Search Results (2,607)

Alcohol-associated liver disease (ALD) contributes substantially to the global burden of cirrhosis and liver-related mortality, driven by ethanol metabolism, oxidative stress, and dysregulated immune signaling. Despite rapidly growing evidence implicating interferon regulatory factors (IRFs) in ALD pathogenesis, an integrated framework linking ethanol-induced danger signals to cell-type-specific IRF programs is lacking. In this comprehensive review, we summarize current knowledge on IRF-centered signaling networks in ALD, spanning DAMP–PAMP sensing, post-translational IRF regulation, and downstream inflammatory, metabolic, and fibrogenic outcomes across various cell types in the liver, including hepatocytes and immune-related cells such as Kupffer cells, monocyte-derived macrophages, dendritic cells, T cells, hepatic stellate cells (HSC), and neutrophils. We also focus on how ethanol-driven DAMP and PAMP signals activate TLR4, TLR9, and cGAS–STING pathways to engage a coordinated network of IRFs—including IRF1, IRF3, IRF4, IRF5, IRF7, and IRF9—that collectively shape inflammatory, metabolic, and cell-fate programs across hepatic cell populations. We further highlight emerging therapeutic strategies such as STING/TBK1 inhibition, NETosis blockade, IL-22-based epithelial repair, and JAK-STAT modulation that converge on IRF pathways. In summary, this review outlines how IRFs contribute to ALD pathogenesis and discusses the potential implications for the development of targeted therapies. Full article

Background/Objectives: Infections remain a leading cause of morbidity and mortality following liver transplantation, with bloodstream infections (BSIs) representing one of the most critical complications. This study aimed to identify factors associated with mortality in liver transplant recipients who developed BSIs over a 10-year period. Methods: This retrospective study was conducted at a tertiary university hospital between 1 April 2014 and 31 December 2024. A total of 467 adult patients underwent liver transplantation during the study period. Among 467 patients, a total of 210 bloodstream infection episodes occurring in 136 patients were included in the study. Results: BSIs occurred in 29.1% (136/467) of patients, with a total of 210 episodes. The median age was 55 years (IQR: 45–63). Most transplants (95.2%) were from living donors. Hepatitis B virus infection (27.1%) was the most common underlying etiology of cirrhosis. The majority of BSIs (61.2%) occurred within the first three months post-transplant. A total of 242 pathogens were isolated, with ESBL-producing Enterobacterales identified in 72.6% and carbapenem-resistant Enterobacterales (CRE) in 30.1% of cases. Notably, carbapenem resistance among Klebsiella spp. was high at 51.78%. The overall mortality rate was 14.28%. Multivariate analysis identified that a high Pitt Bacteremia Score (hazard ratio [HR] 1.502, 95% confidence interval [CI] 1.361–1.657, p < 0.001) and CRE infection (HR 3.644, 95% CI 1.380–9.620, p = 0.009) were independent predictors of mortality. Conclusions: BSIs are a significant post-transplant complication with high antimicrobial resistance. The Pitt bacteremia score is a strong predictor of mortality and may guide early risk stratification and clinical management in liver transplant recipients. Full article

