The current management of colorectal cancer liver metastasis (CRCLM) patients involves a multidisciplinary approach with surgical resection remaining the primary curative option. The advances in liver surgery have improved outcomes, enabling more patients to undergo surgery successfully. In addition, the development of imaging software has improved the preoperative planning and patient selection for surgery and other interventions. Systemic therapies, such as targeted therapies and immunotherapies have enhanced the chances of complete resection. Targeted agents in combination with chemotherapy, have shown efficacy in downstaging tumors and increasing resectability.

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, with 25% of patients presenting with metastases; of these, 8% have synchronous liver and peritoneal metastases. Although the concurrent presence of liver and peritoneal metastases was previously considered an absolute contraindication, the feasibility of combined surgery is now being re-evaluated. This study assesses 41 patients who underwent liver surgery for CRC metastases at our center between October 2021 and February 2024. Among these patients, 7 underwent concomitant cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) due to the presence of synchronous liver and peritoneal metastases. We employed simple linear regression to identify parameters that influenced the development of postoperative complications, classified by the Clavien-Dindo (CD) system. The statistical analysis showed only the operative time, the CRS+HIPEC procedure and the length of hospital stay as significative variables on CD outcome, while the different types of liver surgery were not significant. This study suggests that combining liver surgery with CRS+HIPEC may be beneficial for selected patients, potentially improving overall survival without a significant increase in postoperative complications. A multidisciplinary approach is essential to achieve a survival advantage without elevating morbidity rates.

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis, published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial-mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

Colorectal cancer is a high-incidence tumor that has a high mortality rate due to its frequent metastasis to the liver. The difference in genes, proteins, and immune microenvironment between the primary and metastatic sites causes them to show different responses to treatment. Colorectal cancer liver metastasis patients also tend to show poorer treatment response and prognosis. Therefore, in this paper, we summarize the heterogeneity exhibited after colorectal cancer liver metastasis from five aspects (gene, transcriptome, protein, metabolism, and immunity), and we found that except for the genetic heterogeneity, the other four aspects exhibite significant heterogeneity, which might serve as a new therapeutic direction and a prognostic marker for patients with liver metastasis. Finally, the therapeutic modalities regarding tumors are rapidly evolving, and we have also summarize the new clinical therapeutic modalities currently proposed based on these heterogeneities, aiming to provide new therapeutic ideas for the clinical treatment of patients with colorectal cancer liver metastases.

Siam weed, scientifically known as Chromolaena odorata and belonging to the Asteraceae family, is a fast-growing plant with prolific seed production. Although it is a traditional medicinal plant, it has become an agricultural weed in Africa and Asia, posing a threat to biodiversity and causing environmental damage. Despite this, C. odorata is highly regarded as a medicinal herb in tropical Africa, with anticancer effects on breast, liver, and colorectal cancer. However, it is important to regulate the intake of the plant extract as it can have a hepatotoxic effect on liver cells at higher doses. Further research needs to be conducted on the plant extract, and proper orientation and knowledge of its oral daily administration are necessary. This review summarizes current scientific investigations using ethanolic and methanolic aqueous extracts of C. odorata leaves on various cancer cells, to uncover its potential as an anticancer agent. The investigations were sourced from online databases like Google Scholar, PubMed, and other online-based journals.

Objective: To investigate the efficacy of a magnetic resonance imaging (MRI) radiomics model in predicting colorectal cancer liver metastasis (CRLM). Methods: A total of 120 patients who underwent baseline MRI examination at the Affiliated Hospital of North Sichuan Medical College from June 2016 to August 2022 and were pathologically confirmed to have colorectal cancer (CRC) were randomly divided into a training group and a validation group. The clinical risk factors and MRI data of all patients were collected. Univariate and multivariate analysis were used to screen the clinically independent risk factors for CRLM. The radiomic features of each sequence were extracted from oblique axial or axial fat-free T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) sequences. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the optimal radiomic features of each sequence. Logistic regression was used to establish a prediction model of each sequence (T2WI and DWI models), a combined radiomics model (M) integrating the features of T2WI and DWI sequences, and a combined imaging-clinical model (U) combining the radiomic features of each sequence with clinically independent risk factors. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the predictive performance of each model. Results: Among the 120 CRC patients enrolled, 57 had liver metastasis, and 63 did not. The tumor markers carcinoembryonic antigen and carbohydrate antigen 19-9 were clinically independent risk factors for CRLM. Three optimal radiomic features were screened from T2WI and DWI sequences through LASSO regression analysis, respectively. The AUC values of the T2WI, DWI, M, and U models were 0.811, 0.803, 0.824, and 0.899 in the training group and 0.795, 0.798, 0.813, and 0.889 in the validation group, respectively. The predictive performance of the combined models was better than that of the single-sequence models. The U model performed best at predicting CRLM. Conclusion: An MRI radiomics model based on CRC primary lesions can predict CRLM well. Our combined model integrating the radiomic features of each sequence and clinically independent risk factors had the best predictive performance.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curable for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists or/and to downstage patients who are beyond Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine Kinase Inhibitors (TKIs) can be used as a bridging systemic therapy to LT in patients with contraindication to locoregional liver-directed therapies. Immune Checkpoint Inhibitors (ICIs) treatment can be utilized either as a monotherapy or as a combination therapy with Bevacizumab or TKIs prior to LT. Acute rejection post liver transplantation is a concern in the context of ICIs treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.

