Clinical and Molecular Hepatology最新文献

Chronic hepatitis B (CHB) infection remains a significant global public health concern. Functional cure, defined as hepatitis B surface antigen (HBsAg) seroclearance with unquantifiable HBV DNA at 24 weeks off treatment, is a desirable endpoint in the treatment of CHB, yet challenging to achieve. Given the limitations of current therapies including nucleos(t)ide analogues (NUCs) and pegylated interferon alpha (Peg-IFNα), novel agents targeting functional cure are emerging. As hepatitis B virus (HBV) is a non-cytolytic virus, liver damage stems from the host immune response towards HBV-infected cells. The innate immune response during the initial phase of HBV infection is crucial in establishing an adequate level of immunity against the virus. However, HBV adopts various mechanisms to evade the host innate immunity, partly contributing to the chronicity of infection. This article provides a comprehensive review on how the HBV life cycle interacts with the host innate immune system. The latest evidence of novel agents targeting the innate immunity will also be covered. Retinoic acid inducible gene I (RIG-I) agonists, toll-like receptor (TLR) agonists, and interferons are therapies that target the HBV evasion strategies against host innate immunity. While small interfering RNAs (siRNAs) and antisense oligonucleotides are originally designed for antigen knockdown and reinvigoration of the adaptive immune response, they have also shown additional impacts on the innate immunity. With ongoing research and innovation in combination strategies, advancement in the management of CHB is anticipated in the future.

Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of cirrhosis and its complications. Given its close association with type 2 diabetes mellitus (T2DM), evaluating whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) can mitigate the progression of liver fibrosis is clinically important. We examined the association between SGLT2i use and liver fibrosis progression in patients diagnosed with MASLD and T2DM.

Methods: We conducted a target trial emulation study using a retrospective, active comparator new-user design among adults with MASLD, T2DM, and low-to-intermediate Fibrosis-4 (FIB-4 ≤2.67) scores who initiated treatment with either SGLT2is or dipeptidyl peptidase-4 inhibitors (DPP4is) at Mass General Brigham or Asan Medical Center from 2013 to 2023. The primary outcome was the progression to advanced fibrosis (FIB-4 >2.67), confirmed on ≥2 occasions within 1 year. The secondary outcome was the development of major adverse liver outcomes (MALO), including incident cirrhosis, decompensation events, hepatocellular carcinoma, or liver transplantation.

Results: Among 16,901 eligible patients, 2,571 propensity score-matched pairs were identified with balanced baseline characteristics. During follow-up (median, 3.7 years), fibrosis progression occurred at a rate of 3.46/100 person-years in SGLT2i users and 4.44 in DPP4i users. SGLT2i use was associated with a lower risk of fibrosis progression (HR, 0.78; 95% CI, 0.67-0.89; p<0.001). No significant difference in MALO incidence was observed. Subgroup analyses showed a consistent association among users of metformin, statins, and aspirin.

Conclusions: SGLT2i use was associated with reduced risk of fibrotic progression compared to DPP4i use in adults with MASLD and T2DM.

Background & aims: The first metabolic dysfunction-associated steatotic liver disease (MASLD) drug was approved with an unsatisfactorily small effect size. This study aimed to determine key factors impacting the cost-effectiveness of a new hypothetical metabolic dysfunction-associated steatotic liver disease (MASLD) drug as well as its treatment efficacy.

Methods: A Markov model reflecting the natural history of MASLD was developed, incorporating fibrosis progression, cardiovascular disease (CVD) risk, and mortality. Treatment effect of Drug X (with $20,000 of annual cost) was assumed to achieve a ≥1 stage fibrosis regression, with a 25% gap of effect size in regression rate over no treatment in the first year. The incremental cost-effectiveness ratio (ICER) over a 20-year horizon was estimated. And sensitivity analyses were conducted to explore uncertainty and identify influential factors.

Results: In the base-case analysis, drug X provided an incremental gain of 1.32 quality-adjusted life years (QALYs) and 1.20 life years (LYs) compared to the no treatment, with an ICER of $68,010/QALY - below the $100,000/QALY willingness-to-pay threshold, indicating that Drug X treatment is cost-effective. Two-way sensitivity analysis further highlighted that the drug should achieve at least a 15% initial regression gap and maintain a minimum 3% sustained durability gap to remain cost-effective. And baseline fibrosis stage distribution also acted as an influencing factor.

Conclusions: Long-term sustained durability of the hypothetical drug, patient distribution based on baseline fibrosis stage, as well as initial treatment response rate are key factors that influence the cost-effectiveness of new MASLD drugs.

Background/aims: Hepatocellular carcinoma (HCC) exhibits substantial morphological and biological heterogeneity. Clinical and molecular relevance of the infiltrative subtype remains poorly defined in the context of cancer immunotherapy. We aimed to evaluate the prognostic impact and molecular features of infiltrative HCC in patients treated with first-line atezolizumab plus bevacizumab (Ate/Bev).

Methods: We included 307 patients with advanced HCC treated with Ate/Bev and classified them into four gross morphological types based on imaging. Multi-omics profiling was conducted on tumor samples. Type IV infiltrative signature was derived and externally validated using five independent HCC cohorts, including IMbrave150.