Background/Objectives: Previous studies have demonstrated that the cessation of liver damage after HCV cure can improve liver function, histological necroinflammation, and portal hypertension. However, scarce data about fibrosis stage or cirrhosis regression have been reported during follow-up. Methods: A prospective study evaluating hepatic biopsies and liver stiffness measurement by vibration-controlled transient elastography (VCTE-LSM) after the end of treatment (EOT) in patients with compensated advanced chronic liver disease (cACLD). Fibrosis was evaluated according to two semi-quantitative grading systems (METAVIR and Laennec) at 6 years after EOT (LB6) and compared with biopsies at 3 years (LB3). Results: Fifty-four patients with LB6 (34 with paired LB3–LB6) were included. Median (IQR) age was 53.9 (48.5–59.3), 38 (70.4%) were men, and 13 (24.1%) were HIV-coinfected. The VCTE-LSM was >15 kPa in 30 (55.6%). The LB6 (81.4 months after EOT) showed non-advanced fibrosis (F1–F2) in 12 (22.4%) patients, bridging (F3) in 26 (48.2%), and cirrhosis (F4) in 16 (29.6%): F4A in 7 (13.0%), F4B in 4 (7.4%), and F4C in 5 (9.3%). The 1-year post-EOT follow-up VCTE-LSM ≤ 8.6 kPa identifies patients without advanced fibrosis (AUROC = 0.929), with a negative predictive value of 88.9% and a positive predictive value of 95.2%. Paired biopsies showed regression in 9 (47.4%) out of 19 patients with cirrhosis: 8 (61.5%) of 13 with F4A but only 1 (16.7%) of 6 with F4B–F4C. Conclusions: Advanced fibrosis persists in most patients with advanced chronic liver disease after HCV eradication. Regression is possible in mild cirrhosis. However, it is a limited and slow event. Full article

Hepatocellular carcinoma (HCC) is the main type of liver cancer and one of the malignancies with the highest mortality rates worldwide. HCC is associated with diverse etiological factors including alcohol use, viral infections, fatty liver disease, and liver cirrhosis (a major risk factor for HCC). Unfortunately, many patients are diagnosed at advanced stages of the disease and receive palliative treatment only. Therefore, early markers of HCC and novel therapeutic approaches are urgently needed. The endocannabinoid system is involved in various physiological processes such as motor coordination, emotional control, learning and memory, neuronal development, antinociception, and immunological processes. Interestingly, endocannabinoids modulate signaling pathways involved in cell survival, proliferation, apoptosis, autophagy, and immune response. Consistently, several cannabinoids have demonstrated potential antitumor properties in experimental models. The participation of metabotropic and ionotropic cannabinoid receptors in the biological effects of cannabinoids has been extensively described. In addition, cannabinoids interact with other targets, including several ion channels. Notably, several ion channels targeted by cannabinoids are involved in inflammation, proliferation, and apoptosis in liver diseases, including HCC. In this literature review, we describe and discuss both the endocannabinoid system and exogenous phytocannabinoids, such as cannabidiol and Δ⁹-tetrahydrocannabinol, along with their canonical receptors, as well as the cannabidiol-targeted ion channels and their role in liver cancer and its preceding liver diseases. The cannabidiol-ion channel association is an extraordinary opportunity in liver cancer prevention and therapy, with potential implications for several environments that are for the benefit of cancer patients, including sociocultural, public health, and economic systems. Full article

Background/Objectives: Hepatocellular carcinoma remains a major cause of death from cancer globally. While ¹⁸F-FDG PET/CT is commonly used for tumor imaging, its sensitivity is limited, especially due to high liver background uptake. Recently, ⁶⁸Ga-FAPI PET/CT, which targets fibroblast activation protein in tumor stroma, has emerged as a promising diagnostic tool. In this study, we aimed to assess the diagnostic performance of ⁶⁸Ga-FAPI-04 PET/CT in HCC patients with and without liver cirrhosis and to explore the relationship between PET metrics, tumor size, and PIVKA-II serum marker. Methods: In this prospective single-center study, 59 patients with confirmed HCC (37 with cirrhosis, 22 without) underwent ⁶⁸Ga-FAPI-04 PET/CT. The standard dose (1.5–2.0 MBq/kg) was administered intravenously, and imaging was carried out 60 min post-injection. Semi-quantitative parameters including SUVmax, SUVmean, and tumor-to-background ratio were calculated. Diagnostic performance was assessed using histopathology and multimodal imaging. Statistical analyses included the Mann–Whitney U test and Spearman correlation. Results: The overall sensitivity for HCC detection was 89.8%, with a specificity of 60% and accuracy of 87%. Sensitivity and specificity showed a tendency to be lower in cirrhotic compared with non-cirrhotic patients, with a notably higher background liver uptake in cirrhosis (SUVmax 3.60 vs. 1.3, p < 0.001), resulting in lower TBR values (3.7 vs. 7.0, p < 0.001). A strong correlation between SUVmax and tumor size was seen in non-cirrhotic HCC, while a moderate association between SUVmax and PIVKA-II levels was observed in cirrhotic patients. Conclusions:⁶⁸Ga-FAPI-04 PET/CT demonstrates high sensitivity for HCC detection and may serve as a complementary imaging modality, particularly when interpreted through conventional cross-sectional imaging. Image interpretation in cirrhotic livers may be challenging due to increased background uptake and reduced TBR. Associations between PET-derived parameters, tumor size, and serum PIVKA-II levels should be considered hypothesis-generating and require validation in larger, multicenter studies with clinical outcome data. Full article