Over the recent years, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder in the developed world, accounting for 20% to 46% of liver abnormalities. Steatosis is the hallmark of NAFLD and is recognized as an important risk factor for complication and death after general surgery, and even more so after liver resection. Similarly, liver steatosis also impacts the safety of live liver donation and transplantation. We aim to review surgical outcomes after liver resection for colorectal-metastases in patients with steatosis, and discuss the most common pre-operative strategies to reduce steatosis. Finally, as illustration, we report the favourable effect of a low-caloric, hyper-protein diet during a two-stage liver resection for colorectal metastases in a patient with severe steatosis.

Objective:This study aims to evaluate the impact of drug-eluting bead transarterial chemoembolization (DEB-TACE) compared to conventional transarterial chemoembolization (cTACE) in patients with hepatocellular carcinoma (HCC), with a specific focus on liver fibrosis progression. By utilizing propensity score matching (PSM), the study seeks to examine the effects of both treatments on liver fibrosis and survival rates, providing evidence to inform clinical decision-making. Methods:This retrospective analysis included HCC patients who underwent DEB-TACE or cTACE at Xuzhou Cancer Hospital between October 2020 and September 2023. Propensity score matching (PSM) was employed to ensure comparability between the two groups based on baseline characteristics, with a 1:1 matching ratio. The primary endpoints included liver fibrosis markers (such as hyaluronic acid, type III procollagen, type IV collagen, and laminin), liver function trends (ALT, AST, TBIL, ALB), and adverse events. Kaplan-Meier methods were used to evaluate progression-free survival (PFS) and overall survival (OS). Results:After PSM, 92 patients were included (46 in the DEB-TACE group and 46 in the cTACE group). Results demonstrated that the DEB-TACE group showed superior outcomes in reducing liver fibrosis markers (e.g., PC-III, IV-C, and LN) compared to the cTACE group. Additionally, the incidence of nausea, vomiting, and postoperative pain was significantly lower in the DEB-TACE group (p < 0.001). Kaplan-Meier analysis revealed that PFS and OS were significantly longer in the DEB-TACE group compared to the cTACE group (p < 0.05). Multivariate logistic regression analysis further confirmed the independent protective effect of DEB-TACE in reducing liver fibrosis progression (OR = 2.39, p = 0.044). Conclusion:This study confirms the advantages of DEB-TACE in treating patients with intermediate to advanced HCC, particularly in slowing liver fibrosis progression and improving survival outcomes. The use of propensity score matching enhances the reliability of these findings. Future studies should continue to explore the potential of DEB-TACE in broader patient populations to optimize treatment strategies for HCC.

Abstract: Background: Irreversible electroporation (IRE) is a form of non-thermal ablation that delivers pulses of high voltage electrical current between electrodes. The role of IRE in the treatment of colorectal hepatic metastases is unestablished. This study is an international ques-tionnaire survey of the use of IRE for colorectal hepatic metastases. Methods: A questionnaire addressing views on the use of IRE for colorectal liver metastases was circulated to clinicians with an interest and/or expertise in this technique. Results: 64 clinicians from 17 different countries replied to the questionnaire. Thirty-six (56%) had experience of treating patients with colorectal liver metastases with IRE. The preferred mode of delivery of IRE was percutaneous treatment under CT guidance. Thirty-three (70% respondents) used IRE exclusively for lesions in proximity to inflow or outflow structures. Twenty (43% respondents) used IRE as their sole ablative treat-ment whilst 19 (40% respondents) used IRE in combination with thermal ablation. The maximum number of lesions that could be treated by IRE was two and preferred size of lesion was

