Livers, Volume 6, Issue 4 (August 2026) – 27 articles

Background/Objectives: As indications of liver transplantation evolve and the burden of obesity rises in the general population, a clear understanding of weight trends among liver transplant (LT) recipients is needed to inform evidence-based guidance for obesity prevention and management across the transplant continuum. The objective of this study was to characterize national trends in body mass index (BMI) among adult liver transplant recipients and to project future trajectories, with attention to key demographic and disease-related subgroups. Methods: Using national-level data on 176,891 LT recipients from the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) database between 1988 and 2022, we analyzed trends in BMI among adult LT recipients, applying linear regression to evaluate temporal trends and identify changes in trajectories. We stratified results by sex, race/ethnicity, age, and liver disease etiology, and derived BMI projections until 2050. Results: We observed that from 1988 to 2022, the mean BMI increased from 24.7 kg/m² (representing normal weight) to 28.9 kg/m² (representing overweight) (p < 0.001). There was a significant decline in the number of LT recipients classified as underweight or normal weight, with a reciprocal increase in overweight and all obesity categories. Based on current trends, the mean BMI of LT recipients is projected to reach 30.1 kg/m² (representing class I obesity) by 2050. Conclusions: Overall, overweight and obesity rates among adult LT recipients have risen dramatically over three decades. Effective prevention and treatment strategies for excess weight are much needed before and after LT. Full article

Background: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy with limited therapeutic options and poor prognosis. The increasing complexity of molecular stratification and treatment selection has stimulated interest in computational and biological modeling approaches for precision oncology. Objective. This narrative review aims to provide a comprehensive overview of digital twins (DTs), DT-enabling computational models, and biological twins (BTs) in CCA, discussing their applications, limitations, and potential integration within hybrid precision medicine frameworks. Methods: A narrative literature review was conducted. To inform the twin-focused sections, a structured PubMed search was performed using predefined keywords related to CCA and twin-related technologies, including organoids, xenografts, organ-on-chip systems. Particular attention was devoted to recent studies addressing computational modeling, patient-derived experimental systems, and translational applications. Results: DT development in CCA is supported by an ecosystem of DT-enabling technologies, including radiomics, artificial intelligence, multi-omics integration, and simulation-based models. However, fully realized medical DTs remain unavailable. BTs, including patient-derived organoids, xenografts, and microfluidic platforms, enable functional validation of therapeutic hypotheses but face challenges related to scalability, standardization, and clinical feasibility. Emerging hybrid DT-BT frameworks seek to combine computational prediction with biological validation through iterative feedback loops, potentially improving patient stratification and treatment personalization. Conclusions: DTs and BTs represent complementary components of an evolving precision oncology ecosystem in CCA. Although technical, biological, regulatory, and implementation challenges remain, the convergence of computational models, longitudinal molecular monitoring, and patient-derived systems may facilitate clinically actionable hybrid twin frameworks. Successful translation will require both technological innovation and healthcare-system improvements to precision medicine access. Full article

Background/Objectives: Transjugular liver biopsy (TJLB) occasionally fails, most commonly because of difficulty in hepatic vein (HV) catheterization. We investigated whether the HV–inferior vena cava (IVC) confluence angle measured on CT or MRI could predict the technical success of TJLB. Methods: This single-center retrospective cohort study included 100 patients who underwent TJLB. Technical success was defined as the successful catheterization of the HV and acquisition of liver tissue. The HV–IVC confluence angle was measured on CT or MRI. Factors were compared between successful and unsuccessful cases. Multivariable Firth logistic regression was performed to assess factors associated with technical failure. ROC analysis was performed to evaluate the discriminatory performance of the HV–IVC confluence angle. Results: TJLB was technically successful in 86 of 100 cases. On univariate analysis, age, sex, height, and HV–IVC confluence angle were associated with TJLB success. The confluence angle was significantly smaller in successful than in unsuccessful cases (43.6 ± 11.1° vs. 59.3 ± 11.2°, p = 0.001). In multivariable Firth logistic regression, age and the confluence angle were associated with technical failure (odds ratios, 1.08 per year and 1.16 per degree, respectively). The area under the curve was 0.85, and the exploratory cutoff was 56°. Conclusions: A larger HV–IVC confluence angle was associated with technical failure and may be a promising imaging biomarker. Given limited measurement feasibility and no external validation, the 56° cutoff should remain exploratory. Full article

Background/Objectives: Interferon-free direct-acting antiviral (DAA) therapy cures chronic hepatitis C virus (HCV) infection, but its short-term effects on health-related quality of life (HRQoL) are captured differently by generic and disease-specific instruments. We examined longitudinal changes in utility scores and HRQoL in a multicenter Japanese cohort. Methods: Adults with chronic HCV completed the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L), the 8-Item Short-Form Health Survey (SF-8), and the Chronic Liver Disease Questionnaire (CLDQ) at baseline and at 12, 24, and 36 weeks after treatment initiation; 48-week data were included when available. Complete-case panels were analyzed for each instrument (SF-8, n = 112; CLDQ, n = 131; EQ-5D-5L, n = 128). Domain trajectories were summarized and compared with baseline. Results: By week 36, SF-8 general health improved significantly from 50.42 to 52.47, whereas vitality (50.73 to 52.55) and mental health (51.02 to 53.05) showed nonsignificant numerical increases. CLDQ showed improvements in worry (5.21 to 5.82) and total score (5.21 to 5.47). EQ-5D-5L utility values remained high and largely stable (0.913 to 0.920), suggesting ceiling effects in patients with relatively good baseline health status. External real-world evidence also suggested better on-treatment HRQoL with ribavirin-free regimens. Conclusions: In Japanese patients with HCV, interferon-free DAA therapy was associated with early improvements in symptom-proximal and mental domains of HRQoL. Generic utility scores changed little over the short term, indicating that disease-specific patient-reported outcome (PRO) instruments and utility measures should be used together for patient-centered assessment and cost–utility modeling. Full article