Patient-derived organoids (PDOs) have emerged as promising preclinical models for studying tumor biology and testing therapeutic strategies in oncology. These three-dimensional culture systems retain key histological, genetic, and functional characteristics of the original tumors, offering a unique opportunity to advance personalized medicine approaches in liver cancer. In this study, we present the methodological framework and preliminary findings of a prospective study aimed at generating and characterizing PDOs from patients with hepatocellular carcinoma (HCC) undergoing surgical resection. Tumor specimens were processed using an optimized protocol for organoid derivation, expansion, and cryopreservation. We evaluated the success rate of organoid establishment and the histo-molecular fidelity to the parental tumor. These early results demonstrate promising engraftment efficiency and maintenance of tumor-specific markers across passages. Our work highlights the potential of PDOs as a reliable and scalable platform for translational research in HCC, setting the stage for future applications in drug screening and biomarker discovery. Full article

Background: This study seeks to evaluate the 23 year experience of the İnonu University Liver Transplantation Institute from a public health perspective by examining demographic patterns, etiological factors, and transplantation trends between 2002 and 2025. Aims: This analysis aims to provide insights into the epidemiological landscape of liver transplantation in Türkiye from a public health perspective. Methods: In this retrospective cross sectional study, we analyzed 4011 liver transplant procedures performed between March 2002 and March 2025. Recipient demographics, disease etiologies, donor characteristics, and patients geographic distribution were assessed to delineate regional health needs and service utilization patterns. Results: A total of 4011 patients were included. The cohort comprised 2618 males (65.3%) and 1393 females (34.7%). Recipients were classified as adult (n = 3232, 80.9%) or pediatric (n = 779, 19.1%). Among adults, infectious etiologies were the most prevalent (35.5%), followed by cryptogenic liver cirrhosis (24.7%). In contrast, pediatric patients most commonly presented with toxic etiologies (29.4%), metabolic disorders (22.6%) and bile duct diseases (15.9%). Most liver transplantations were performed using living donors (n = 3481, 86.8%), while deceased donors accounted for 530 procedures (13.2%). Additionally, 244 living donor liver transplantations were performed via liver paired exchange (LPE). Conclusions: These findings may inform resource allocation, health policy development, and the optimization of transplantation services. This center-based model offers a useful framework for characterizing regional health needs and strengthening community health, particularly through prevention, screening, and early intervention strategies for liver diseases. Full article

