Purpose: The prognosis of patients with unresectable hepatocellular carcinoma (HCC) and compensated cirrhosis is influenced by cancer progression. Data on the incidence and the prognostic role of clinical hepatic decompensation (CHD) following immune checkpoint inhibitor therapy are lacking. We aimed to assess whether early CHD within 3 months from commencement of systemic therapy affects overall survival (OS) of patients treated with atezolizumab plus bevacizumab or sorafenib. Patients and Methods: Individual patient data from the IMbrave150 trial were analyzed. Cumulative incidence of CHD was assessed by competing risk analysis against HCC radiologic progression. Early CHD and HCC radiologic progression were assessed as predictors of OS by the time-dependent Cox model. Results: The 3- and 12-month rates of CHD were 7% and 12%, respectively, whereas the 3- and 12-month rates of HCC radiologic progression were 23% and 52%, respectively. Albumin–bilirubin grade 2 [subdistribution HR (sHR) = 1.79, 95% confidence interval (CI), 1.01–3.19; P = 0.049], INR (sHR = 1.97, 95% CI, 1.64–2.37; P < 0.001), and presence of neoplastic macrovascular invasion (sHR = 2.01, 95% CI, 1.14–3.54; P = 0.020) were independently associated with higher risk of CHD. Early CHD (HR = 7.56, 95% CI, 4.47–12.8) and early HCC radiologic progression (HR = 5.92, 95% CI, 4.03–8.69), as first events, were independently associated with higher mortality. Conclusions: This study provides robust evidence that early CHD is associated with the highest risk of death in patients with unresectable HCC undergoing systemic treatment. Within well-compensated participants, albumin–bilirubin, INR, and macrovascular invasion identify a population at higher risk of decompensation. Inclusion of clinical decompensation events in future prospective clinical trials may improve characterization of OS from systemic therapy of HCC.

Importance: The recent change in terminology from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction‐associated fatty liver disease (MAFLD) and metabolic dysfunction‐associated steatotic liver disease (MASLD) highlights the link between hepatic steatosis and metabolic dysfunction, taking out the stigmata of alcohol.Objective: We compared the effects of NAFLD and MAFLD definitions on the risk of overall and cardiovascular (CV) mortality, liver‐related events (LRE), nonfatal CV events (CVE), chronic kidney disease (CKD), and extra‐hepatic cancers (EHC).Data Sources and Study Selection: We systematically searched four large electronic databases for cohort studies (published through August 2023) that simultaneously used NAFLD and MAFLD definitions for examining the risk of mortality and adverse CV, renal, or oncological outcomes associated with both definitions. In total, 21 eligible cohort studies were identified. Meta‐analysis was performed using random‐effects modelling.Results: Compared with those with NAFLD, individuals with MAFLD had significantly higher rates of overall mortality (random‐effect OR 1.12, 95% CI 1.04–1.21, p = .004) and CV mortality (random‐effect OR 1.15, 95% CI 1.04–1.26, p = .004), and a marginal trend towards higher rates of developing CKD (random‐effect OR 1.06, 95% CI 1.00–1.12, p = .058) and EHC events (random‐effect OR 1.11, 95% CI 1.00–1.23, p = .052). We found no significant differences in the risk LREs and nonfatal CVE between MAFLD and NAFLD. Meta‐regression analyses identified male sex and metabolic comorbidities as the strongest risk factors related to the risk of adverse clinical outcomes in MAFLD compared to NAFLD.Conclusions and Relevance: Individuals with MAFLD have higher rates of overall and CV mortality and higher rates of developing CKD and EHC events than those with NAFLD, possibly due to the dysmetabolic risk profile related to MAFLD.

