Livers doi: 10.3390/livers6030054

Authors: Antonio Salvati Lorenzo Bertellotti Francesco Faita Daniela Campani Giovanni Petralli Simone Cappelli Ferruccio Bonino Maurizia Rossana Brunetto

Background: Small intestine bacterial overgrowth (SIBO) is associated with steatohepatitis (SH) in subjects with metabolic-associated steatotic liver disease (MASLD). The impact of ileocecal valve (ICV) incontinence, a major cause of SIBO in patients with MASLD, remains unknown because of the unmet need for a non-X-ray-dependent diagnosis. Methods: Exploiting water as contrast medium and colonic irrigation via a hydro-colon machine (Clean Colon Srl, Monza, Italy), we developed a new abdominal ultrasound (US) procedure for diagnosing and grading ICV incontinence. In a pilot, observational, feasibility and safety study, we correlated a new ICV incontinence parameter with irritable bowel syndrome (IBS, ROMA IV criteria), serum transaminases (AST, ALT), platelet counts, FIB-4, US liver steatosis and stiffness (LS, measured by Shear Wave and Transient Elastography, SWE and TE). Results: We prospectively studied 32 consecutive subjects with IBS who underwent a pre-colonoscopy colon cleansing after informed consent: 19 males (59%), body mass index (BMI) 26.6 ± 2.6 kg/m2, age 57 ± 19 years, 16 (50%) with US liver steatosis. The half-hour (27 min, range 20–35 min) procedure was safe and well tolerated except in two males with prostate hypertrophy. ICV incontinence was graded (after 2500–3000 mL irrigation) according to cecum/right-colon distention with/without (immediate or delayed) reflux into terminal ileum (TI): 0 = cecum distension without TI reflux; 1 = cecum distension with TI reflux; 2 = absence of cecum distension with TI reflux. Cecum/right-colon distention (grade 0 or 1) was perceived by the patients whereas the right colon irrigation with complete ICV incontinence (grade 2) was symptomless. ICV continence associated with LS (p ≤ 0.0001). A histologic diagnosis of non-alcoholic steatohepatitis was confirmed in a 35-year-old obese male with SIBO and LS > 8 kPa (8.7/8.5 kPa by SWE/TE):steatosis (grade S3) with hepatocyte ballooning, lobular inflammation (grade 6/8) without fibrosis (stage 0/4, F0). Conclusions: The new US-based approach provides a feasible, easy-to-perform, mini-invasive tool for the diagnosis and grading of ICV incontinence. Preliminary results prompt prospective studies investigating the impact of ICV incontinence as a possible co-factor of steatohepatitis in patients with MASLD.

Livers doi: 10.3390/livers6030053

Authors: Ilias D. Vachliotis Vasileios Rafailidis Athanasios D. Anastasilakis Nikoletta Pyrrou Stergios A. Polyzos

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. Accurate staging of hepatic fibrosis is pivotal for risk stratification; however, ultrasonography (US)-based elastography techniques may yield variable results across various technologies and manufacturers. The present study aimed to assess the concordance of liver stiffness (LS) measurements between two different US elastography technologies and manufacturers in patients with MASLD. Methods: This cross-sectional study included 68 postmenopausal women with MASLD. LS was measured using two-dimensional shear wave elastography (2D-SWE) on a LOGIQ™ E10 device and both 2D-SWE and point SWE (pSWE) on an Acuson Sequoia device. Hepatic steatosis was quantified using the ultrasound-guided attenuation parameter (UGAP). Results: The LS measurements were 5.0 ± 1.3 kPa with 2D-SWE on LOGIQ™ E10, 4.3 ± 1.5 kPa with 2D-SWE on Acuson Sequoia, and 3.8 ± 0.8 kPa with pSWE on Acuson Sequoia. A significant, but low correlation was found between LOGIQ™ E10 2D-SWE and Acuson Sequoia pSWE (rs = 0.25, p = 0.045), and a moderate correlation between Acuson Sequoia 2D-SWE and pSWE (rs = 0.37, p = 0.002). No correlation was shown for 2D-SWE between the two different manufacturers. Bland–Altman analysis showed moderate-to-poor agreement of LS values between the three different US elastography techniques. Conclusions: LS measurements differed across US elastography technologies and manufacturers in postmenopausal women with early-stage MASLD. These findings highlight the need to standardize existing US elastography devices before elastography-derived LS can be applied interchangeably in MASLD diagnostic algorithms.

Livers doi: 10.3390/livers6030052

Authors: Rahma Ennadi Hicham Esselmani Youssef Nadir Mustapha Najimi Mohamed Merzouki

Background: Liver diseases are an increasing public health concern in Morocco; reliable national population-based estimates of liver fibrosis and cirrhosis in Morocco are currently unavailable. Existing evidence is largely limited to selected high-risk groups and hospital-based cohorts. Generating reliable prevalence data is crucial for designing evidence-based screening pathways, targeting high-risk groups and informing prevention and treatment policies. Objectives: Our aim was to comprehensively review studies on the prevalence of liver fibrosis and cirrhosis in Morocco, focusing on characterizing study populations, specifically high-risk populations and hospital-based cohorts, diagnostic methods and thresholds used. The review also summarizes hospital-based cirrhosis cohorts without merging them with prevalence estimates, and identifies gaps in the literature, particularly the absence of population-based prevalence studies and national epidemiological data in Morocco. Methods: The study systematically reviewed literature up to 26 October 2025, including studies conducted in Morocco among high-risk populations or hospital-based cirrhosis cohorts, using multiple databases. Two reviewers independently screened and extracted data, assessing bias with the Joanna Briggs Institute (JBI) checklist. Due to heterogeneity in study populations and diagnostic approaches, a narrative synthesis was performed. Hospital-based cohorts were analyzed separately to provide contextual information and were not included in prevalence estimates. Results: From 1198 records, four Moroccan studies providing prevalence data on liver fibrosis and cirrhosis were included, primarily involving patients with hepatitis C, HIV, or rheumatoid arthritis. Additionally, three hospital-based cirrhosis cohorts were incorporated for a contextual analysis of disease severity and complications. In total, seven studies were included, with prevalence and hospital-based data analyzed separately to ensure clarity. Conclusions: Current evidence on liver disease in Morocco is limited but suggests a significant burden among high-risk groups. The findings highlight major gaps in national epidemiological data and underscore the urgent need for comprehensive nationwide data and improved diagnostic tools to guide effective screening, prevention, and resource allocation.

Livers doi: 10.3390/livers6030051

Authors: Satoshi Sato Mai Mineta Keita Mikami Masakazu Tobinai Nao Ishidoya Keisuke Furusawa Kaede Miyashiro Kenta Yoshida Chikara Iino Daisuke Chinda Tatsuya Mikami Shigeyuki Nakaji Koichi Murashita Hirotake Sakuraba

Background: Steatotic liver disease (SLD) and sarcopenia are lifestyle-related conditions for which prevention is critical. The phase angle, which is derived from impedance, reactance, and resistance values obtained via bioelectrical impedance analysis, has emerged as a potential marker of sarcopenia. Additionally, amino acids have been implicated in the pathogenesis of both SLD and sarcopenia. This epidemiological study investigated the association between SLD and sarcopenia in a general population cohort. Methods: This cross-sectional study included 281 participants with metabolic dysfunction-associated steatotic liver disease (MASLD), 72 with metabolic alcohol-associated liver disease (MetALD), and 54 with alcohol-associated liver disease (ALD). Associations between phase angle, Mac-2-binding protein glycosylation isomer (M2BPGi) as a marker of liver fibrosis, and serum amino acid levels were analyzed. Results: The phase angle was significantly higher in the MetALD group than in the MASLD and ALD groups. Multivariate analysis identified MASLD as an independent risk factor for a low phase angle compared with MetALD. M2BPGi levels were lower in MetALD than in MASLD, and M2BPGi showed a negative correlation with the phase angle. Furthermore, MetALD was characterized by lower serine and glutamine levels than MASLD, with serine demonstrating a negative correlation with the phase angle. Conclusions: Although the possibility of residual confounding factors cannot be excluded, the present study suggests that phase angle may serve as a sensitive marker for the early decline in muscle mass in patients with SLD, comparable to grip strength and skeletal muscle mass index.

Livers doi: 10.3390/livers6030050

Authors: Mona Dawood Axel Guthart Ednah Ooko Ralf Weiskirchen Thomas Efferth Joelle C. Boulos

Background/Objectives: Hepatocellular carcinoma (HCC) is challenging to treat with chemotherapy. Immunotherapy has shown moderate responses in inflammatory and immunosuppressive tumor environments. Hepatic cytochrome P450 monooxygenases (CYPs) play a crucial role in xenobiotic and drug metabolism, as well as lipid and steroid metabolism. We aimed to investigate whether CYP expression and various parameters of the innate and adaptive immune system are prognostic factors for the survival of HCC patients. Methods: HCC biopsies (n = 370) from The Cancer Genome Atlas (TCGA) database were analyzed using Kaplan–Meier statistics and the KMPlotter algorithm. Parameters such as immune cell infiltration, DNA mutation rates, and neoantigen load were selected for survival analysis and subjected to hierarchical cluster analysis. The expression of candidate CYP genes in tumors was compared to that in normal liver tissues. Furthermore, tumor infiltration of innate immune cells (basophilic and eosinophilic granulocytes, natural killer cells), adaptive immune cells (CD4+ memory and CD8+ cytotoxic T cells, regulatory T cells, type 1 and type 2 helper T cells), and mesenchymal stem cells was examined. Results: High expression of CYP19A1 and CYP26B1 was associated with shorter survival, whereas high expression of CYP3A5, CYP3A43, CYP7A1, and CYP27A1 was linked to longer survival. Mutation rates combined with CYP expression showed a correlation with five out of six CYP genes, while a high neoantigen load produced less definitive results. A specific cluster exhibiting high CYP expression and immune cell counts or mutation/neoantigen rates was associated with shorter survival, while another cluster was linked to longer survival. Conclusions: CYPs involved in the metabolic regulation of HCC, including CYP3A5, CYP3A43, CYP7A1, CYP19A1, CYP26B1, and CYP27A1, were found to have prognostic value for patient survival. Combined signatures that include CYP expression, mutational rates, and immune cell infiltration into tumors further enhanced the prognostic value for patient survival. This suggests that CYPs may influence the creation of a tumor-specific metabolic microenvironment that impacts immune functions. These combined signatures could be utilized for patient stratification to personalize tumor treatment and develop novel combination therapies aimed at optimizing treatment outcomes, such as combining transarterial chemoembolization (TACE) with immune checkpoint inhibitors.

Livers doi: 10.3390/livers6030049

Authors: Tinashe A. Mazhindu Vincent Nyangwara Michalina A. Montaño Edith Matsikidze Onesai Chihaka Charley Jang Margaret Z. Borok Collen Masimirembwa Ntokozo Ndlovu

Background: Infection with HIV increases the risk of developing hepatocellular carcinoma, and the albumin–bilirubin grade assesses liver function and has been shown to be prognostic. We evaluated the albumin–bilirubin score/grade and the HIV status of hepatocellular carcinoma patients in Zimbabwe and explored the impact on median survival. Methods: A 10-year retrospective observational study of hepatocellular carcinoma patients was conducted at a single tertiary-level cancer center in Harare, Zimbabwe. Survival probabilities were estimated using the Kaplan–Meier method, and differences between groups were compared using the log-rank test and Cox proportional hazards regression. Results: A total of 95 participants were evaluated, of whom 72.6% were male. Most HCC cases were diagnosed using imaging and serum alpha-fetoprotein, with 59% presenting at Barcelona Clinic Liver Cancer stage C or D. Compared with patients who were HIV-negative, patients who were HIV-positive (OR 2.2; 95% CI 1.54–5.26, p = 0.0008) or had an unknown HIV status (OR 4.2; 95% CI 2.2–8; p < 0.0001) had higher odds of being at ALBI grade 3 at the time of HCC diagnosis. ALBI grade 1 patients had better median survival compared to grade 2 and 3 patients, though this result was statistically insignificant (grade 2: HR = 1.45, 95% CI: 0.30–7.13; grade 3: HR = 1.47, 95% CI: 0.28–7.60). Regarding HIV status, median survival was 2.4 months for HIV-positive patients and 2.6 months for HIV-negative patients (p = 0.51); HIV positivity was not significantly associated with median survival (HR = 1.50, 95% CI: 0.46–4.91). Only 30.5% of patients received cancer therapy, all of which was palliative, with no observed survival benefit. Conclusions: The majority of hepatocellular carcinoma patients in Zimbabwe were diagnosed at an advanced stage, with hepatitis B or C viral infections and alcohol consumption identified as primary risk factors. Median survival rates were low. Neither HIV infection nor ALBI score grading had a significant impact on median survival.

Livers doi: 10.3390/livers6030048

Authors: Izabela de Castro Santiago Janaina de Alcântara Lemos Ivan Maulaz Silva Anna Eliza Maciel de Faria Mota Oliveira Diego dos Santos Ferreira

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory/fibrotic form, metabolic-dysfunction-associated steatohepatitis (MASH), represent a growing global health burden. This progression is driven by complex mechanisms involving metabolic dysregulation, chronic inflammation, oxidative stress, and progressive fibrosis. To date, effective pharmacological therapies remain limited. Pentacyclic triterpenes have attracted increasing attention due to their broad biological activities and ability to modulate multiple molecular pathways implicated in chronic liver disease. This review aims to provide a mechanistic overview of the potential role of pentacyclic triterpenes in MASLD and MASH. Methods: A literature review was conducted using major scientific databases (PubMed and Web of Science) to identify experimental studies investigating pentacyclic triterpenes in metabolic liver diseases. Selected studies were analyzed according to triterpene structural classification, reported bioactivities, molecular targets, and experimental evidence from in vitro and in vivo models of MASLD/MASH or related pathogenic processes. Results: Pentacyclic triterpenes, especially ursolic acid, oleanolic acid, and glycyrrhizin, exhibit hepatoprotective effects including regulation of lipid metabolism, attenuation of oxidative and endoplasmic reticulum stress, suppression of pro-inflammatory signaling, inhibition of inflammasome activation, and reduction in hepatic stellate cell activation and extracellular matrix deposition. These effects involve modulation of signaling pathways, including AMPK, NF-κB, NLRP3, TGF-β, FXR, and MAPK. Preclinical evidence demonstrates improvements in steatosis, inflammation, and fibrosis in experimental models. Conclusions: Pentacyclic triterpenes emerge as multitarget modulators of MASH pathophysiology. However, translating preclinical evidence into well-designed clinical trials is necessary to validate their safety and efficacy in humans.

Livers doi: 10.3390/livers6030047

Authors: Osvaldo Huchim-Mendez Ruben R. Lozano-Salazar Alejandro D. Munive-Ramirez Jorge E. Mendicuti-Carrillo Erick Rochel-Perez Nina Isabel Mendez Dominguez

Porcelain gallbladder (PGB) has historically been considered a premalignant condition, although recent evidence questions the strength of its association with gallbladder carcinoma. Objective: To describe the occurrence and characteristics of malignancy in patients with porcelain gallbladder, as well as clinical, imaging, and surgical characteristics reported in clinal cases. Methods: A systematic review of case reports and case series (≤5 patients) was conducted following PRISMA 2020 guidelines. PubMed/MEDLINE, ScienceDirect, and Redalyc from database inception through March 2026. Individual patient data were extracted including demographic characteristics, imaging findings, calcification pattern, surgical management, histopathology, and outcomes. Descriptive statistics were performed. Results: Fifty-four individual cases of porcelain gallbladder were identified. Patients were predominantly female (70.4%), with ages ranging from 6 to 98 years. Complete calcification was reported in 85.2% of cases. Histopathological confirmation was available in 45 cases (83.3%). Thirteen patients had gallbladder carcinoma associated with porcelain gallbladder, corresponding to 28.9% of those with pathological examinations. Incomplete calcification showed higher frequency of malignancy compared with complete calcification. Mortality was reported in three patients (5.6%), all with malignant disease. Conclusions: The proportion of malignancy observed in published case reports reflects a selected dataset and should not be interpreted as an estimate of population risk. These findings provide descriptive insights into clinical presentations and management patterns, supporting hypothesis generation rather than risk estimation.

Livers doi: 10.3390/livers6030046

Authors: Denise Bonente Sara Gargiulo Ludovica Livi Matteo Gramanzini Tiziana Tamborrino Lisa Gherardini Giovanni Inzalaco Lorenzo Franci Mario Chiariello Virginia Barone

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a global health priority affecting approximately 30% of the population. It represents the hepatic manifestation of metabolic syndrome, potentially progressing from simple steatosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. This review aims to compare current knowledge of MASLD in mouse models and humans, focusing on pathophysiology, histological phenotypes, and the role of preclinical imaging as a non-invasive translational screening tool. Methods: A literature search was conducted in PubMed and Web of Science to identify English-language publications from January 2020 to March 2026 on murine models and imaging techniques for MASLD, using pertinent keywords. Attention was given to highlighting similarities and differences between human and murine approaches. Results: MASLD arises from complex interactions between genetics, sedentary lifestyles, and imbalanced diets. While mouse models have been refined to capture the multifactorial interplay driving disease progression and are still essential for drug development, no single model fully mirrors the human condition. Histological assessment remains an essential tool for MASLD staging, in both humans and mouse models. However, imaging is increasingly emerging as an important complementary technique to non-invasively investigate MASLD. Conclusions: Mouse models are essential to address specific mechanistic and therapeutic questions, but understanding of their limitations and strengths is crucial for translational research. Integrating phenotype-driven approaches in both humans and mice, combining traditional histology, quantitative imaging, and metabolic profiling, as well as longitudinal, combined, and humanized preclinical models, will enhance translational alignment and accelerate the development of therapies for MASLD.

Livers doi: 10.3390/livers6030045

Authors: Kamlesh K. Bhopale Mukund P. Srinivasan

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disease worldwide, affecting approximately 25% of the global population. MAFLD represents a broad disease spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The availability of experimental models that faithfully reproduce human metabolic and hepatic pathology is essential for elucidating disease mechanisms and advancing therapeutic development. This review aims to critically evaluate commonly used rodent models of MAFLD and provide guidance for model selection based on specific research objectives. Methods: A narrative, semi-systematic literature search was performed using PubMed Central, Ovid MEDLINE, and Google Scholar. Rodent models were classified according to their mode of disease induction, including diet-induced, genetically engineered, chemically or pharmacologically induced, and combination models. Models were assessed based on frequency of use, relevance to different stages of MAFLD progression, metabolic fidelity, and suitability for mechanistic studies and preclinical therapeutic evaluation. Results: Diet-induced models incorporating high fat, fructose, and cholesterol most closely recapitulate human metabolic dysfunction and are highly relevant for translational research and drug screening. Nutrient-deficient diets induce rapid steatohepatitis and fibrosis but lack key features of metabolic syndrome. Genetic models enable the targeted interrogation of specific metabolic and inflammatory pathways, whereas chemical and combination models accelerate fibrosis and HCC development. No single rodent model fully reproduces the entire spectrum of human MAFLD. Conclusions: Rodent models remain indispensable tools for MAFLD research; however, their applicability depends on alignment with the defined experimental goals. Careful selection of models based on disease stage, dominant pathogenic mechanisms, and translational intent is essential for improving reproducibility and clinical relevance. This review provides a practical framework to guide investigators in choosing appropriate preclinical models for mechanistic studies and therapeutic development in MAFLD.

Livers doi: 10.3390/livers6030044

Authors: Ahmed Tawheed Abdulla A. Mahmoud Hussein Hassan Aly Mohamed El-Kassas

Dysfunction-associated steatotic liver disease (MASLD) is a newly introduced term for the condition previously known as nonalcoholic fatty liver disease (NAFLD). MASLD affects 38% of the global population and is now diagnosed based on the presence of steatosis but also with cardiometabolic risk factors indicating metabolic dysfunction. Chronic hepatitis B (CHB), another significant public health issue, impacts over 296 million people worldwide, or approximately 3.2% of the global population. Studies have consistently reported a complex relationship between MASLD and CHB. Previous studies indicate that MASLD may protect against high viral loads, while other studies indicate that coexisting MASLD and CHB may lead to more advanced fibrosis and an elevated risk of HCC. Additionally, numerous studies highlight a strong association between CHB and metabolic syndrome components. This review article examines the relationship between CHB and MASLD, considering what has been previously published.