Abstract Introduction Minimally invasive approaches to oncological liver resection is common in many hepatobiliary centres. This study aims to compare the key oncological and survival outcomes of patients with colorectal liver metastases (CRLM) undergoing laparoscopic or open resections using propensity score matching (PSM). Methods A single-centre retrospective study was performed using a prospective database of patients undergoing liver resection for CRLM between January 2016 and December 2019. Different co-variates were selected for matching using PSM. Pre-matching and post-matching analyses were compared. Surgical and survival outcomes were analysed. Results In total, 303 patients who met the inclusion criteria were identified: 214 underwent open liver resection (OLR) and 91 laparoscopic liver resection (LLR). LLR had a significantly reduced length of intensive treatment unit (ITU) and overall in-patient stay but longer pringle and operative times. In the unmatched cohort, the median overall and disease-free survival time was significantly longer in patients undergoing laparoscopic compared with open surgery. A PSM model demonstrated significantly reduced blood loss and length of hospital stay, with a significantly greater Pringle and operative time in the LLR group. Differences seen in overall and disease-free survival were lost with propensity score matching, possibly due to lack of bi-lobar disease within the minimally invasive group. Conclusion In selected patients with CRLM, LLR presents similar survival and oncological outcomes with the advantages of the short-term results associated with the laparoscopic approach.

Oxidative stress plays an essential role in the pathological processes that trigger various chronic liver diseases and contributes to the development of hepatocarcinogenesis. Antioxidants from natural sources trap free radicals by converting them into non-harmful products and minimize oxidative stress, playing a crucial function in the treatment of free radical-induced diseases. However, the activity of these antioxidants is limited due their poor bioavailability, which is why various nano-drug delivery systems have been developed to improve their stability, promote smooth release, and targeted delivery for liver cancer treatment. Specifically, this review aims to report recent scientific findings of novel nano-formulations containing natural antioxidant molecules targeted for the treatment of liver cancer.

Ulleung County, one of the most medically vulnerable areas in South Korea, requires public attention because of the high incidence of liver cancer. This study was conducted as a part of the Ulleung Liver Cancer Prevention and Management Project. The purpose of this study was to estimate the community prevalence of hepatitis B and C viruses and to identify the associated risk factors. The Project’s interagency workgroup established a procedure for conducting blood sampling and health behavior surveys at the Ulleung Public Community Health Center. A total of 1,792 residents aged 40 years and older voluntarily participated in the study between 2019 and 2022. The hepatitis B surface antigen (HBs Ag) and hepatitis C virus antibody (anti-HCV) positive rates in Ulleung were 7.19% and 1.37%, respectively. Low education level and lifetime smoking were associated with HBsAg positivity, whereas cupping therapy at non-medical institutions was associated with anti-HCV positivity. The odds of HBs Ag positivity were lower among those with tattoos than among those without. There was a difference in the risk factors associated with hepatitis B and C viral infection. While a high HBs Ag positivity rate alone may not fully explain the high incidence of liver cancer in Ulleung, it may be a contributing factor.

Late-stage epithelial ovarian cancer (EOC) involves widespread dissemination of malignant disease throughout the peritoneal cavity, often accompanied by ascites. EOC metastasis relies on the formation of multicellular aggregates, called spheroids. Given that Liver Kinase B1 (LKB1) is required for EOC spheroid viability and LKB1 loss in EOC cells decreases tumor burden in mice, we investigated whether the LKB1 complex controls invasive properties of human EOC spheroids. LKB1 signalling was antagonized through CRISPR/Cas9 genetic knockout of LKB1 and/or RNAi-dependent targeting of STE20-related kinase adaptor protein (STRAD; an LKB1 activator). EOC spheroids expressing nuclear GFP (green) or mKate2 (red) constructs were embedded in Matrigel for real-time live-cell invasion monitoring. Migration and invasion were also assessed in spheroid culture using Transwell chambers, spheroid reattachment, and mesothelial clearance assays. The loss of LKB1 and STRAD signalling decreased cell invasion through Matrigel and Transwell membranes, as well as mesothelial cell clearance. In the absence of LKB1, zymographic assays identified a loss of matrix metalloproteinase (MMP) activity, whereas spheroid reattachment assays found that coating plates with fibronectin restored the invasive potential. A three-dimensional EOC organoid model demonstrated that organoid area was greatly reduced by LKB1 loss. Overall, our data indicated that LKB1 and STRAD facilitated EOC metastasis by promoting MMP activity and fibronectin expression. Given that LKB1 and STRAD are crucial for EOC metastasis, targeting LKB1 and/or STRAD could disrupt the dissemination of EOC, making inhibitors of the LKB1 pathway an alternative therapeutic strategy for EOC patients.

