Background & Aims: Metabolic dysfunction (MD)-associated steatotic liver disease (MASLD) is defined by steatotic liver disease (SLD) in the presence of at least one cardiometabolic risk factor (CMRF)—obesity, type 2 diabetes, dyslipidemia, or hypertension—in the absence of alternative causes. MASLD may progress to steatohepatitis (MASH) and advanced fibrosis (AF), significantly increasing the risk of hepatocellular carcinoma (HCC). While cardiovascular risk is known to escalate with MD severity, the impact of cumulative CMRF burden on HCC development remains poorly characterized. This study aimed to assess differential HCC risk and timing by stratifying MASLD-AF patients according to distinct CMRF combinations.MethodsBiochemical, clinical, and Liver Stiffness (LSM) data from 1921 SLD individuals, archived in the Health Documents Digitization Repository of the “Luigi Vanvitelli” University Hospital (January 2010–Oct 2020), were retrospectively analyzed to identify subjects fulfilling EASL-proposed MASLD criteria and exhibiting LSM-AF. A non-redundant permutation of CMRFs—obesity (Obe), dysglycaemia or type 2 diabetes (Gly), dyslipidemia (Lip), and elevated blood pressure (Press)—was applied, yielding 4 groups with 15 distinct MD profiles: Group 1) One CMRF (n:311) [1a: Obe (n:130); 1b: Gly (n:40); 1c: Lip (n:91); 1d: Press (n:50)]; Group 2) Two CMRFs (n:840) [2a: Obe-Gly (n: 140); 2b: Obe-Lip (n:120); 2c: Obe-Press (n:150); 2d: Gly-Lip (n:130); 2e: Gly-Press (n:140); 2f: Lip-Press (n:160)]; Group 3) Three CMRFs (n:680) [3a: Obe-Gly-Lip (n:190); 3b: Obe-Lip-Press (n:170); 3c: Obe-Gly-Press (n:140); 3d: Gly-Lip-Press (n:180)]; Group 4) Four CMRFs (Obe-Gly-Lip-Press) (n:90). HCC diagnosis and staging (BCLC) were retrospectively recorded over a 5-year follow-up (Fig.1). Results Patients with >3 CMRFs exhibited significantly higher HCC risk [HR: 3.12, p: 0.001]. Within this subgroup, Gly-Lip-Press, Obe-Gly-Lip [HR: 1.129, p: 0.034], and Obe-Gly-Lip-Press [HR: 2.21, p: 0.002] showed progressively increasing 5-year HCC incidence and decreasing median time to occurrence (48.2 vs 41.3 vs 28.1 months; p<0.0001). Notably, the BCLC-C stage at diagnosis was more frequent in Obe-Gly-Lip (31%) compared to other Group 3 profiles (<10%; p<0.0001) (Fig. 2). Conclusions CMRF-based stratification reveals substantial heterogeneity in HCC risk among MASLD-AF patients, supporting the implementation of personalized surveillance strategies taking into account the metabolic burden.

Hepatocellular carcinoma (HCC) represents a major global health challenge and the third leading cause of cancer-related mortality worldwide. Its epidemiological burden is rapidly increasing, largely driven by the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), which is now recognized as the most common chronic liver disease globally. Notably, MASLD frequently coexists with type 2 diabetes mellitus (T2DM), sharing several features, including the interplay of common genetic, metabolic, and environmental factors, thus contributing to a complex multifactorial pathogenesis. Relevantly, patients affected by both conditions represent a subgroup at particularly high risk of liver disease progression and hepatocarcinogenesis. In this population, metabolic and inflammatory disturbances act synergistically to create a pro-tumorigenic hepatic environment where insulin resistance (IR) plays a crucial role, by driving hepatic lipotoxicity, mitochondrial dysfunction, and inflammatory signaling with oxidative stress, thereby establishing a permissive environment for worsening steatosis and malignant transformation. Increasing evidence supports the concept of MASLD as a multisystem disorder reflecting the systemic nature of metabolic dysfunction. Within this framework, beyond IR, extrahepatic factors have also emerged as important contributors to steatosis progression, worsening of T2DM, and modulation of HCC risk. In particular, the gut-liver axis has gained recognition as a key regulator of hepatic homeostasis, integrating signals from the intestinal microbiota, immune responses, and metabolic pathways. Dysregulation of this crosstalk promotes systemic inflammation and metabolic imbalance, exacerbating IR and fostering a pro-oncogenic hepatic environment. This review examines the interconnected metabolic and immune mechanisms linking IR and gut-liver axis dysfunction to HCC development in patients with MASLD and T2DM, highlighting their implications for risk stratification and precision-based therapeutic strategies.