Livers doi: 10.3390/livers6030043

Authors: Vittoria Benintende Luca Bettazzoni Nicola Reggidori Chiara Ambrosi Monica Patrignani Luca Ielasi

Sarcoidosis is a multisystemic inflammatory disease defined by non-caseating granuloma formation in involved organs. The liver is the third most implicated organ after the lungs and lymph nodes. Due to its frequently asymptomatic presentation, the true prevalence of hepatic sarcoidosis may be understated. Increased levels of alkaline phosphatase and gamma-glutamyl transferase are the most frequent biochemical abnormalities. The liver biopsy is still the gold standard and reveals non-caseating granulomas in almost all cases. The use of corticosteroids and ursodeoxycholic acid results in a significant decrease in biochemical parameters. However, the clinical course of hepatic sarcoidosis is diverse and requires individualized management strategies, especially to prevent hepatic complications. This review aims to synthesize the current evidence on epidemiology, pathogenesis, diagnostic approaches, and therapeutic strategies for this disease.

Livers doi: 10.3390/livers6030042

Authors: Manuj Mayank Shah Sarah Hussain Binuri Hapuarachchy Reed Towle Jenkins David J. Farhat Heather McDade Al-Faraaz Kassam Elizabeth A. King Russell Wesson Sharon Weeks Andrew M. Cameron Allan B. Massie Dorry L. Segev Ahmet Gurakar Benjamin Philosophe

Purpose: Simultaneous liver–kidney transplantation (SLK) eligible candidates may receive SLK or liver-alone transplant (LA) with access to kidney transplant after initial LA (KAL). We aimed to characterize SLK-eligible recipient outcomes according to treatment approach. Methods: This study utilized 2017–2023 SRTR data to identify SLK-eligible deceased donor liver transplants. Recipients were placed into two groups based on whether SLK was performed; non-SLK patients were sub-stratified into LA and KAL cohorts. After baseline comparisons, 2-year patient and graft survival outcomes were characterized by univariable and multivariable Cox proportional hazard regression and Kaplan–Meier analysis. Results: Among 4879 candidates identified, 3746 (76.8%) underwent SLK, 1023 (21.0%) LA, and 110 (2.3%) KAL. SLK recipients maintained the highest eGFRs at 6 months, 1 year, and 2 years post-transplant (p < 0.01). Compared to SLK recipients, non-SLK recipients had a higher 2-year risk of mortality (aHR 2.46, p < 0.01), all-cause events (aHR 1.91, p < 0.01), and liver graft failure (HR 1.55, p = 0.02). LA conferred a higher 2-year mortality risk (aHR 2.98, p < 0.01) and all-cause event risk (aHR 2.25, p < 0.01), while KAL had comparable mortality risk to SLK (aHR 0.43, p = 0.40). Conclusions: When SLK-eligible candidates undergo transplants, SLK remains the optimal path forward, even when a safety net kidney can be performed.

Livers doi: 10.3390/livers6030041

Authors: Alessandro Serafini Clara Gaetani Laura Bergamasco Stefano Cirillo Teresa Gallo Marco Gatti Paolo Fonio Riccardo Faletti

Background: Neuroendocrine neoplasms are frequently diagnosed after the detection of liver metastases, often when the primary tumor remains occult. Accurate non-invasive differentiation of neuroendocrine liver metastases (NELMs) from other focal hepatic lesions is therefore crucial. This study aimed to characterize the magnetic resonance imaging (MRI) features of NELMs using hepatocyte-specific contrast agents and to identify a potential radiologic “signature” that may suggest a neuroendocrine origin. Methods: This retrospective study included three cohorts: patients with histologically confirmed NELMs (n = 51; 146 lesions), patients with colorectal cancer liver metastases (n = 18; 46 lesions), and patients with benign hepatic hemangiomas (n = 28; 51 lesions). All subjects underwent standardized liver MRI with Gd-EOB-DTPA. Lesions were evaluated for size, diffusion-weighted imaging characteristics, apparent diffusion coefficient values, arterial-phase enhancement, T2-weighted signal, hepatobiliary-phase appearance, and hemorrhagic components. Statistical analyses included univariate and multivariate testing and receiver operating characteristic curve analysis. Results: NELMs commonly demonstrated arterial hyperenhancement, diffusion restriction, and variable T2 and hepatobiliary-phase signal heterogeneity. Compared with colorectal metastases and hemangiomas, NELMs showed distinctive patterns, particularly higher rates of hepatobiliary-phase heterogeneity and arterial enhancement. Lesion size, ADC metrics, T2 heterogeneity, and hemorrhage were significant discriminators. Conclusions: Hepatocyte-specific MRI enables identification of characteristic imaging features of NELMs. An integrated assessment of morphologic, diffusion, and hepatobiliary-phase findings may facilitate early recognition of neuroendocrine metastases, even when the primary tumor is unknown, improving diagnostic confidence and clinical management.

Livers doi: 10.3390/livers6030040

Authors: Antonios Katsounas Amer Nashtar Jasmin Weninger Michael Steckstor Despoina Koulenti Joshua D. Nosanchuk Mustafa Özcürümez Ali Canbay Peter M. Rath

Background: Advanced cirrhosis induces profound CD4+ T-cell depletion through splenic sequestration and immune dysregulation. Pneumocystis jirovecii pneumonia risk thresholds remain undefined in non-HIV immunocompromised populations, necessitating investigation in cirrhotic patients. Objectives: To investigate the potential association between peripheral CD4+ T-cell counts and opportunistic infections (OI)—specifically Pneumocystis jirovecii (PJ)—in hospitalized patients with liver disease, and to characterize clinical outcomes across immunological risk strata. Methods: We retrospectively analyzed 455 adults hospitalized in a single institution with hepatic disorders. CD4+ T-cell counts were available in 227/455 patients. Among these, 22 patients met predefined immunological risk criteria (CD4+ < 500/µL and/or HIV positivity) and were classified into three immunological risk clusters (IRCs): IRC-A (HIV−, CD4+ < 200/µL; n = 9), IRC-B (HIV+, CD4+ < 200/µL; n = 7), and IRC-C (HIV−, CD4+ 200–499/µL; n = 6). PJ PCR testing was evaluated when available. Results: Among 455 patients, in-hospital mortality was 103/455 (22.6%). Of the 22 immunologically at risk patients, 15/22 had cirrhosis. PJ PCR was performed in 8/22 patients (IRC-A: 2; IRC-B: 4; IRC-C: 2), with 3/8 positive (37.5%): IRC-A (1/2), IRC-B (1/4), IRC-C (1/2). Ct values ranged from 27.0 to 31.7. Two PJ-PCR–positive cirrhotic patients (IRC-A: n = 1; IRC-C: n = 1) survived without specific anti-PJ therapy; one HIV-positive patient (IRC-B) received trimethoprim-sulfamethoxazole and survived. In-hospital mortality was 5/9 (55.6%) in IRC-A, 2/7 (28.6%) in IRC-B, and 3/6 (50.0%) in IRC-C; none of the deaths were attributable to PJ pneumonia. Conclusions: Severe CD4+ T-cell depletion (<200/µL) was common among cirrhotic patients and associated with PJ detection (3/8 tested), but not with PJ-related mortality (0/3). Mortality was primarily driven by hepatic decompensation and bacterial infections. CD4+ assessment may improve risk stratification in cirrhosis; however, prospective, multicenter studies are warranted to validate these findings and to evaluate CD4-guided strategies for the prevention of opportunistic infections.

Livers doi: 10.3390/livers6030039

Authors: Keara Kirkness Derek A. Mann

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and accounts for over 800,000 deaths worldwide, making it a major global health concern. Unfortunately, despite major advances in systemic treatments, such as the introduction of atezolizumab and bevacizumab, patient objective response rates fall below 30%. HCC most commonly develops against a background of chronic liver disease and cirrhosis, although single gene mutations can also drive HCC development, progression, and metastasis. Around 25% of HCC patient tumours carry mutations in TP53, the gene encoding the tumour-suppressor protein p53. p53 is a central regulator of genomic stability, cell-cycle arrest, apoptosis, senescence, and metabolic homeostasis, and its dysfunction is a frequent event in hepatocarcinogenesis. Accumulating evidence highlights the critical role of p53 in liver fibrosis, inflammation, and shaping of the HCC tumour microenvironment (TME). This review summarizes the role of p53 and its negative regulators Mdm2 and MdmX in HCC development and progression, with an emphasis on how p53 shapes the TME in favour of tumour progression. We also evaluate current and emerging p53-targeted therapeutic strategies, including Mdm2/MdmX inhibitors, mutant p53 reactivators, and rational combinations with immunotherapies. Finally, we discuss major challenges in translating p53-based therapies to the clinic, such as tumour heterogeneity, underlying liver dysfunction, and the development of therapeutic resistance. A deeper understanding of p53 biology in chronic liver disease may unlock new avenues for effective HCC prevention and treatment.

Livers doi: 10.3390/livers6030038

Authors: Morgan Godwin Sharon J. Brown Gabriel Mateus Bernardo Harrington Srinivasa C. Budithi John S. Riddell Charlotte H. Hulme Karina T. Wright

Background: Emerging evidence indicates that the liver plays a key role in spinal cord injury (SCI) pathophysiology. Method: This study reanalysed published proteomic datasets from rat models and patients with SCI using bioinformatics and literature/database searches. The aim was to identify liver-specific molecular signatures in SCI blood samples and to link these to severity and neurological recovery at various time points (acute/sub-acute and chronic). Results: Across species, a high proportion of injury severity and neurological recovery-associated proteins were linked to liver function. Notably, non-improvers exhibited prolonged sub-acute proinflammatory responses. These changes were not restricted to classical acute-phase reactants but reflected coordinated alterations in hepatic metabolic and synthetic pathways. Pathway analysis consistently highlighted Liver X Receptor /Retinoic X Receptor (LXR/RXR), complement system/cascade and DHCR24 signalling pathways, with predicted directional changes linked to recovery status. Several proteins were identified and categorised as markers of liver dysfunction, metabolic function, complement/coagulation factors and/or acute-phase proteins. Alpha-2-HS-glycoprotein (AHSG) and afamin (AFM) were commonly dysregulated across species datasets, suggesting conserved roles in inflammation and lipid metabolism. Further associations with liver pathologies such as fibrosis and cirrhosis, particularly in non-improvers, were identified. Conclusion This work builds on emerging evidence of hepatic involvement in SCI by providing cross-species, time-resolved proteomic support for altered liver-associated protein output following injury. Together, these findings underscore the central role of hepatic responses in SCI, highlighting liver-associated proteins and pathways as candidate biomarkers that may aid in stratifying recovery trajectories and informing clinical prognostication.

Livers doi: 10.3390/livers6030037

Authors: Mehul Jariwala Tristan Kerr Mohit Kehar

Liver involvement in pediatric rheumatologic diseases is an increasingly recognized but often underappreciated clinical issue. Systemic autoimmune and autoinflammatory disorders including juvenile idiopathic arthritis, systemic lupus erythematosus, juvenile dermatomyositis, systemic vasculitis, and mixed connective tissue disease can all affect hepatic structure and function. The mechanisms of injury are multifactorial, encompassing immune-mediated inflammation, macrophage activation, drug-induced toxicity, and metabolic alterations. Hepatic manifestations range from asymptomatic transaminase elevations to fulminant liver failure, frequently influenced by immunosuppressive therapy and comorbid infections. Early recognition through routine biochemical monitoring, imaging, and targeted autoantibody testing is essential for differentiating primary disease activity from treatment-related injury. Timely, multidisciplinary management involving pediatric rheumatology and hepatology teams can prevent progression to chronic liver disease and optimize outcomes. This review summarizes the current understanding of hepatic pathology in pediatric rheumatology, highlighting diagnostic algorithms, monitoring strategies, and emerging therapeutic considerations.

Livers doi: 10.3390/livers6030036

Authors: Ahmad Mahamid Aasem Abu Shtaya Saif Abu Mouch Riad Haddad Abdel-Rauf Zeina Fadi Abu Baker

Background: Liver regeneration after hepatectomy is critical for recovery, yet post-hepatectomy liver failure (PHLF) remains a significant challenge. While GLP-1 RAs have shown metabolic and hepatic benefits in conditions like metabolic dysfunction–associated steatotic liver disease, and GLP-2 is known for intestinotrophic properties, their specific roles in PHLF are not well-defined. This narrative review aims to examine the roles of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and Glucagon-like peptide-2 (GLP-2) in liver regeneration following partial hepatectomy. Methods: A narrative review was conducted, involving a structured appraisal of preclinical, translational, and clinical studies. Relevant literature was identified through comprehensive searches of PubMed and EMBASE databases, limited to English-language publications available up to 1 May 2025. Results: GLP-1 RAs demonstrate therapeutic potential in chronic metabolic liver diseases, but their role in acute hepatic regeneration appears unfavorable, with animal models showing attenuated regenerative responses and impaired liver mass restoration. Conversely, preclinical studies indicate that GLP-2 administration enhances liver regeneration, and human data reveal increased circulating GLP-2 levels post-resection, particularly in PHLF patients, showing dynamics inverse to GLP-1. Conclusions: GLP-1 RAs appear to inhibit acute hepatic regeneration following hepatectomy, while GLP-2 exhibits pro-regenerative activity in preclinical models and favorable dynamics in humans post-resection.

Livers doi: 10.3390/livers6030035

Authors: Ryan Njeim Omar Abureesh Ali Sohail Ryan Tam Liliane Deeb

The recent redefinition of steatotic liver diseases, introducing metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), reflects a growing consensus among liver societies and marks a paradigm shift in disease classification. MASLD subsumes former categories of nonalcoholic fatty liver disease (NAFLD) and incorporates metabolic criteria alongside moderate alcohol intake, while MASH replaces nonalcoholic steatohepatitis (NASH), aligning terminology with disease mechanisms. This evolution clarifies the diagnostic criteria and minimizes stigma, facilitating more consistent epidemiological and clinical investigations. Recent advances in noninvasive diagnostics, including vibration-controlled transient elastography, magnetic resonance elastography, shear-wave elastography, and the Enhanced Liver Fibrosis test, have improved the identification and stratification of patients with advanced fibrosis. Current guidelines recommend targeted screening in populations at elevated metabolic risk, enabling earlier intervention and personalized management. Population studies indicate that MASLD affects over one-third of adults and is a major contributor to cardiovascular and metabolic morbidity. Therapeutic progress is highlighted by the approval of novel agents such as resmetirom and semaglutide for the treatment of MASH with fibrosis. Emerging dual and triple agonists, as well as sodium–glucose cotransporter inhibitors, offer additional promise, although further research is required to define their long-term efficacy and safety. As the disease prevalence escalates globally, the integration of multidisciplinary care, the ongoing refinement of diagnostic tools, and the expansion of therapeutic options will remain essential to optimizing outcomes for affected individuals.

Livers doi: 10.3390/livers6030034

Authors: Ivana Jukic Ivona Matulic Tina Becic Mislav Radic Josipa Radic Damir Fabijanic Jonatan Vukovic

Background: Cigarette smoking exposes the human body to a complex mixture of toxic and carcinogenic compounds that can exert widespread biological effects across different organ systems. From addictive responses and consequence maladaptive neuroendocrine responses, cigarette smoke delivers a variety of reactive oxygen species, polycyclic aromatic hydrocarbons, nitrosamines, and heavy metals that collectively contribute to oxidative stress, inflammation, endothelial dysfunction, and metabolic disruption. The liver, as the primary organ responsible for xenobiotic metabolism, plays a central role in processing these harmful substances and is therefore uniquely susceptible to their effects. This narrative review will aim to provide an overview of the current evidence of cigarette smoking effects on hepatic structure and function and discuss clinical implications. Methods: This narrative review synthesizes evidence from in vitro studies, animal models, and human clinical research examining the effects of cigarette smoking on liver biology. Mechanistic pathways of injury, metabolic and vascular alterations, and clinical consequences for liver disease were considered. Results: Smoking influences hepatic function both directly—through biotransformation pathways generating reactive intermediates—and indirectly via vascular impairment, immune modulation, hormonal alterations, and changes in lipid and glucose metabolism. Emerging evidence indicates that cigarette smoking contributes to hepatic steatosis, accelerates fibrosis progression, worsens outcomes in viral and alcohol-related liver disease, and increases the risk of hepatocellular carcinoma. Conclusions: Cigarette smoking exerts multifaceted deleterious effects on the liver. Recognition of smoking as a modifiable risk factor for liver-related morbidity underscores the importance of smoking cessation in patients with or at risk for liver disease and highlights implications for research and clinical practice.

Livers doi: 10.3390/livers6020033

Authors: Husam Mikati Anas Aljabi Reena Cherian Shawn Lewis Leah Blatzer Tamoore Arshad Matthew Ambrosio Richard K. Sterling

Background: Direct-acting antivirals (DAAs) achieve high sustained virologic response (SVR) in hepatitis C virus (HCV) patients with cirrhosis, yet the risk of hepatic decompensation or hepatocellular carcinoma (HCC) persists. Fibrosis-4 (FIB-4), a pre-treatment index that predicts advanced fibrosis, is linked to HCC risk post SVR. We compared post-SVR outcomes and care engagement, and determined the optimal pre-treatment FIB-4 index to predict the risk of HCC or decompensation in HCV patients with cirrhosis treated at the Department of Corrections (DOC) and non-DOC clinics. Methods: HCV patients with cirrhosis treated with DAAs since 2014 in the HCV Treatment Registry were included. Cirrhosis was defined by elastography, imaging, or clinical criteria. Patients with prior decompensation or HCC were excluded. Outcomes (HCC, decompensation) were collected from records. The FIB-4 index was compared between DOC and non-DOC groups. Results: Among 2104 cirrhotic patients (mean age 54; 76% male), 53% were treated in DOC via telemedicine and 47% in non-DOC clinics. HCC developed in 4.8% and decompensation in 8.1%. DOC patients had lower FIB-4 scores and SVR, partly from higher loss to follow-up (9% vs. 1%). Of 1581 with follow-up, surveillance was more common in non-DOC, which also had higher HCC and decompensation. A higher baseline FIB-4 index independently predicted HCC and decompensation (cutoffs: 3.24, 3.7; AUROC 0.79, 0.75, respectively). Conclusions: Despite SVR, cirrhotic patients—especially with a high FIB-4 index—remain at risk for HCC and decompensation. Outcomes differ by care setting, highlighting the need for continued AASLD-recommended surveillance post-SVR.

Livers doi: 10.3390/livers6020032

Authors: Dante Pio Pallotta Francesco Tovoli Elisa Barbaro Andrea De Sinno Matteo Cappelli Aimone Chiorat Ernestina Santangeli Fabio Piscaglia

Autoimmune hepatitis (AIH) has long been regarded as an organ-specific disorder. However, increasing evidence supports its systemic nature, with extrahepatic manifestations representing key aspects of clinical management. These manifestations can affect musculoskeletal, gastrointestinal, haematologic, and other systems. They also reflect the complex interplay between systemic inflammation, concomitant autoimmune diseases, and drug-related toxicity. A careful evaluation is therefore essential to distinguish between these scenarios, especially for symptoms like fatigue and cytopenias. This narrative review provides a comprehensive, symptom-based overview of extrahepatic clinical and laboratory findings in AIH. By integrating current evidence with practical diagnostic considerations, it aims to offer clinicians a patient-centred and clinically relevant framework for navigating the multifaceted systemic landscape of AIH.

