding clinical characteristics of the two diagnostic criteria populations were compared. The prevalence rates of MAFLD and NAFLD were 21.03% and 18.83%, respectively. After an average 2.28-year follow-up, the incidence densities of MAFLD and NAFLD were 41.58 per 1,000 person-years and 37.69 per 1,000 person-years, respectively. With the increase of baseline age, body mass index (BMI), and waist circumference (WC) levels, the prevalence and incidence of MAFLD and NAFLD were on the rise (all p_trend<0.05). Among the total patients diagnosed at baseline or follow-up, most patients had both MAFLD and NAFLD, accounting for 78.84% and 82.88%, respectively. Compared with NAFLD, MAFLD patients had greater proportions of males and metabolic diseases (diabetes, dyslipidemia), and had higher BMI, WC, liver enzymes, blood glucose, and lipid levels in the baseline diagnosis patients (p<0.05). Additionally, lean MAFLD patients had higher metabolic disorders than lean NAFLD patients (p<0.05). Compared with NAFLD, the newly proposed definition of MAFLD is more practical and accurate, and it can help identify more fatty liver patients with high-risk diseases. Full article

Change of gut microbiota composition is associated with the outcome of hepatitis B virus (HBV) infection, yet the related mechanisms are not fully characterized. The objective of this study was to investigate the immune mechanism associated with HBV persistence induced by gut microbiota dysbiosis. C57BL/6 mice were sterilized for gut-microbiota by using an antibiotic (ABX) mixture protocol, and were monitored for their serum endotoxin (lipopolysaccharide [LPS]) levels. An HBV-replicating mouse model was established by performing HBV-expressing plasmid pAAV/HBV1.2 hydrodynamic injection (HDI) with or without LPS, and was monitored for serum hepatitis B surface antigen, hepatitis B e antigen, HBV DNA, and cytokine levels. Kupffer cells (KCs) were purified from antibiotic-treated mice and HBV-replicating mice and analyzed for IL-10 production and T cell suppression ability. ABX treatment resulted in increased serum LPS levels in mice. The KCs separated from both ABX-treated and LPS-treated HBV-replicating mice showed significantly increased IL-10 production and enhanced ability to suppress IFN-γ production of TCR-activated T cells than the KCs separated from their counterpart controls. HDI of pAAV/HBV1.2 in combination with LPS in mice led to a delayed HBV clearance and early elevation of serum IL-10 levels compared to pAAV/HBV1.2 HDI alone. Moreover, IL-10 function blockade or KC depletion led to accelerated HBV clearance in LPS-treated HBV-replicating mice. Our results suggest that dysbiosis of the gut microbiota in mice leads to endotoxemia, which induces KC IL-10 production and strengthens KC-mediated T cell suppression, and thus facilitates HBV persistence. 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

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

Although only a single serotype of hepatitis E virus (HEV), the causative agent of hepatitis E, has been identified, there is great genetic variation among the different HEV isolates reported. There are at least four major recognized genotypes of HEV: genotypes 1 and 2 are mainly restricted to humans and linked to epidemic outbreaks in nonindustrialized countries, whereas genotypes 3 and 4 are zoonotic in both developing and industrialized countries. Besides human strains, genotype 3 and 4 strains of HEV have been genetically characterized from swine, sika deer, mongooses, sheep, and rabbits. Currently, there are approximately 11,000 human and animal sequences of HEV available at the International Nucleotide Sequence Database Collaboration. HEV is the major cause of waterborne outbreaks of hepatitis in areas of poor sanitation. Additionally, it is responsible for sporadic cases of viral hepatitis in not only endemic but industrialized countries as well. Transmission of HEV occurs predominantly by the fecal-oral route, although parenteral and perinatal routes have been reported. HEV infection develops in most individuals as a self-limiting, acute, icteric hepatitis; with mortality rates around 1%. However, some affected individuals will develop fulminant hepatic failure, a serious condition that is frequently fatal without a liver transplant. This complication is particularly common when the infection occurs in pregnant women, where mortality rates rise dramatically to up to 25%. Among the preventive measures available to avoid HEV infection, two separate subunit vaccines containing recombinant truncated capsid proteins of HEV have been shown to be highly effective in the prevention of disease. One of them, HEV 239, was approved in China, and its commercialization by Innovax began in November 2012 under the name Hecolin^®. Full article

Alcohol is a leading cause of liver disease and is associated with significant morbidity and mortality. Several factors, including the amount and duration of alcohol consumption, affect the development and progression of alcoholic liver disease (ALD). ALD represents a spectrum of liver pathology ranging from fatty change to fibrosis to cirrhosis. Early diagnosis of ALD is important to encourage alcohol abstinence, minimize the progression of liver fibrosis, and manage cirrhosis-related complications including hepatocellular carcinoma. A number of questionnaires and laboratory tests are available to screen for alcohol intake. Liver biopsy remains the gold-standard diagnostic tool for ALD, but noninvasive accurate alternatives, including a number of biochemical tests as well as liver stiffness measurement, are increasingly being utilized in the evaluation of patients with suspected ALD. The management of ALD depends largely on complete abstinence from alcohol. Supportive care should focus on treating alcohol withdrawal and providing enteral nutrition while managing the complications of liver failure. Alcoholic hepatitis (AH) is a devastating acute form of ALD that requires early recognition and specialized tertiary medical care. Assessment of AH severity using defined scoring systems is important to allocate resources and initiate appropriate therapy. Corticosteroids or pentoxifylline are commonly used in treating AH but provide a limited survival benefit. Liver transplantation represents the ultimate therapy for patients with alcoholic cirrhosis, with most transplant centers mandating a 6 month period of abstinence from alcohol before listing. Early liver transplantation is also emerging as a therapeutic measure in specifically selected patients with severe AH. A number of novel targeted therapies for ALD are currently being evaluated in clinical trials. Full article