In the past thirty years, childhood obesity rates have risen significantly worldwide, affecting over 340 million children in affluent nations. This surge is intricately tied to metabolic disorders, notably insulin resistance, type 2 diabetes mellitus (T2DM), and the continually evolving spectrum of metabolic-associated (dysfunction) steatotic liver disease (MASLD). This review underscores the alarming escalation of childhood obesity and delves comprehensively into the evolving and dynamic changes of nomenclature surrounding diverse conditions of hepatic steatosis, from the initial recognition of non-alcoholic fatty liver disease (NAFLD) to the progressive evolution into MASLD. Moreover, it emphasizes the crucial role of pediatric endocrinologists in thoroughly and accurately investigating MASLD onset in children with T2DM where each condition influences and exacerbates the progression of the other. The review critically highlights the inadequacies of current screening strategies and diagnosis, stressing the need for a paradigm shift. A proposed solution involves the integration of hepatic magnetic resonance imaging assessment in the diagnostic arsenal for children showing insufficient glycaemic control and weight loss post-T2DM diagnosis, thereby complementing conventional liver enzyme testing. This holistic approach aims to significantly enhance diagnostic precision, fostering improved outcomes in this vulnerable high-risk pediatric population.

Drug-induced liver disease represents one of the main problems in the therapeutic field. As with most pathologies, also in this case various risk factors can be recognised, such as age, sex, but also the gut microbiota. Therefore all drugs on the market can, in fact, cause hepatotoxicity of varying degrees. Drugs used in the treatment of IBD can also cause these adverse effects and even lead to DILI. In this review, the various classes of drugs used in the treatment of IBD were taken into consideration and the various adverse effects on the liver were illustrated. In particular, a major role has emerged regarding hepatotoxicity of immunosuppressants. Biological drugs, however, seem to be responsible for these complications to a much lesser extent.

Rationale: Post-hepatectomy liver failure (PHLF) remains a significant risk for patients undergoing partial hepatectomy (PHx). Reliable prognostic markers and treatments to enhance liver regeneration are lacking. Plasma nanoparticles, including lipoproteins, exosomes, and extracellular vesicles (EVs), can reflect systemic and tissue-wide proteostasis and stress, potentially aiding liver regeneration. However, their role in PHLF is still unknow. Methods: Our study included 9 patients with hepatocellular carcinoma (HCC) undergoing PHx: 3 patients with PHLF, 3 patients undergoing the Associating Liver Partition and Portal vein Ligation for Staged hepatectomy (ALPPS) procedure and three matched controls without complications after PHx. Patient plasma was collected before (PRE), 1 and 5 days (POD1, POD5) after PHx. EVs were isolated by ultracentrifugation and extracted proteins subjected to quantitative mass spectrometry using a super-SILAC mix prepared from primary and cancer cell-lines. Results: We identified 2625 and quantified 2570 proteins in EVs in PHx patients. Among these, 53 proteins were significantly upregulated and 32 were downregulated in patients with PHLF compared to those without PHLF. Furthermore, 110 proteins were upregulated and 78 were downregulated in PHLF compared to patients undergoing ALPPS. The EV-proteomic signature in PHLF indicates significant disruptions in protein translation, proteostasis, intracellular vesicle biogenesis, as well as alterations in proteins involved in extracellular matrix (ECM) remodeling, metabolic and cell cycle pathways, present already before PHx. Conclusion: Longitudinal proteomic analysis of EV´s circulating in human patient plasma undergoing PHx uncovers proteomic signatures associated with PHLF which reflect dying hepatocytes and endothelial cells and are present before PHx already. Our results support EVs as potential biomarkers and therapeutic targets for liver regeneration and failure.

