The transcription factor sex-determining region Y-related high-mobility group-box gene 9 (SOX9) plays a critical role in organ development. Although SOX9 has been implicated in regulating lipid metabolism in vitro, its specific role in metabolic dysfunction-associated steatohepatitis (MASH) remains poorly understood. This study aimed to investigate the role of SOX9 in MASH pathogenesis and explored the underlying mechanisms.

MASH models were established using mice fed either a methionine- and choline-deficient (MCD) diet or a high-fat, high-fructose diet. To evaluate the effects of SOX9, hepatocyte-specific SOX9 deletion or overexpression was performed. Lipidomic analyses were conducted to assess how SOX9 influences hepatic lipid metabolism. RNA sequencing was employed to identify pathways modulated by SOX9 during MASH progression. To elucidate the mechanism further, HepG2 cells were treated with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor to test whether SOX9 acts via AMPK activation.

SOX9 expression was significantly elevated in hepatocytes of MASH mice. Hepatocyte-specific SOX9 deletion exacerbated MCD-induced MASH, whereas overexpression of SOX9 mitigated high-fat, high-fructose-induced MASH. Lipidomic and RNA sequencing analyses revealed that SOX9 suppresses the expression of genes associated with lipid metabolism, inflammation, and fibrosis in MCD-fed mice. Furthermore, SOX9 deletion inhibited AMPK pathway activation, while SOX9 overexpression enhanced it. Notably, administration of an AMPK inhibitor negated the protective effects of SOX9 overexpression, leading to increased lipid accumulation in HepG2 cells.

Our findings demonstrate that SOX9 overexpression alleviates hepatic lipid accumulation in MASH by activating the AMPK pathway. These results highlight SOX9 as a promising therapeutic target for treating MASH.

The quantitative effects of alcohol consumption on cirrhosis and hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) infection are unknown. This study aimed to establish a dose-dependent model of alcohol consumption on the risks of cirrhosis and HCC.

PubMed, Embase, the Cochrane Library, Web of Science, and four Chinese databases were searched for studies published from their inception to 15 May 2024. A random-effects model was used to pool the data on the incidence of cirrhosis and HCC, and a dose-dependent model of alcohol’s effect on cirrhosis and HCC was established.

A total of 33,272 HBV patients from 45 studies were included. Compared with non-drinkers, the overall pooled odds ratio (OR) for cirrhosis was 2.61 (95% confidence interval [CI]: 1.46–4.66; I2 = 94%, p < 0.001), and the OR for HCC was 2.27 (95% CI: 1.50–3.43; I2 = 90%, p < 0.001) among drinkers. Compared with low-level drinkers, the estimated pooled OR for cirrhosis was 2.34 (95% CI: 1.59–3.44; I2 = 87%, p < 0.001), and the OR for HCC was 2.42 (95% CI: 1.90–3.09; I2 = 80%, p < 0.001) among high-level drinkers. Furthermore, a linear dose-dependent analysis showed that each daily consumption of 12 g of alcohol increased the risk of cirrhosis by 6.2% and the risk of HCC by 11.5%.

Alcohol dose-dependently increases the risks of cirrhosis and HCC in patients with HBV infection, and patients with daily alcohol consumption of more than 12 g should be strictly monitored.

