Clinical and Molecular Hepatology最新文献

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a spectrum of pathology involving fatty liver disease that may progress to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The prevalence of MASLD and metabolic dysfunction-associated steatohepatitis (MASH) continues to increase, mirroring the rise in global prevalence of related comorbidities such as obesity and type 2 diabetes mellitus. Due to the alarming rise of these comorbidities, a greater proportion of the population is at risk for developing MASLD and MASH. As such, there has been a significant effort to develop effective therapies for MASLD and MASH. Recently, the U.S. Food and Drug Administration approved resmetirom, a selective thyroid hormone receptor-beta agonist, as the first treatment for patients with MASH. In India, the Drug Controller General of India approved saroglitazar, a dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist, for the treatment of MASLD. Currently, we have various drug classes, including liver-specific therapies, in Phase 3 development with even more agents earlier in the pipeline. This review will discuss prospective therapies in later stages of development such as thyroid hormone receptor-beta agonists, PPAR agonists, glucagon-like peptide-1 receptor agonists, fibroblast growth factor 21 agonists, and fatty acid synthase inhibitors.

Through the implementation of hepatitis B vaccination and effective antiviral treatment over the past four decades, the hepatitis B surface antigen (HBsAg) seroprevalence of the vaccinated generation dramatically decline. The incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) also decreases. However, the elimination of HBV is still a challenge to achieve. Novel HBV biomarkers, including quantitative HBsAg, hepatitis B virus core-related antigen and HBV RNA are promising in predicting clinical phases, risks of disease progression and HBV functional cure. Current antiviral therapies, nucleoside/nucleotide and pegylated alpha-interferon, effectively decrease HCC incidence in chronic hepatitis B (CHB) patients and minimize the recurrence of HCC in patients receiving curative therapy. Novel agents under development to achieve HBV cure include direct-acting antivirals that target various stages of the HBV lifecycle and host targeting agents that enhance HBV-specific immunity. The action plans for eliminating hepatitis B in the future are universal HBV screening, early and simplified treatment as well as precision lifelong management for CHB patients. This narrative review will summarize and discuss global strategies and initiatives aimed at eliminating HBV infection.

Background/aims: Hepatocellular carcinoma (HCC) frequently recurs after curative treatment, posing challenges to long-term survival. Although contrast-enhanced multiphasic computed tomography (CECT) is commonly used for detecting recurrence, it is associated with risks such as radiation exposure and contrast agent reactions. This study aimed to compare the diagnostic performance of non-contrast magnetic resonance imaging (NC-MRI) with CECT for detecting recurrent HCC.

Methods: In this prospective multicenter intra-individual head-to-head comparison trial (study identifier: NCT05690451, KCT0006395), participants who had undergone curative treatment for HCC and remained recurrence-free for over two years were enrolled. Each participant underwent three follow-up imaging sessions at 2-6-month intervals using both CECT and NC-MRI. The primary outcome was the detection accuracy of each modality, analyzed using the generalized estimating equation analysis. Secondary outcomes included sensitivity and specificity.

Results: The study included 203 participants with a total of 528 paired imaging sessions, identifying recurrent HCC in 22 cases (10.8%). Among these, 21 cases involved intrahepatic recurrence with a median tumor size of 1.3 cm, and one case had aortocaval lymph node metastasis. NC-MRI achieved a detection accuracy of 96.6% (196/203), higher than CECT's 91.6% (186/203) (P=0.006). NC-MRI also showed greater sensitivity (77.3% [17/22] vs. 36.4% [8/22]; P=0.012), while specificity was comparable between NC-MRI and CECT (98.9% [179/181] vs. 98.3% [178/181]; P=0.999).

Conclusion: NC-MRI demonstrated higher sensitivity and accuracy compared to CECT in detecting recurrent HCC in patients who had been disease-free for over two years following curative treatment, indicating its potential as a preferred imaging modality for this purpose.

Background/aims: Excessive lipid accumulation in hepatocytes is a critical cause of metabolic dysfunction-associated steatotic liver disease (MASLD) progression. Ankyrin repeat and SOCS box protein 3 (ASB3) is an E3 ubiquitin ligase that mediates diverse disease processes; however, the direct substrates of ASB3 in lipid metabolism and its role in MASLD remain unexplored.

Methods: We generated ASB3 knockout mice fed a high-fat diet to induce MASLD. Oxygen consumption and fatty acid oxidation (FAO) were used to assess lipid metabolism. LC-MS/MS and IP were used to verify the ASB3 target protein. Correlation analysis was conducted on the cohort of MASLD patients vs. the control group.

Results: Loss of the ASB3 E3 ubiquitin ligase in hepatocytes strengthens mitochondrial FAO, thereby influencing energy consumption to decrease triglyceride storage and lipid accumulation. Quantitative lysine ubiquitination proteomics revealed that ASB3 directly mediated the ubiquitin levels at two sites (K180 and K639) in carnitine palmitoyl transferase 1A (CPT1A), a rate-limiting enzyme of FAO, to induce CPT1A degradation. Moreover, both constitutive and hepatocyte-specific ASB3 knockout enhance FAO and delay lipid accumulation, liver steatosis, and MASLD progression in a CPT1A-dependent manner. Hepatic ASB3 deficiency also delays fibrosis in MASLD. Analysis of public databases and liver tissue samples from MASLD patients revealed that ASB3 was highly expressed in MASLD patients and was negatively correlated with CPT1A.

Conclusion: Our study reveals the key roles of ASB3 in the development of MASLD and suggests a novel therapeutic potential for MASLD.