Background: Hepatic malignancies are a major global health burden, with rising incidence, high mortality, and frequent diagnosis at advanced or unresectable stages. Although surgical resection, locoregional therapies, and systemic treatments have improved outcomes, many patients remain ineligible for curative strategies because of tumor burden, anatomical constraints, or liver dysfunction. Liver transplantation (LT) has therefore evolved from a treatment limited to selected hepatocellular carcinoma (HCC) cases within strict morphological criteria to a broader oncologic option guided by tumor biology and treatment response. This review provides an updated overview of the expanding role of LT in hepatic malignancies and the transition toward precision transplant oncology. Methods: We conducted a narrative review of current evidence on LT in HCC, cholangiocarcinoma (CCA), and colorectal liver metastases (CRLM), focusing on candidate selection, neoadjuvant strategies, molecular profiling, immunological aspects, and future perspectives. Results: In HCC, expanded criteria and bridging/downstaging strategies, including immunotherapy, have increased transplant eligibility, although concerns remain regarding rejection risk and post-transplant management. In CCA, especially perihilar disease, standardized neoadjuvant protocols followed by LT have achieved encouraging long-term survival in highly selected patients, whereas intrahepatic CCA remains investigational within prospective biomarker-driven studies. In CRLM, once considered an absolute contraindication, recent evidence supports LT in selected patients with liver-confined and biologically favorable disease, emphasizing the importance of tumor kinetics, molecular features, and response to systemic therapy. Conclusions: Integration of molecular oncology, immunology, and advanced therapies is redefining LT indications for hepatic malignancies. Future progress will depend on biomarker-driven selection, precision medicine, and multidisciplinary decision-making to optimize outcomes while addressing ethical challenges in organ allocation.

Background & Aims: A higher risk of hepatocellular carcinoma (HCC) has been widely reported in patients with chronic hepatitis C virus (HCV) infection who achieve a sustained virologic response (SVR12) induced by direct-acting antivirals (DAAs), presenting with Steatotic Liver Disease (SLD) and cardiometabolic risk factors (CMRFs) indicative of metabolic dysfunction (MD). Two years after the Delphi consensus, the potential benefits of adopting Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) rather than Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) criteria in defining the disease progression risk remain undefined.The present study compared MASLD and MAFLD criteria in estimating the 5-year risk of de novo HCC occurrence in SLD patients achieving DAAs-induced HCV SVR12.Methods: The anthropometrical, biochemical, clinical, Liver Stiffness Measurement (LSM), and Controlled Attenuation Parameter (CAP) data stored in the “Luigi Vanvitelli” University Hospital Health Documents Digitization Archive of 751 HCV-SVR12-SLD patients (January 2015-May 2020) were included. After properly excluding lean individuals (i.e., Body Mass Index < 25 kg/m2) and patients with other causes of chronic liver damage (n.101), the MAFLD and MASLD criteria were separately applied, ultimately identifying the following groups: HCV-SVR12-MASLD (n.163), HCV-SVR12-MASLD/MAFLD (n.390), and HCV-SVR12-MAFLD (n.97). HCC occurrence was diagnosed according to the EASL guidelines and retrospectively reported along a 5-year follow-up (Figure 1).Results: At baseline, no significant clinical differences emerged among the groups, and a similar distribution of LSM-advanced fibrosis (AF) was reported in HCV-SVR12-MASLD and HCV-SVR12-MAFLD [53 (32.51%) vs 34 (35.05%), chi-square, p > 0.05].Compared to MASLD, MAFLD diagnostic criteria better estimated the risk of HCC [HR: 1.936, C.I. 95%: 1.083-2.375, p:0.035], even after stratifying for AF baseline presence (chi-square, p < 0.0001) (Figure 2). Multivariate competing risk analysis (adjusted for sex, age, diabetes, steatosis, SVR achieving time, CAP, and fibrosis severity) revealed diabetes (aHR: 2.051, p:0.001), high-sensitivity-C-reactive protein (aHR: 1.351; p:0.02), and Homeostatic-model-assessment-for-insulin-resistance (aHR: 1.219; p:0.02) as variables significantly associated with this outcome.Conclusions: MAFLD criteria better estimate the de novo HCC risk in SLD patients achieving DAAs-induced HCV SVR12.