Results: Infiltrative morphology, encompassing pure and mixed forms, was present in 42.7% of advanced HCC and associated with advanced disease features and compromised liver function. Patients with type IV infiltrative HCC showed lowest objective response rate (14.6%) and worst progression-free (median, 2.8 months) and overall survival (median, 7.1 months). Infiltrative morphology remained an independent predictor of poor outcomes after multivariable adjustment for confounders, including intrahepatic tumor extent. Genomic profiling revealed enriched TP53 and ATM loss-of-function mutations in type IV infiltrative HCC. Transcriptomic and proteomic analyses identified consistent activation of tumor proliferation, epithelial-mesenchymal transition, TGF-β signaling, and immunosuppressive pathways in type IV infiltrative HCC. Type IV infiltrative signature was significantly associated with poor survival across external datasets and retained independent prognostic value.

Conclusions: Infiltrative HCC is a clinically aggressive and molecularly distinct subtype of advanced HCC. Morphological classification and type IV infiltrative signatures may guide risk stratification and therapeutic decision-making in advanced HCC treated with immunotherapy.

The knowledge accumulated over the past two decades has revealed that the natural history of metabolic dysfunction-associated steatotic liver disease (MASLD) and the drivers of the disease severity are not only complex but also exhibit variation among patients. This intricate clinical scenario entails major therapeutic and management implications. In this review, we provide a comprehensive examination of recent advancements in our understanding of MASLD heterogeneity, drawing insights from multiomics and panomics studies. The discussion herein explores the instrumental role of panomics in MASLD research, elucidating the potential for the identification of molecular subtypes that exhibit divergent survival outcomes or heterogeneous responses to various treatments. Furthermore, we provide insights into the challenges in addressing disease heterogeneity and potential solutions. Finally, the most advanced technological advancements and prospective research directions in the domain of MASLD research are delineated, with the objective of facilitating the implementation of personalized diagnosis and interventions.

Background/aims: Gut microbiome plays a pivotal role in metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis, yet, associated functional mechanisms and host responses of specific microbial species remain insufficiently characterized. This study investigated the Bacteroides eggerthii therapeutic effects on MASLD by integrating multi-omics analysis and experimental validation in a Western diet-induced mouse model.

Methods: Candidate strains were identified using 16S rRNA gene sequencing of fecal samples from individuals with and without MASLD or obesity. B. eggerthii, a species significantly depleted in both groups, was selected for functional evaluation. Male C57BL/6J mice were fed a Western diet (WD) or WD supplemented with B. eggerthii (WD+B) for 12 weeks. Liver histology, serum biochemistry, fecal microbiome and metabolome profiling, and hepatic and intestinal transcriptomic analyses were performed. Anti-steatotic effects of B. eggerthii-derived metabolites were validated in vitro.

Results: Bacteroides eggerthii supplementation significantly improved liver weight, inflammation, fibrosis, and steatosis in WD+B group compared to WD alone. PICRUSt-based LEfSe analysis revealed choloylglycine hydrolase activity enrichment in gut microbiota, and strain-specific qPCR confirmed colonization in mouse colon. Integrated transcriptomic analyses revealed lipid and bile acid signaling pathway restoration, including CD36, FXR, and FGF15. Untargeted metabolomics identified elevated 2-hydroxyisocaproic acid (HICA) as a strain-derived metabolite in feces and B. eggerthii culture supernatants. In vitro, HICA significantly reduced lipid accumulation in free fatty acid-induced steatosis models.

Conclusion: Bacteroides eggerthii ameliorates MASLD via gut-liver axis modulation, including bile acid metabolism and hepatic lipid signaling. These underscore its therapeutic potential and highlight HICA as a novel microbiome-derived metabolite with anti-steatotic activity.

Background/aims: Cholestatic liver disease (CLD) is a pathological condition characterized by impaired bile formation, secretion, and excretion. However, the key pathophysiological mechanisms of CLD remain elusive, and therapeutic efficacy is unsatisfactory.

Methods: We administered berberine (BBR) or dihydroberberine (dhBBR) in bile duct ligation-, ANIT-, and mdr2-/- CLD mouse models to evaluate the anti-CLD effect. We conducted fecal microbiota transplantation to determine the role of gut microbiota in BBR's effect. We conducted a randomized, controlled clinical trial to evaluate the effects of BBR in patients with CLD.

Results: Oral BBR alleviates cholestatic liver injury in multiple mouse models. Gut microbes can transform BBR into dhBBR, which suppresses 5-HT production in gut enterochromaffin cells by antagonizing tryptophan hydroxylase 1 (TPH1) activity and downregulating Tph1 transcription. This further ameliorates CLD by interrupting the 5-HT/5HTR axis. A clinical study validated that BBR improved blood biochemical indicators in patients with CLD and decreased 5-HT levels.

Conclusions: BBR is transformed by gut microbiota to ameliorate CLD via inhibiting 5-HT, suggesting potential novel strategies for further clinical use.