Livers

The incidental discovery of focal liver lesions (FLLs) has reached unprecedented levels due to the widespread use of high-resolution imaging, yet unenhanced ultrasound often lacks the specificity required for definitive characterization. This review identifies Contrast-Enhanced Ultrasound (CEUS) as a transformative diagnostic pillar for common benign focal liver lesions (BFLLs). By utilizing strictly intravascular second-generation microbubble agents, CEUS enables continuous, real-time visualization of microvascular hemodynamics. This high temporal resolution allows clinicians to identify pathognomonic vascular signatures, such as the “iris-diaphragm” centripetal fill-in of hemangiomas and the rapid centrifugal “spoke-wheel” hyperperfusion characteristic of focal nodular hyperplasia (FNH). Critically, this review highlights the unparalleled safety profile of CEUS. Because microbubbles are not excreted by the kidneys and carry no risk of nephrotoxicity, CEUS is an essential diagnostic option for patients with renal failure. Furthermore, the lack of ionizing radiation and the ability to perform examinations bedside provide a safe and versatile solution for pregnant patients and those with contraindications to traditional cross-sectional imaging. This review serves as a comprehensive informational framework, equipping clinicians with detailed pathological, clinical, and radiological insights into common entities like hemangiomas, FNH, and hepatocellular adenomas (HCA). It correlates fundamental histological features—such as the “map-like” glutamine synthetase staining in FNH—with essential clinical management strategies. While multiparametric MRI remains the premier tool for complex subtyping and molecular mapping—particularly for differentiating hepatocellular adenoma variants—CEUS is established as a cost-effective and radiation-free initial diagnostic solution. This review equips clinicians with a comprehensive framework of pathological, clinical, and radiological insights to optimize the management of common benign hepatic incidentalomas Full article

Background/Objectives: Progressive familial intrahepatic cholestasis type 1 (PFIC1) is a rare autosomal recessive liver disorder caused by mutations in the ATP8B1 gene, leading to defective bile acid secretion and severe clinical outcomes. A milder, episodic form of the disease, benign recurrent intrahepatic cholestasis (BRIC), is also associated with ATP8B1 mutations. PFIC1 patients frequently present with extra-hepatic symptoms. Interestingly, cystic fibrosis (CF) patients also develop liver dysfunction, and we previously showed that CFTR expression is significantly reduced in PFIC1 patients. Methods: In this study, we investigated the relationship between ATP8B1 and CFTR by comparing gene expression and protein maturation in PFIC1 (Byler) and BRIC cell lines to wild-type controls. Results: Both ATP8B1 and CFTR transcripts were markedly decreased in mutant cells, resulting in lower protein synthesis. Distinct ATP8B1 isoforms were identified: a 140 kDa mature form in wild-type cells, a 145 kDa variant in BRIC cells, and a 180 kDa form in PFIC1 cells. Using antibodies targeting the N- and C-terminal domains, we demonstrated that wild-type ATP8B1 undergoes sequential maturation—first at Gly308 in the endoplasmic reticulum, then at Gly556, a region containing the D554N PFIC1 mutation site—yielding a 74 kDa nuclear peptide with transcriptional cofactor characteristics. This peptide contains an NR box flanked by STAT5 binding motifs and a potential PKA phosphorylation site, suggesting interaction with the Small Heterodimer Partner (SHP) and regulation of FXR and HNF1α expression, which are both known to modulate CFTR transcription. Immunoprecipitation experiments revealed a physical association between ATP8B1 and CFTR, supporting a chaperone role for ATP8B1 in CFTR trafficking and membrane insertion. PDZK1 was also found to interact with ATP8B1, potentially stabilizing CFTR at the apical membrane through PDZ-domain interactions. Conclusions: Collectively, our results identify ATP8B1 as a multifunctional protein that not only ensures the correct trafficking and membrane localization of CFTR but should also regulate its transcription via a nuclear signaling pathway. These findings provide new insights into the molecular link between PFIC1 and cystic fibrosis-associated liver disease. Full article

