As metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) grow increasingly prevalent, it is essential to improve understanding of the contributing factors and how these conditions may interact. Metabolic and alcohol-related liver injury frequently co-occur, prompting the introduction of the term metabolic dysfunction and alcohol-associated liver disease (MetALD) to describe individuals with MASLD who also consume significant amounts of alcohol. Among the exposures relevant to MetALD, dietary fructose is of particular interest because it shares multiple mechanisms of hepatotoxicity with alcohol. This review synthesizes current evidence for hepatotoxic interactions, emphasizing areas most relevant to MetALD pathogenesis. Epidemiologic data indicate substantial overlap between populations with high fructose and alcohol exposure, while clinical studies increasingly associate combined exposure with greater fibrosis progression and adverse liver outcomes. Several mechanistic pathways have been shown to overlap in terms of their interactions with fructose and ethanol, including endogenous fructose generation, cytochrome P450 2E1 (CYP2E1) induction, mitochondrial dysfunction, dysregulated lipid metabolism, uric acid-driven inflammasome signaling, and disruption of the gut–liver axis. Emerging evidence suggests that these pathways interact in ways that may amplify injury beyond the effects of either exposure alone. Greater integration of the alcohol and metabolic liver disease fields will be necessary to clarify mechanistic interactions, determine risk factors, and develop effective interventions for this increasingly common form of liver injury.
Background: Non-alcoholic fatty liver disease (NAFLD), now largely encompassed by the metabolic dysfunction-associated steatotic liver disease (MASLD) framework, is a leading cause of chronic liver disease worldwide and is closely linked to obesity, insulin resistance, type 2 diabetes (T2D), and cardiometabolic dysfunction. Although hepatic lipid accumulation and metabolic injury remain central to its pathogenesis, increasing evidence implicates the intestinal microbiota as a modulator of disease onset and progression through the gut–liver axis. Objectives: This narrative review summarizes current evidence linking gut microbiota to NAFLD/MASLD, with emphasis on functional microbial alterations relevant to the gut–liver axis, disease severity, microbiota-related biomarkers, and microbiota-targeted interventions. Methods: The literature search for this narrative review was mainly performed using PubMed/MEDLINE (which produced 200 results since 2023). The search addressed the relationship between gut microbiota, NAFLD/MASLD, and gut–liver axis dysfunction. Results: Early studies mainly focused on disease-associated bacterial taxa; however, no consistent microbial signature has been reproduced across populations, disease stages, and methodological platforms. This limitation supports a shift from a taxonomic view of dysbiosis toward a functional interpretation. Different microbial communities may converge on shared pathogenic outputs, including impaired epithelial barrier integrity, microbial translocation, lipopolysaccharide-driven Toll-like receptor 4 activation, bile acid remodelling, altered short-chain fatty acid production, endogenous ethanol generation, choline and trimethylamine-N-oxide metabolism, and tryptophan-derived indole signalling. These mechanisms may influence hepatic steatosis, inflammatory activation, and fibrogenesis. Conclusions: Current data support the microbiota as a biologically plausible disease modifier, but not yet as a standalone diagnostic or therapeutic target; clinical translation will require longitudinal, multi-omics, and function-oriented studies.
Metabolic dysfunction-associated steatohepatitis (MASH) represents a systems-level disorder driven by the interplay of metabolic stress, bile acid dysregulation, gut microbiota remodeling, and immune activation. Because no single experimental platform recapitulates the full spectrum of human disease—from steatosis and fibrosis to spontaneous hepatocellular carcinoma (HCC)—model selection must be guided by the dominant biological mechanism under investigation rather than by phenotypic similarity alone. This review proposes a mechanism-oriented framework for model selection, illustrated by representative experimental systems, including the intensified high-fat/high-cholesterol diet supplemented with cholate (iHFC diet) and Tsumura–Suzuki obese diabetic (TSOD) and non-obese (TSNO) mouse models. The iHFC diet provides a reproducible platform for interrogating the bile acid–microbiota–macrophage axis in fibro-inflammatory progression, whereas TSOD mice represent a valuable system in which spontaneous MASH–HCC development can emerge under chronic metabolic imbalance without engineered oncogenic triggers. TSNO mice serve as a controlled background for dissecting bile acid-dependent susceptibility. We further integrate hepatocyte mitochondrial dysfunction, immune remodeling, and stellate cell activation into this triadic framework and position additional diet-induced, genetic, and in vitro models within a complementary translational landscape. Together, this mechanism-centered framework provides a practical roadmap for rational model selection and enhanced translational precision in MASH and metabolic hepatocarcinogenesis research.