Livers doi: 10.3390/livers6020031

Authors: Srikiran Ramarapu Marcos Gomes Shinobu Itagaki Matthew Quinn Benson Braydon Rucker

Liver transplantation (LT) is the definitive treatment for patients with end-stage liver disease. Since its inception in the 1960s, transplant medicine has undergone substantial advances in surgical technique, immunosuppression, organ preservation, and organ allocation policies. According to the 2023 WHO census, approximately 47,180 LT procedures occur worldwide each year, with living donors contributing to up to 23% of cases. Additional milestones include the expansion of transplant eligibility to patients with hilar cholangiocarcinoma and advanced colorectal liver metastasis, the incorporation of viscoelastic testing into perioperative blood management algorithms, and the increasing use of mechanical circulatory support for pre-transplant optimization. In parallel, medical training has evolved to meet the complexities associated with these high-risk procedures. Structured fellowship programs now provide focused expertise, and guide investigations to resolve complex clinical dilemmas. Experience accumulated over decades has improved clinicians’ ability to manage the expanding spectrum of comorbidities seen in contemporary transplant candidates. Key perioperative challenges include accurate assessment of fluid status, optimization of intravascular volume, management of vasoplegia, intraoperative renal replacement therapy, treatment of right-ventricular failure, and the mitigation of severe lactic acidosis. As transplant recipients increasingly present at older ages and with multiple comorbidities, perioperative management has become more demanding. One emerging strategy for select high-risk patients involves performing concurrent surgical procedures within a single operative session. This narrative review focuses on the intraoperative management of five variables that proved challenging during the first case of concurrent liver transplantation and off-pump coronary artery bypass surgery in our institution.

Livers doi: 10.3390/livers6020030

Authors: Ahmad Hassan Ali Alhareth Al-Juboori Deepthi S. Rao Jamal A. Ibdah Nanda Deepa Thimmappa Ayman H. Gaballah Ghassan M. Hammoud

Background and goals: The outcomes of patients with primary sclerosing cholangitis (PSC) in central Missouri are unknown. The University of Missouri–Columbia services 600,000 individuals in central Missouri. Our aims were (a) to examine the outcomes of PSC patients receiving care at our academic institution, and (b) to identify the predictors of PSC-related serious adverse events. Methods: A retrospective study of patients with PSC in a non-transplant center. The primary outcome was the development of ≥1 of PSC-related serious adverse event for (1) progression to cirrhosis, or (2) development of cholangiocarcinoma. Results: From 2000 to 2018, 42 patients fulfilled the criteria for the diagnosis of PSC. A total of 55% of the patients were male, and 79% had associated inflammatory bowel disease (IBD). The median follow-up from time of diagnosis of PSC until the last follow-up or death was 5.5 years. A total of 57% of the patients developed ≥ 1 PSC-related adverse event; 36% (8/22) of those who progressed to decompensation underwent liver transplantation. The median time from diagnosis of PSC until progression to decompensation was 6.3 years; the median time from decompensation to transplantation was 10.8 years. A total of 12% of the patients developed ≥ 1 cancer (cholangiocarcinoma = 2; gallbladder cancer = 2; colon cancer = 1; and hepatocellular carcinoma = 1). The overall mortality was 9.5%. The median time from PSC diagnosis until death was 10.2 years. A Cox hazards regression analysis showed only age (HR = 1.16; p = 0.032; 95% CI, 1.01–1.13) and serum bilirubin (HR = 1.42; p = 0.036; 95% CI, 1.03–2.69) at the time of PSC diagnosis were independently associated with PSC-related serious events. Conclusions: Age and bilirubin are important predictors of PSC-related outcomes.

Livers doi: 10.3390/livers6020028

Authors: Laura M. Frago Alfonso Gómez-Romero María E. Casado Sandra Canelles María Jiménez-Hernáiz Purificación Ros Daniel Azorín-Cuadrillero Jesús Argente Gabriel Á. Martos-Moreno Vicente Barrios

Background/Objectives: Carbohydrate-restricted diets (CHRs) are increasingly employed in the treatment of obesity. We aimed to investigate the effects of a CHR on hepatic lipid anabolism and its association with changes in the proinflammatory environment and insulin signaling. Methods: Forty-eight C57BL/6J female mice were used in this study. We aimed to analyze the impact of a CHR on the hepatic proinflammatory profile and its relationship with changes in insulin signaling and fatty acid anabolism in obese female mice after two months on a high-fat diet. We also examined the impact of a one-month chow diet after CHR. Blood samples were collected, and the liver was processed during all-time study periods for analyses of biochemical, hormonal, and inflammatory markers, as well as possible changes in leptin and insulin signaling pathways. Results: Compared with chow-fed mice, CHR mice showed increased interleukin (IL)-1β and IL-2 levels, as well as leptin-related signaling in the liver. There was also a decrease in the expression of fatty acid synthase and the phosphorylation of ATP-citrate lyase, which was associated with a reduction in the activation of the insulin receptor, Akt, the mammalian target of rapamycin, cAMP-response element-binding protein, and glycogen synthase kinase 3β. The subsequent reintroduction of a chow diet after CHR resulted in lower hepatic free fatty acid and triglyceride levels than in obese mice without previous CH restriction. Conclusions: This study suggests that CHR inhibits de novo hepatic lipogenesis in obese mice by attenuating insulin signaling in a low-grade proinflammatory state.

Livers doi: 10.3390/livers6020029

Authors: Angelo Corso Faini Alberto Calleri Michele Pinon Cristina Chiadò Pier Luigi Calvo Tiziana Vaisitti Silvia Deaglio

Genetic liver diseases encompass a heterogeneous group of conditions that disrupt hepatic development, structure, or function. Advances in high-throughput sequencing have revealed the molecular basis of many disorders previously defined only by clinical or biochemical features, transforming diagnostic and therapeutic approaches. This review proposes a mechanistic framework that distinguishes diseases arising from developmental abnormalities from those caused by functional impairments in hepatocellular or biliary physiology. It outlines how defects in transporters, enzymes, signaling pathways, intracellular trafficking, and mitochondrial function converge to produce diverse hepatic phenotypes. Moreover, translational aspects are discussed such as how the growing integration of genetic testing into clinical practice enables precise diagnosis, informs prognosis and therapy, and refines disease classification. Finally, the review discusses future directions in the field, emphasizing the role of multi-omic approaches, organoid modeling, and data sharing in elucidating unresolved pathogenic mechanisms and advancing precision hepatology.

Livers doi: 10.3390/livers6020027

Authors: Eleni V. Geladari Kyriaki A. Papachristodoulou Stavros M. Kanaloupitis Apostolos A. Evangelopoulos Vasileios A. Sevastianos

Porto-sinusoidal vascular disorder (PSVD) is an umbrella term proposed by the Vascular Liver Disease Interest Group (VALDIG) in 2019. It refers to a group of non-cirrhotic vascular liver diseases that cause portal hypertension. These were previously described as idiopathic non-cirrhotic portal hypertension, hepatoportal sclerosis, nodular regenerative hyperplasia, and incomplete septal fibrosis. PSVD is characterized by injury and remodeling of portal venules and sinusoids. Immune dysregulation, prothrombotic states, infections, medications (e.g., oxaliplatin, thiopurines), toxins (e.g., arsenic), and genetic susceptibility often drive this process. Clinically, PSVD ranges from asymptomatic patients with only abnormal liver tests to severe complications of portal hypertension, such as variceal bleeding, ascites, and portal vein thrombosis. Patients typically have preserved liver synthetic function, helping distinguish PSVD from cirrhosis. Diagnosis is based on VALDIG criteria and requires an adequate liver biopsy that shows no cirrhosis. It also requires specific combinations of clinical signs of portal hypertension and characteristic histological lesions, such as obliterative portal venopathy, nodular regenerative hyperplasia, and incomplete septal fibrosis. Non-invasive tools, including imaging and liver stiffness measurement, are supportive. They often show discordance between marked portal hypertension and low liver stiffness, suggesting a non-cirrhotic cause. Management follows cirrhosis-based portal hypertension guidelines. This includes non-selective beta-blockers, endoscopic variceal ligation, TIPS, anticoagulation in selected patients, and liver transplantation for refractory or end-stage disease. Prognosis is generally better than in cirrhosis, with a 5-year transplant-free survival rate of approximately 85% compared to 60% in matched cirrhotics. However, major gaps remain in the true epidemiology, the natural history of early or subclinical PSVD, validated non-invasive biomarkers, and disease-modifying therapies.

Livers doi: 10.3390/livers6020026

Authors: Yoshinori Ozeki Takayuki Masaki Nao Imaishi Chiaki Yonezu Machiko Morita Yumi Mori Takaaki Noguchi Shotaro Miyamoto Yuichi Yoshida Koro Gotoh Yuichi Endo Masafumi Inomata Hirotaka Shibata

Background and Objectives: This study investigated the correlation of the liver-to-spleen (L/S) Hounsfield unit ratio on abdominal CT with liver function and diabetic indicators before and after laparoscopic sleeve gastrectomy (LSG), comparing patients with and without diabetes mellitus (DM and non-DM groups). Methods: Patients undergoing LSG were categorized into DM and non-DM groups. Metabolic parameters and abdominal CT scans were assessed preoperatively and one year postoperatively. Correlations among these variables were analyzed, and intergroup comparisons were performed. Results: Preoperative body weight and postoperative weight loss were comparable between the DM and non-DM groups. Before surgery, the DM group showed significantly higher levels of fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), aspartate transaminase (AST), alanine transaminase (ALT), and γ-glutamyl transpeptidase (γ-GTP). After LSG, both groups exhibited significant reductions in FPG, HbA1c, AST, ALT, and γ-GTP, along with a significant increase in the L/S ratio. The reduction in γ-GTP was more pronounced in the DM group. In the DM group, changes in glycemic markers (FPG and HbA1c) were significantly correlated with changes in liver enzymes and with the change in L/S ratio. Conclusions: LSG reduced body weight and fat mass and improved glucose metabolism and liver function in patients with obesity, regardless of their diabetes status. Improvements in liver enzymes and/or the L/S ratio were more marked in diabetic patients and might be closely linked to better glycemic control following surgery.

Livers doi: 10.3390/livers6020025

Authors: Julia Horwacik Mateusz Maligłówka Łukasz Bułdak Bogusław Okopień

The liver produces the majority of plasma proteins, maintaining the metabolic homeostasis. The dysregulation of liver protein synthesis underlies many systemic conditions. Therefore, there is a great potential in therapies that inhibit the hepatic protein production. This is the mechanism of action of antisense oligonucleotides (ASOs) and small interfering RNA (siRNA). These therapeutics have undergone rapid development and are revolutionizing the pharmacological landscape of many liver-related diseases (e.g., inclisiran in familial hypercholesterolemia). Furthermore, gene-editing technologies that allow a direct correction of impaired genes in the liver are currently being evaluated. They hold a promise for future advances in treatment, especially of monogenic disorders such as hereditary transthyretin amyloidosis or alpha-1 antitrypsin deficiency. In this review, we describe the most relevant systemic diseases caused by dysfunction of protein synthesis in liver cells, in which significant therapeutic progress has been made over the last decades. Moreover, we present currently available drugs and their mechanisms of action, including six siRNA agents and five ASOs that have been approved to date. Finally, we discuss emerging strategies, focusing on novel RNA-based therapeutics that are the subjects of ongoing clinical trials.

Livers doi: 10.3390/livers6020024

Authors: Kizuki Yuza Miho Akabane Timothy M. Pawlik

Background: Intrahepatic cholangiocarcinoma (ICC) is an uncommon but increasingly recognized primary liver malignancy with a poor prognosis. Although surgical resection offers the only realistic opportunity for cure, recurrence is common and the optimal integration of surgery with systemic and liver-directed therapies continues to evolve. Summary: This review summarizes contemporary evidence on the diagnosis and multidisciplinary management of ICC with particular emphasis on surgical, systemic, locoregional, and transplant-based strategies. Cross-sectional imaging plays a central role in staging and assessing resectability including evaluation of vascular invasion and the future liver remnant. Upfront resection is appropriate for selected patients with resectable disease and preserved liver function, with margin-negative resection and lymphadenectomy remaining key oncologic goals. Systemic therapy continues to evolve with cytotoxic chemotherapy forming the backbone of treatment for advanced disease and immunotherapy and targeted agents demonstrating promise in biomarker-defined subgroups. Locoregional modalities such as hepatic arterial infusion therapy and radioembolization may provide disease control in liver-dominant ICC and are increasingly used within a multidisciplinary framework. Liver transplantation remains investigational but may offer favorable outcomes in highly selected early-stage disease.

Livers doi: 10.3390/livers6020023

Authors: Terence N. Moyana

Primary biliary cholangitis (PBC) is an autoimmune-mediated disease characterized by chronic, non-suppurative, small-duct lymphocytic cholangitis. The prognosis largely depends on early disease recognition and treatment. Suboptimal response to first-line therapy (ursodeoxycholic acid) is associated with risk for disease progression. Reliable biomarkers are also required to enhance risk stratification. The traditional gold standard for assessing fibrosis is liver biopsy, but it is invasive and unsuitable for serial evaluations. Hence, trends are towards non-invasive surrogate biomarkers (blood-based and imaging biomarkers respectively) which have a much better safety profile. Blood-based biomarkers include: (i) Fibrosis-4 [Fib-4], (ii) Aspartate Aminotransferase to Platelet Ratio Index [APRI], (iii) Enhanced Liver Fibrosis score [ELF], and (iv) total bile acid to platelet ratio [TPR]. They show much potential but are not particularly sensitive tests. Ultrasound-based imaging biomarkers are increasingly being utilized for liver stiffness measurement (LSM), with vibration-controlled transient elastography (VCTE) emerging as the preferred technique. However, despite its growing popularity, VCTE is limited by technical issues. Hence, currently, none of the non-invasive tests fulfill the prerequisites to be the new gold standard as defined by the FDA. Nonetheless, there may be value to combining LSM with various serum biomarkers such as Fib-4, APRI, as aforementioned. The hope is to create nomograms for predicting liver-related events and decision tree algorithms. Newer studies are investigating microbiota in the gut-liver axis, biomolecules such as nanovesicles/nanofibers, and metabolic reprogramming as it pertains to e.g., proteomics and lipidomics. These approaches hold much promise, and if validated, could significantly change the management of PBC.

Livers doi: 10.3390/livers6020022

Authors: Mohamad Amer Nashtar Stamatina Georgitsi Jan Best Michael Steckstor Philipp Aurich Mustafa Özcürümez Ali Canbay Antonios Katsounas

Background/Aims: Sepsis as an acute cause of liver dysfunction is associated with high mortality. Routine infection/inflammation markers—C-reactive-protein (CRP), procalcitonin (PCT), and leukocyte count (LeuC)—are frequently used for risk stratification in septic patients. This study aimed to evaluate these markers as predictors of short-term and 12-month mortality in septic patients with distinct liver dysfunction phenotypes. Methods: This single-center retrospective pilot analysis involved adults with sepsis and varying degrees of liver dysfunction—acute liver failure (ALF), acute-on-chronic liver failure (ACLF), or acute-on-cirrhosis (ACOC)—treated in intermediate or intensive care units between 2016 and 2017. At sepsis onset, patients were categorized into ACOC, ACLF, and ALF groups. Only patients with recorded CRP, PCT, and LeuC measurements 24 h before, on the day of, and 24/48 h after sepsis onset were included in the analysis. Associations with in-hospital and 12-month mortality were analyzed using Firth bias-reduced logistic regression, ROC analysis, and internal validation by bootstrapping and cross-validation. Results: 49 patients were included (ACOC n = 21; ACLF n = 20; ALF n = 8). In-hospital and 12-month mortality rates were 34.7% and 61.2%, respectively, with the highest long-term mortality observed in the ACOC group (76.2%). In the ACOC group, PCT 24 h before sepsis onset independently predicted in-hospital mortality (OR ~5 per PCT doubling; AUC 0.94), with an optimal rule-in cut-off of 1.0 ng/mL (specificity 1.00, PPV 1.00). PCT was not predictive in ACLF/ALF, and CRP/LeuC offered limited prognostic value. Conclusions: In this hypothesis-generating analysis, PCT 24 h before sepsis onset shows a phenotype-specific association with early mortality in ACOC. Larger, prospective multicenter studies are needed to validate PCT-guided risk stratification.

Livers doi: 10.3390/livers6020021

Authors: Jordan Zheng Ting Sim Xiaojia Ge Hsien Min Low Chau Hung Lee

Background: Gadoxetic acid-enhanced MRI is essential for detecting and characterizing focal liver lesions. However, transient severe motion artifacts in the arterial phase can degrade image quality. Gadoxetic acid dilution has been proposed to mitigate these artifacts, but its impact on multiple arterial phase acquisition remains unclear. Objective: To evaluate the effect of gadoxetic acid dilution on image quality across multiple arterial phases in liver MRI, incorporating a phase-by-phase analysis. Methods: This retrospective study included 81 patients (52 men, 29 women; mean age 70.1 years) who underwent serial gadoxetic acid-enhanced MRI with undiluted and diluted contrast (1:1 saline dilution). MRI was performed on 1.5 T and 3.0 T scanners with a standardized injection rate of 1.0 mL/s. Two radiologists independently rated anatomic conspicuity, respiratory motion artifacts, and overall image quality using a Likert scale (1 to 5 with higher scores indicating better quality). A phase-by-phase analysis was conducted after a three-month washout period. Wilcoxon signed-rank tests were used for statistical comparisons, and inter-rater agreement was assessed with quadratic kappa coefficients. Results: Inter-observer agreement was substantial (ƙ = 0.602–0.702). Phase-by-phase analysis revealed significant improvement in image quality for the first three arterial phases (p = 0.003, 0.005, 0.050). Although the diluted method showed higher scores, the differences were not statistically significant in anatomic conspicuity (3.73 vs. 3.59, p = 0.110), respiratory artifacts (3.54 vs. 3.41, p = 0.291), and overall image quality (3.67 vs. 3.51, p = 0.083). Conclusions: Gadoxetic acid dilution improves image quality in early arterial phases of liver MRI, suggesting its potential to reduce motion artifacts.

Livers doi: 10.3390/livers6020020

Authors: Mahinaz Mohsen Rohan Karkra Esli Medina-Morales Joshua E. Pagán-Busigó Ethan Shamsian Michael Bebawy Sakina Paracha Charmi Patel Riya Sutariya Paul Gaglio

Primary Biliary Cholangitis (PBC) is a chronic, immune-mediated cholestatic liver disease characterized by progressive intrahepatic bile duct destruction, leading to pruritus, fatigue, cirrhosis, and eventually hepatocellular carcinoma. Early diagnosis has improved with the development of sensitive serologic assays (e.g., antimitochondrial antibodies, antinuclear antibodies) and the introduction of newer biomarkers. Risk stratification has become standardized with the help of GLOBE and UK-PBC scores, alongside non-invasive tools such as vibration-controlled transient elastography, enabling earlier intervention. Ursodeoxycholic acid (UDCA) is the first-line therapy; however, 30–40% of patients show an incomplete response, increasing their risk of liver failure and mortality. Second-line therapies have emerged which provide viable treatment avenues for those who do not respond to UDCA or are unable to tolerate it. However, in certain situations, such as decompensated cirrhosis, carcinoma, or refractory pruritus, liver transplantation constitutes the only curative therapy. While PBC has excellent post-liver transplant (post-LT) outcomes, patients with PBC face higher waitlist mortality as they tend to have lower MELD scores. Management post-LT includes the use of UDCA, immunosuppressants, and surveillance for recurrent PBC. Our review highlights the recent advances in medical management and transplant risk stratification of patients at risk of decompensation, as well as the perioperative transplant period outcomes and long-term post-transplant management strategies in patients with PBC.

Livers doi: 10.3390/livers6020019

Authors: Tomislava Skuhala Anja Dragobratović Luka Marinković Kristina Ramljak Marin Rimac Arijana Pavelić Snjezana-Zidovec Lepej

Antitubercular drug-induced liver injury (ATDILI) poses a significant obstacle to successful tuberculosis treatment, including for tuberculous lymphadenitis. Its global incidence varies considerably, typically ranging from 2% to 30%, influenced by factors like patient demographics, co-morbidities, and geographical context. Despite some findings suggesting potentially lower rates in tuberculous lymphadenitis, the inherent hepatotoxic nature of standard anti-TB drugs means the risk remains clinically relevant. Key risk factors for ATDILI encompass older age, female gender, pre-existing liver conditions, HIV co-infection, malnutrition, alcoholism, and genetic polymorphisms, particularly in N-acetyltransferase 2 which affects isoniazid metabolism. The mechanisms of injury are drug-specific: isoniazid primarily causes hepatocellular damage via oxidative stress from toxic metabolites, while rifampicin induces cholestasis and endoplasmic reticulum stress, and pyrazinamide is linked to mitochondrial dysfunction. Management involves prompt withdrawal of antitubercular therapy when liver enzyme thresholds are exceeded, followed by careful reintroduction. Challenges are amplified in resource-limited settings due to higher prevalence of risk factors and limited access to consistent monitoring and sophisticated diagnostics. Promising advancements include safer regimens like the 3-month once-weekly isoniazid-rifapentine (3HP) for latent TB, which significantly reduces hepatotoxicity. The development of shorter active TB regimens and novel anti-TB drugs with improved safety profiles further aims to enhance treatment adherence and reduce ATDILI incidence, ultimately improving patient outcomes globally.