Liver radioembolization is a treatment option for unresectable liver cancers, performed by infusion of 90Y or 166Ho loaded spheres in the hepatic artery. As tumoral cells are mainly perfused via the liver artery unlike hepatic lobules, a twofold tumor to normal liver dose ratio is commonly obtained. To improve tumoral cells killing while preserving lobules, co-infusion of arterial vasoconstrictor has been proposed but with limited success: the hepatic arterial buffer response (HABR) and hepatic vascular escape mechanism hamper the arterioles vasoconstriction. The proposed project aims to take benefit of the HABR by co-infusing a mesenteric arterial vasodilator: the portal flow enhancement inducing the vasoconstriction of the intra sinusoids arterioles barely impacting liver tumors that are mainly fed by novel and anarchic external arterioles. Animal studies were reviewed and dopexamine was identified as a promising safe candidate reducing by 4 the hepatic lobules arterial flow. A clinical trial design is proposed. A four to sixfold improvement of the tumoral to normal tissue dose ratio is expected, pushing the therapy towards a real curative intention, especially in HCC where ultra-selective spheres delivery is often not possible.

Alcoholic liver disease (ALD) develops when the immunotolerant environment of the liver is compromised due to excessive alcohol consumption. ALD progression involves variations in the expression of multiple genes, resulting in liver inflammation and the development of a leaky gut. Molecular mechanism involved for ALD progression is still unclear, and due to that there are currently no FDA-approved drugs available for its treatment. In this study, the protective effects of Graphene oxide nanoparticles (GO) was investigated against ethanol-induced damage in the gut-liver axis in in vitro. GO was synthesized using a modified Hummer's method and characterization was done. Given the general concerns regarding nanoparticle toxicity, assessment of cell viability, lipid accumulation, DNA damage, cell death, and the generation of reactive oxygen species (ROS) were conducted using various techniques. Furthermore, gene expression of pro- and anti-inflammatory cytokines was done using RT-qPCR. The findings revealed that GOs promoted cell viability even against ethanol treatment. Additionally, lipid accumulation significantly decreased when cells were treated with GO alongside ethanol compared to ethanol treatment alone, with similar trends observed for other assays. Gene expression analysis indicated that GO treatment reduced the expression of proinflammatory cytokines while enhancing the expression of antioxidant genes. Moreover, GO treatment led to improvements in gut permeability and a reduction in proinflammatory cytokines in colon cells damaged by ethanol. These findings suggest that GO holds promise as a drug carrier, exhibiting no observed toxic effects. By shedding light on the protective effects of GO against ethanol-induced damage, this study contributes to the burgeoning field of nanoparticle-mediated therapy for ALD.

Liver cancers give rise to a heavy burden of health care worldwide. Understanding the tumour microenvironment (TME) underpins the development of precision therapy. Single-cell RNA sequencing (scRNA-seq) technology has generated high-quality cell atlases of the TME, but its wider application faces enormous costs for various clinical circumstances. Fortunately, a variety of deconvolution algorithms can instead repurpose bulk RNA-seq data, alleviating the need for generating scRNA-seq datasets. In this study, we reviewed major public omics databases for relevance in this study and utilized 8 RNA-seq and 1 microarray datasets from clinical studies. To decipher the TME of liver cancer, we estimated the fractions of liver cell components by deconvoluting the samples with Cibersortx using three reference scRNA-seq atlases. We also confirmed that Cibersortx can accurately deconvolute cell types/subtypes of interest. Compared with non-tumorous liver, liver cancers showed multiple decreased cell types forming normal liver microarchitecture, as well as elevated cell types involved in fibrogenesis, abnormal angiogenesis and disturbed immune responses. Survival analysis shows that the fractions of five cell types/subtypes significantly correlated with patient outcomes, indicating potential therapeutic targets. Therefore, deconvolution of bulk RNA-seq data with scRNA-seq atlas references can be a useful tool to help understand the TME.