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors comprising three isoforms—PPARα, PPARγ, and PPARβ/δ—that regulate hepatic lipid metabolism, glucose homeostasis, inflammation, bile acid synthesis, and fibrogenesis. Because liver diseases involve overlapping metabolic, inflammatory, cholestatic, and fibrotic pathways, PPAR agonists have emerged as a versatile therapeutic class across a spectrum of hepatic conditions. PPARα agonists (e.g., fenofibrate) promote fatty acid β-oxidation and suppress de novo lipogenesis; PPARγ agonists (e.g., pioglitazone) improve insulin sensitivity and exert anti-inflammatory and antifibrotic effects; and PPARδ agonists (e.g., seladelpar) regulate bile acid and cholesterol metabolism. Dual agonists (elafibranor [PPARα/δ] and saroglitazar [PPARα/γ]) and pan-PPAR agonists (lanifibranor [PPARα/γ/δ] and bezafibrate) aim to simultaneously address multiple pathogenic mechanisms. In primary biliary cholangitis (PBC), elafibranor and seladelpar received accelerated FDA approval in 2024 based on phase 3 trials (ELATIVE and RESPONSE, respectively), demonstrating significant biochemical response rates of 51% and 62% versus 4% and 20% with the placebo. Long-term open-label extension data from the ELATIVE trial have demonstrated sustained improvements in cholestatic biomarkers and stabilization of fibrosis markers over three years, with durable benefits on fatigue and pruritus. The ASSURE open-label study has confirmed the durability of seladelpar’s effects on biochemical response and pruritus through up to two years of treatment. Saroglitazar, a dual PPARα/γ agonist, has shown positive topline phase 3 results in the EPICS-III trial and received an FDA priority review designation. Bezafibrate has shown a survival benefit in large retrospective analyses and is used as a second-line therapy in Europe and Japan; notably, bezafibrate functions as a dual PPAR/pregnane X receptor (PXR) agonist, inducing CYP3A4 and efflux transporters that contribute to bile acid detoxification. In metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), pioglitazone remains the most extensively studied PPAR agonist, with meta-analytic evidence supporting MASH resolution and fibrosis reduction regardless of diabetes status. Lanifibranor demonstrated histological improvement in the phase 2b NATIVE trial and is currently in phase 3 development (NATiV3). PPAR agonists have also demonstrated therapeutic effects on liver fibrosis inhibition through direct modulation of hepatic stellate cell activation and suppression of fibrogenic signaling. This narrative review synthesizes the molecular pharmacology of PPAR isoforms; the available clinical and preclinical evidence for mono-, dual-, and pan-PPAR agonists; and their therapeutic applications across MASLD/MASH, alcohol-associated liver disease (ALD), PBC, primary sclerosing cholangitis (PSC), intestinal failure-associated liver disease (IFALD), and advanced chronic liver disease (ACLD). The evolution from single-isoform to multi-isoform PPAR agonism reflects the recognition that overlapping pathogenic mechanisms in liver diseases may require broader receptor coverage for optimal therapeutic efficacy. Full article

Background: Acute liver failure (ALF) is a rare, yet potentially fatal clinical syndrome characterized by the rapid deterioration of hepatic function in individuals without pre-existing liver disease, typically occurring over a period of days to weeks. It is associated with substantial morbidity and mortality, particularly in low-income settings, and is clinically defined by the presence of jaundice, coagulopathy, and hepatic encephalopathy. Among its various etiologies, acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury and ALF, especially in industrialized countries such as the United States and the United Kingdom. In the present study, we compared two experimental approaches for inducing APAP-mediated ALF in mice: oral and intraperitoneal (IP) administration. Methods: While most studies reported in the literature rely on a single route of administration, this comparative analysis provides a more comprehensive evaluation of the advantages and limitations associated with each method, thereby enhancing the reproducibility and translational relevance of experimental ALF models. Results: Our results demonstrate that both administration routes effectively recapitulate key clinical and biochemical features of human ALF, including hepatic encephalopathy, marked elevations in serum transaminases, and high mortality rates. However, the effective APAP dose required to achieve these outcomes differed between the two routes, with 400 mg/kg for IP administration and 500 mg/kg for oral administration, as would be expected based on pharmacokinetic considerations. From a clinical assessment perspective, the use of adapted scoring systems, such as the O’Grady criteria, is essential for evaluating encephalopathy in animal models. Notably, oral administration via gastric gavage requires greater technical expertise, which may influence experimental consistency. Conclusions: Taken together, these findings underscore the importance of route selection in experimental design and highlight the value of comparative approaches for optimizing preclinical models of ALF. Full article

Primary sclerosing cholangitis (PSC) is a rare cholangiopathy strongly associated with inflammatory bowel disease (IBD), particularly ulcerative colitis. PSC-IBD defines a clinically quiescent but biologically aggressive colitis phenotype, characterized by extensive yet often asymptomatic mucosal inflammation and disproportionately elevated risks of colorectal cancer—approximately 3- to 5-fold higher than in IBD alone—and cholangiocarcinoma (CCA), with IBD comorbidity representing an independent risk factor for hepatopancreatobiliary malignancy. The pathogenesis remains incompletely understood but involves genetic susceptibility, immune dysregulation—including aberrant lymphocyte trafficking and an imbalance between T helper 17 (Th17) and regulatory T (Treg) cells—intestinal barrier dysfunction, and gut–liver axis perturbations involving alterations in the microbiota and bile acid homeostasis. Within the biliary tree, chronic inflammation activates peribiliary glands (PBGs), which harbor stem/progenitor cells. PBG hyperplasia may contribute to periductal fibrosis through Hedgehog signaling and epithelial-to-mesenchymal transition and may represent a key step in PSC-associated cholangiocarcinogenesis. The true burden of PSC-IBD is likely underestimated, as PSC may remain clinically silent for years. Bidirectional screening is therefore essential: all patients with PSC should undergo ileocolonoscopy with biopsies regardless of symptoms, whereas patients with IBD and cholestatic liver biochemistry—particularly elevated gamma-glutamyl transferase or alkaline phosphatase—should undergo magnetic resonance cholangiopancreatography. No medical therapy has demonstrated a clear ability to alter the natural history of PSC, and liver transplantation remains the only definitive treatment for advanced disease. This review integrates current evidence on the epidemiology, pathophysiology, and management of PSC-IBD, critically examining unmet needs in timely diagnosis, mechanistic understanding, and therapeutic development, with particular attention to non-invasive biomarkers, microbiota-directed strategies, individualized risk stratification, and disease-modifying endpoints. Full article