Livers doi: 10.3390/livers6020018

Authors: Ester Borroni Roberta Annamaria Cirsmaru Antonia Follenzi Simone Merlin

The liver plays a fundamental role in maintaining homeostasis thanks to the numerous functions performed by this organ. Non-inherited metabolic liver diseases, inherited metabolic liver diseases, and liver cancers are pathological conditions affecting liver function and that can lead to its failure. To date, for end-stage liver diseases—where the remaining hepatic tissue is no longer capable of regenerating sufficiently rapidly—or for metabolic diseases involving the liver, liver transplantation remains the standard and ideal therapeutic approach. However, this is limited by donor availability, surgical costs, and the tangible risk of autoimmune rejection, which may occur at varying intervals post-surgery. Furthermore, for the duration of their lives, transplant recipients must undergo systemic immunosuppressive treatment to prevent rejection; this is associated with high costs and severe side effects, including infections and secondary malignancies. In this review, we discuss these pathologies and how recent cell-based therapies and/or gene therapy approaches have emerged as promising alternatives that can provide either temporary restoration of hepatic function or long-term benefits, potentially reducing the global burden of liver disorders.

Livers doi: 10.3390/livers6020017

Authors: Mustafa Al-Nakeb Nils Haep

Transmembrane 6 superfamily 2 (TM6SF2) was first described as a key regulator of hepatic lipid metabolism and lipoprotein secretion. Today, TM6SF2 is recognized to influence broader mechanisms in liver physiology and pathology. The protein has been linked to influence protein stability, very-low density lipoprotein (VLDL) assembly and secretion, hepatic lipid accumulation and development of Chronic liver disease (CLD). Furthermore, the TM6SF2 E167K variant has attracted scientific interest as it is associated with an increased risk of MASLD and other progressive liver diseases. This review provides an overview of the current knowledge of TM6SF2 and the E167K variant on hepatic lipid metabolism, VLDL mechanisms, protein interactions, CLD and antitumor immunity.

Livers doi: 10.3390/livers6020016

Authors: Angeliki Tsakou George Notas Constantinos Xidakis Ioannis Tsomidis Argyro Voumvouraki Elias Kouroumalis

Background. Somatostatin and its synthetic analog octreotide are suppressive hormones that have been used in the treatment of variceal bleeding or bleeding from portal hypertensive gastropathy. They are also used in the treatment of some cancers, including hepatocellular carcinoma (HCC). Experimental evidence reported that they have potentially useful effects on liver inflammation and fibrosis, acting on Kupffer cells (KCs) and hepatic stellate cells (HSCs). However, clinical data is missing. Therefore, the effect of somatostatin and octreotide was studied on several fibrosis mediators in patients with compensated cirrhosis. Patients and Methods. Fifty-eight patients with HCV-related compensated cirrhosis treated with either somatostatin or octreotide for bleeding from portal gastropathy were compared with twenty-nine healthy controls matched for age and sex. Serum levels of three metalloproteases (MMP1, MMP2 and MMP9) and their inhibitors, TIMP1 and TIMP2, were measured. Additional fibrosis and inflammation mediators—such as nitric oxide (NO), TNFα, soluble ICAM-1, and the CC chemokines RANTES (CCL5) and MIP1a (CCL3)—were also measured. Results. Serum levels of MMP1, MMP2, MMP9 and TIMP1 were significantly decreased in cirrhosis (p < 0.01). TIMP2 levels were increased (p < 0.01). RANTES levels were also significantly decreased (p < 0.01), but NO, TNFα, MIP1a and sICAM-1 were significantly increased (p < 0.01). Administration of somatostatin had no effect on MMP2 or MMP9 but significantly decreased all other mediators. Octreotide had similar but milder effects, but it had no effects on MIP1a and sICAM-1 were demonstrated. Conclusions. Somatostatin and octreotide modulate factors implicated in the progression of fibrosis in the short term. Whether they could be used in the long term as treatment for liver diseases with progressive fibrosis or in cases with intense inflammatory reactions, such as alcoholic hepatitis, requires further investigation.

Livers doi: 10.3390/livers6020015

Authors: Tanja Elger Muriel Huss Johanna Loibl Patricia Mester Andreas Albert Arne Kandulski Martina Müller Hauke Christian Tews Christa Buechler

Background/Objectives: Systemic levels of the adipokine adiponectin are elevated in chronic liver disease including primary sclerosing cholangitis (PSC). Inflammatory bowel disease (IBD) and PSC are closely associated diseases, but in IBD serum adiponectin levels are near normal. Urinary and fecal biomarkers have been suggested to be superior to the corresponding serum protein for disease diagnosis, but urinary and fecal adiponectin have not been analyzed in PSC. The aim of this study was to evaluate the adiponectin in human serum, urine, and feces as a potential diagnostic tool for PSC. Methods: Serum and urine samples were collected from 74 IBD patients, 40 PSC patients (35 patients with PSC and IBD (16 patients for urine) and 5 patients with PSC without underlying IBD), and 17 controls. Feces samples from 53 IBD patients and 11 PSC patients (8 of them with PSC-IBD) were available for this study. Adiponectin levels were analyzed by enzyme-linked immunosorbent assay. Results: Urinary and serum adiponectin levels in IBD patients and controls were comparable. Urinary, fecal and serum adiponectin in patients with ulcerative colitis and Crohn’s disease were similar and did not change, even with higher fecal calprotectin, a marker of intestinal inflammation in IBD. The three IBD patients with a high Gastrointestinal Symptom Rating Scale score as a marker for clinical activity had highly elevated urinary adiponectin. Systemic adiponectin levels were significantly elevated in the PSC-IBD cohort relative to the IBD-only group, suggesting its potential utility in clinical screening. Urinary and fecal adiponectin levels were similar between the cohorts. In PSC/PSC-IBD, serum adiponectin did not increase with higher fibrosis scores. Serum, urine, and fecal adiponectin were not correlated in both patient cohorts, except for a negative association of fecal and urine adiponectin in PSC. Conclusions: This exploratory study revealed preliminary findings suggesting an association between urinary adiponectin and severe gastrointestinal symptoms in IBD. In PSC-IBD, serum adiponectin is higher compared to IBD patients and continuous measurement may be used for PSC-IBD screening.

Livers doi: 10.3390/livers6020014

Authors: Natalie Commins Rohit Gupta Andrew Sloss Tehara Wickremeratne Roger Wilson Jonathan Langton Brooke Gaggin James O’Beirne

Background and Aim: Adjuvant therapy after curative intent treatment for hepatocellular carcinoma (HCC) is a significant unmet need. The IMbrave050 study demonstrated improved recurrence-free survival (RFS) in patients with high-risk HCC receiving adjuvant atezolizumab and bevacizumab post-curative treatment compared to active surveillance. However, the IMbrave050 cohort was predominantly Asian, largely underwent surgical resection, and had chronic liver disease (CLD) mainly due to hepatitis B features that differ markedly from the Australian setting, where microwave ablation (MWA) is more common and hepatitis B-related CLD is less prevalent. Given these differences, this study aimed to explore the performance of the IMbrave050 risk criteria in an Australian population of patients with early-stage HCC undergoing curative treatment to determine if the criteria identified patients with a high risk of recurrence who may benefit from adjuvant treatment. Method: We performed a retrospective 5-year study of 50 patients with early-stage HCC undergoing MWA with curative intent or liver resection. Patients were stratified into high- and low-risk groups using the IMbrave050 criteria. The primary outcomes were RFS and overall survival (OS) in the high- and low-risk cohorts. Results: For patients who underwent liver resection, the 1-year RFS was 77.8% and 100% in high- and low-risk patients respectively (p = NS). In those who underwent MWA, the 1-year RFS was 89.5% in the high-risk cohort and 73.3% in the low-risk cohort (p = NS). OS at 1-year was 100% in all cohorts (p = NS). Conclusions: In this Western cohort receiving predominantly ablation as curative therapy the current high-risk criteria do not reliably distinguish between those with increased risk of early recurrence and those without. Criteria defining high-risk may need to be refined to better identify patients who may benefit from adjuvant therapy in this setting.

Livers doi: 10.3390/livers6010013

Authors: Liliana Gheorghe Antoanela Curici Speranta Iacob

Background/Objectives: Chronic hepatitis B (HBV) and C (HCV) remain major public health challenges in Romania despite vaccination and antiviral therapy. Understanding infection patterns in different healthcare settings is essential for targeted elimination strategies. Methods: We conducted the prospective screening phase of the RE-LINK project (January–June 2025) through two nationwide private laboratory networks. Adults undergoing routine testing were screened for HBsAg and anti-HCV. HBsAg-positive samples were further analyzed for HBV DNA, HBeAg, anti-HBe, anti-HDV, and HDV RNA, while anti-HCV-positive cases were tested for HCV RNA. Risk factors were assessed using chi-square and logistic regression analyses. Results: Among 9149 individuals (66.6% women with a median age of 53 years), HBsAg prevalence was 2.9%, and anti-HCV was 1.3%, both increasing significantly with age (p < 0.001). Of all HBsAg-positive individuals, 12.5% had undetectable HBV DNA, 70.4% had low viremia (<2000 IU/mL), and 17.1% had high viral loads. Anti-HDV antibodies were detected in 2.3% of HBsAg-positive subjects, all with detectable HDV RNA (range 1250–680,000 IU/mL). Significant risk factors for HBsAg positivity were male sex, older age, urban residence, physician-indicated testing, neuropsychiatric comorbidity, family or parental hepatitis, and institutional/orphanage care, while HBV vaccination and moderate alcohol use were protective. Anti-HCV positivity correlated with older age, cardiovascular disease, elevated transaminases, transfusions, surgery, and HIV co-infection. Only 20.2% of anti-HCV-positive individuals were viremic. Conclusions: Private-laboratory screening reveals residual low-replicative HBV and declining viremic HCV, while community programs uncover HDV and advanced disease in vulnerable groups. A coordinated approach integrating private, community, and hospital-based pathways can accelerate elimination efforts and ensure that HDV is not overlooked.

Livers doi: 10.3390/livers6010012

Authors: Vinay Jahagirdar Priyanka Parajuli Skylar Hargrove Richard K. Sterling

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously called non-alcoholic fatty liver disease (NAFLD), has become a leading cause of chronic liver disease in people living with HIV (PLWH), especially in the era of effective antiretroviral therapy (ART). As the life expectancy of PLWH continues to increase, non-AIDS-related comorbidities such as metabolic syndrome, insulin resistance, and cardiovascular disease have become more prevalent, contributing to a rising incidence of MASLD and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). Studies have shown that the prevalence of MASLD in PLWH ranges from 30% to 50%, with biopsy-based estimates of non-alcoholic steatohepatitis (NASH) approaching 49% and advanced fibrosis up to 23%. This burden is influenced not only by traditional metabolic risk factors but also by HIV-specific mechanisms, including chronic immune activation, lipodystrophy, microbial translocation, and mitochondrial dysfunction associated with ART exposure. Despite its high prevalence and clinical significance, MASLD remains underdiagnosed in PLWH. This scoping review aimed to systematically map the existing literature on MASLD in people living with HIV, including epidemiology, risk factors, diagnostic approaches, fibrosis assessment, and management strategies. Understanding the unique interplay between HIV infection and metabolic liver disease is essential for the early diagnosis and prevention of progression to cirrhosis and hepatocellular carcinoma in this growing patient population.

Livers doi: 10.3390/livers6010011

Authors: Fabiola Justina Fumero León Flor Helene Pujol

It is known that the composition of the intestinal microbiota (IM) is associated with the pathogenesis of viral hepatitis. Hepatitis C virus (HCV) is an RNA virus that affects about 50 million people worldwide. HCV infection is considered a major risk factor for developing liver cirrhosis and hepatocellular carcinoma. The liver is closely related to bacterial components derived from the bacteria of the IM through the gut–liver axis, influencing host susceptibility to certain diseases, such as the development of hepatopathy associated with HCV infection. This review specifically evaluates the association of HCV infection with the bacterial IM, focusing on key aspects, such as the evolving intestinal dysbiosis during the natural history of the infection and the effect of treatment (antibiotics, direct-acting antivirals, pre/probiotics, and diet) in the management of these patients, in the different stages of the disease, up to HCC.

Livers doi: 10.3390/livers6010010

Authors: Katerina Gioti Iliana Tzotza Irene Belouka Christine Kottaridi Apostolos Beloukas

Background/Objectives: Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide, posing significant health challenges due to its high morbidity and mortality rates. Emerging evidence indicates that non-apoptotic cell death mechanisms, including pyroptosis and cuproptosis, play crucial roles in HCC progression. Natural compounds have been widely investigated as potential primary or adjunct therapies targeting these cell death pathways. This review summarizes recent advances on the application of natural products that influence pyroptosis and cuproptosis in HCC. Methods: A comprehensive critical review of in vitro and in vivo studies examining the effects of natural compounds on HCC was conducted. Results: Several natural molecules demonstrate cytotoxic and cytostatic effects against HCC by modulating pyroptosis and cuproptosis pathways. Conclusions: Natural products exhibit promising potential as adjuvant therapies in hepatocellular carcinoma by selectively inducing or modulating pyroptosis and cuproptosis pathways. These mechanisms contribute to enhanced cancer cell death, underscoring the therapeutic value of targeting non-apoptotic cell death processes in HCC management.

Livers doi: 10.3390/livers6010009

Authors: Rodanthi Syrigou Dimitra Tiganiti Kyriakos Kintzoglanakis Vasileios Lekakis Dimitrios S Karagiannakis

Background and Aim: The management of patients with chronic Hepatitis B Virus (HBV) HBeAg-negative infection in the indeterminate-grey zone (GZ) remains debatable. We conducted a systematic review and meta-analysis to compare these patients with those with chronic HBV HBeAg-negative infection (inactive carriers; IC/HBeAg-negative), regarding the severity of liver inflammation and fibrosis and the risk of developing hepatocellular carcinoma (HCC). Methods: A literature search was conducted to identify all published studies comparing GZ/HBeAg-negative patients with IC/HBeAg-negative patients. Data on the severity of liver inflammation and fibrosis were extracted, and pooled relative risks (RR) and 95% confidence intervals (CI) were calculated. The risk of HCC was estimated by pooled hazard ratios (HR). A random-effects meta-analysis model was performed using R v4.1.2. Results: Eleven studies were finally included. GZ/HBeAg-negative patients had significantly higher mean HBV-DNA and alanine transferase (ALT) levels, compared to their IC/HBeAg-negative counterparts (4089.9 ± 4840.5 vs. 215.9 ± 318.1 IU/mL; p = 0.0004, and 39.6 ± 26.9 IU/L and 20.1 ± 7.6 IU/L/; p < 0.0001, respectively). GZ/HBeAg-negative patients showed a trend towards a higher risk of significant liver inflammation (RR: 5.11; 95%CI: 0.68–38.33; p = 0.1), F2/F3 fibrosis (RR: 2.13; 95%CI: 0.89–5.1; p = 0.09), and cirrhosis (RR: 14.39; 95%CI: 0.5–417.08; p = 0.12), respectively, compared to IC/HBeAg-negative patients. After a median follow-up of 6.2 years, the former group demonstrated a significantly higher risk of developing HCC (HR: 4.7; 95% CI: 1.4–15.6; p < 0.0001). Conclusions: GZ/HBeAg-negative patients have a higher risk of developing HCC compared to IC/HBeAg-negative patients, which raises concerns about the potential need to initiate treatment in this patient group.

Livers doi: 10.3390/livers6010008

Authors: Jesus de Vicente-Sanchez Fernando Gilsanz-Rodriguez Antonio Perez-Ferrer

Background/Objectives: Intraoperative bleeding remains one of the major challenges in pediatric liver transplantation (PLT), contributing significantly to perioperative morbidity, transfusion-related complications, and prolonged recovery. Although viscoelastic testing has improved intraoperative hemostatic management, there are currently no validated preoperative tools capable of predicting bleeding risk in this vulnerable population. Methods: We conducted a prospective, single-center observational study including 43 consecutive pediatric patients who underwent orthotopic liver transplantation between May 2008 and August 2009. A comprehensive dataset encompassing demographic, clinical, biochemical, and surgical variables was collected. A multivariable linear regression model was developed to predict intraoperative blood loss (IBL). Variable selection was guided by Mallows’ Cp criterion to ensure optimal model fit and clinical interpretability. Model performance was assessed using adjusted R2, diagnostic residual analysis, and internal validation to verify regression assumptions. Results: Six independent predictors of IBL were identified: presence of ascites, prior abdominal surgery, operative time, baseline fibrinogen concentration, platelet count, and recipient weight. The final model explained 35.2% of IBL variance (adjusted R2 = 0.352; F = 7.68; p < 0.001). Model diagnostics confirmed linearity, normal distribution of residuals, and homoscedasticity, supporting its robustness and reliability. Conclusions: This multivariable model provides an interpretable, clinically applicable framework for individualized preoperative estimation of blood loss in PLT. It may assist in planning perioperative patient blood management strategies and serve as a foundation for future decision-support systems. Limitations include the single-center design and modest sample size; however, internal validation supported the stability and reliability of the model.

Livers doi: 10.3390/livers6010007

Authors: Luisa Cavalletto Elisabetta Bernardinello Ilenia Mezzocolli Silvia De Carlo Mirko Schipilliti Eleonora Bertoli Liliana Chemello

Background and Objectives: The increase in rates of cirrhosis and hepatocellular carcinoma (HCC) due to HCV infection supported the implementation of screening programs for control of this infection in Italy. The HepCoVe network has collected cases with chronic hepatitis C (CHC) in the Veneto region of North-East Italy since the 2000s. This platform allowed us to (a) compare the characteristics of the HCV cohort exposed to parenteral risk before or after 1995 (introduction of mandatory HCV testing), and (b) track the changes induced by IFN-based therapy and the novel direct-acting antivirals (DAA). Methods: From January 2000 to December 2005, 2703 prospectively recruited cases with CHC were analyzed and followed up for 16.2 ± 8.4 years, by a per protocol analysis. Results: Two epidemic waves occurred; the first, related to blood transfusions and infection with the HCV-1b and 2a/2c genotypes, affecting an elderly population, and the second, spread through drug addiction, among young people and with a prevalence of HCV-1a, 3a/3b and 4c/4d. Patients treated with DAA had more advanced liver disease; despite this, they achieved the highest SVR rate, compared to those who received an IFN-based regimen (95.1% vs. 61.5%; p < 0.01). The 10-year HCC incidence rate by KM was 0.81, 3.75, and 1.26 per 100 person-years (p-y) in cases with or without SVR and in the untreated group, respectively (p < 0.001). Conclusions: The period of exposure to HCV in Italy (born from 1939 to 1989) was supported by two epidemic waves. Unknowing cases of HCV infection are disappearing, particularly those included in the first cohort, among the “boomers”. Despite the eradication of HCV in all treated cases, antiviral therapy does not completely eliminate the risk of HCC onset.

Livers doi: 10.3390/livers6010006

Authors: Kayli Winterfeldt Shadab A. Siddiqi

The liver plays a central role in numerous physiological processes, with one of its most critical functions being the regulation of lipid homeostasis through both the biogenesis and secretion of very low-density lipoproteins (VLDLs) and fatty acid oxidation. By forming and secreting VLDLs, the liver mitigates the influx of potentially toxic free fatty acids from the bloodstream and repurposes them for energy utilization throughout the body. Fatty acid oxidation is equally essential for maintaining hepatic lipid balance, and its disruption can lead to lipid accumulation and metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD). Even subtle alterations in these processes can have profound health consequences, contributing to chronic liver diseases and atherosclerosis—the leading cause of cardiovascular morbidity and mortality worldwide. Despite their importance, many aspects of hepatic VLDL formation, secretion, and fatty acid oxidation remain poorly understood. This narrative review highlights the pivotal role of the liver in maintaining lipid balance, summarizes current knowledge on fatty acid uptake and processing, provides an in-depth analysis of VLDL biogenesis and secretion, and underscores the need for continued research in this critical area of human health.