Few cases of tenofovir resistance have been reported, and the appropriate treatment for such cases remains unclear. We aimed to share a case of a chronic hepatitis B mono-infected patient with potential tenofovir resistance who required combined lamivudine and tenofovir therapy to achieve adequate viral suppression. The patient’s viral load (plasma) was monitored using the cobas® hepatitis B virus Test on the cobas® 6800 system. Hepatitis B antiviral drug resistance (AVDR) mutations were assessed by amplicon-based sequencing. Plasma was extracted using the MagNa Pure 24 system, and polymerase chain reaction targeting the polymerase gene (860bp) was performed. Sequencing was conducted on GridION R10.4.1 flow cells, and the resulting FASTQ files were analyzed using DeepChek®-HBV Software. We describe a female patient in her 60s with chronic hepatitis B who was e-antigen positive. She met treatment criteria in May 2020, when her alanine transaminase levels were 1.5 times above the upper limit of normal. She was initially started on entecavir but had to switch to tenofovir alafenamide in June 2020 due to a rash. Despite three years of tenofovir therapy, her viral load remained unsuppressed. AVDR testing identified two suspected tenofovir resistance mutations (V191I and A317S). Since no mutations associated with lamivudine resistance were detected, the patient was treated with a combination of lamivudine and tenofovir, achieving viral suppression after four months. Although rare, tenofovir resistance should be considered in patients with persistent viremia despite long-term therapy. AVDR sequencing facilitated the detection of potential tenofovir resistance and guided treatment decisions, leading to successful viral suppression in this case.

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 ptrend<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.

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.

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.

Hepatic injury and subsequent hepatic failure due to both intentional and non-intentional overdose of acetaminophen (APAP) has affected patients for decades, and involves the cornerstone metabolic pathways which take place in the microsomes within hepatocytes. APAP hepatotoxicity remains a global issue; in the United States, in particular, it accounts for more than 50% of overdose-related acute liver failure and approximately 20% of the liver transplant cases. The pathophysiology, disease course and management of acute liver failure secondary to APAP toxicity remain to be precisely elucidated, and adverse patient outcomes with increased morbidity and mortality continue to occur. Although APAP hepatotoxicity follows a predictable timeline of hepatic failure, its clinical presentation might vary. N-acetylcysteine (NAC) therapy is considered as the mainstay therapy, but liver transplantation might represent a life-saving procedure for selected patients. Future research focus in this field may benefit from shifting towards obtaining antidotal knowledge at the molecular level, with focus on the underlying molecular signaling pathways.

Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and is proposed to replace the previous name, nonalcoholic fatty liver disease (NAFLD). Globally, MAFLD/NAFLD is the most common liver disease, with an incidence rate ranging from 6% to 35% in adult populations. The pathogenesis of MAFLD/NAFLD is closely related to insulin resistance (IR), and the genetic susceptibility to acquired metabolic stress-associated liver injury. Similarly, the gut microbiota in MAFLD/NAFLD is being revaluated by scientists, as the gut and liver influence each other via the gut-liver axis. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis has a key role in the pathological progression of MAFLD/NAFLD, and inhibition of ferroptosis may become a novel therapeutic strategy for the treatment of NAFLD. This review focuses on the main mechanisms behind the promotion of MAFLD/NAFLD occurrence and development by the intestinal microbiota and ferroptosis. It outlines new strategies to target the intestinal microbiota and ferroptosis to facilitate future MAFLD/NAFLD therapies.

Hepatic cysts (HCs) are frequently discovered incidentally on abdominal imaging. The prevalence of HCs has been reported as high as 15–18% in the United States. Although most cysts are benign, some are malignant or premalignant. It is important to diagnose cystic lesions in order to properly manage them. Imaging with conventional ultrasound, computed tomography, magnetic resonance imaging, or contrast-enhanced ultrasound can be used to further characterize and diagnose HCs. Ultrasound is typically the first-line imaging modality, whereas more advanced imaging can help narrow down the specific lesion. Contrast-enhanced ultrasound is a newer modality, recently approved in the United States, which offers non-invasive evaluation in real-time. The first step in diagnosis is stratifying risk by differentiating simple and complex cysts. There are several features that can help identify HCs, including septae, mural consistency, calcifications, and quality of cystic fluid. Simple cysts are mainly congenital cysts, but also occur in polycystic liver disease. Complex cysts include mucinous neoplasms, echinococcal cysts, hemorrhagic cysts, cystic hepatocellular carcinoma and other rare lesions. Treatment is indicated in symptomatic cysts or those suspicious for malignant or premalignant features. Treatment modalities include fenestration, aspiration sclerotherapy, or surgical resection.