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and remains a major therapeutic challenge due to its marked inter- and intratumoral heterogeneity, diverse etiologies, and high propensity for therapeutic resistance. This review summarizes the biological complexity of HCC and current therapeutic challenges, with a particular focus on the RNA-binding protein human antigen R (HuR) as an emerging therapeutic target. Methods: A comprehensive narrative review of peer-reviewed literature was conducted, focusing on HCC pathogenesis, molecular heterogeneity, tumor microenvironment, mechanisms of therapeutic resistance, and recent advances in treatment. Emphasis was placed on studies investigating the biological functions of HuR and its therapeutic potential in HCC. Results: HCC progression is driven by complex interactions among genetic, epigenetic, metabolic, and environmental factors, resulting in substantial tumor heterogeneity and variable therapeutic responses. Dysregulated oncogenic signaling and immunosuppressive tumor microenvironment collectively contribute to resistance against current therapies, including multikinase inhibitors and immune checkpoint inhibitors. Although emerging strategies, such as combination immunotherapy, metabolic targeting, epigenetic modulation, and precision medicine, have shown encouraging preclinical and clinical results, their efficacy remains limited by tumor complexity and adaptive resistance. HuR functions as a master post-transcriptional regulator that stabilizes and promotes the translation of numerous mRNAs encoding oncogenic, inflammatory, and pro-survival factors. Accumulating preclinical evidence demonstrates that pharmacological inhibition of HuR suppresses multiple tumor-promoting pathways and enhances therapeutic sensitivity, supporting its potential as a novel therapeutic strategy for HCC. Conclusions: The biological complexity of HCC necessitates multifaceted, precision-based therapeutic approaches. Although additional HCC-specific mechanistic and translational studies are needed, targeting HuR represents a promising strategy to overcome tumor heterogeneity, therapeutic resistance, and disease progression. Continued integration of molecular profiling, advanced omics technologies, and rational combination therapies will be essential for translating these advances into improved clinical outcomes for patients with HCC. Full article

Background/Objectives: Metabolically dysregulated-associated steatotic liver disease (MASLD) is a complex, multifactorial disorder characterised by hepatic lipid accumulation, insulin resistance, oxidative stress, and dysfunction of the gut–liver axis. Given its intricate pathophysiology, multi-target nutritional strategies represent a promising complementary approach. This study aimed to evaluate the biological effects of a multi-component nutraceutical formulation using an integrated in vitro platform replicating intestinal, hepatic, and pancreatic–liver interactions. Methods: The formulation was tested on Caco-2 intestinal cells to assess cell viability, transepithelial electrical resistance (TEER), probiotic functional properties, and glucose absorption. Intestinally processed metabolites were then applied to HepaRG liver cells under hyperglycemic (glucose) or lipotoxic conditions (oleic acid/palmitic acid) to analyse lipid accumulation, cholesterol biomarkers (HMGR, LDL), bile acid production, and cellular damage (ALT, AST). Finally, a pancreas–liver co-culture model (EndoC-βH5 and HepaRG) was employed to investigate insulin secretion and downstream hepatic metabolic signalling (IRS1, GLUT2, glycogen). Results: The formulation preserved intestinal barrier integrity and enhanced probiotic functionality, including aggregation and hydrophobicity. In hepatic models, the treatment significantly reduced intracellular lipid accumulation and triglycerides, while increasing bile acid production and improving cholesterol profiles. Under steatotic stress, it lowered transaminase levels and downregulated lipogenic signalling. In the pancreas–liver axis model, the formulation restored glucose-stimulated insulin secretion and improved hepatic metabolic signalling by increasing IRS1 levels and glycogen synthesis, indicating enhanced insulin sensitivity. Conclusions: These findings support the biological plausibility of a multi-target nutraceutical approach for MASLD. The formulation demonstrates coordinated beneficial effects on intestinal barrier function, hepatic lipid management, and glucose metabolism, providing a strong rationale for further clinical investigation. Full article

The hepatic crown-like structure (hCLS) is a shell-like aggregate of macrophages surrounding a large lipid-laden dying hepatocyte. This feature was initially assumed to simply be a response to increased inflammatory stress during steatotic liver disease, but recent studies have shown that the hCLS is a critical site for lipid processing, inflammation regulation, fibrosis modulation and macrophage development. Furthermore, advances in lineage tracing and transcriptomic analysis have provided information on the nature of the macrophage subtypes present in the hCLS. The hCLS consists of a heterogeneous mixture of macrophages that arise largely from bone marrow-derived infiltrating macrophages (IMs) but also have some of the properties of Kupffer cells (KCs). Most of the cells are variations of Lipid-Associated Macrophages (LAMs) expressing surface proteins such as GPNMB, TREM2, CD9, CD36, CD63 and CD11c. In addition, a class of LAM-like KCs is also present and these typically express many of the LAM proteins along with KC lineage proteins such as VSIG4 and CLEC4F. The hCLS plays an important role in lipid disposition and inflammation but conflicting evidence appears to support roles in fibrogenesis, extracellular matrix remodeling, and matrix degradation. This review aims to describe the critical findings and discoveries made regarding hCLSs and their role in macrophage development and function in steatotic liver diseases. Full article