Background/Objectives: Hexavalent chromium [Cr(VI)] is a toxic metal that enters the environment due to natural and anthropogenic processes. The liver is a major target organ of Cr(VI) exposure through drinking water, resulting in an increased risk of exposed individuals developing chronic liver diseases and cancers. Cr(VI) exposure is also associated with neurological dysfunction. Essential metal dyshomeostasis is a well-characterized biomarker of liver and neurological diseases, but the role Cr(VI) plays in altering essential metal levels in both organs is poorly understood. Methods: Male and female Hartley guinea pigs were exposed to 0 or 5 mg Cr(VI)/L in drinking water for 90 days. Chromium accumulation and essential metal levels in the liver, blood and brain were analyzed using inductively coupled plasma mass spectrometry. Results: Chromium significantly accumulated in a sex-dependent manner in the livers and blood of guinea pigs given 5 mg Cr(VI)/L in their drinking water, with sex- and region-specific chromium deposition observed in the brain. The livers and blood of female guinea pigs were more vulnerable to Cr(VI) exposure, as evident in the significant chromium accumulation and dyshomeostasis of several essential metals, including hepatic magnesium, zinc and potassium. Conversely, male guinea pigs were more vulnerable to Cr(VI)-induced essential metal dyshomeostasis in the brain, with significant changes in molybdenum and cobalt in nearly half of the 11 brain regions assessed. Conclusions: This study begins the process of establishing a novel model to study Cr(VI)-induced hepatotoxicity, neurotoxicity and organ crosstalk. Overall, Cr(VI) induced sex-dependent essential metal dyshomeostasis in the liver and blood, along with sex- and region-specific essential metal dyshomeostasis in the brain. These results suggest essential metal dyshomeostasis may play an important role in Cr(VI)-induced liver and neurodegenerative diseases, and these effects should guide future mechanistic investigations.
Introduction: Hepatitis B virus (HBV) genotypes exhibit distinct geographic distributions and may differ in virological expression. In low-endemic settings such as Canada, where chronic HBV burden is largely migration-driven, clinical cohorts provide a unique opportunity to characterize genotype diversity and its relationship with sociodemographic and baseline virological markers. Methods: We conducted a retrospective cohort study of patients with chronic HBV infection and available genotype results followed in The Ottawa Hospital Viral Hepatitis Program (TOHVHP) between 2001 and 2025. Results: Among 778 patients (median age 42.5 years; 52.3% male), 94.3% were born outside Canada, representing 78 countries and predominantly Asian (51.4%) and Black (34.8%). Six genotypes were identified: A (19.8%), B (25.6%), C (21.0%), D (17.4%), E (15.9%), and F (0.4%). Distribution reflected global migration patterns, with B/C predominating in East and Southeast Asia, E in West Africa, A in East Africa and the Caribbean, and D across the Middle East and North Africa, South Asia, and Europe/Central Asia. Younger age was observed among African-associated genotypes and among Black and Arab/MENA populations. Genotype-ethnicity patterns were concordant (A/E predominantly Black; B/C > 95% Asian; D heterogeneous). Genotypes B and C were independently associated with higher HBV DNA compared with genotype A. Overall, 10.7% of patients were HBeAg-positive, with genotype C showing the highest prevalence (23.7%) and an independent association with HBeAg positivity (aOR 8.3, 95% CI 2.0–34.9). Younger age and male sex were associated with higher HBV DNA and HBeAg positivity. Conclusions: In this immigration-rich Canadian cohort, HBV genotype distribution closely reflected global epidemiology and was strongly structured by country and region of birth. Baseline virological activity also differed by genotype and host factors, supporting integration of HBV genotype with sociodemographic context when characterizing chronic HBV in diverse migrant-receiving populations.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 (ANALING) 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 ANALING 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 ANALING 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 ANALING 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 ANALING 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.