Background: Alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (PIVKA-Il) are established biomarkers for hepatocellular carcinoma (HCC). The ASAP score, incorporating age, sex, AFP, and PIVKA-II, may improve diagnosis, but data from Indian populations are limited. We compared the diagnostic performance of AFP, PIVKA-II, and ASAP in a large tertiary referral cohort from India. Methods: In this single-center cross-sectional study, consecutive adults with chronic liver disease and healthy controls evaluated at AIG Hospitals, Hyderabad, from January to December 2025 were included. HCC was diagnosed using standard imaging criteria. AFP and PIVKA-II were measured by a chemiluminescent microparticle immunoassay, and ASAP was calculated for each participant. Diagnostic performance was assessed using receiver operating characteristic (ROC) and precision–recall analyses at standard and optimized cut-offs derived from the Youden index and F1-score. Results: Among 1305 participants, 686 were cirrhotic controls, 278 had cirrhotic HCC, 130 were non-cirrhotic controls, and 37 had non-cirrhotic HCC. At standard cut-offs, AFP (20 ng/mL) showed high specificity but low sensitivity, especially for early-stage HCC (93.3% and 29.6%). PIVKA-II (40 mAU/mL) showed high sensitivity but poor specificity (82.7% and 26.4%). ASAP (0.526) provided the best balance, with 69.4% sensitivity and 52.2% specificity in early-stage HCC, 82.0% and 52.2% in cirrhotic HCC, and 81.9% and 55.5% overall. ROC analysis demonstrated superior discrimination for ASAP across cirrhotic, non-cirrhotic, and etiologic subgroups, including metabolic-dysfunction-associated steatotic liver disease (MASLD) HCC. Optimized cut-offs, particularly higher thresholds for PIVKA-II (71.3–98.1 mAU/mL) and ASAP (0.6–0.9), improved the diagnostic balance. Conclusions: The ASAP score modestly outperforms AFP and PIVKA-II, offering better overall diagnostic accuracy for HCC in a MASLD-dominant cohort. Lower cut-offs may improve early detection, but performance in very-early-stage disease remains suboptimal and hence there is limited benefit in surveillance-relevant settings. Higher population-specific cut-offs are required for Indian populations. These findings support the use of these biomarkers as complementary tools alongside imaging for risk stratification rather than standalone screening tests. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

Background/Objectives: Post-hepatectomy biliary leakage (BL) remains a major source of postoperative morbidity. While traditional risk models treat BL as a single clinical entity, its chronological presentation follows distinct patterns that raise the hypothesis of distinct underlying pathophysiological mechanisms. This study aimed to stratify post-hepatectomy biliary fistulas into early and late onset to identify unique independent risk factors and clarify their separate risk profiles. Methods: This retrospective cohort study evaluated 370 patients who underwent hepatic resection between 2020 and 2024. BL was defined according to the International Study Group of Liver Surgery criteria. Based on the bimodal distribution of diagnostic timing within the cohort, patients were stratified by the postoperative day (POD) of diagnosis into Early Biliary Leakage (EBL, diagnosed on POD ≤ 7) and Late Biliary Leakage (LBL, diagnosed on POD > 7). Independent predictors were identified using binary and multinomial logistic regression models. Results: The overall incidence of BL was 9.7% (36/370), with diagnostic peaks occurring at PODs 3 and 11. EBL accounted for 55.6% of leaks, while LBL accounted for 44.4%. In multivariable analysis, an operative time exceeding 5 h was the sole independent global predictor for overall leakage (OR = 6.9; 95% CI 2.4–19.4; p < 0.001). For EBL, independent predictors were tumor proximity to major intrahepatic vessels (OR = 4.1; 95% CI 1.5–11.6; p = 0.007) and an operative time exceeding 5 h (OR = 5.2; 95% CI 1.4–19.2; p = 0.012). For LBL, an operative time exceeding 5 h was the single independent predictor, carrying a substantial risk (OR = 12.2; 95% CI 2.6–56.7; p = 0.001). Histologically, cholangiocarcinoma was significantly overrepresented in the leakage cohort compared to non-leak patients (41.7% vs. 11.7%; p = 0.05). Conclusions: Stratifying post-hepatectomy biliary leakage by diagnostic timing highlights critical differences in patient pathways and hospital readmission rates. While EBL are identified during the initial stay, LBL present insidiously after an uneventful first week, causing a higher 30-day readmission rate (62.5% vs. 30.0%, p = 0.091). Clinical surveillance and patient education at discharge are essential to identify late biliary complications early. Full article