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the leading global cause of chronic liver disease, driving cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), and a disproportionate burden of major adverse cardiovascular events (MACEs). Fibrosis stage remains the strongest prognostic hepatic determinant, yet liver biopsy and Hepatic Venous Pressure Gradient (HVPG)—despite their diagnostic value—are invasive and unsuitable for population-level risk assessment. Over the past two decades, non-invasive tools (NITs), including serological scores, elastography-based techniques, and composite models, have transformed fibrosis and portal hypertension (PH) evaluation, though their accuracy declines in obese or comorbid patients and their ability to predict long-term hepatic and extrahepatic outcomes remains limited. These gaps have catalyzed the emergence of AI-driven, multimodal predictive systems capable of integrating biochemical, imaging, clinical, and histopathological data into individualized and dynamically updated risk profiles. This narrative review synthesizes current evidence on traditional and next-generation NITs, highlighting how AI-enhanced approaches may overcome long-standing diagnostic constraints and enable a unified assessment of hepatic and cardiometabolic risk. Collectively, these innovations outline a path toward precision hepatology, with the potential to reshape surveillance strategies, refine prognostic stratification, and improve outcomes across the full spectrum of MASLD. Full article

Introduction: COVID-19, in addition to its direct detrimental respiratory infection, is associated with multiple systemic complications involving different organs, including the liver. COVID-19 has been associated with liver injury through multiple mechanisms, including direct viral effects on liver cells, immune-mediated injury, cytokine-driven inflammation, ischemic hepatitis, microvascular thrombosis, and sepsis-related multiorgan dysfunction. Acute liver failure (ALF) is the acute form of liver damage, which has a high mortality, and recovery is dependent on various factors. We studied the effect of COVID-19 on clinical outcomes such as mortality, length of stay, and need for non-invasive and invasive ventilation in patients with acute liver failure. Methods: We performed a retrospective cohort analysis using the Nationwide Inpatient Sample (NIS) database from 2020 to 2022. Adult patients admitted to the hospital with acute liver failure were divided into 2 groups based on their COVID-19 infection status. We analyzed differences in mortality, length of stay, need for non-invasive and invasive ventilation, acute kidney injury, need for renal replacement therapy, and total charges to evaluate the effects on outcomes, and the results were then adjusted for demographic and hospital factors. Results: Of 633,155 patients with acute liver failure, 66,785 had concurrent COVID-19 infection, while 566,370 did not. Patients with concurrent COVID-19 infection had significantly higher in-hospital mortality (63.9% vs. 36.0%) and greater utilization of noninvasive ventilation (14.9% vs. 6.4%), invasive mechanical ventilation (68.9% vs. 41.7%), higher incidence of acute kidney injury (81.4% vs. 70.3%) and higher need for renal replacement therapy (26.8% vs. 16.9%). They also experienced longer hospital stays (17.1 vs. 10.7 days) and higher total charges ($345,072 vs. $221,268). The findings were statistically significant after adjusting for demographics and clinical factors. Conclusions: Patients hospitalized with acute liver failure and concurrent COVID-19 infection experienced worse clinical outcomes, including higher in-hospital mortality, greater need for ventilatory support and renal replacement therapy, and higher hospital resource utilization. Notably, COVID-19 was independently associated with worse outcomes even among patients with fewer baseline comorbidities. These findings underscore the importance of early recognition of COVID-19 in patients presenting with acute liver failure, as well as prompt, multidisciplinary management to optimize clinical outcomes. Full article

Background: Nutrition and nutrition-related interventions are a salient yet under-recognized component of preventing the development of and complications of metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, malnutrition affects a significant proportion of patients with MASLD, yet remains under-treated in the primary care setting. The objective of this narrative review is to synthesize the available evidence regarding nutritional screening, diet, and supplements in patients with MASLD. This review is aimed at primary care physicians to improve the recognition of malnutrition in MASLD patients and provide appropriate nutritional guidance. Methods: Between November 2025 and June 2026, the authors conducted a literature review using the PubMed database. Search terms included combinations of the following: MASLD, non-alcoholic fatty liver disease (NAFLD), malnutrition, sarcopenia, nutritional screening, Mediterranean diet, micronutrients, and physical activity. Randomized controlled trials (RCTs), systematic reviews, and meta-analyses addressing nutritional outcomes in liver disease were prioritized, and consensus guidelines were incorporated where primary trial evidence was limited. Evidence was appraised by study design, risk of bias, and endpoint; recommendations resting on expert opinion or extrapolation from cirrhosis populations are identified as such. Results: Author review of the studies yielded the following conclusions. Nutritional assessment should be risk-stratified by fibrosis stage using liver disease-specific tools, as BMI and body weight are unreliable in MASLD. Weight loss has been shown to improve histological and clinical progression in MASLD. The Mediterranean diet has the strongest support for steatosis reduction among the dietary interventions discussed. Coffee consumption is consistently associated with reduced fibrosis risk in observational data, but no randomized evidence exists. GLP-1 receptor agonists achieve histological MASH resolution in up to 63% of patients but require concurrent nutritional monitoring to mitigate lean mass loss. Systemic barriers, including time constraints and limited dietitian access, remain the primary impediment to primary care implementation. Conclusions: Primary care physicians are central in managing many aspects of care for patients with MASLD. This review highlights the established evidence behind diet, exercise and malnutrition prevention in the primary care setting. Full article