Livers doi: 10.3390/livers6010005

Authors: Haris Imsirovic Jui-Hsia (Cleo) Hung Asnake Y. Dumicho Douglas Manuel Derek R. MacFadden Curtis L. Cooper

Introduction: The health care burden of chronic hepatitis B virus (CHB) infection can be reduced by appropriate workup, treatment, and monitoring. Methods: As a primary objective, we determined whether adequate initial hepatitis B virus (HBV) laboratory workup in CHB patients is associated with improved CHB complications risk. Secondary outcomes assessed included: mortality, hospitalization, emergency department, and liver specialist visits. We conducted a retrospective cohort study from 1 January 2012 to 31 December 2018. Participants were followed from 12 months post index event until outcome occurrence, death, loss of eligibility, or 31 March 2023. Health administrative data from Ontario, Canada was utilized. The study cohort included individuals with at least one positive result of either hepatitis B surface antigen, hepatitis B e antigen, or HBV DNA viral load documented during the study window. The exposure of interest was defined as adequate laboratory workup, defined as having subsequent quantitative HBV DNA, and alanine aminotransferase testing completed within 12 months of the index event. CHB-related complications were assessed using previously validated diagnostic codes. Modified Poisson regression modelling was used to estimate relative risks. Results: The study cohort consisted of 30,794 CHB patients, with a mean age 45.7 years. The majority were male (53.5%) and within the lowest two income quintiles (50.2%). In total, 68.0% underwent adequate workup. Individuals with adequate workup were more likely to be older, male, urban based, and of the highest racialized and newcomer populations quintile. The risk for CHB complications was 1.50 (95% CI 1.36–1.65) times greater among those with adequate workup. By multivariable analysis, adequate workup was associated with a lower risk of mortality (RR 0.78; 95% CI 0.69–0.87), all-cause hospitalizations (RR 0.77; 95% CI 0.74–0.80), all-cause (RR 0.77; 95% CI 0.75–0.78), and liver-related (RR 0.67; 95% CI 0.60–0.75) ED visits. Conclusions: Adequate CHB clinical workup is associated with improved patient outcomes. Our findings advocate for the comprehensive evaluation of CHB patients using key laboratory tests to optimize clinical management and improve long-term health outcomes. We identified gaps in the workup of young adults, females, and those residing in rural settings, which should be addressed to ensure equity of HBV care.

Livers doi: 10.3390/livers6010004

Authors: Costantino Sgamato Stefano Andrea Marchitto Debora Compare Pietro Coccoli Vincenzo Colace Stefano Minieri Carmen Ambrosio Gerardo Nardone Alba Rocco

Background/Objectives: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer and cancer-related death worldwide. Beyond the well-known factors influencing the risk of HCC, experimental data from animal models and observational human studies support a significant role of the gut microbiota (GM) in HCC initiation and progression. Dysbiosis and increased intestinal permeability synergistically disrupt the ‘gut–liver axis,’ exposing the liver to bacterial metabolites and microbial-associated molecular patterns, thereby contributing to hepatocarcinogenesis. While these findings have expanded our understanding of HCC pathogenesis, a critical translational gap persists as most data derive from preclinical settings, with limited validation in large-scale clinical studies. Methods: This narrative review aimed to contextualise the current evidence on the GM-HCC axis and its clinical translatability. A literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science up to July 2025 using Medical Subject Headings and related keywords, including HCC, GM, dysbiosis, intestinal permeability, gut–liver axis, microbial metabolites, inflammation/immune modulation, and microbiota-targeted interventions (probiotics, antibiotics, and faecal microbiota transplantation). Reference lists of relevant articles were also screened to identify additional studies. Results: Preclinical models consistently indicate that dysbiosis and impaired gut barrier function can promote hepatic inflammation, immune dysregulation, and pro-tumorigenic signalling through microbe-derived products and metabolite perturbations, supporting a contributory role of the GM in hepatocarcinogenesis. In humans, HCC and advanced chronic liver disease are associated with altered microbial composition and function, increased markers of intestinal permeability, and changes in bile acid and other metabolite profiles; however, reported signatures are heterogeneous across cohorts and analytical platforms. Conclusions: The GM is a biologically plausible and experimentally supported contributor to HCC initiation and progression, with potential for biomarker development and therapeutic targeting. However, clinical translation is limited by predominantly preclinical/associative evidence, interindividual variability, and non-standardised microbiome methods. Large longitudinal studies and adequately powered randomised trials are needed to establish causality, validate biomarkers, and determine whether GM modulation improves HCC prevention, detection, stratification, or outcomes.

Livers doi: 10.3390/livers6010003

Authors: Boris Focko Martin Jozef Péč Zuzana Miertová Jakub Jurica Andrej Miert Lucia Kubíková Peter Tudík Norbert Nagy Patrik Lecký Ivana Ságová Tomáš Bolek Daniel Ján Havaj Ľubomír Skladaný Marián Mokáň Matej Samoš

Introduction: The prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is rapidly increasing, possibly becoming the leading cause of chronic liver disease (CLD) in the coming years. Samaglutide (a long-acting glucagon-like peptide receptor agonist 1—GLP-1RA) therapy might be connected with an improved liver function. The aim of the presented study was to assess the impact of semaglutide administered at submaximal doses on biopsy-free scoring systems in patients with obesity and MASLD. Methods: We performed an observational, prospective, post-marketing study. The research included 30 patients (21 being women, mean age 47 ± 14 years) with obesity (Body mass index/BMI/39.7 ± 5.78 kg/m2) and known MASLD. All patients received semaglutide dosed initially 0.25 mg s.c. weekly, which was uptitrated (to a maximal dose of 1.5 mg) over 6 months. MASLD biopsy-free scoring systems (BFSS: SAFE, Fib-4, BARD, NAFLD Fibrosis Score, Fatty Liver Index—FLI, and Hepatic Steatosis Index—HSI) were assessed before and after 6 months of therapy. Results: In this study, a significant change (decrease) in FLI (92.4 ± 9.85 vs. 75.3 ± 21.0, p <  0.001), HSI (50.7 ± 6.78 vs. 45.0 ± 6.42, p < 0.001) and SAFE score (30.8 ± 80.7 vs. 11.2 ± 81.6, p < 0.033) was observed. The changes in the remaining BFSS (BARD, Fib-4 and NAFLD Fibrosis Score) were nonsignificant (p = 0.501; p = 0.303; p = 0.503). Conclusions: In our study, administration of sub-maximally dosed semaglutide was connected with improved FLI, HIS, and SAFE BFSS, suggesting the efficacy of submaximal semaglutide for improvement in MASLD.

Livers doi: 10.3390/livers6010002

Authors: Jonathan Abdelmalak Simone I. Strasser Natalie L. Ngu Claude Dennis Marie Sinclair Avik Majumdar Kate Collins Katherine Bateman Anouk Dev Joshua H. Abasszade Zina Valaydon Daniel Saitta Kathryn Gazelakis Susan Byers Jacinta Holmes Alexander J. Thompson Jessica Howell Dhivya Pandiaraja Steven Bollipo Suresh Sharma Merlyn Joseph Rohit Sawhney Amanda Nicoll Nicholas Batt Myo J. Tang Stephen Riordan Nicholas Hannah James Haridy Siddharth Sood Eileen Lam Elysia Greenhill Daniel Clayton-Chubb John Lubel William Kemp Ammar Majeed John Zalcberg Stuart K. Roberts

Background: Hepatocellular carcinoma (HCC) poses a significant public health challenge in Australia, with poorer survival observed in non-metropolitan populations. This study investigated whether survival disparities persist between non-metropolitan and metropolitan patients if only those with early-stage HCC treated at metropolitan tertiary referral centres are considered. Methods: We performed a retrospective cohort study across ten Australian tertiary centres involving patients with a new diagnosis of Barcelona Clinic Liver Cancer (BCLC) stage 0 or A, recorded from 1 January 2016 to 31 December 2020. Residential postcodes were entered using the Modified Monash (MM) model to define metropolitan versus non-metropolitan residence. The primary endpoint was adjusted for all-cause mortality. Results: Our study included 854 patients (metropolitan n = 612, and non-metropolitan n = 242) with a median follow-up of 42.6 months. We found no significant survival or mortality differences between the two groups with the unadjusted Kaplan–Meier survival analysis (log-rank test p = 0.612) and with the Cox proportional hazards regression analysis (adjusted HR 0.93, 95% CI 0.64–1.34, p = 0.690). As expected, tumour burden, Child–Pugh Score, and Charlson Comorbidity Index (CCI) were significant predictors of mortality. Conclusions: Our findings suggest that previously observed survival disparities may stem from delayed diagnosis and reduced access to tertiary care in non-metropolitan regions and highlight the need for improved HCC surveillance and referral pathways, particularly for rural and Indigenous communities, to mitigate geographic inequities.

Livers doi: 10.3390/livers6010001

Authors: Ralf Weiskirchen

This comment discusses a recent review by Wu and colleagues on multimodal artificial intelligence in gastroenterology and hepatology. The review outlined advancements in endoscopic, radiomics, pathologic, and multi-omics technologies. Additionally, it highlights persistent barriers, such as data heterogeneity, “black box” opacity, reimbursement uncertainty, and third-party data security risks. The comment also discusses current payment models for autonomous algorithms and emphasizes the importance of robust governance frameworks. Beyond summarizing recent progress, this commentary proposes a pragmatic, five-point roadmap to facilitate the safe and fair deployment of multimodal artificial intelligence in digestive disease care in the future, including standardization, explainability, federated governance, equitable reimbursement, and sustainability metrics. By implementing these action items, stakeholders can transform promising algorithms into clinically validated, workflow-compatible, and economically viable tools.

Livers doi: 10.3390/livers5040068

Authors: Paschalina Dafnou Ioannis Elefsiniotis Theodoula Adamakidou Nikoletta Margari Stelios Parissopoulos Lambrini Kourkouta Konstantinos Giakoumidakis Eleni Dokoutsidou

Background/Objectives: Seasonal influenza, pneumococcal disease, and COVID-19 pose major public health challenges, particularly for individuals with chronic illnesses. This study examined vaccination coverage for influenza, pneumococcal disease, and SARS-CoV-2 among patients with chronic liver disease and cirrhosis and explored the sociodemographic and clinical factors influencing it. Methods: A cross-sectional study, conducted from March 2022 to July 2023 at two university hepatology outpatient clinics in Athens, Greece. The study population consisted of patients with a diagnosis of chronic liver disease (hepatocellular carcinoma and hepatitis) and liver cirrhosis. Results: A convenience sample size of 300 patients (age ≥ 30) participated. Regarding their vaccination, 88.3% were vaccinated against SAR-COVID-19, 44.8% against pneumococcus, and 54.7% against seasonal influenza this year. Patients’ belief that annual vaccination is the best method for influenza prevention was found to be significantly higher among older patients and those with comorbidities. Additionally, patients who had been vaccinated against seasonal influenza (this year or every year), against pneumococcus, or SARS-CoV-2 agreed significantly that annual vaccination is the best method for influenza prevention. In addition, patients who were informed about vaccination by their doctor/nurse agreed significantly more with that. Multiple logistic regression found that a four times greater probability of being fully vaccinated according to the national vaccination program was found in patients who were informed about vaccination by a doctor/nurse. Moreover, as patients’ age increased, so did the probability of being fully vaccinated. Conclusions: The study’s findings are significant and can be utilized within national public health initiatives and by healthcare professionals during patient interactions, ensuring that younger patients and those apprehensive about vaccine efficacy and safety receive focused attention to facilitate adherence to annual vaccinations and all vaccines included in national programs.

Livers doi: 10.3390/livers5040067

Authors: Kaila Fennell Maya Mahmoud Kamran Qureshi

Background: Methotrexate (MTX), a widely used therapeutic agent, is associated with hepatotoxicity. While cumulative MTX dosage has historically been linked to liver injury, recent evidence highlights the potential role of metabolic syndrome (MetS) as a key contributor. Objective: We evaluate the association between MetS and MTX-associated liver injury using vibration-controlled transient elastography (VCTE) and liver biopsy in patients suspected to have MTX-related liver injury. Design: This retrospective study analyzed 59 patients with chronic MTX use who underwent VCTE in hepatology clinics between 2016 and 2024. Patients with alternative causes of liver injury were excluded. MetS was defined per standard criteria as the presence of ≥3 criteria: diabetes, hypertension, BMI ≥ 30 kg/m2, hypertriglyceridemia, or low HDL levels. Measurements: Liver stiffness measurement (LSM) and steatosis (CAP) were measured via VCTE, and liver biopsy data were reviewed for steatohepatitis. ANCOVA was used to assess the effect of MetS on liver disease while controlling for cumulative MTX dosage. Results: Of the 59 patients (mean age: 62 years; mean BMI: 34.3 kg/m2), 36 (61%) met the criteria for MetS. CAP values were significantly higher in patients with MetS (p < 0.001) independent of cumulative MTX dosage. Transformed LSM values also showed a significant association with MetS (p = 0.028). Logistic regression identified MetS as a significant predictor of biopsy-confirmed steatosis and steatohepatitis (p < 0.001) and higher NAFLD activity score (p = 0.002), whereas cumulative MTX dosage was not (p = 0.47). Conclusions: MetS is strongly associated with liver injury in chronic MTX users, independent of cumulative MTX dosage. These findings suggest metabolic factors as key mediators of MTX-induced hepatotoxicity. Prospective, multicenter studies are needed to confirm these findings and improve non-invasive monitoring strategies.

Livers doi: 10.3390/livers5040066

Authors: Avery K. Fortier Kimberly M. Feeney Matthew L. Holzner Joseph DiNorcia Ron Shapiro Leona Kim-Schluger Sander S. Florman L. Leonie van Leeuwen M. Zeeshan Akhtar

Background/Objectives: The donor liver shortage has created an urgent need to utilize higher-risk grafts for transplantation. Normothermic machine perfusion enables ex vivo graft assessment prior to transplantation, offering a route to expand access safely. However, proposed performance metrics often fail to differentiate dysfunctional grafts from functional grafts. Organs showing borderline results require careful deliberation as clinicians seek to balance recipient safety with waiting list access. The crucial question remains: are we discarding organs appropriately? Methods: To address this question, we describe a novel “secondary perfusion” model. We suggest that organs declined for transplantation after normothermic perfusion be subjected to an additional trial of cold ischemia and warm reanimation, mimicking reperfusion. Results: We present a protocol description and proof-of-concept case study using a marginal donor liver, showing how secondary perfusion enabled confirmation of predicted dysfunction. Conclusions: We share a protocol for modeling the performance of discarded organs in a recipient. We aim for this proof of concept to enable further investigation of existing viability criteria and better inform clinical decision-making.

Livers doi: 10.3390/livers5040065

Authors: Eleni Myrto Trifylli Christiana Charalambous Nikolaos Spiliotopoulos Nikolaos Papadopoulos Anastasia Oikonomou Spilios Manolakopoulos Melanie Deutsch

Androgen receptor (AR) signaling has a pivotal role in hepatic lipid homeostasis, as well as in core metabolic functions such as lipogenesis, fatty acid oxidation, and insulin sensitivity. Dysregulation of AR function has been demonstrated in both animal and human studies to disrupt these crucial metabolic pathways, thereby promoting hepatic steatosis. Several causes can lead to AR dysregulation, including genetic mutations or polymorphisms, epigenetic and post-transcriptional modifications, as well as various endocrine disturbances. Prompted by a diagnostically challenging case of a lean 34-year-old male with persistent ALT-predominant transaminasemia, unexplained suboptimal dyslipidemia despite adherence to drug therapy and a healthy lifestyle, and chronically elevated creatine phosphokinase levels irrespective of statin use or exercise intensity, we highlight the overlooked mechanistic link between AR dysfunction and liver–muscle disruption in lean-MASLD patients. Considering the pivotal role of AR in liver–muscle crosstalk, we emphasize the importance of evaluating AR signaling pathways through targeted genetic testing in cases of lean-MASLD among the male population, as well as addressing other extrahepatic manifestations, such as neuromuscular diseases, closely related to AR dysfunction. This clinical strategy may ultimately optimize lean-MASLD management, particularly in view of the emerging utilization of AR-targeted therapeutic modalities, and may also facilitate the management of systemic manifestations associated with altered AR signaling pathways.

Livers doi: 10.3390/livers5040064

Authors: Sibi Krishna Thiyagarajan Arielle Jacover Alfredo Verastegui Katherine Poruk John A. Stauffer

Background: Surgical resection (SR) and liver transplantation (LT) are the main curative options for non-hepatocellular carcinoma (non-HCC) liver malignancies, including colorectal liver metastases (CRLMs), intrahepatic cholangiocarcinoma (iCCA), hilar cholangiocarcinoma (hCCA), and neuroendocrine tumor liver metastases (NETLMs). Resection aims for negative margins and adequate hepatic reserve, while LT offers treatment for unresectable disease but is limited by donor scarcity, immunosuppression, and ethical constraints. Methods: A targeted literature search (2005–2025) was conducted using PubMed and Google Scholar with predefined MeSH terms combining “liver resection,” “hepatectomy,” and “liver transplantation” across non-HCC malignancies. Relevant studies, reviews, and guidelines were included. Results: For CRLMs, SR remains standard with 5-year overall survival (OS) up to 58%, while LT offers 60–83% in highly selected unresectable cases. In iCCA, resection achieves median survival around 40 months, and LT yields OS up to 69% in very early or neoadjuvant-controlled disease. For hCCA, the Mayo protocol combining neoadjuvant therapy with LT provides 5-year OS of 65–80%. In NETLMs, LT achieves 63–97% OS under strict criteria. Conclusions: SR remains first-line for resectable non-HCC malignancies, while LT provides superior outcomes in unresectable yet biologically favorable disease, emphasizing careful selection and organ allocation.

Livers doi: 10.3390/livers5040063

Authors: Aya A. Ezzat Salma N. Tammam Ralf Weiskirchen Sarah K. Schröder-Lange Samar Mansour

Background: Liver fibrosis is a progressive pathological condition characterized by excessive extracellular matrix deposition, driven by activated hepatic stellate cells (aHSCs). Effective therapeutic strategies require targeting aHSCs and agents capable of reversing their activated phenotype. Methods: In this study, we developed chitosan nanoparticles loaded with atorvastatin (AS) and JQ1 and functionalized them with varying densities of retinol (Rt) to exploit aHSC targeting. Results: In vitro, Rt-NPs demonstrated enhanced uptake in GRX cells, with optimal performance observed at high Rt density (HRt-NPs). In vivo biodistribution in CCl4-induced fibrotic and healthy mice revealed that LRt-NPs achieved superior hepatic accumulation in fibrotic livers compared to unmodified and HRt-NPs, underscoring the importance of optimal ligand density for targeting. Western blot analysis showed that treatment of GRX cells with Rt-AS-NPs and Rt-JQ1-NPs either individually or combined significantly reduced the expression of fibronectin, vimentin, and PDGFR-β, key markers of HSC activation, with combination therapy providing more significant effects. Conclusions: This work highlights the potential of Rt-chitosan NPs loaded with AS and JQ1 as an effective dual-drug system for targeted antifibrotic therapy, offering enhanced hepatic selectivity, improved safety, and potent aHSC deactivation.