Portal vein thrombosis (PVT) is characterized by the formation of a thrombus (blood clot) within the portal vein system, including main portal vein and its intrahepatic portal vein branches, and may extend to the superior mesenteric vein or splenic vein. The emergence of PVT is linked to diverse risk factors, encompassing liver conditions with cirrhosis, abdominal infections, previous abdominal surgeries, malignancies, inherited or acquired thrombophilias, and systemic hypercoagulable conditions. Recent studies revealed a possible connection between the occurrence of PVT and either contracting corona virus disease 2019 (COVID-19) or receiving a COVID-19 vaccination. Current treatment strategies were primarily based on symptom management, extent, and progression of thrombosis, but their efficacy was inconsistent and suboptimal. Untimely or inadequate treatment can lead to the progression of the thrombus and increase the risk of complications, such as portal hypertension, variceal bleeding, and hepatic decompensation, posing a significant risk to the patient's life. Thus, early and appropriate initiation of pharmacologic and interventional treatments, as well as more aggressive strategies, is crucial for the management and prevention of PVT progression and recurrence. This review focuses on the literature on the recent advancements in the treatment of PVT using various therapeutic modalities, including anticoagulant therapy, thrombolysis, thrombectomy, interventional therapy and liver transplant in cirrhotic patients. In addition, we discuss pearls and pitfalls of these strategies for PVT, highlighting recent progress, identifying knowledge gaps, and proposing avenues towards precision management.

Mendelian randomization (MR), a powerful statistical tool for causal inference, has been widely applied in various fields of medical research, even extending to economics and psychology. In hepatology, MR has been utilized to identify risk factors and potential therapeutic targets for liver diseases, including metabolic dysfunction-associated steatotic liver disease, cholestatic and autoimmune liver diseases, and hepatobiliary cancer. MR can provide evidence of causation via associations between genetic variants, modifiable exposures and liver disease occurrence or outcomes, using large existing datasets. However, results from MR studies are sometimes scattered, biologically not plausible or even controversial between analyses, potentially reflecting a trend of inappropriate application of this method (e.g., inappropriate selection of genetic instruments, insufficient assessment of horizontal pleiotropy, compromised statistical power, and neglected genetic diversity among different populations), and thus hinder the translation of MR findings from bench to bedside. Assessing these critical issues and pinpointing bona fide evidence are essential but quite challenging for clinicians. In this review, we aim to introduce the MR method to hepatologists and provide a comprehensive overview of the current MR findings that are relevant for hepatologists. Furthermore, we will discuss how to evaluate the quality of MR publications, interpret MR findings, and illustrate good practice of using MR studies in hepatology.

Background/aims: Prediction of short-term mortality in patients with acute-on-chronic liver failure (ACLF) admitted to the intensive care unit (ICU) may enhance effective management.

Methods: To develop, explain, and validate a predictive machine learning (ML) model for short-term mortality in patients with ACLF with two or more organ failures (OFs). Utilizing a large ICU cohort with detailed clinical information, we identified ACLF patients with two or more OFs according to the EASL-CLIF and NACSELD definitions. ML model was developed for each definition to predict 30-day mortality. The Shapley value was estimated to explain the models. Validation and calibration of these models were performed.

Results: Of 5,994 patients with cirrhosis admitted to ICU, 1,511 met NACSELD criteria, and 1,692 met EASL-CLIF grade II or higher criteria. The CatBoost ACLF (CBA) model had the greatest accuracy in the NACSELD cohort (area under curve [AUC] of 0.87), while the Random Forest ACLF (RFA) model performed best in the EASL-CLIF cohort (AUC of 0.83). Both models showed robust calibration. The models were explained by SHAP score analysis, yielding a rank list, and the top twelve predictors were selected. Both simplified models demonstrated similar performance (CBA model: AUC 0.89, RFA model: AUC 0.81) and significantly outperformed contemporary scoring systems, including CLIF-C ACLF and MELD 3.0. The models were validated in both internal and external cohorts. A simple-to-use online tool was created to predict mortality rates.

Conclusion: We presented explainable, well-validated, and calibrated predictive models for ACLF patients with two or more OFs, which outperformed existing predictive scores.

Intermediate-stage hepatocellular carcinoma (HCC) encompasses a diverse patient population that requires individualized treatment strategies and a multidisciplinary approach. Recent advancements in systemic therapy have expanded the therapeutic options for intermediate-stage HCC, allowing for combination strategies such as systemic therapy with transarterial chemoembolization (TACE) and upfront systemic therapy for individuals deemed unsuitable for TACE. Additionally, the ongoing development of treatment modalities for intermediate-stage HCC has improved the potential for curative conversion and tumor downstaging. Nevertheless, consensus on the optimal management of intermediate-stage HCC remains limited. Thus, the primary aim of this study was to develop a set of consensus guidelines for the management of intermediate-stage HCC. To address this gap, the Taiwan Liver Cancer Association (TLCA) established a working group to develop a multidisciplinary strategy for managing intermediate-stage HCC. Here, we present eight consensus statements formulated by this expert panel, which outline criteria for TACE unsuitability, treatment recommendations based on TACE eligibility, and considerations for various modalities, including conventional TACE, drug-eluting bead TACE, and transarterial radioembolization, as well as the appropriate timing for initiating systemic therapy to enable curative conversion and downstaging. These statements provide specific, evidence-based recommendations for clinicians, addressing treatment pathways based on TACE eligibility and other key considerations for intermediate-stage HCC management. The development of this consensus guideline is intended to aid clinicians in selecting the most appropriate treatment pathway for intermediate-stage HCC, support personalized treatment planning, and ultimately enhance the feasibility of achieving curative conversion.