Background: Accurate post-treatment imaging assessment of hepatocellular carcinoma (HCC) is essential for guiding retreatment, transplantation eligibility, and prognosis. The Liver Imaging Reporting and Data System Treatment Response Algorithm (LI-RADS TRA) was updated in 2024, introducing refinements across contrast-enhanced ultrasound (CEUS), CT/MRI, and radiation-based therapies, including the TR-Nonprogressing category. We aimed to systematically review current evidence on the diagnostic performance, reproducibility, and clinical implications of LI-RADS TRA v2024 for post-treatment assessment of HCC across imaging modalities and locoregional therapies. Methods: A systematic search of PubMed, Embase, Scopus, Web of Science, and CENTRAL was conducted according to PRISMA 2020 guidelines. Original studies applying LI-RADS TRA v2024 (or comparisons with earlier versions or mRECIST) after locoregional therapies were included. Outcomes of interest comprised diagnostic accuracy metrics, inter-reader and inter-modality agreement, temporal behavior of TRA categories, and prognostic associations. Given substantial heterogeneity, results were synthesized narratively. Results: Six studies met inclusion criteria. After thermal ablation, CEUS applying the non-radiation TRA v2024 showed very high specificity (approximately 88–100%) and excellent negative predictive value (about 94–98%), with substantial-to-almost-perfect inter-reader agreement (κ up to 0.92) and excellent inter-modality agreement with CT/MRI (ICC ≈ 0.90). After transarterial chemoembolization, CEUS performance was time-dependent, with higher sensitivity at early follow-up (~15 days) and higher specificity at later assessment (~30 days). On MRI, non-radiation TRA v2024 combined with ancillary features improved sensitivity and, in some analyses, accuracy compared with v2017 and v2024 without ancillary features, while remaining more specific than mRECIST. In radiation-based therapies, the radiation TRA v2024 captured delayed-response patterns through the TR-Nonprogressing category, which demonstrated meaningful temporal evolution and prognostic separation from TR-Viable. Surgical validation confirmed preserved diagnostic performance against histology. Conclusions: Despite heterogeneous data, available evidence supports LI-RADS TRA v2024 as a clinically useful framework that improves clarity, reproducibility, and actionability of post-treatment HCC imaging. CEUS is particularly effective after ablation; timing is critical after TACE, ancillary features should be routinely applied on MRI, and TR-Nonprogressing appropriately reflects radiation biology while preserving prognostic value. Full article

Background/Objectives: The use of extended-criteria donors (ECDs) is rapidly increasing, with higher risks for impaired outcomes after liver transplantation (LT). Normothermic machine perfusion (NMP) can enhance graft viability assessment, though lactate clearance as a viability marker lacks consensus in clinical practice. Methods: This study analyzed 213 adult liver transplants using NMP from October 2022 to January 2024. Perfusate lactate levels were measured with an Epoc^® reader and five lactate-based viability criteria were evaluated for predicting post-LT outcomes. Results: All livers cleared lactate at 6 h of NMP (median 0.51 mmol/L). However, 33 livers failed at least one lactate viability criterion. Thirteen livers (6.1%) were discarded based on traditional criteria, but discard rates would have been higher using Groningen (14.6%) or Brisbane (11.2%) criteria for lactate. Outcomes for the recipients of livers that failed the lactate criteria were comparable to those of recipients with livers meeting all criteria, including biliary complications (p = 0.63), graft survival (>0.99), and 6-month CCI (p = 0.89). ROC analysis revealed poor predictive value for graft survival for lactate clearance criteria (AUC 0.50), while lactate was outperformed by MEAF score (AUC 0.67). Conclusions: Lactate clearance alone does not predict outcomes, highlighting the need for further validation of alternative viability. Full article

Background: Metastatic liver tumors (MLT) and parasitic liver cysts (PLC) are common liver conditions that often exhibit similar imaging characteristics, making accurate diagnosis challenging using imaging alone. This overlap can result in diagnostic errors and delayed treatment, particularly in resource-limited settings or when invasive procedures such as biopsies are not feasible due to risk or unavailability. This study aimed to develop a reliable and transparent machine learning approach to distinguish MLT from PLC using radiomic features derived from computed tomography (CT). Methods: We propose an explainable radiomics-based machine learning framework for the non-invasive, accurate, and interpretable discrimination of MLT and PLC, designed to assist radiologists in reducing diagnostic ambiguity and expediting patient management. This retrospective study included 30 adult patients, comprising 15 with liver metastases and 15 with pathologic hepatic cysts. Radiomic features were extracted from pre-treatment CT scans using PyRadiomics. Feature selection was performed using three complementary methods: Mutual Information, Lasso regression, and LightGBM importance ranking. HistGradientBoosting classifiers were then trained on each selected feature set. Results: Model performance was evaluated using 5-fold cross-validation and assessed with ROC AUC, accuracy, precision, recall, and F1-score. SHAP analysis was applied to interpret the models and identify key radiomic biomarkers. Statistical comparisons were performed using DeLong’s test for AUCs, McNemar’s test for classification agreement, and paired t-tests for metrics such as accuracy and F1-score. The Mutual Information-based model achieved the highest mean AUC (0.9717 ± 0.0267), significantly outperforming the other models (p < 0.035). Key features contributing to classification included texture entropy, interquartile range, and gray level non-uniformity. Conclusion: We developed a robust and interpretable machine learning framework for differentiating metastatic liver tumors from parasitic liver cysts using CT-derived radiomic features. The integration of Mutual Information feature selection, ensemble learning, and SHAP explainability ensured high diagnostic accuracy, strong calibration, and transparency. The proposed framework demonstrates substantial clinical relevance and holds promise for real-world implementation. Full article