Background & Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern, often progressing to steatohepatitis (MASH) and advanced fibrosis (AF). Beyond insulin resistance, recent evidence implicates damage-associated molecular patterns (DAMPs) and gut-derived pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), in driving MASLD progression via innate immune activation, inflammation, and reactive oxygen species (ROS) generation. The concept of trained immunity (TI)—a memory-like response in innate immune cells—has emerged as a key mechanism, involving metabolic reprogramming and heightened inflammatory output. Bisphenol A (BPA), a widespread endocrine disruptor, has been identified as a TI trigger capable of inducing immunometabolic remodeling in monocytes. This study investigates the role of chronic BPA exposure in MASLD progression through TI-mediated innate immune activation.Methods: Ten healthy controls and twenty MASLD patients (10 MASLD-SS, 10 MASLD-SH) undergoing liver biopsy were enrolled. At baseline (T0) and after a 3-month BPA-free diet (T1), BPA serum levels were quantified (LC-MS/MS), and cytokines (IL-1β, IL-6, TNF-α) were assessed (ELISA). Monocytes were isolated and subjected to a TI-BPA protocol (BPA priming, LPS rechallenge), followed by cytokine profiling and metabolic assessment (Seahorse XFb, ROS assay).Results: At T0, BPA levels progressively increased from controls to MASLD-SS and MASLD-SH, with significantly elevated cytokines in MASLD-SH vs MASLD-SS (all p<0.0001). TI-BPA-stimulated MASLD-SH monocytes produced higher IL-1β, IL-6, and TNF-α than other groups (all p<0.001). Seahorse analysis revealed increased glycolysis and reduced mitochondrial respiration in MASLD-SH vs MASLD-SS (ECAR/OCR, all p<0.0001) (Figure). The BPA-free diet significantly reduced BPA levels (T1 vs T0, p=0.0002), especially in MASLD-SH. At T1, “enhanced trained response” prevalence was higher in MASLD-SH vs MASLD-SS (82% vs 31%, p<0.0001), with no metabolic differences between groups (Figure).Conclusions: BPA promotes trained immunity and immunometabolic reprogramming in MASLD, exacerbating inflammation and disease progression. These findings underscore the impact of environmental exposures and support TI-targeted interventions in MASLD management.

Background/Objectives: Adequate bowel preparation (BP) is crucial for effective colorectal cancer (CRC) surveillance in ulcerative colitis (UC). While active inflammation is known to negatively impact cleansing, data regarding predictors of BP quality specifically in UC patients with inactive disease remain limited. This study aimed to investigate risk factors for inadequate BP in UC patients in clinical/endoscopic remission and to compare the efficacy of 1L-PEG-ASC versus 2L-PEG regimens. Methods: A multicentric, retrospective, cohort study was conducted across eight Italian centers. Consecutive adult outpatients with UC undergoing colonoscopy between January-2021 and December-2022 who were in endoscopic and clinical remission were included. Boston Bowel Preparation Scale (BBPS) was assessed in patients undergoing 1L-PEG-ASC or 2L-PEG bowel preparation. Univariable and multivariable logistic regression analyses were performed to identify risk factors for inadequate BP and compare outcomes between PEG regimens. Results: A total of 379 patients were included (58% M, mean age 52.3 ± 15.4 years). The overall rate of adequate BP was 90.5%. Traditional risk factors, including demographic, clinical, and endoscopic characteristics, were not predictive of inadequate preparation in this remission cohort. Comparing regimens, 1L-PEG-ASC yielded significantly higher median total BBPS scores compared to 2L-PEG (8 [IQR 7–9] vs. 6 [IQR 6–8]; p < 0.001) and a higher exam completion rate (99.5% vs. 95.7%; p = 0.02), although the difference in adequate BP rates did not reach statistical significance (92.6% vs. 87.7%; p = 0.12). Multivariable analysis confirmed that 2L-PEG was independently associated with lower odds of achieving higher BBPS scores (OR 0.30; 95% CI 0.20–0.45). Conclusions: In UC patients with clinical and endoscopic remission, BP adequacy rates are high and comparable to the general population, suggesting that traditional IBD-related risk factors are less relevant in the absence of active inflammation. However, the 1L-PEG-ASC regimen demonstrated superior cleansing quality and exam completion rates compared to 2L-PEG. These findings support the prioritization of 1L-PEG-ASC to optimize mucosal visualization during CRC surveillance in this population.