Hepatic ischemia–reperfusion injury (IRI) is a major clinical challenge in liver surgery and transplantation, contributing to postoperative complications and graft dysfunction. The pathogenesis of hepatic IRI is complex and multifactorial, involving ischemia-induced metabolic consequences, oxidative stress, inflammatory responses, endothelial dysfunction, and the activation of immune pathways upon reperfusion. Despite extensive research efforts, the translation of preclinical findings into effective clinical interventions remains limited. This review provides a critical overview of the principal models used to investigate hepatic IRI. Conventional two-dimensional in vitro systems, including monoculture and co-culture models, offer controlled environments for mechanistic studies and high-throughput screening, but fail to fully reproduce the structural and cellular complexity of the liver microenvironment. Animal models, particularly those based on mice, rats, and pigs, remain essential for studying the systemic and multicellular aspects of hepatic IRI. Nevertheless, species-specific physiological differences, ethical concerns, high costs, and limited translational predictability represent significant limitations. In this context, three-dimensional liver models have emerged as promising alternatives capable of bridging the gap between in vitro systems and animal experimentation. By more accurately recapitulating tissue architecture, cell–cell interactions, and functional heterogeneity, 3D platforms offer enhanced physiological relevance and translational potential. We discuss the strengths and limitations of each experimental approach and highlight the role of advanced 3D models as complementary tools that may enable more accurate investigations of hepatic IRI and accelerate the development of effective therapeutic strategies. Full article

Liver fibrosis is the common pathway through which chronic liver injury progresses to cirrhosis, portal hypertension, liver failure, hepatocellular carcinoma, and systemic complications. Its burden is increasing worldwide, driven mainly by metabolic dysfunction-associated steatotic liver disease, alcohol-related liver disease, viral hepatitis, and cardiometabolic comorbidity. Current evidence supports a clinically practical approach centered on early risk recognition, non-invasive fibrosis assessment, etiologic treatment, lifestyle and metabolic risk reduction, and timely referral of patients with suspected advanced fibrosis. Although advanced cirrhosis may remain only partly reversible, fibrosis can regress when the injurious stimulus is controlled, making prevention of progression a realistic therapeutic goal. This review provides a clinically actionable framework for the assessment, management, and prevention of liver fibrosis, integrating current insights into epidemiological trends, etiopathogenesis, non-invasive and portal-hypertension assessment, sex-specific effects, hepatic and extrahepatic outcomes, and treatment strategies. It highlights the potential for fibrosis regression when the underlying etiologic factor is controlled and emphasizes the stages (F0–F2) at which reversibility is most achievable. Additionally, the paper outlines key research priorities to address current knowledge gaps in biomarker discovery, precision medicine, and artificial intelligence-assisted risk stratification, while defining priorities for personalized screening, multidisciplinary care, and combination antifibrotic research. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality worldwide, due to poor prognosis and limited curative options in advanced stages. Though immune checkpoint inhibitor (ICI)-based combinations have been the first-line therapies, with higher survival compared to tyrosine kinase inhibitors (TKIs), most patients progress within six months and evidence-based guidance for subsequent therapy remains limited. This review summarizes second- and third-line treatment strategies after ICI failure, while highlighting critical research gaps and future advancements needed. Methods: We performed a comprehensive literature review of PubMed, Embase, Cochrane, and major conference proceedings (ASCO, ESMO, AASLD) up to August 2025, including retrospective cohorts, post hoc trial analyses, simulation models, and ongoing prospective trials on second-line therapy in patients with metastatic HCC who progressed on first-line therapy. Discussion and Conclusions: TKIs remain the most widely used second-line option after ICI failure. Lenvatinib, a multi-targeted TKI with strong VEGF inhibition, has shown higher progression-free survival (PFS) compared with sorafenib through tumor vasculature normalization and enhanced T cell infiltration. Other multi-targeted TKIs, like cabozantinib and regorafenib, have shown survival benefits in later line settings. In TKI-refractory or ineligible patients, treatment options are limited, and enrollment in clinical trials is recommended. Retrial of ICIs may be considered in highly selected patients, but evidence remains limited, and this approach is not standard. Concomitant locoregional therapies (LRTs) are useful in oligoprogression where systemic therapy is inadequate, but their integration with systemic therapy is underexplored, and no phase III trials yet define optimal sequencing post-ICI failure. Additionally, we describe novel therapeutic strategies such as chimeric antigen receptor T cell therapy (CAR-T) in HCC. Full article