Overt hepatic encephalopathy (OHE) is a defining decompensation event in liver cirrhosis, associated with substantial morbidity, mortality, and high readmission rates. For the bedside clinician, managing OHE presents a complex diagnostic and investigative challenge that extends well beyond the simple administration of laxatives. This review synthesizes core recommendations from the 2022 EASL and the recent 2026 ACG guidelines to provide a structured, evidence-based framework for acute inpatient management. We emphasize that OHE diagnosis remains a clinical endeavor, where serum ammonia is valuable primarily for its high negative predictive value rather than as a confirmatory biomarker. Successful resolution hinges on a proactive ‘detective approach’ to identify and correct precipitating factors—such as infections, gastrointestinal bleeding, and iatrogenic dehydration—which drive clinical deterioration. Furthermore, we highlight the critical role of the ‘four pillars’ of management, including structured discharge planning, caregiver education, and nutritional support to ensure effective secondary prophylaxis. By bridging the gap between the latest international clinical consensus and bedside practice, this review provides essential strategies to optimize OHE management, minimize recurrence, and ultimately reduce the healthcare burden of this pleomorphic syndrome. Full article

Background/Objectives: The glucocorticoid receptor (GR) is essential for regulating liver energy balance, metabolism, and inflammation. Stress and other factors can impair its function, resulting in glucocorticoid-resistant metabolic liver disease. GR mainly exists in two forms: the glucocorticoid-binding isoform, GRα, and the non-binding isoform, GRβ. The GRβ isoform typically exhibits minimal signaling activity beyond its role as a dominant-negative regulator of GRα, thereby decreasing glucocorticoid responsiveness and potentially causing resistance. Methods: To explore GRβ signaling independent of GRα, we developed mice with adenovirus-induced overexpression of GRβ (GRβ-Ad) and control mice with a vector (Vec-Ad). After five days on a standard diet, these mice received either vehicle or dexamethasone treatment. Liver tissues were collected, and we performed RNA sequencing and advanced PamGene kinome analysis to detect pathway changes in GRβ-Ad mice compared with controls. Results: Significant increases were observed in the expression of genes that inhibit fatty acid oxidation, inflammation, and liver cancer development. There was also a marked difference in serine/threonine kinase activity between GRβ-Ad and control mice. Conclusions: The findings suggest that elevated GRβ levels affect kinase pathways that modulate glucocorticoid signaling, disrupt liver lipid metabolism, and are associated with cancer pathways. Further research is needed to determine whether GRβ functions similarly in humans and to assess its potential contribution to hepatocellular carcinoma (HCC). Full article

Background: Early recurrence following curative-intent hepatectomy for colorectal liver metastases (CRLMs) remains a significant clinical challenge. This study investigates risk factors for recurrence within 6 and 12 months and evaluates the impact of salvage surgery on long-term survival. Methods: We conducted a retrospective cohort study of 109 patients who underwent liver resection for CRLMs between 2013 and 2024. The primary outcome was the identification of predictors for early recurrence using Cox proportional-hazards models. The secondary outcomes focused on overall survival (OS) stratified by the timing of recurrence and subsequent treatment. Results: High tumor burden (>4 metastases) was an independent predictor of recurrence at both 6 months (HR 3.526; p = 0.008) and 12 months (HR 3.115; p = 0.004). Intraoperative blood loss >1000 mL was significantly associated with 6-month recurrence (HR 3.356; p = 0.004) and 12-month recurrence (HR 2.171; p = 0.041). For the 12-month window, independent predictors included AJCC T3/T4 stage (HR 6.513; p = 0.011) and RAS mutation (HR 2.740; p = 0.006). Notably, patients with early recurrence who underwent salvage re-hepatectomy achieved 5-year OS rates that did not statistically differ from those without recurrence (p = 0.907 for <6 months; p = 0.433 for <12 months); however, these subgroup analyses are highly underpowered. Conclusions: High tumor burden (>4 metastases), RAS mutations, significant blood loss (>1000 mL), and primary tumor T3/T4 identify patients at high risk for early recurrence. While aggressive salvage re-hepatectomy is associated with prolonged survival in select patients, the non-significant p-values in our small salvage cohorts cannot be interpreted as evidence of survival equivalence. The observed survival benefits in the salvage cohort are heavily confounded by inherent selection biases, and therefore, the true extent of this ‘rescue’ effect must be interpreted with extreme caution and validated in larger, adequately powered multicenter studies. Full article

Background/Objectives: There is a critical disparity between donor organs and recipients awaiting liver transplantation. Normothermic machine perfusion (NMP) has emerged as a promising strategy with which to address this shortage. This study aimed to evaluate the association between NMP and short-term outcomes following liver transplantation using a large, multivariable-adjusted national dataset. Methods: A retrospective analysis of the de-identified United Network for Organ Sharing (UNOS) database was conducted for adult liver transplant recipients between January 2020 and July 2024. Standard and deceased donor data were merged according to donor identification number. Multivariable logistic and Cox regression models were used to evaluate patient mortality, graft failure, and hospital length of stay (LOS). Results: Among 34,115 patients, adjusted regression demonstrated lower one-year patient mortality (OR 0.68, CI 0.54–0.86, p = 0.001) and graft failure (OR 0.72, CI 0.60–0.87, p = 0.001) with NMP compared to static cold storage. NMP was also associated with reduced 30-day (OR 0.67, CI 0.47–0.95, p = 0.03) and 90-day mortality (OR 0.72, CI 0.54–0.94, p = 0.02) and shorter LOS (HR 1.06, CI 1.01–1.12, p = 0.02). Kaplan–Meier and Cox analyses showed no significant differences in overall patient mortality or graft failure. Conclusions: NMP was associated with improved short-term survival in time-independent analysis; however, it failed to reach significance in time-dependent Cox regression. These findings suggest that NMP could play a role in improving short-term outcomes and expanding the donor pool for liver transplant candidates. Additional studies are needed to fully elucidate the impact of NMP on short-term survival outcomes. Full article