Livers doi: 10.3390/livers5040062

Authors: Yue Liu Guoping Dong Jie Yu Ping Liang

Background: Intratumour heterogeneity (ITH) is one of the key characteristics of cancer and is closely associated with patient prognosis, treatment resistance, and tumor metastasis. Nevertheless, the study of ITH in hepatocellular carcinoma (HCC) remains limited. Methods: The present study elucidated the influence of ITH on the tumor microenvironment (TME) in HCC. We applied Non-negative Matrix Factorization (NMF) analysis to a cohort of 78 single-cell RNA sequencing (scRNA-seq) HCC samples to systematically characterize ITH. Furthermore, by integrating spatial transcriptomics (ST) data from five HCC patients, we comprehensively analyzed the spatial organization and functional properties of distinct niches within HCC. We conducted a detailed analysis of the cell-type co-localization relationships within the TME and constructed a comprehensive atlas of HCC spatial organization. Results: We observed a co-localization relationship between hypoxia tumor cells, plasmalemma vesicle-associated protein (PLVAP+) endothelial cells (EC), and vascular endothelial growth factor A (VEGFA+) cancer-associated fibroblasts (CAF), suggesting a key role for hypoxia tumor cells in VEGFA+ CAF transformation and tumor angiogenesis. We identified a unique boundary region enriched with dendritic cells1 (DC1), interferon-expressing tumor cells, lymphatic EC, C–X–C Motif Chemokine Ligand 10 (CXCL10+) macrophages (Mac), and secreted phosphoprotein 1 (SPP1+) Mac located between the tumor-infiltrating immune cells and tumor regions. Furthermore, we found that CXCL10+ Mac and SPP1+ Mac, despite co-localizing in the boundary region, exhibit distinct functions, which may be attributed to their unique spatial locations, with the former being closer to the immune-infiltrated region and the latter more proximal to the tumor area. Conclusions: Our study highlights the critical role of spatial interactions between tumor cells and the microenvironment in HCC. The findings offer new insights into ITH and underscore the importance of spatial organization in understanding cancer biology and designing future precision therapies.

Livers doi: 10.3390/livers5040061

Authors: Wei-Ting Lin Madeline Novack Suthat Liangpunsakul Chiung-Kuei Huang Hui-Yi Lin Po-Hung Chen Tung-Sung Tseng Peng-Sheng Ting

Background/Objectives: Dietary quality is a driver of metabolic dysfunction-associated steatotic liver disease (MASLD). Men and women often have different levels of adherence to medical advice, but the effect of gender on adherence to dietary advice as a function of awareness of MASLD is understudied. We aim to investigate the differences in diet quality between men and women who are aware of their diagnosis of MASLD compared to their undiagnosed counterparts. Methods: We utilized the National Health and Nutrition Examination Survey 2017–2020 to identify a nationally representative sample of subjects with MASLD, 127 of whom reported a diagnosis of MASLD (diagnosed MASLD), and 1703 of whom did not report an existing diagnosis of MASLD but met criteria of the disease based on vibration-controlled transient elastography results and cardiometabolic criteria (undiagnosed MASLD). Results: In a gender-stratified analysis of diet quality as a function of reported MASLD diagnosis, women with diagnosed MASLD were more likely than women with undiagnosed MASLD to consume less added sugar and more total and whole fruits. Women with diagnosed MASLD had a 3.06 higher healthy eating index score than undiagnosed women, after adjusting for confounders such as demographics, comorbidities, lifestyle behaviors, and metabolic risk factors. In men, total diet quality did not differ based on awareness of MASLD diagnosis. Conclusions: Women with diagnosed MASLD have superior diets compared to their undiagnosed counterparts. Gender-specific approaches to counseling and prospective studies that investigate causes of gender-driven differences in dietary behavior in the context of MASLD are needed.

Livers doi: 10.3390/livers5040060

Authors: Hartmut Jaeschke Mitchell R. McGill

Basic science is critical for understanding fundamental biological processes and disease mechanisms [...]

Livers doi: 10.3390/livers5040059

Authors: Justin Ong Vivian H. LeTran Christopher Wong Jonathan Tchan Selena Zhou Ariana Chen Kali Zhou

Background: Social determinants of health critically impact outcomes along the care continuum of patients with hepatocellular carcinoma (HCC). This systematic review summarizes the effect of socioeconomic status (SES) factors on HCC outcomes in the United States. Methods: Electronic databases were queried for the concepts of “liver cancer”, “health disparities”, and “socioeconomic factors” on 1 March 2021. Eligible studies included an individual- or area-level SES measure such as income, education, employment, and insurance and one of the following outcomes across the clinical continuum of HCC care: incidence, screening/surveillance, diagnosis, treatment, survival, and end-of-life. Results: Of 3331 studies screened, a total of 63 studies encompassing 179 separate analyses were included in our narrative synthesis: 13 on incidence, 5 on surveillance, 19 on diagnosis, 79 on treatment, 61 on survival, and 2 on end-of-life. Insurance was the most frequent SES measure represented (50%), followed by mostly area-level income (39%), education (9%), and employment (2%). The included studies were heterogeneous regarding both SES definitions (e.g., individual vs. area-level measures) and outcome reporting. Trends of worse outcomes were generally observed with lower indicators across all SES domains and HCC outcomes, particularly in analyses using national cancer registry data (e.g., SEER and NCDB). Unadjusted racial and ethnic disparities in outcome were attenuated in six out of 23 analyses that adjusted for an SES measure. Conclusions: Our findings highlight the need for social risk screening and interventions early in the HCC care pathway. Future research should focus on HCC surveillance and end-of-life/survivorship, with greater emphasis on examination of modifiable individual-level social determinants.

Livers doi: 10.3390/livers5040058

Authors: Marcello Dallio Mario Romeo Fiammetta Di Nardo Carmine Napolitano Paolo Vaia Claudio Basile Annachiara Coppola Alessia Silvestrin Giusy Senese Marco Niosi Alessandro Federico

Background/Objectives: In the present study, the Metabolic dysfunction-associated fatty liver disease (MAFLD) and Metabolic dysfunction-associated steatotic liver disease (MASLD) diagnostic criteria were applied to evaluate the relative performance in predicting short-term advanced fibrosis (AF) progression (AFpr) and hepatocellular carcinoma (HCC), as well as an ancillary outcome, i.e., the occurrence of acute cardiovascular events (ACEs) in steatotic liver disease (SLD) patients. Methods: We retrospectively analyzed the data stored in the University Hospital (UH)’s Official Health Documents Digitization Archive of 931 SLD patients, with a follow-up of 3 years. Based on the Body Mass Index (BMI), patients were subdivided into lean “L” (BMI < 25 kg/m2) (n = 134) and not-lean “NL” (n = 797), and, subsequently, into NL-MASLD (n = 206), NL-MASLD/MAFLD (n = 481), NL-MAFLD (n = 110), L-MASLD (n = 39), L-MASLD/MAFLD (n = 68), and L-MAFLD (n = 27). All study outcomes (AFpr, HCC, and ACE) were primarily evaluated in NL-SLD and by conducting a sub-analysis of L-SLD individuals. Results: MASLD and MAFLD criteria similarly estimated [p = 0.076] the overall 3-year risk of AF progression in NL-SLD. In the L-SLD sub-analysis, MAFLD criteria better estimated the overall 3-year risk of AF progression [p = 0.006]. Multivariate competing risk analysis (adjusted for sex, age, diabetes, steatosis, and fibrosis severity) revealed diabetes [adjusted Hazard Ratio (aHR) = 2.113, p = 0.001], high-sensitivity C-reactive protein (aHR = 1.441; p = 0.02), and Homeostatic Model Assessment for Insulin Resistance (aHR = 1.228; p = 0.03) as being associated with AF progression in L-MAFLD. Compared to MAFLD, MASLD diagnostic criteria similarly estimated the 3-year risk of HCC occurrence both in NL [HR = 1.104, C.I. 95%: 0.824–1.593, p = 0.741] and L [HR = 1.260, C.I. 95%: 0.768–2.104, p = 0.701] patients. Finally, no significant differences were reported between the MAFLD or MASLD criteria for ACE risk occurrence in all study groups. Conclusions: The MAFLD criteria better estimate the AF progression risk, limited to L-SLD patients.

Livers doi: 10.3390/livers5040057

Authors: Benjamin Ngoi Hardeep Kaur Annabel Lane Darshan Nitchingham Amirhossein Norozi Olga Sukocheva Kathy Pietris Joanne Morgan Joan Ericka Flores Edmund Tse

Background/Objectives: Late presentations of advanced hepatocellular carcinoma (HCC) indicate a lack of detection of underlying cirrhosis and a need to identify clinical and socioeconomic risk factors contributing to early-stage HCC recognition. This study tested associations between early diagnostics of HCC and demographic, socioeconomic, clinical, and healthcare-related indicators. Methods: A retrospective analysis of clinical data accumulated between February 2018 and February 2024 was completed at a quaternary care centre (South Australia). Results: We identified 388 cases of newly diagnosed HCC during a six-year period. There were 131 (33.7%) patients with early-stage (Barcelona clinic liver cancer (BCLC) stage 0–A) and 257 (66.3%) patients with late-stage (BCLC B–D) HCC. Late-stage HCC was found in 66.3% of patients, with half of the cohort not having a diagnosis of cirrhosis at the time of HCC detection. A retrospectively calculated Fibrosis Index (FIB-4) of >3.25 was present in nearly half of patients with newly diagnosed HCC with no prior diagnosis of cirrhosis. Engagement with healthcare (p < 0.05), a history of liver cirrhosis (p < 0.001), and gastroenterologist-led care with surveillance programmes (p < 0.001) was associated with early-stage presentation and curative treatment. Late-stage HCC was associated with male sex (p = 0.041), failing to attend appointments (p < 0.001), and liver function tests ordered by general physicians (p = 0.002) or non-gastroenterologist specialists (p = 0.023). Logistic regression analysis indicated that engaging in a surveillance programme, assessment by a gastroenterologist, and Model for End-Stage Liver Disease scores were important factors contributing to early detection of HCC; the area under the curve for this model on the ROC analysis was 0.892 (95% CI 0.855–0.929). Conclusions: Better cirrhosis detection is required, given that 60% of patients had a retrospectively calculated FIB-4 > 3.25. Routine use of non-invasive scores by all healthcare providers may increase engagement with surveillance and improve HCC screening.

Livers doi: 10.3390/livers5040056

Authors: Elena Gangitano Rebecca Rossetti Giusy Simeone Mariaignazia Curreli Orietta Gandini Stefania Mariani Carla Lubrano

Background/Objectives: Patients with isolated adult-onset growth hormone (GH) deficiency may present with hepatic steatosis and metabolic dysfunction. The effect of replacement therapy on metabolic phenotype has not been exhaustively studied yet. Methods: Patients with isolated adult-onset GH deficiency (GHD) were enrolled and prescribed GH-replacement therapy. DEXA scans for assessing body composition, anthropometric and biochemical parameters were evaluated at baseline and after 12 months of therapy. A fatty liver index, hepatic steatosis index and Fibrosis 4-test were calculated at baseline and after 12 months of therapy. Results and Conclusions: In our cohort, GH replacement therapy in adults with isolated adult-onset GHD is associated with weight loss and reduction of BMI (p < 0.001), amelioration in body composition with reduction in fat mass and trunk fat (respectively, p = 0.023 and p = 0.02), amelioration in lipid profile (significant reduction of total and LDL cholesterol and increase in HDL cholesterol) and reduction in fatty liver index (p = 0.021). Further long-term, randomized studies with bigger cohorts and advanced diagnostics are needed to confirm these results of our exploratory study.

Livers doi: 10.3390/livers5040055

Authors: Krzysztof Łupina Adrian Nowak Aleksandra Jabłońska Anna Potaczek Julia Salacha Łucja Ilkiewicz Aleksandra Kalisz Jakub Janczura

Herb-induced liver injury (HILI) is an increasingly recognized cause of liver damage, associated with the widespread global use of herbal products. Despite its rising incidence, HILI remains underrecognized and underreported due to the absence of specific biomarkers, limited regulatory oversight, and the complexity of multi-ingredient formulations. Diagnostic efforts rely heavily on the Roussel Uclaf Causality Assessment Method (RUCAM), with clinical presentations often nonspecific and dominated by hepatocellular patterns of injury. Epidemiological data demonstrate regional variation, with notably higher case numbers in Asia and the Americas. Mechanistically, HILI may result from either intrinsic (predictable, dose-dependent) or idiosyncratic (unpredictable, immune-mediated) reactions. Genetic predispositions, including certain HLA alleles, have been identified as risk factors. Hepatotoxicity is often linked to specific phytochemicals such as pyrrolizidine alkaloids, catechins, anthraquinones, and diterpenoids, which may contribute to oxidative stress, mitochondrial damage, or immune activation. Additionally, product inconsistencies and contamination complicate risk assessment and safety evaluation. Current management focuses on immediate discontinuation of the suspected product and supportive care, though severe cases may require liver transplantation. Future directions include the development of specific diagnostic tools, implementation of globally harmonized regulatory standards, improved pharmacovigilance systems, and enhanced public and professional education. Addressing these priorities is crucial for reducing HILI-related morbidity while supporting the safe use of herbal therapies.

Livers doi: 10.3390/livers5040054

Authors: Jasmin Weninger Michael Pohl Mustafa Özçürümez Oliver Götze Ali Canbay

Background/Objectives: The 13C-Methacetin Breath Test (MBT) is a non-invasive tool to evaluate hepatic microsomal function via exhaled 13CO2, reflecting cytochrome P450 1A2 (CYP1A2)-mediated metabolism. Despite decades of evidence demonstrating its utility in diagnosing cirrhosis, stratifying liver disease severity, and predicting outcomes, MBT adoption remains limited due to methodological inconsistencies and variable diagnostic thresholds. This review aimed to summarize MBT data in adults and assess its diagnostic and prognostic performance. Methods: A literature review was conducted using PubMed, Web of Science, and Scopus. Eligible studies included those applying oral or intravenous methacetin with defined reference values or diagnostic cutoffs. Outcomes of interest were percent dose recovery (PDR), cumulative PDR (cPDR), and LiMAx® values. Due to heterogeneity in protocols, units, and endpoints, results were synthesized narratively. Results: Healthy individuals typically demonstrated rapid metabolism (e.g., cPDR30 10–15%), whereas cirrhotic patients showed significantly reduced values (e.g., cPDR30 ≈ 1%). Diagnostic cutoffs varied widely (<0.35% to <8%), reflecting methodological and population differences. MBT reliably identified advanced liver disease but showed inconsistent sensitivity for early-stage fibrosis and metabolic dysfunction-associated steatotic liver disease. Variability in dosing, timing, measurement duration, and analytic technique limited cross-study comparability. Conclusions: MBT is a validated, dynamic marker of liver function with both diagnostic and prognostic relevance. However, inconsistent protocols and thresholds hinder its clinical implementation. Standardization of MBT procedures, reference ranges, and reporting metrics is essential. A harmonized protocol (“MBT-60”), supported by multicenter validation, demographic stratification, and direct comparison with structural and serologic liver tests, is recommended to facilitate MBT integration into routine hepatology practice.

Livers doi: 10.3390/livers5040053

Authors: Joshua S. Badshah Ryan M. Lee Andrea Reitsma Marc L. Melcher Olivia M. Martinez Sheri M. Krams Daniel J. Delitto Varvara A. Kirchner

Background: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis due to late-stage presentation and ineffective systemic therapies. Targeting the tumor microenvironment (TME) in ICC offers new therapeutic possibilities, particularly through tumor-associated macrophages (TAM), which can both promote and inhibit tumor progression. The current study utilized multi-omics analysis to characterize the gene signature of TAM and explore its therapeutic potential in ICC. Methods: Public GEO datasets provided the basis for analysis. Single-cell RNA sequencing (scRNA-seq) data from five ICCs, three adjacent non-tumorous tissues (ANTs), and four healthy liver samples were examined with Python. To validate scRNA-seq findings, bulk RNA-seq data from 27 ICC and 27 matched ANT samples were assessed using R. Differentially expressed genes were identified with adjusted p-values <0.01 and log2-fold changes >1 or <−1. CIBERSORT pipeline analyzed 22 immune cell subtypes in bulk RNA-seq data. STRING database analyzed the contribution of unique TAM-related genes to networks of protein–protein interactions. Results: TAM population demonstrated phenotypic heterogeneity exhibiting partial gene signatures of inflammatory (MS1) and anti-inflammatory (MS2) macrophages. Unique TAM-associated markers, TREM2, CD9, and PRMT10, showed variable expression within the TAM subpopulation. Bulk RNAseq analysis confirmed the scRNA-seq results, highlighting overexpression of TREM2 and CD9 in most ICC samples versus ANT. Immune cell deconvolution revealed decreased MS1 and MS2 macrophages in ICC, and alterations in adaptive immune profile, suggesting immunotolerant TME. STRING database defined TREM2-LGALS3 axis as a potential target for anti-tumor therapies. Conclusions: TAM represents a unique heterogenous population which is primarily found in ICC TME versus ANT or healthy liver tissue The non-uniform expression of unique gene signature demonstrates additional heterogeneity in the TAM subpopulation and suggests that TREM2+ TAM may be desirable targets for anti-TREM2-LGALS3 immunotherapy.

Livers doi: 10.3390/livers5040052

Authors: Silvia Muller de Moura Sarmento Gênifer Erminda Schreiner Laura Smolski dos Santos Camila Berny Pereira Elizandra Gomes Schmitt Vinicius Tejada Nunes Rafael Tamborena Malheiros Clóvis Klock Chaline Casanova Petry Itamar Luís Gonçalves Vanusa Manfredini

Background/Objectives: Vitamin D is recognized as a key modulator of metabolic diseases, including metabolic-dysfunction-associated steatotic liver disease (MASLD), in which its deficiency contributes to both disease onset and progression. Despite the widespread and often prolonged use of vitamin D supplementation, optimal serum levels in individuals with MASLD remain unclear and warrant further investigation. Methods: In this study, hepatic steatosis was induced in male and female Wistar rats over a 45-day period. The animals were then divided into five groups (control, 2500, 7000, 14,000, and 21,000 IU/kg/week of cholecalciferol). After four weeks of treatment, the animals were euthanized, and blood samples were collected for biochemical, hormonal, inflammatory, oxidative stress analyses and liver architecture evaluation. Results: High-dose vitamin D supplementation in rats with MASLD induced dose-dependent metabolic, inflammatory, and oxidative changes, with some sex-specific differences. Urea and alanine aminotransferase levels increased at higher doses in both sexes, suggesting potential nephrotoxic and hepatotoxic effects, while creatinine and aspartate aminotransferase remained stable. Adiponectin levels decreased consistently, and leptin levels rose across all doses, indicating a shift toward a pro-adipogenic profile. Pro-inflammatory molecules (IL-1β, IL-6, IL-8, TNF, C-reactive protein) increased progressively with dose, while IL-10 followed a U-shaped curve. Oxidative stress markers showed elevated protein carbonylation only at the highest dose, a slight reduction in TBARS, and a peak in total antioxidant status at 7000 IU/kg/week. Conclusions: High-dose vitamin D triggers antioxidant responses but drives harmful inflammatory and metabolic shifts in MASLD.

Livers doi: 10.3390/livers5040051

Authors: Ethan Shamsian Michael Bebawy Zachary Israeli Mahinaz Mohsen Rohan Karkra Steven Rella Raphael Shankman Paul Gaglio

Metabolic-associated steatotic liver disease is currently one of the most common causes of liver disease in the world, affecting a large portion of the global population; these patients are at risk of developing advanced liver fibrosis and cirrhosis. Noninvasive tests (NITs), including lab tests such as FIB-4, NAFLD Fibrosis Score and the Aspartate Aminotransferase-to-Platelet Ratio Index, are widely used for fibrosis risk stratification, but their accuracy across various racial, ethnic, and age groups remains poorly characterized. This review examines disparities in NIT performance across these populations and the need for tailored screening strategies. A comprehensive, narrative literature review highlighted significant variability in NIT performance, with studies in African American, Hispanic and Asian patients all revealing mixed results when the performance of NITs was used to assess fibrosis levels. Additionally, the age of patients may influence fibrosis testing, as older adults tend to have higher false-positive rates due to age-based biases. Although imaging modalities like VCTE and MRE may offer superior accuracy in the noninvasive assessment of hepatic fibrosis, they face accessibility limitations and have rarely been validated in specific racial groups. This review concludes that current NITs for MASLD risk stratification needs to be recalibrated with population-specific and age-adjusted thresholds, and future research should focus on inclusive validation studies and integrating clinical judgment to improve screening accuracy.