Aggressive systemic mastocytosis [ASM] is a rare hematologic disorder characterized by mast cell infiltration of extracutaneous organs. Hepatic involvement is uncommon and rarely progresses to fibrosis or portal hypertension. We present a 60-year-old male with abdominal distension, hepatosplenomegaly, and thrombocytopenia, ultimately diagnosed with ASM after bone marrow and liver biopsies confirmed mast cell infiltration. Despite treatment with avapritinib, he developed noncirrhotic portal hypertension and expired due to multisystem complications. This case highlights the need to consider ASM in patients with cryptogenic liver disease and underscores the importance of early diagnosis and multidisciplinary management in improving outcomes. Full article

Background/Objectives: Hypothermic oxygenated perfusion (HOPE) improves graft preservation in whole liver transplantation, yet evidence supporting its use in split grafts for pediatric transplantation remains limited. Mitochondrial injury assessed during HOPE through spectroscopic measurement of flavin mononucleotide (FMN) has been associated with graft function in whole-organ transplantation. Here, we evaluate a human liver assessment pathway integrating mitochondrial viability testing with ex situ liver splitting during HOPE. Methods: Following standard procurement and transport, twelve discarded extended criteria human donor livers were evaluated for split feasibility and underwent HOPE (VitaSmart^®). Donors were between 40 and 72 years with a BMI of 23.4–42.7 kg/m² and 4–22 h of cold storage prior to HOPE. After two hours of portal-venous HOPE treatment, different split procedures were performed. Perfusates and tissues were analyzed for mitochondrial injury and inflammatory responses. Results: Four grafts met previously reported FMN thresholds for transplant suitability in whole-graft HOPE studies (FMN ≤ 0.02 μg/mL at 60 min). Livers with low FMN release demonstrated lower Complex I and II injury, greater ATP recovery, and reduced inflammatory signaling during HOPE. Conclusions: These findings indicate that mitochondrial injury during HOPE can be monitored during ex situ splitting and suggest that FMN-guided metabolic assessment may support graft evaluation within split liver transplantation pathways for pediatric recipients. Full article

Geranylgeranoic acid (GGA) is an endogenous acyclic diterpenoid metabolite of the mevalonate pathway that has been implicated in programmed cell death in hepatoma cells and may contribute to the elimination of premalignant hepatocytes. Recent metabolomic studies have identified 2,3-dihydrogeranylgeranoic acid (2,3-diGGA), an α-saturated derivative of GGA with reduced cell-death-inducing activity compared with GGA. This concise review examines the hypothesis that diversion of bioactive GGA toward 2,3-diGGA formation represents a metabolic shift that may attenuate hepatic tumor surveillance and influence hepatocellular carcinoma susceptibility. The review summarizes current evidence for endogenous GGA biosynthesis through the mevalonate pathway, MAO-B- and CYP3A4-associated GGA formation, and the tissue- and age-associated distribution of GGA and 2,3-diGGA. It also discusses the proposed 2,3-diGGA-forming activity, whose molecular identity remains unknown, and evaluates the potential utility of the GGA/2,3-diGGA ratio as a candidate biomarker. Finally, future experimental strategies are outlined to identify the responsible enzyme, clarify causality in cellular and animal models, and validate this metabolic framework in human liver tissues, chronic liver disease cohorts, and HCC-associated settings. Full article

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