Wilson’s disease (WD) is traditionally known as a monogenic disorder of copper transport, but immune activation is now being increasingly recognized in a subset of patients. In a single-center retrospective cohort study of 86 treatment-naïve WD patients who were rigorously diagnosed using the Leipzig score, Jiang et al. systematically evaluated the prevalence, clinical impact, and prognostic significance of autoimmune phenomena (AP), defined by autoantibody positivity and/or elevated immunoglobulin G (IgG). They found that 55.8% of patients met the criteria for AP, with about half showing at least one autoantibody, primarily low-titer antinuclear antibodies (ANAs), indicating that immune activation is common in newly diagnosed WD. Notably, patients with WD and AP (AP-WD) had more advanced hepatic dysfunction at baseline, including higher bilirubin levels, worse synthetic function, greater cirrhosis and ascites burden, and higher composite liver scores, as well as increased urinary copper excretion. Histological analysis in a subset of patients who underwent biopsy showed more intense portal inflammation and plasma cell infiltration in AP-WD, suggesting a distinct immunopathological phenotype. Over a 60-month period, AP-WD patients had a higher incidence of liver-related adverse events (death or liver transplantation), with a nearly fourfold increased hazard compared to patients without AP. Collectively, these findings support AP as a clinically significant modifier of disease expression and outcome in WD, emphasizing the importance of routine assessment of autoantibodies and IgG at diagnosis to improve risk stratification and guide follow-up care. Full article

Background/Objectives: Accurate liver iron content (LIC) quantification and monitoring are crucial for managing patients with hematological disorders. Biopsy-based LIC assessment is invasive and prone to sampling errors. This study aimed to develop a simple and safe method for calibrating MR scanner to accurately measure LIC. Methods: Five certified test objects with increasing aqueous Fe³⁺ solutions were used for R2* relaxometry to create a calibration curve with equation for converting R2* value to iron content (mg/g), using two different MR scanners. Additionally, two sets of test objects (aqueous and gelled solutions to mimic liver tissue) were developed to evaluate the feasibility of using homemade test objects. Our method was compared with two existing methods (Wood et al.’s equation and the Iron Calculator App) in 59 hematological patients, using the certified test object method as reference. We also compared our method with biopsy-based iron quantification (inductively coupled plasma optical emission spectroscopy) in four patients. Results: The equations derived from our homemade test objects were comparable to those from certified test objects across both MRI scanners. The literature methods consistently overestimated LIC compared to our method. For biopsy validation, our method was more accurate in two out of four cases. Conclusions: Our homemade calibration method offers a simple, reliable alternative for LIC quantification. The type of test object (aqueous or gelled) showed no significant difference. While biopsy-based methods remain useful, our MRI-based approach is quicker and avoids the limitations of biopsy sampling. This method, relying on the relationship between iron concentrations and relaxation times, could provide a more comprehensive and accurate assessment of liver iron levels. Full article

Background/Objectives: The ANALI and DiStrict scores are novel quantitative magnetic resonance cholangio-pancreatography (MRCP)-derived scoring systems designed to predict outcomes in primary sclerosing cholangitis (PSC). However, as their prognostic utility and inter-reader reproducibility are not widely validated, their utility in clinical practice is currently limited. This study aimed to assess the reproducibility and prognostic performance of the ANALI without gadolinium (ANALI_NG) and DiStrict scores in predicting liver-related outcomes in patients with PSC. Methods: We conducted a multicentre retrospective cohort study enrolling adult patients with large-duct PSC and at least one MRCP from the time of diagnosis. MRCPs were scored by five blinded senior abdominal radiologists with inter- and intra-reader agreement assessed via intraclass correlation coefficients. Multivariate Cox proportional models were used to evaluate the prognostic value of the ANALI_NG and DiStrict scores, with a composite endpoint of liver transplantation, hepatic decompensation, or liver-related death. Results: Eighty-nine patients with a median of 5.5 years (IQR 3.4–9.2) of follow-up were included. The ANALI_NG score showed higher intra-reader agreement (ICC 0.87, 95% CI 0.82–0.92 vs. ICC 0.64, 95% CI 0.36–0.79) and similar inter-reader agreement (ICC 0.71, 95% CI 0.63–0.78 vs. ICC 0.67, 95% CI 0.59–0.75) compared to the DiStrict score. Only the ANALI_NG score was associated with liver-related events, which remained significant when adjusted for age and sex (aHR 1.28, 95% CI 1.01–1.63) and MELD (aHR 1.69, 95% CI 1.22–2.34). Conclusions: The ANALI_NG score is a reproducible, MRI-derived scoring system that is independently associated with liver outcomes and has higher intra-reader agreement compared to the DiStrict score. Full article

Background & Aims: Accurate assessment of liver fibrosis is important for the management of pediatric chronic liver disease (CLD). Transient Elastography (TE) has emerged as a validated non-invasive method for accurately assessing hepatic fibrosis, yet it remains available only in specialized centers and requires specialized equipment. We aimed to develop and internally validate a novel, simple, blood-based scoring system—the pediatric-adapted liver score (PAL score)—to predict advanced fibrosis as defined by liver stiffness, measured using TE across diverse etiologies. Methods: A retrospective study was conducted on 107 pediatric patients with CLD who underwent liver stiffness measurement through TE. Advanced fibrosis was defined as a liver stiffness measurement corresponding to the F3 METAVIR stage or above. Independent predictors of advanced fibrosis were identified using multivariable logistic regression with manual backward elimination. To facilitate bedside utility, the regression model was simplified into a ratio-based index. Performance was assessed via the area under the receiver operating characteristic curve (AUROC) and validated using bootstrap resampling (10,000 iterations). Results: Gamma-glutamyl transferase (GGT), platelets, and albumin were identified as independent predictors of fibrosis. The simplified PAL score demonstrated good discrimination with an AUROC of 0.901 (95% CI: 0.84–0.95). While statistically equivalent to the adult-derived GGT-to-platelet ratio (GPR) and S-Index, the PAL score incorporates parameters of hepatic synthesis and portal hypertension that are absent from other ratios and is easier to calculate at the patient’s bedside. At a clinically practical integer cut-off of 5.0, the score achieved a sensitivity of 95.5% and a negative likelihood ratio of 0.06, effectively ruling out advanced fibrosis. Bootstrap validation confirmed the stability of the model (bootstrap-corrected AUC 0.901). Conclusions: The PAL score is the first simple fibrosis index derived for a diverse pediatric population. Highlighting its primary strength as a highly effective screening tool, the score achieves a sensitivity of 95.5% and a negative likelihood ratio of 0.06 at a user-friendly cut-off of 5. These robust metrics allow clinicians to confidently rule out advanced fibrosis, offering an accessible triage alternative in primary care settings where transient elastography is unavailable. Full article