Livers doi: 10.3390/livers5040050

Authors: Kevin Verhoeff Sukhdeep Jatana Ahmer Irfan Gonzalo Sapisochin

Background: The National Surgical Quality Improvement Program (NSQIP) database provides one of the largest repositories of surgical outcome data—guiding local, national, and international quality improvement and research. We aim to describe a model to estimate Clavien–Dindo complication (CDC) rates from NSQIP data to enable comprehensive outcome measurement, allowing an NSQIP-based surrogate measure for longer-term outcomes. Methods: This is a validation study of a model to estimate CDCs from NSQIP data for pancreaticoduodenectomy (PD) and hepatic resection (HR). The primary objective of this study is to evaluate whether our method to estimate CDCs ≥ 3 outcomes from NSQIP data results in similar serious complication rates to large benchmark studies on outcomes following PD and HR. Secondary outcomes evaluate whether specific NSQIP outcomes provide adequate information to estimate CDC grades I-V following PD and HR. Results: We evaluated 20,575 patients undergoing PD, with 71.3% having pancreatic ductal adenocarcinoma. Comparing CDCs ≥ 3 complications for NSQIP and benchmark PD patients, we estimated a 23.2% rate with our model, which was significantly lower than the reported 27.6% in the benchmark study (p < 0.001). Additionally, the benchmark reported higher complication rates for every CDC grade compared to our estimates using NSQIP PD patients (p < 0.001). Further, we evaluated 29,809 patients within NSQIP undergoing HR, where most patients with a diagnosis listed had colorectal cancer metastases (30.8%). Compared to the benchmark HR study (n = 2159), the NSQIP patients were less likely to have hepatic resection for malignancy (57.7% vs. 84.0%; p < 0.001). Comparing CDCs ≥ 3 complications following HR demonstrated that rates were clinically similar (13.0% vs. 15.8%) but statistically different between the benchmark study and NSQIP data (p < 0.001). Additionally, the NSQIP patients had lower rates of estimated complications for nearly all CDC grades (p < 0.001). Conclusions: This is the first reported method to estimate aggregate morbidity from NSQIP data. Results demonstrate that despite differences in this and comparator cohorts, this model may underestimate CDC grade 1–2 complications but provide similar rates of CDCs ≥ 3 complications compared to benchmark studies. Future studies to validate or modify this estimation method are warranted and may allow extrapolation of short-term NSQIP measures to oncologic, quality of life, and long-term outcomes.

Livers doi: 10.3390/livers5040049

Authors: Manuel Moreno-Ceballos Fabian M. Cortes-Mancera Han Moshage Johanna C. Arroyave-Ospina

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is associated with poor clinical prognosis and high mortality, despite the advances related to therapeutic options for HCC. Therefore, exploring alternative therapeutic options and their associated mechanisms is relevant and urgently needed. Natural products may be an important source of novel anti-cancer compounds. Coffee consumption is associated with protective effects against liver diseases, but the molecular mechanisms underlying these benefits remain poorly understood. Objectives: In this study, we evaluated the in vitro effects of green (GC) and roasted coffee (RC) extracts, alongside chlorogenic acid (CGA), on the proliferation of HepG2 hepatocellular carcinoma cells. Results: Both coffee extracts and CGAs significantly reduced HepG2 cell viability and cell proliferation in a dose-dependent manner. GC at 500 µg/mL and CGA at 400 and 800 µM significantly induced caspase-3 activity. In addition, HepG2 cells treated with coffee extracts (500 and 1000 µg/mL) resulted in dose-dependent membrane permeabilization, leading to an increased number of necrotic cells. Despite these anti-proliferative effects, TOP/FOP luciferase assays revealed minimal activation of the Wnt/β-catenin signaling pathway. Among canonical Wnt target genes, only c-Myc expression was notably downregulated after treatment. Moreover, β-catenin protein levels and subcellular localization remained largely unchanged. Conclusions: These findings suggest that coffee extracts and chlorogenic acids inhibit HepG2 cell proliferation, highlighting their hepatoprotective properties, even in cells containing mutations that constitutively activate Wnt signaling.

Livers doi: 10.3390/livers5040048

Authors: Menelaos Papakonstantinou Areti Danai Gkaitatzi Paraskevi Chatzikomnitsa Vasileios Papagiannis Vasileios N. Papadopoulos Alexandros Giakoustidis Dimitrios Giakoustidis

Background: Liver cancer, either primary or metastatic, is a leading cause of cancer-related deaths and in many cases is presented in stages requiring major hepatectomy. Adequate future liver remnant (FLR) volume is essential before any major hepatectomy. Portal vein embolization (PVE) has long been the standard technique for preoperative liver hypertrophy, but liver venous deprivation (LVD) has emerged as a novel method, potentially offering faster and superior results. The aim of this study is to compare FLR hypertrophy outcomes between LVD and PVE in patients undergoing major hepatectomy for liver malignancy. Methods: A systematic literature search was conducted across PubMed, Cochrane library, and clinicaltrials.gov for studies assessing FLR volume changes after LVD or PVE in patients with primary or secondary liver tumors undergoing liver resection. Data extraction was performed independently by two reviewers. The study protocol was registered in PROSPERO and was prepared according to the PRISMA guidelines. Results: Twelve retrospective cohort studies were included in this systematic review. Liver venous deprivation consistently demonstrated superior FLR hypertrophy, with a faster and higher percentage increase compared to PVE. Time to resection was also shorter in the LVD groups in most studies. Safety outcomes were comparable, with no consistent difference in post-procedural complications or mortality. Conclusions: Liver venous deprivation may potentially be a safe and effective alternative to PVE, offering more robust and rapid FLR hypertrophy with similar morbidity and mortality rates. While current evidence supports its superiority in selected patients, future validation with larger prospective clinical trials is essential before it can be adopted as standard management of patients with insufficient FLR volume.

Livers doi: 10.3390/livers5030047

Authors: Ralf Weiskirchen Tilman Sauerbruch

Liver fibrosis is a significant challenge in hepatology, as it represents the common pathway of chronic liver injury due to various causes such as viral hepatitis, metabolic dysfunction-associated steatotic liver disease (MASLD), intoxication, alcohol-related liver disease, autoimmune conditions, and genetic disorders [...]

Livers doi: 10.3390/livers5030046

Authors: Mario Romeo Carmine Napolitano Paolo Vaia Fiammetta Di Nardo Silvio Borrelli Carlo Garofalo Luca De Nicola Alessandro Federico Marcello Dallio

Ascites and renal dysfunction are among the most frequent and severe complications of decompensated advanced chronic liver disease (dACLD), often representing two interrelated manifestations of a shared pathophysiological continuum. Recurrent ascites and refractory ascites pose significant therapeutic challenges and are frequently associated with kidney impairment, particularly hepatorenal syndrome. Recent advances have reshaped the understanding of the underlying mechanisms, moving beyond the classical paradigm of peripheral arterial vasodilation to encompass systemic inflammation, gut dysbiosis, and cirrhosis-associated immune dysfunction (CAID). These insights have prompted a shift from uniform treatment protocols toward personalized, multidisciplinary strategies. Therapeutic innovations such as long-term albumin infusion, a transjugular intrahepatic portosystemic shunt, and the Alfapump® system offer promising options, though each requires careful patient selection. Emerging approaches—including fecal microbiota transplantation and peritoneal dialysis—further expand the therapeutic landscape. Ultimately, early risk stratification, the integration of non-invasive tools, and individualized care models are essential to improving outcomes in this high-risk population. This review synthesizes current evidence and highlights future directions for the tailored management of dACLD patients with ascites and renal dysfunction.

Livers doi: 10.3390/livers5030045

Authors: Jessica Y. Idowu Caylie McKimens Bruno Hagenbuch

Background: We have previously demonstrated that the function and expression of the Na+/taurocholate cotransporting polypeptide (NTCP) and the organic cation transporter 1 (OCT1) are affected by increasing free or unesterified cholesterol in the plasma membrane by an acute incubation with cholesterol for 30 min. In the current study we wanted to extend these findings to a more chronic condition to mimic what would be seen in obese patients. Methods: We incubated HEK293 cells that stably express NTCP or OCT1 for 24 h with 0.05 mM cholesterol and determined their function by measuring uptake of radioactive taurocholate or MPP+. Expression at the plasma membrane was quantified with a biotinylation assay combined with Western blots. Results: Incubation with cholesterol increased the cholesterol content of the cells by about 2-fold. Transport mediated by NTCP and OCT1 was decreased. Membrane expression for both transporters showed a slight decrease, and when kinetics were normalized for the membrane expression, the Vmax for NTCP-mediated taurocholate uptake slightly decreased, but the Vmax and the capacity (Vmax/Km) for OCT1-mediated MPP+ uptake increased by 2.5-fold and 3-fold, respectively. Acyl-Coenzyme A acyltransferase inhibitors enhanced the decrease in transport function, potentially due to retention of more free cholesterol in the plasma membrane. Conclusions: Chronic increases in free cholesterol in the plasma membrane can result in increased or decreased transporter function and expression. In the case of OCT1, which is involved in the uptake of the anti-diabetic drug metformin into hepatocytes, the 3-fold increase in transport capacity might affect drug therapy.

Livers doi: 10.3390/livers5030044

Authors: Zain Tariq Affan Faisal Sreevani Maheswaran Narendra R. Battula Paulo N. Martins Maheswaran Pitchaimuthu

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with liver metastases (CRLM) representing a common and often incurable manifestation. While surgical resection combined with chemotherapy remains the standard for resectable disease, a significant subset of patients presents with unresectable CRLM. Recent advances have positioned liver transplantation (LT) as a promising therapeutic option for select patients with unresectable CRLM. This review synthesizes current evidence from landmark studies—including the SECA and TRANSMET trials—and emerging data from North American cohorts, highlighting the evolution of patient selection criteria, prognostic indicators such as the Oslo score and metabolic tumor volume, and the role of living-donor and extended-criteria grafts. Outcomes from recent studies demonstrate that LT can achieve 5-year overall survival rates exceeding 70% in well-selected patients, rivaling those of traditional transplant indications. Ongoing trials such as SECA-III and SOULMATE aim to refine indications and address organ allocation challenges. Collectively, these findings suggest that LT can offer long-term survival benefits comparable to traditional transplant indications, marking a paradigm shift in the management of metastatic CRC.

Livers doi: 10.3390/livers5030043

Authors: Annachiara Crocetta Maria-Anna Giannelou Agata Benfante Lorys Castelli Lemonica Koumbi

Irritable Bowel Syndrome (IBS) and Metabolic dysfunction-associated fatty liver disease (MAFLD) have traditionally been viewed as disorders of distinct organ systems. IBS is a gut–brain axis disorder characterized by abdominal pain, altered bowel habits, and psychological comorbidities. MAFLD, recently redefined to emphasize its metabolic underpinnings, is the hepatic manifestation of systemic metabolic dysfunction. Growing evidence suggests that these conditions share overlapping pathophysiological mechanisms linked through disruption of the gut–liver–brain axis (GLBA), including psychological stress, gut dysbiosis, impaired intestinal permeability, systemic inflammation, and altered neuroendocrine signaling. Neuroimaging studies further reveal functional alterations in brain regions responsible for interoception, emotional regulation, and stress responsiveness in both disorders. This narrative review explores how psychological distress influences the onset and progression of IBS and MAFLD via GLBA dysfunction and stress-induced epigenetic reprogramming. A targeted literature search of major biomedical databases, supplemented by manual screening, identified relevant observational, clinical, neuroimaging, and molecular studies. Findings indicate that chronic psychological distress activates the hypothalamic–pituitary–adrenal (HPA) axis, elevates cortisol, disrupts gut microbiota, and reduces vagal tone; amplifying intestinal permeability and microbial translocation. These changes promote hepatic inflammation and gastrointestinal symptoms. Stress-related epigenetic modifications further impair GLBA communication, while psychological and lifestyle interventions may reverse some of these molecular imprints. Recognizing the shared neuromodulation and epigenetic mechanisms that link IBS and MAFLD opens promising avenues for integrated therapeutic strategies targeting the GLBA to improve outcomes across both conditions.

Livers doi: 10.3390/livers5030042

Authors: Esmeralda Celia Marginean

Herbal and dietary supplements (HDS) are used by over half of American adults and represent a multi-billion-dollar industry. More recently, they have gained popularity, in part due to promotion on multiple social media platforms. However, the Food and Drug Administration (FDA) does not regulate these products rigorously, and up to 20% of acute liver injuries are attributed to HDS. The true incidence of HDS hepatotoxicity is unknown but thought to be underreported. According to the World Health Organization (WHO), HDS-induced liver injuries are now the fifth most common cause of liver disease–associated death. The most common type of supplements associated with liver injury are bodybuilding and weight loss supplements. This study represents a comprehensive literature review of HDS-induced liver injury with a focus on the two most common culprits: bodybuilding supplements and weight loss supplements. Future strategies recommended to mitigate hepatotoxicity include strengthening regulatory oversight through mandatory product listing, enhancing post-market surveillance with standardized reporting and registries, improving product quality via ingredient verification and contaminant testing and, possibly, implementing standardized risk labeling.

Livers doi: 10.3390/livers5030041

Authors: Isabella D. Cooper Lucy Petagine Adrian Soto-Mota Tomás Duraj Andrew Scarborough Nicolas G. Norwitz Thomas N. Seyfried Maricel A. Furoni Yvoni Kyriakidou

Background: As the growing global population continues to age, the risk of chronic metabolic diseases, including cardiovascular disease, neurodegenerative disorders, type 2 diabetes mellitus, and fatty liver disease, increases considerably. Driven largely by lifestyle factors and metabolic dysfunction, this escalating health crisis is placing mounting pressure on healthcare systems and contributing to significant economic costs. Insulin resistance and hyperinsulinaemia are major drivers of these disorders, emphasising the need for early detection and intervention. Changes in liver enzymes, such as alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), commonly assessed in routine laboratory testing, can serve as biomarkers of early-stage insulin resistance, offering a potentially underutilised window for intervention and disease prevention. Correspondingly, low-carbohydrate ketogenic diets have shown to be effective in reversing insulin resistance, metabolic disease, and liver disease. Objectives: We chose to explore the relationship between suppressing ketosis and changes in liver enzymes in the Ketosis Suppression and Ageing cohort. Methods: Ten lean (BMI 20.5 kg/m2 ± 1.4), healthy young women (age 32.3 ± 8.9 years) who habitually followed a ketogenic diet maintaining nutritional ketosis (NK) for an average of 3.9 years (±2.3) were exposed to a higher carbohydrate diet, in line with standard healthy eating guidelines for a 21-day phase and then transitioned back to a ketogenic diet. Results: Carbohydrate challenge and suppression of ketosis increased insulin resistance score HOMA-IR by 2.13-fold (p = 0.0008), GKI by 22.28-fold (p = 0.0024), and liver markers ALT by 1.85-fold (p = 0.0010), GGT, 1.29-fold (p = 0.0087) and the ALT/AST, 1.30-fold (p = 0.0266), reflecting an adverse pattern suggestive of hepatic insulin resistance. Conclusions: These results support the clinical utility of liver markers as early and directional signs of hyperinsulinaemia.

Livers doi: 10.3390/livers5030040

Authors: Mihnea Horia Strain Maike Koch Basem Salayma Lkhagvadorj Byambaa Sven Wylenga Sven Müller Christopher D. Intemann Johannes König

Background: Perihilar cholangiocarcinoma (pCCA), especially the periductal-infiltrating subtype, is notoriously difficult to diagnose due to subtle imaging findings and the absence of a mass. Case Presentation: We describe a 56-year-old man with morbid obesity and deep vein thrombosis (DVT), admitted for severe cholestatic jaundice. Initial ultrasound and two ERCPs were inconclusive, with only mild hilar duct dilation on CT. MRI was not possible due to the severe weight of the patient. Only at the 3rd ERCP with digital cholangioscopy were irregular mucosa and tumor infiltration observed, and a biopsy confirmed moderately to poorly differentiated adenocarcinoma. The patient deteriorated rapidly after discharge, returning in septic shock. Despite laparoscopy excluding cholecystitis and cirrhosis, he died from multiorgan failure. Autopsy revealed diffuse hilar tumor infiltration, nodal metastases, and fatal pulmonary tumor embolism (Bismuth IV). Conclusions: This case highlights the necessity of early escalation to cholangioscopy in unresolved cholestasis, the importance of recognizing paraneoplastic thrombosis, and the value of autopsy in clarifying cause of death.

Livers doi: 10.3390/livers5030039

Authors: Luisa Sousa Sofia Marques Silva Francisca Rego Rui Nunes Hugo M. Oliveira

Chronic liver disease is a significant global cause of morbidity and mortality. While early-stage liver cirrhosis is often asymptomatic, it can progress to a decompensated phase known as end-stage liver disease (ESLD), resulting in a high symptom burden, diminished quality of life, and frequent hospitalizations. Palliative care is a form of specialized care aimed at addressing the needs of patients; however, it remains underutilized in ESLD patients. Globally, the integration of palliative care into ESLD is impeded by several barriers. Certain factors—such as advanced age, the presence of hepatocellular carcinoma (HCC), and transplant listing status—have been associated with higher rates of palliative care referral. This review provides a comprehensive analysis of the current literature, emphasizing the benefits of palliative care interventions in ESLD, including improved symptom control and enhanced quality of life. It also underscores the impact on caregivers and healthcare systems, notably in reducing hospital readmissions. We advocate for a paradigm shift toward proactive, patient-centered models that integrate symptom management, advance care planning, and psychosocial support alongside disease-specific treatments for patients with ESLD.

Livers doi: 10.3390/livers5030038

Authors: Said A. Al-Busafi Thuwiba A. Al Baluki Ahmed Alwassief

Background: Alcoholic liver disease (ALD) contributes substantially to global liver-related morbidity and mortality. In conservative societies such as Oman, data on ALD are scarce due to stigma and legal constraints. This study aims to characterize the clinical spectrum, complications, and outcomes of ALD in Oman, providing the first detailed analysis from a tertiary care setting in the country. Methods: We retrospectively analyzed 131 Omani patients with documented unhealthy alcohol use from 2012 to 2018 at Sultan Qaboos University Hospital. ALD diagnosis was based on clinician judgment per EASL guidelines and DSM-5 criteria, where applicable. Data included demographics, clinical/laboratory findings, and radiologic/endoscopic features. Associations with complications and mortality were assessed using chi-square tests and logistic regression. Results: Of 131 patients, 84 (64.1%) were diagnosed with ALD: fatty liver (34.5%), alcoholic hepatitis (20.2%), cirrhosis (40.5%), and hepatocellular carcinoma (4.8%). Cirrhosis was significantly more prevalent in patients aged 50 years or older (OR = 2.53, 95% CI: 1.02–6.28; p = 0.048). Ascites and portal hypertension were strongly associated with mortality (OR = 5.20, CI: 1.85–14.6 and OR = 6.13, CI: 2.04–18.4, respectively; p < 0.01). Overall mortality in ALD was 28.6%, increasing to 44.1% in cirrhotics. Conclusion: ALD is a significant yet underrecognized problem in Oman, with high rates of late-stage presentation and mortality. Early detection and culturally tailored strategies are needed to improve care outcomes.

Livers doi: 10.3390/livers5030037

Authors: Rita Kamoua Rebecca Reese Risha Annamraju Tian Chen Colleen Doyle Adriana Parella Amelia Liu Yazan Abboud Craig Rohan Jeffrey B. Travers

Liver cirrhosis, a progressive and often irreversible condition, exerts widespread systemic effects, with the skin frequently serving as a visible window into the extent of hepatic dysfunction. Cutaneous manifestations, such as spider angiomas, palmar erythema, jaundice, and pruritus, not only reflect underlying pathophysiologic changes but also serve as important, non-invasive diagnostic and prognostic markers of disease severity. Early detection of such cutaneous findings may allow for early treatment, optimize patient management, and improve outcomes. This review addresses the various cutaneous manifestations of liver cirrhosis, their pathogenesis, and their prognostic and diagnostic importance, emphasizing the need for heightened clinical awareness of the improvement in patient care.