Liver fibrosis is a common pathological result of chronic hepatic injury caused by various factors, such as viral hepatitis, alcohol-induced liver disease, and metabolic dysfunction-associated steatohepatitis (MASH). It is characterized by an excessive deposition of extracellular matrix, which disrupts the architecture of the liver and can lead to cirrhosis, liver failure, and hepatocellular carcinoma. Globally, nearly 10% of the population has significant fibrosis, with its prevalence increasing with age, obesity, and metabolic syndrome. Despite its significant clinical impact, early detection of liver fibrosis is still limited due to insufficient diagnostic technologies and low public awareness. The increasing burden of MASH emphasizes the urgent need for scalable therapeutic strategies. Currently, liver transplantation is the only definitive treatment, but it is limited by donor shortages and the need for lifelong immunosuppression. However, fibrosis is now recognized as a dynamic and potentially reversible process if the underlying cause is addressed. This shift in understanding has prompted efforts to develop pharmacological agents that target hepatic stellate cell activation, immune system interactions, and metabolic dysfunction. Advances in organoid platforms, multi-omics, and non-invasive diagnostics are accelerating translational research in this area. This review aims to synthesize current knowledge about the molecular drivers of fibrosis, bottlenecks in the current anti-fibrotic drug discovery process, and emerging therapeutic approaches to inform precision medicine strategies and reduce the global burden of chronic liver disease. Full article

Objective: To analyze demographic traits, clinical complications, and healthcare use in patients with chronic liver disease across major etiologies in a large Romanian cohort. Methods: A retrospective study (2019–2023) of 2359 patients with chronic hepatitis C (CHC), hepatitis associated with alcohol (ALH), cirrhosis associated with alcohol (ALC), or non-alcoholic cirrhosis (NALC). Data on demographics, clinical outcomes, and hospitalizations were analyzed using descriptive statistics, regression modeling, and clustering in IBM SPSS 27.0.1. Results: CHC patients were oldest (mean 67.5 ± 12.3 years), while ALH patients were youngest (56.0 ± 11.0 years). CHC prevalence increased with age (10.0% in ≤30-year-olds to 87.1% in ≥81-year-olds; γ = 0.535, p < 0.001). Females comprised 60–70% of CHC cases, males > 85% of ALH and >78% of ALC. Mean hospitalization duration decreased from 13.80 days (2019) to 9.10 days (2023), yet cirrhotic patients had the longest stays (NALC: 16.37 ± 14.34; ALC: 17.66 ± 12.96) versus CHC (10.38 ± 10.14). Etiology was the strongest predictor of hospitalization length. Portal hypertension (PH) was the most common complication (54.3%), with males bearing more severe hepatic complications (ascites—38.3%; PH—66.8%). Conclusions: Hospital-based Romanian cohort analysis revealed that patient presentation and outcomes are fundamentally shaped by the interplay of etiology, sex, and age. We found a distinct female predominance in CHC, a pronounced male predominance in alcohol-related diseases, and evolving trends in non-alcoholic cirrhosis. These determinants dictate specific epidemiological patterns, hospitalization burdens, and complication risks, underscoring the critical need for a paradigm shift toward personalized, etiology-driven, and sex-tailored clinical management. Full article

Background: Progressive familial intrahepatic cholestasis (PFIC) describes a group of genetically heterogeneous disorders. Several mutations in the ATP-Binding Cassette Subfamily B Member 4 (ABCB4) gene have been confirmed to cause reduced phosphatidylcholine levels in bile, leading to a deficiency of biliary vesicles and instability of mixed in micelles. The disease spectrum ranges from PFIC type 3 (PFIC3) to milder conditions. Herein, we present a rare case of PFIC3 in a young woman, emphasizing the importance of early detection and management. Methods: The patient was diagnosed using next-generation sequencing, with genetic testing and analysis performed by the Chengdu Hua Chuang Testing Institute. Variant pathogenicity was evaluated according to the American College of Medical Genetics and Genomics guidelines and classified into five categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. Nomenclature was assigned following the Human Genome Variation Society standards. Results: Contrast-enhanced abdominal computed tomography demonstrated liver cirrhosis with marked splenomegaly. Histological examination of liver biopsy specimens using hematoxylin and eosin and Masson staining further confirmed cirrhotic changes. Genetic testing was subsequently performed and revealed a likely pathogenic variant, c.2757T > A (p. Tyr919Ter), in exon 22 of the ABCB4 gene, which was also detected in the patient’s mother but absent in her father. Finally, PFIC3 was diagnosed. Following initiation of ursodeoxycholic acid therapy, the patient showed moderate improvement in liver function tests, underscoring a clinical case with therapeutic implications. Conclusions: Molecular genetic analyses of ABCB4 are essential for the accurate diagnosis of PFIC3. Clinicians should consider cholestatic liver diseases, particularly PFIC, as a differential diagnosis in cases of liver cirrhosis with unknown etiology, especially in young patients who lack prior symptoms or a family history of liver disease. Full article