Large language models (LLMs) are transforming the medical landscape by enhancing access to information, diagnostics, treatment customization, and medical education, especially in areas like Gastroenterology. LLMs utilize extensive medical data to improve decision-making, leading to better patient outcomes and personalized medicine. These models are instrumental in interpreting medical literature and synthesizing patient data, facilitating real-time knowledge for physicians and supporting educational pursuits in medicine. Despite their potential, the complete integration of LLMs in real-life remains ongoing, particularly requiring further study and regulation. This review highlights the existing evidence supporting LLMs’ use in Gastroenterology, addressing both their potential and limitations. Recent studies demonstrate LLMs’ ability to answer questions from physicians and patients accurately. Specific applications in this field, such as colonoscopy, screening for colorectal cancer, and hepatobiliary and inflammatory bowel diseases, underscore LLMs’ promise in improving the communication and understanding of complex medical scenarios. Moreover, the review discusses LLMs’ efficacy in clinical contexts, providing guideline-based recommendations and supporting decision-making processes. Despite these advancements, challenges such as data completeness, reference suitability, variability in response accuracy, dependency on input phrasing, and a lack of patient-generated questions underscore limitations in reproducibility and generalizability. The effective integration of LLMs into medical practice demands refinement tailored to specific medical contexts and guidelines. Overall, while LLMs hold significant potential in transforming medical practice, ongoing development and contextual training are essential to fully realize their benefits.

Background: International regulatory agencies recommend testing drug therapy for patients with noncirrhotic high-risk metabolic dysfunction-associated steatohepatitis (MASH) because they are at risk of liver-related events(LRE). We aimed to compare the risk of LRE in MASLD patients stratified for F2-F4 fibrosis and MASH. Methods: 1938 consecutive patients with biopsy-proven MASLD were enrolled. High-risk MASH was defined as MASH with F2-F4 fibrosis. LSM was measured by transient elastography. LRE were recorded during follow-up. Cox multivariate models were used to assess the association between high-risk MASH or F2-F4 fibrosis without MASH, of LSM(≥8 or ≥10 Kpa) and of AGILE 3+ with LRE. The diagnostic performance for the prediction of LRE was assessed using the area under the receiver operating characteristic(AUROC) curves. Results: The observed 5-year actuarial rate of LRE was 0.4%,0.2%,5.1% and 6.6% in patients with F0-F1 fibrosis without MASH, F0-F1 fibrosis with MASH, F2-F4 fibrosis without MASH, and high-risk MASH, respectively. At multivariate Cox regression analysis using F0-F1 fibrosis without MASH as reference, both F2-F4 fibrosis without MASH (adjusted hazard ratio[aHR] 9.96) and high-risk MASH (aHR 10.14) were associated with LRE. In the 1074 patients with available LSM, LSM≥10 KPa(aHR 6.31) or AGILE 3+ >0.67 (aHR 27.45) independently predicted the development of LRE and had similarly acceptable 5-year AUROC to high-risk MASH and F2-F4 fibrosis(0.772,0.818,0.739, and 0.780, respectively). Conclusions: The risk of LRE is similar in patients with high-risk MASH and with F2-F4 fibrosis without MASH. The use of LSM≥10 KPa or AGILE 3+ >0.67 could be an accurate option to identify MASLD patients worthy to be included in clinical trials. Export

Non-alcoholic fatty liver disease (NAFLD) is an emerging chronic liver disease worldwide. Curcumin and andrographolide are famous for improving hepatic functions, being able to reverse oxidative stress and release pro-inflammatory cytokines, and they are implicated in hepatic stellate cell activation and in liver fibrosis development. Thus, we tested curcumin and andrographolide separately and in combination to determine their effect on triglyceride accumulation and ROS production, identifying the differential expression of genes involved in fatty liver and oxidative stress development. In vitro steatosis was induced in HepG2 cells and the protective effect of curcumin, andrographolide, and their combination was observed evaluating cell viability, lipid and triglyceride content, ROS levels, and microarray differential gene expression. Curcumin, andrographolide, and their association were effective in reducing steatosis, triglyceride content, and ROS stress, downregulating the genes involved in lipid accumulation. Moreover, the treatments were able to protect the cytotoxic effect of steatosis, promoting the expression of survival and anti-inflammatory genes. The present study showed that the association of curcumin and andrographolide could be used as a therapeutic approach to counter high lipid content and ROS levels in steatosis liver, avoiding the possible hepatotoxic effect of curcumin. Furthermore, this study improved our understanding of the antisteatosis and hepatoprotective properties of a curcumin and andrographolide combination.