Background: Menopause represents a critical physiological transition associated with hormonal changes that influence both metabolic health and quality of life (QoL). Metabolic dysfunction-associated steatotic liver disease (MASLD), a common metabolic condition, is closely linked to menopause; however, its independent contribution to QoL impairment remains unclear. This study aimed to investigate the interplay between menopausal status, metabolic dysfunction, MASLD, and QoL in midlife women. Methods: A cross-sectional observational study was conducted including 80 women aged 45–55 years, comprising both premenopausal and menopausal participants. Clinical, anthropometric, biochemical, and imaging data were collected. MASLD was diagnosed using magnetic resonance imaging in the presence of metabolic dysfunction. Metabolic assessment included glucose, insulin, liver enzymes, C-reactive protein, and indices of insulin resistance (HOMA-IR) and sensitivity (QUICKI). QoL was evaluated using the Utian Quality of Life (UQOL) scale. Associations were examined using univariate and multivariable linear regression models. Results: MASLD prevalence was significantly higher in menopausal women compared with non-menopausal women (61.9% vs. 15.8%, p < 0.001). Metabolic parameters, particularly insulin resistance and body mass index, were strongly associated with MASLD. The mean total UQOL score indicated moderate QoL. In multivariable analysis, menopausal status was the only independent predictor of reduced total QoL (b = −4.93, p = 0.01) and occupational health domain (b = −4.60, p = 0.001). MASLD and metabolic parameters were not independently associated with overall QoL. Correlation analyses revealed modest associations between metabolic markers and specific QoL domains, particularly occupational and physical health. Conclusions: Menopause is the primary determinant of reduced QoL in midlife women, particularly affecting functional domains, while MASLD does not independently impact QoL despite its strong association with metabolic dysfunction. These findings suggest that menopausal status may play a more prominent role in quality-of-life outcomes than MASLD in women undergoing the menopausal transition. However, the cross-sectional design does not allow conclusions regarding causal or mechanistic relationships. Full article

Background: Ventral hernias are a common complication following abdominal surgery, occurring in up to 20% of patients after midline laparotomy and as many as 43% of those who undergo orthotopic liver transplantation (OLT). These hernias pose unique challenges due to chronic immunosuppression, impaired wound healing, and the anatomic disruption caused by subcostal and “Mercedes-Benz” incisions. As survival after OLT continues to improve, the need for durable, infection-resistant abdominal wall reconstruction has become increasingly important. Methods: We performed a single-institution retrospective review of all OLT patients undergoing abdominal wall reconstruction by the senior author between June 2014 and April 2026. Our approach emphasizes component separation to reestablish myofascial continuity, biologic onlay reinforcement with human acellular dermal matrix (HADM), and multipoint fixation in a progressive tension pattern. Results: Forty patients (43 encounters) were included. Mean age was 55.7 ± 10.2 years, mean BMI was 31.2 ± 4.9 kg/m², and 60.0% were obese. The majority presented with recurrent hernias (67.4%), and 41.9% had prior mesh in situ. Component separation was performed in all cases, and intraoperative Botox in 18.6%. HADM was used in 83.7% of encounters. At a mean follow-up of 34.0 months, there was 1 hernia recurrence (2.3%). The surgical site occurrence rate was 14.0%, with seroma as the most common complication (9.3%). There were no 30-day mortalities. Conclusions: By integrating biologic and mechanical principles, this reconstructive strategy provides a durable solution for abdominal wall repair in liver transplant recipients. A 2.3% recurrence rate and 14.0% surgical site occurrence rate compare favorably to published benchmarks in the transplant population. Full article

Ex vivo liver perfusion (EVLP) sustains human or large animal livers outside the body under near-physiological conditions, enabling functional monitoring for lactate clearance, bile production, and oxygen consumption and allowing targeted therapeutic interventions. Originally developed to optimize donor grafts for transplantation, EVLP has evolved into a powerful translational research platform bridging preclinical discovery and early clinical translation. This review discusses EVLP as a platform for gene therapy, immunotherapy, pharmacology, and personalized medicine, with particular emphasis on gene- and immune-based interventions as mechanistically mature exemplars. We consolidate advances in pharmacological testing and toxicity modeling, viral and non-viral gene delivery, genome engineering, and immunomodulation using perfused livers. We further describe emerging applications, including autologous EVLP pathways for organ-confined therapy, ex vivo liver surgery, and bioengineering strategies such as biliary organoid repair, RNA interference, and mitochondrial transfer. We highlight how these applications align with a paradigm shift in biomedical research, including the NIH’s recent initiative to prioritize human-based experimental models over animal-only studies. By leveraging transplant-declined or surgically resected organs that would otherwise be unused, ex vivo perfusion bridges the gap between pre-clinical testing and clinical practice, enabling real-time evaluation of interventions in functional human tissue. We discuss both the scientific opportunities afforded by EVLP and the technical, biosafety, and ethical challenges that must be addressed to enable responsible clinical translation. Full article