Background: Liver cirrhosis increases perioperative risk in colorectal cancer surgery, yet data on long-term outcomes remain limited. In this study, we evaluated postoperative morbidity, mortality, and survival in cirrhotic patients. Methods: In this single-center retrospective cohort, 53 cirrhotic patients undergoing elective colectomy or proctectomy (2011–2022) were propensity score-matched 1:1 with non-cirrhotic controls. Perioperative variables, complications, and survival were analyzed. Subgroup analyses were performed for right hemicolectomy and non-right hemicolectomy procedures. Kaplan–Meier and logistic regression analyses were implemented to assess outcomes and risk factors. Results: Cirrhotic patients had higher preoperative MELD-Na scores and lower albumin and hemoglobin levels. They experienced greater blood loss, longer operative times, more ICU admissions, and higher rates of major complications (18.9% vs. 3.8%, p = 0.01). Mortality was higher at in-hospital (7.5% vs. 0%), 3-month (9.4% vs. 0%), and 60-month (66% vs. 28.3%) intervals, and these patients’ overall survival was shorter (70.7 vs. 116.8 months, p < 0.001). The subgroup analysis showed that the adverse impact of cirrhosis persisted for both right hemicolectomy and non-right hemicolectomy procedures, with significantly worse long-term survival in cirrhotic patients. Postoperative complications after right hemicolectomy did not differ significantly between groups. Among cirrhotic patients, Child–Turcotte–Pugh class B predicted worse survival than class A (40.1 vs. 84.8 months, p = 0.006). Preoperative hypoalbuminemia (<3.5 g/dL) independently predicted long-term mortality (HR = 3.93). Conclusions: Elective colorectal surgery in patients with cirrhosis is associated with increased perioperative complications and significantly reduced long-term survival. However, postoperative outcomes after right hemicolectomy in cirrhotic patients were comparable to those of non-cirrhotic patients, despite their persistently poorer long-term survival. Optimization of nutritional status and careful preoperative assessment of hepatic reserve are essential to improving outcomes in this high-risk population. Full article

Background: Cirrhosis represents the final common pathway of chronic liver injury, arising from diverse etiologies such as metabolic, viral, autoimmune, and alcohol-related liver diseases. Despite similar exposures, disease progression varies considerably among individuals, suggesting a genetic contribution to susceptibility and outcome. Objective: This narrative review examines how specific genetic variants influence the risk, progression, and phenotypic expression of cirrhosis. It provides a structured synthesis of established and emerging gene associations, emphasizing their biological mechanisms and potential clinical relevance. Methods: This narrative review synthesizes evidence from all major biomedical and scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar, as well as reference lists of relevant articles, covering literature published between 2005 and 2025 on genetic polymorphisms associated with cirrhosis and its etiological subtypes. Content: Variants are categorized into four mechanistic domains—metabolic regulation, immune modulation, liver enzyme activity, and ancestry-linked expression patterns—representing a novel integrative framework for understanding genetic risk in cirrhosis. Well-characterized variants such as PNPLA3, TM6SF2, HSD17B13, and MBOAT7, along with less commonly studied loci and chromosomal alterations, are discussed in relation to major etiologies, including MASLD/MASH, viral hepatitis, alcohol-related liver disease, and autoimmune conditions. Conclusions: Genetic insights into cirrhosis offer pathways toward early risk stratification and personalized disease management. While polygenic risk scores and multi-omic integration show promise, their clinical translation remains exploratory and requires further validation through large-scale prospective studies. Full article