Introduction: Hepatic cirrhosis represents the final stage of most chronic liver diseases and is commonly driven by viral, alcoholic, metabolic, or mixed etiologies. In recent years, both the epidemiology and clinical presentation of cirrhosis have been rapidly evolving; however, contemporary national data characterizing this scenario are lacking.Aims: To describe the current epidemiological profile and initial clinical presentation of hepatic cirrhosis in Italy during 2024.Patients and Methods: In this prospective, multicenter study, patients with cirrhosis were consecutively enrolled from 11 tertiary hepatology centers evenly distributed across Italy. Eligible participants included individuals with a new diagnosis of cirrhosis or those presenting for the first time to these centers in 2024. Demographic, socioeconomic, etiological, clinical, and laboratory parameters were collected at baseline. The relative impact of individual risk factors was explored using a Pareto chart analysis.Results: Among 1,195 enrolled patients, metabolic dysfunction–associated steatosis liver disease (MASLD) was the most prevalent etiology (345 patients, 28.8%), following by viral etiology (245 patients, 20.5%), Alcohol Liver Disease, (ALD) (232 patients, 19.4%) and other causes (122 patients, 10.2%), but 251 patients (21.0%) had a mixed etiology (Met-ALD, Met- virus, ALD-virus, Met-ALD-virus). In the Pareto analysis of individual risk factors, arterial hypertension ranked first, followed by type 2 diabetes mellitus, alcohol abuse, obesity, HCV infection, HBV infection (figure 1). Despite the growing metabolic burden, viral hepatitis remains a major contributor, representing 41.2% (202 patients of 490) of etiology, among patients at their access to the centers, but with cirrhosis already known, confirming the persistent epidemiological weight of viral etiologies despite antiviral therapies and vaccination programs.Conclusions: This study highlights the evolving epidemiology of cirrhosis, characterized by the increasing contribution of MASLD and the predominance of early-stage, compensated disease (Child-Pugh A) at diagnosis. The comorbidity profile associated with cirrhosis is also emphasized: among the risk factors, arterial hypertension was the most prevalent, although diabetes and obesity exert a more direct pathogenetic impact on hepatic injury. Viral hepatitis continues to impose a considerable clinical burden, underscoring the need to reinforce vaccination strategies, screening programs, and linkage-to-care pathways. Finally, these findings demonstrate how, nowadays, the complexity of managing cirrhosis has increased, being hepatic risk factors frequently overlapped (with one in five patients exhibiting multiple comorbidities), thereby contributing to an increased disease burden.

Peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) are ligand-activated nuclear transcription factors that orchestrate key metabolic and immuno-inflammatory networks governing hepatic homeostasis. By regulating fatty acid oxidation, insulin signaling, bile acid metabolism, and hepatic stellate cell activation, PPARs integrate metabolic and inflammatory cues central to the pathogenesis of chronic liver disorders. Chronic liver diseases (CLDs) constitute a major and growing global health burden. Metabolic dysfunction-associated steatotic liver disease (MASLD), now affecting up to one-third of the adult population worldwide, is closely linked to type 2 diabetes, cardiovascular disease, and major liver-related events. In parallel, chronic immune-mediated cholestatic liver diseases continue to pose important therapeutic challenges. Although ursodeoxycholic acid remains the standard first-line therapy for primary biliary cholangitis (PBC), and several second-line therapeutic options are now available, a substantial proportion of patients exhibit an incomplete biochemical response, while effective disease-modifying therapies for primary sclerosing cholangitis (PSC) remain lacking. Across etiologies, persistent metabolic stress, immune-mediated injury, and maladaptive fibrogenesis represent convergent pathogenic pathways. In MASLD, PPAR agonists have shown promising effects on steatosis, necroinflammatory activity, and fibrosis regression in randomized clinical trials, positioning them among the most advanced pharmacological strategies currently under investigation. In cholestatic liver diseases, selective and dual PPAR agonists have demonstrated significant improvements in cholestasis, pruritus, and markers of disease activity, supporting their role as second-line or adjunctive therapy. This review critically appraises the current preclinical and clinical evidence on the role of PPARs in CLDs, delineates the underlying molecular mechanisms, and discusses future therapeutic perspectives. Although the available evidence is encouraging, most clinical studies have primarily demonstrated improvements in surrogate biochemical and histological endpoints rather than hard clinical outcomes. Ongoing phase III trials and long-term outcome studies will be essential to define the role of PPAR agonists within future therapeutic algorithms for CLDs.