Livers doi: 10.3390/livers5030036

Authors: Irina Ivanova Sonya Banova-Chakyrova Pavlina Boykova-Vylcheva Yana Bocheva

Background: Early diagnosis of hepatocellular carcinoma (HCC) and monitoring of therapeutic results remain clinical challenges. Methods: In a prospective study, we evaluated the diagnostic capabilities of the serum level of glypican-3 in 70 patients with chronic advanced compensated liver disease: 40 cases with confirmed HCC and 30 cases with chronic viral hepatitis with bridging fibrosis or cirrhosis as a control group. The glypican-3 concentration was analyzed in the context of the disease characteristics. Results: The mean level of glypican-3 in HCC patients was 50.84 ± 75.98 ng/mL, significantly higher compared to the control group of 5.69 ± 10.43 ng/mL. A progressive increase in alpha-fetoprotein in accordance with the stage of neoplastic disease was observed, but this tendency was not assessed for glypican-3. Two cut-off levels can be suggested for glypican-3: 2.5 ng/mL to exclude HCC with an optimal sensitivity of 85%, and 33.7 ng/mL for confirmation of HCC, with a specificity of 96.7%. The diagnostic accuracy of serum glypican-3 was 80.0% for HCC, 82.1% for alpha-fetoprotein, and 87.4% for both tumor markers. Conclusions: This pilot study suggests a complementary role of glypican-3 with alpha-fetoprotein and better diagnostic performance when combining tumor biomarkers.

Livers doi: 10.3390/livers5030035

Authors: Giuliano Pasquale Ramadori

After the first release of synthalin B (dodecamethylenbiguanide) in 1928 and its later retraction in the 1940s in Germany, the retraction of phenformin (N-Phenethylbiguanide) and of Buformin in the USA (but not outside) because of the lethal complication of acidosis seemed to have put an end to the era of the biguanides as oral antidiabetics. The strongly hygroscopic metformin (1-1-dimethylbiguanide), first synthesized 1922 and resuscitated as an oral antidiabetic (type 2 of the elderly) compound first released in 1959 in France and in other European countries, was used in the first large multicenter prospective long-term trial in England in the UKPDS (1977–1997). It was then released in the USA after a short-term prospective trial in healthy overweight “young” type 2 diabetics (mean age 53 years) in 1995 for oral treatment of type 2 diabetes. It was, however, prescribed to mostly multimorbid older patients (above 60–65 years of age). Metformin is now the most used oral drug for type 2 diabetes worldwide. While intravenous administration of biguanides does not have any glucose-lowering effect, their oral administration leads to enormous increase in their intestinal concentration (up to 300-fold compared to that measured in the blood), to reduced absorption of glucose from the diet, to increased excretion of glucose through the stool, and to decrease in insulin serum level through increased hepatic uptake and decreased production. Intravenously injected F18-labeled glucose in metformin-treated type 2 diabetics accumulates in the small and even more in the large intestine. The densitometry picture observed in metformin-treated overweight diabetics is like that observed in patients after bowel-cleansing or chronically taking different types of laxatives, where the accumulated radioactivity can even reach values observed in colon cancer. The glucose-lowering mechanism of action of metformin is therefore not only due to inhibition of glucose uptake in the small intestine but also to “attraction” of glucose from the hepatocyte into the intestine, possibly through the insulin-mediated uptake in the hepatocyte and its secretion into the bile. Furthermore, these compounds have also a diuretic effect (loss of sodium and water in the urine) Acute gastrointestinal side effects accompanied by fluid loss often lead to the drugs’ dose reduction and strongly limit adherence to therapy. Main long-term consequences are “chronic” dehydration, deficiency of vitamin B12 and of iron, and, as observed for all the biguanides, to “chronic” increase in fasting and postprandial lactate plasma level as a laboratory marker of a clinical condition characterized by hypotension, oliguria, adynamia, and evident lactic acidosis. Metformin is not different from the other biguanides: synthalin B, buformin, and phenformin. The mechanism of action of the biguanides as antihyperglycemic substances and their side effects are comparable if not even stronger (abdominal pain, nausea, vomiting, diarrhea, fluid loss) to those of laxatives.

Livers doi: 10.3390/livers5030034

Authors: Sacha El Khoury Sami N. Al Harake Tya Youssef Carl E. Risk Naim G. Helou Natalie M. Doumet Karl Aramouni Sami Azar Sonia M. Najjar Hilda E. Ghadieh

Metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis are cardiometabolic twin disorders with shared underlying pathophysiological mechanisms such as insulin resistance and chronic inflammation. This review explores the salient role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in linking hepatic dysfunction to cardiovascular disease. Findings in mice with genetic modulation of Ceacam1 gene established a critical role for CEACAM1 protein in regulating insulin and lipid metabolism and endothelial integrity and modulating immune response. Loss of CEACAM1 in hepatocytes impairs insulin clearance, causing chronic hyperinsulinemia, a process that ultimately leads to insulin resistance and hepatic and extra-hepatic fat accumulation, which in turn causes inflammatory infiltration. This prompts a paradigm shift that positions impaired hepatic CEACAM1 function as a mechanistic underpinning of the link between insulin resistance, MASH, and atherosclerosis.

Livers doi: 10.3390/livers5030033

Authors: Natalie Eppler Elizabeth Jones Forkan Ahamed Yuxia Zhang

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease worldwide, affecting approximately 25–30% of the global adult population and highlighting the urgent need for effective therapeutics and prevention strategies. MASLD is characterized by excessive hepatic lipid accumulation and can progress, in a subset of patients, to metabolic dysfunction-associated steatohepatitis (MASH), a pro-inflammatory and pro-fibrotic condition associated with increased risk of liver cirrhosis and hepatocellular carcinoma. Although the molecular drivers of MASLD progression remain incompletely understood, several key metabolic pathways—such as triglyceride handling, cholesterol catabolism, bile acid metabolism, mitochondrial function, and autophagy—are consistently dysregulated in MASLD livers. This narrative review summarizes primary literature and highlights insights from recent reviews on the multifaceted role of the mRNA-binding protein Human antigen R (HuR) in the post-transcriptional regulation of critical cellular processes, including nutrient metabolism, cell survival, and stress responses. Emerging evidence underscores HuR’s essential role in maintaining liver homeostasis, particularly under metabolic stress conditions characteristic of MASLD, with hepatocyte-specific HuR depletion associated with exacerbated disease severity. Moreover, comorbid conditions such as obesity, type 2 diabetes mellitus, and cardiovascular disease not only exacerbate MASLD progression but also involve HuR dysregulation in extrahepatic tissues, further contributing to liver dysfunction. A deeper understanding of HuR-regulated post-transcriptional networks across metabolic organs may enable the development of targeted therapies aimed at halting or reversing MASLD progression.

Livers doi: 10.3390/livers5030032

Authors: Silvio Caringi Antonella Girardi Francesca Ratti Paolo Magistri Andrea Belli Giuseppe Memeo Tommaso Maria Manzia Francesco Izzo Nicola De’Angelis Fabrizio Di Benedetto Luca Aldrighetti Riccardo Memeo

Background: Breast cancer is a widespread disease and, when metastatic, has a bleak prognosis. The surgical approach for BCLM has had a limited role, but robotic surgery could find an important place. Methods: Data were collected from a multicenter retrospective database that includes 1070 consecutive robotic liver resections performed in nine European hospital centers from 2011 to 2023. Of the entire series, 35 were performed for BCLM in five European hospital centers. Results: The post-operative complication rate was 11.44%, but no severe complications occurred. The mean hospital stay was 4.65 days. One patient (2.85%) was readmitted to the hospital within 90 days after discharge and died due to heart failure, with a 90-day mortality of 2.85%. Conclusions: Robotic liver resection for BCLM is feasible and safe when performed in experienced centers by surgeons who have completed the learning curve.

Livers doi: 10.3390/livers5030031

Authors: Anastasia Ntikoudi Anastasia Papachristou Alketa Spirou Eleni Evangelou Athanasios Tsartsalis Eugenia Vlachou George Mastorakos

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver condition. Its prevalence is estimated to further increase. The gut–liver axis, which represents both anatomical and functional connections, contributes significantly to the development of MASLD. Dysbiosis, characterized by an imbalance in gut microbiota, can exacerbate the disease by increasing intestinal permeability, which permits harmful bacteria and their components to enter the bloodstream. This review sought to explore the impact of probiotics, prebiotics, and synbiotics on the treatment of MASLD. Method: The methodology for scoping reviews in accordance with Prisma-ScR guidelines was followed. A comprehensive search was conducted in databases such as PubMed, Scopus, and Medline. Out of 1390 studies screened, 25 were selected for the final analysis. Results: The findings of this scoping review highlight the therapeutic potential of probiotics, prebiotics, and synbiotics in the management and treatment of MASLD, as showcased by the existing literature. Conclusions: This scoping review offers important insights into the advantages of probiotics, prebiotics, and synbiotics in the treatment of MASLD. The limitations identified in this study emphasize the necessity for larger, long-term, and geographically diverse studies in order to obtain more solid scientific results.

Livers doi: 10.3390/livers5030030

Authors: Cristina Stasi Tommaso Marzotti Filippo Nassi Giovanna Giugliano Sabrina Pacini Silvia Rentini Riccardo Accioli Raffaele Macchiarelli Luigi Gennari Pietro Enea Lazzerini Stefano Brillanti

Background. To meet the WHO’s viral hepatitis elimination goal by 2030, the Minister of Health (Italy) introduced free HCV screening among people born between 1969 and 1989 and those at greater risk (people in the care of the addiction services and detained). Aims. To estimate the following: (i) the prevalence of HCV in hospitalized patients born before 1969 not included in the free HCV screening, (ii) the prevalence of transaminase values outside the range, and (iii) the HBV prevalence in a subgroup of patients. Methods. Anti-HCV antibodies and transaminase values were prospectively evaluated in patients born before 1969 and admitted to the Santa Maria alle Scotte Hospital in Siena. The first screening (October 2021–July 2022) was conducted in the Internal Medicine Division (cohort 0), and the second one (May 2024–October 2024) in Internal Medicine, Gastroenterology, and Geriatric Units (cohorts 1–3), including clinical features and HBV markers in a subgroup of patients. Results. Overall, 774 subjects underwent HCV screening. In the first screening period, 1.4% (8/567) of patients were anti-HCV+, of whom 0.7% were HCV RNA+ (4/567). In the second, 3.9% of patients (8/207) were anti-HCV+ and 0.9% were viremic (2/207). Overall, HCV prevalence was 0.8%. Of 96 patients in the gastroenterology cohort, 8 patients were at risk for occult HBV infection (8.3%). Conclusions. Our study demonstrates a chronic HCV infection prevalence of 0.8% in hospitalised patients born before 1969 and a prevalence of 8.3% of people at risk for occult HBV infection in a subgroup of patients residing in South-Eastern Tuscany, confirming that an opportunistic screening can identify the unrecognized people affected by viral hepatitis.

Livers doi: 10.3390/livers5030029

Authors: Romeo G. Mihăilă Samuel B. Todor Marius D. Mihăilă

Hepatosplenomegaly can occur in extrahepatic diseases such as Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), which may involve the liver and vasculature. In myelofibrosis, extramedullary hematopoiesis can be present in the liver, even within hepatic sinusoids. Liver biopsies in MPN patients have shown platelet aggregates obstructing these sinusoids. Both liver and spleen stiffness are significantly higher in myelofibrosis, correlating with the severity of bone marrow fibrosis. Spleen stiffness is also elevated in myelofibrosis and polycythemia Vera compared to essential thrombocythemia. MPNs are a leading cause of splanchnic vein thrombosis in the absence of cirrhosis or local malignancy, especially in the presence of the JAK2V617F mutation. This mutation promotes thrombosis through endothelial dysfunction and inflammation. It is found in endothelial cells, where it enhances leukocyte adhesion and upregulates thrombogenic and inflammatory genes. Hepatic sinusoidal microthromboses in MPNs may contribute to portal hypertension and liver dysfunction. MPN therapies can also affect liver function. While hepatocytolysis has been reported, agents such as Hydroxycarbamide and Ruxolitinib exhibit antifibrotic hepatic effects in experimental models. Overall, MPNs are linked to chronic inflammation, increased thrombotic risk—particularly splanchnic thrombosis—and atherogenesis.

Livers doi: 10.3390/livers5030028

Authors: Andrew Battle Julie Mudd Golo Ahlenstiel Eric Kalo

Liver cirrhosis poses major challenges for both individual health and global healthcare systems. Recent studies have challenged the traditional and predictable linear course of cirrhosis, demonstrating marked heterogeneity in the patterns of the first decompensating events. This review presents an updated epidemiology of cirrhosis and its main causes, outlines an overview of the clinical features, and explores the evolving concepts of the spectrum of decompensation. It further delineates recent advancements in the diagnosis, prognostic scoring, and management of decompensated cirrhosis and the subsequent clinically challenging complications of portal hypertension. Emerging innovations in non-invasive imaging, diagnostic serum biomarkers, and etiology-specific therapies, together with the development of novel liver support systems, underscore a paradigm shift toward a multimodal approach for cirrhosis care. Furthermore, the integration of precision medicine into clinical practice holds promise for reshaping the future of liver cirrhosis management in the coming decades.

Livers doi: 10.3390/livers5020027

Authors: Ananda Baral

Albumin is the most abundant protein synthesized exclusively by the hepatocytes in the liver. Once secreted into plasma, it helps in the maintenance of osmotic pressure, as well as the exertion of defensive roles such as anti-oxidative and anti-inflammatory functions. Dysregulation in the synthesis and clearance of albumin is observed in various hepatic and extra-hepatic diseases. Abnormal levels of albumin could be either a cause or an effect of various pathological ailments, including hepatic, cardiac, renal, neurological, etc. Owing to its long half-life and multiple binding sites in its heart-shaped structure, it interacts with various internal agents, such as hormones, or external substances like drugs, which is why transportation can be one of its many functions. Additionally, albumin’s drug interactions, as well as displacement of albumin–drug binding, could have serious clinical consequences, and careful considerations should be made in determining an appropriate drug regimen to achieve a desired therapeutic outcome with minimal side effects. Moreover, albumin also undergoes several post-translational modifications that can influence its physiological roles, including drug binding and antioxidant functions. Furthermore, it has a complicated role in physiology, where it can help in maintaining plasma oncotic pressure and prevent endothelial cell apoptosis but can have adverse effects on the lungs and kidneys. These adverse effects are mainly attributed to ER stress and inflammasome activation. This narrative review provides an overview of the general biology of albumin and its effects in physiology, with a focus on its beneficial and adverse effects and the underlying molecular mechanisms.

Livers doi: 10.3390/livers5020026

Authors: Sho Uemura Yasushi Hasegawa Hideaki Obara Minoru Kitago Hiroshi Yagi Yuta Abe Shutaro Hori Masayuki Tanaka Yutaka Nakano Yuko Kitagawa

Background: De novo malignancies (DNMs) after liver transplantation (LT) are a major cause of long-term mortality. However, no definitive screening protocol has been established due to their diversity. This study aimed to evaluate DNM diagnosis methods, screening protocols, and prognoses. Methods: This retrospective study included 231 adult LT recipients from April 1997 to March 2021. Disease-specific survival (DSS) was analyzed to assess the impact of screening on prognosis. Most recipients underwent serum tests every three months, annual gastrointestinal endoscopy, and chest-abdominal CT as part of routine surveillance. Results: Twenty-five DNMs were diagnosed in 22 patients, with median age of 61 years (range, 23–72), of whom 13 (59.1%) were female. The duration from transplantation to DNM diagnosis of DNM was 88 months (range, 4–195). DNM was diagnosed as follows: seven patients (31.8%) through screening (screening group) and 15 patients (68.2%) by other means (non-screening group). Curative treatment was achieved in all of the patients diagnosed by screening, whereas it was possible in only 60.0% of patients diagnosed by other means (p = 0.026). DSS in the screening group was significantly longer than that in the non-screening group (p = 0.024). Conclusions: While screening was associated with earlier-stage diagnosis and improved outcomes in some patients, the overall efficacy of the protocol requires further validation in larger studies.

Livers doi: 10.3390/livers5020025

Authors: Sooraj Vellatt Jonathan Soldera

Background: Sarcopenia, defined as the progressive loss of skeletal muscle mass and strength, is a critical predictor of morbidity and mortality in patients with cirrhosis. In chronic liver disease, sarcopenia exacerbates adverse clinical outcomes and deteriorates quality of life. Physical activity, particularly resistance training, has demonstrated beneficial effects in reversing muscle depletion in various chronic conditions. Aim: This systematic review aimed to evaluate the impact of resistance training on sarcopenia among cirrhotic patients, with a focus on both pre-liver transplant and post-liver transplant populations, to improve clinical outcomes and enhance quality of life. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. PubMed/MEDLINE databases were searched for randomized controlled trials (RCTs) using a standardized search command combining MESH terms and Boolean operators. Studies meeting eligibility criteria and reporting improvements in sarcopenia following resistance training were selected for data extraction. Results: Out of 109 references identified, 12 RCTs were included—10 in pre-transplant and 2 in post-transplant populations. Across studies, resistance training led to measurable improvements in key outcomes: peak VO2 increased by up to 5.3 mL/kg/min, 6 min walk distance improved by 18–97 m, quadriceps muscle thickness increased by up to 1.05 cm, and grip strength gains ranged from 0.4 to 3.8 kg. Postoperative studies reported reductions in fatigue severity scores and length of hospital stay, along with improvements in respiratory pressures and peripheral muscle strength. Conclusions: Resistance training is effective in ameliorating sarcopenia in cirrhotic patients, thereby enhancing pre-transplant status and postoperative quality of life. Clinically, structured exercise programs should be routinely implemented.

Livers doi: 10.3390/livers5020024

Authors: Tai L. Guo Fatma Eldefrawy Kevin M. Guo

Bisphenol analogs and their derivatives have been identified in human tissue and our living environment. There are major concerns over exposure to bisphenol analogs, especially the low-dose- and mixture-related toxicities, as they are considered potential endocrine-disrupting chemicals that may cause adverse effects in multiple organ systems. The liver is a critical organ responsible for an array of functions, e.g., metabolism, immunity, digestion, detoxification and vitamin storage, in addition to being a leading chemical target site. In this literature review of multiple species, we discussed the metabolism of bisphenol analogs in the liver, which was followed by discussions of bisphenol analog-induced liver toxicity in various species, including humans, rodents (mice and rats) and other species (chicken, pig, sheep, etc.). Further, the mechanisms of action and markers of liver damage such as oxidative stress, apoptosis, inflammation and fibrosis were discussed. It was concluded that bisphenol analogs can produce toxic effects on the liver in different species through various mechanisms, including epigenetic modifications and disruptions of the cell signaling pathways, gene expression, microbiome and metabolome. More research should be conducted to study the toxicity of bisphenol analogs other than bisphenol A and the underlying mechanisms of action, and in particular the potential for causing dysbiosis. Understanding the mechanisms of liver injury holds promise for improving the prediction of liver toxicity from bisphenol analogs and other environmental chemicals, and their risk assessment and legislation.

Livers doi: 10.3390/livers5020023

Authors: Razvan Cerban Mirela Chitul Speranta Iacob Daria Gheorghe Diana Georgiana Stan Liana Gheorghe

Background: Hepatitis delta virus (HDV) was recently proven to be directly carcinogenic on hepatocytes via different mechanisms compared to hepatitis B virus (HBV). Our study evaluated the differences between hepatocellular carcinoma (HCC) behaviour in both cases. Methods: A retrospective tertiary care centre study was conducted and included all HBsAg-positive adult patients admitted from the 1st of January 2021 to the 31st of December 2022. IBM SPSS 29.0 was used for statistics. Patients were split into a control group, HBV + HCC, and a study group, HBV + HDV + HCC. Results: A total of 679 patients were included, with an estimated prevalence of HCC in the HDV population of 20.8% versus 9.1% in the control group, p < 0.001, with an OR = 2.263 and a CI 95% of (1.536–3.333), p = 0.001. Younger patients developed HCC in the HBV monoinfection group (mean ± SD, 50.65 ± 12.302 years vs. 51.4 ± 13.708, p = 0.457). Study group patients had smaller tumours (maximum diameter: 32.66 ± 23.181 mm vs. 56.75 ± 38.09 mm, p = 0.002), lower AFP values (177.24 ± 364.8 ng/mL vs. 183.07 ± 336.77 ng/mL, p = 0.941) and predominantly loco-regional treatment. BCLC classification (p = 0.001) and the AFP-Duvoux score (p = 0.001) showed more advanced HCC in HBV monoinfection, with access to mainly systemic therapies (p < 0.001). Conclusions: HCC is more frequent in HDV-infected patients, leading to a different HCC pattern, with smaller tumours, less advanced neoplasia and less access to curative treatment compared to HBV-monoinfection-associated HCC.