A 25-year-old woman with decompensated liver cirrhosis and complete inferior vena cava (IVC) occlusion was referred to our department for liver transplantation. The etiology of cirrhosis was Budd-Chiari syndrome (BCS) related to systemic lupus erythematosus, autoimmune hepatitis, and primary biliary cholangitis (AIH-PBC) overlap syndrome. Transplantation was feasible due to an extensive collateral circulation of pre-vertebral veins that drained blood from the lower extremities and both kidneys to the azygos-hemiazygos veins. This venous anomaly enabled the excision of the obstructed retrohepatic IVC, followed by an alternative anastomosis of the suprahepatic IVC to the right atrium without reconstruction of the infrahepatic IVC. Despite good venous patency and normalization of liver graft function, the patient developed cecum perforation, cardiovascular and respiratory insufficiency, which led to the patient’s death two months after transplantation. This case report supports an individual approach and highlights the feasibility of liver transplantation despite an extensive IVC thrombosis. To our knowledge, it is the first description of the application of a deceased donor liver transplantation in patients with AIH-PBC overlap syndrome and lupus-related BCS. A concise review of published literature on IVC-atrial anastomosis in adult liver transplant recipients is provided, and the technique is discussed based on our recent experience. Full article

The liver is the primary site of synthesis for most coagulation factors and the central organ responsible for maintaining hemostatic equilibrium. In individuals with advanced liver disease, significant disruptions in coagulation homeostasis occur and consequently predispose patients to both thrombotic and bleeding complications. This review summarizes the pathophysiologic basics of liver cirrhosis-associated coagulopathies and discusses the diagnosis and treatment of common procoagulant conditions such as portal vein thrombosis and post-transplant hepatic artery thrombosis. The review also systematically addresses the most common bleeding complications, including spontaneous, portal hypertension-related, and periprocedural bleeding. The proper pre-procedural assessment of the bleeding risk is often required due to the great number of invasive procedures to which these patients are frequently subjected. The viscoelastic testing (thromboelastogram and thromboelastometry) seems to emerge as the most appropriate diagnostic method. Specific treatment recommendations for the correction of coagulation abnormalities and the management of severe thrombocytopenia are hereby presented. Full article

Background/Objectives: Direct-acting antivirals (DAAs) have revolutionized the management of chronic hepatitis C virus (HCV) infection. However, real-world data on the effectiveness and safety of DAA therapy in patients with history orthotopic liver transplantation (OLTx) remain limited. This study aimed to evaluate the clinical characteristics, effectiveness, and safety of DAA therapy in liver transplant recipients with chronic hepatitis C in a nationwide, real-world cohort. Methods: A retrospective analysis was performed of all consecutive adult patients who underwent OLTx before starting DAA therapy between July 2015 and December 2024 within the EpiTer-2 project, which included 20,586 patients treated because of chronic hepatitis C. Results: A total of 141 patients participated in the study, with most of them being men (66%) and aged 50 years or older. Most patients (80%) had comorbidities, and nearly a quarter of the population had cirrhosis of the transplanted liver at the start of antiviral therapy. The median time from OLTx to initiation of antiviral therapy was 24 months. Overall, SVR was achieved in 96.4% of patients in the intention-to-treat analysis and in 98.6% after excluding patients lost to follow-up. The treatment was well tolerated. Serious adverse events were reported in five patients. During DAA treatment and 12 weeks of follow-up after treatment, two deaths were reported. Subgroup analysis by time from OLTx to antiviral therapy (≤24 vs. >24 months) revealed no differences in effectiveness and safety despite some baseline clinical variations. Conclusions: DAA therapy in liver transplant recipients with chronic HCV infection is highly effective and well-tolerated. Full article