The liver diseases are posing serious threat to human health associated with abusive use of allopathy medicines, especially in developing economies like Pakistan. The strengthening of detoxification system using natural products might be a suitable option to minimize the liver problems. In this current research, Zingiber officinale and Azadirachta indica were evaluated for their hepatoprotective role. For the purpose, 20 Sprague Dawley rats were equally divided into four groups i.e., negative control, paracetamol positive control, 2.5% ginger and 2% neem powder, respectively. During 42 days study, the levels of bilirubin and liver enzymes significantly elevated due to liver damage. Although, the values dropped (20-25%) in treatment group. Serum glucose and serum lipid profile increased in positive control group, but reduced (5-10%) in both ginger and neem groups. The serum protein profile declined in liver damage group, however, improved (~5%) in treatment groups. The hematological parameters slightly declined in liver damage group, but increased in ginger and neem groups. Moreover, the white blood cells differential count and renal parameters showed abnormal values in liver damage group, but improved after treatment. This study is promising and highlighted the hepato-protective role of neem and ginger that may open several avenues of research.

Abstract Background andAims: During liver transplantation, hepatocellular carcinoma (HCC) recurrence remains a critical challenge for patient survival. Targeted therapies, such as Sorafenib and Regorafenib, have been utilized to manage relapsed HCC in this unique setting. This study aimed to assess the efficacy of Sorafenib and Regorafenib in patients with HCC who experienced recurrence after liver transplantation. We focused on survival outcomes, treatment responses, and the management of side effects in this patient group. Methods: We conducted a retrospective analysis of 73 patients who experienced HCC recurrence post-liver transplantation between 2012 and 2022, across 11oncology centers in Turkey. Patients were categorised according to Child-Pugh classification and treated with Sorafenib as first-line therapy and Regorafenib in case of progression. Survival rates were analysed by Kaplan-Meier method and risk factors were evaluated by Cox regression analysis. Results: Of the 73 patients included in the study, 62 were male (84,9%) and 11 were female (15,1%) with a mean age of 61,5 ± 10,9 years. All patients received sorafenib as first-line treatment. Among patients who experienced progression with sorafenib or discontinued treatment due to toxicity, 45,2% (n=33) continued treatment with regorafenib. The median progression-free survival (PFS1) time with Sorafenib was 5,6 months and the one-year survival rate was 24,3%. The median progression-free survival (PFS2) time with Regorafenib, which was administered as second-line treatment, was also calculated as 5,9 months. Overall survival (OS) duration was determined as 35,9 months. The most common side effects associated with both drugs included fatigue, hand-foot syndrome and hypertension. Significantly better survival outcomes were shown in the Child-Pugh A group compared to other patients. Conclusion: These results suggest that Sorafenib and Regorafenib treatments offer a survival advantage in patients with relapsed HCC post-transplantation. However, individualized treatment strategies and close follow-up are crucial for optimizing outcomes. Further studies are needed to refine therapeutic protocols and enhance the care of this specific patient group.

Colorectal liver metastases (CRLM) patients combined with hepatic lymph node metastases was a negative prognostic factor associated with outcomes. Up to now, there was still lack of a reliable method to identify the status of hepatic lymph nodes. The aim of this study was to investigate the predictive ability of mono-exponential, bi-exponential, and stretched-exponential diffusion-weighted imaging (DWI) models to distinguish between benign and malignant hepatic lymph nodes in CRLM patients who underwent neoadjuvant chemotherapy prior to surgery. In total, 97 CRLM patients with pathologically proved hepatic lymph node status were included. Various quantitative parameters, including the apparent diffusion coefficient (ADC) from mono-exponential model, D, D*, and f derived from intravoxel incoherent motion (IVIM) model, as well as DDC and α from stretched-exponential model (SEM), were measured. Multivariate analysis revealed that the pre- treatment DDC value and the short diameter of the largest lymph node after treatment were independent predictors of metastatic hepatic lymph nodes. A nomogram combining these two factors demonstrated excellent performance in distinguishing between benign and malignant lymph nodes in CRLM patients, with an area under the curve (AUC) of 0.873. Therefore, the nomogram can serve as a preoperative assessment tool for determining the status of hepatic lymph nodes and aiding in the decision-making process for surgical treatment in CRLM patients.

Background/Objectives: Alcohol can directly damage the liver, causing steatosis, steatohepatitis, cirrhosis, and hepatocellular cancer. The aim of this study was to examine 28-day survival in hospitalized patients with alcohol-related liver disease (ALD) cirrhosis, as well as to develop and validate a new survival prediction model. Methods: A total of 145 patients with ALD cirrhosis were included, 107 were diagnosed with acute decompensation (AD) and 38 with acute-on-chronic liver failure (ACLF). The new LIV-IN (LIVer mortality INpatients) score was calculated using the following variables: hepatic encephalopathy (HE), hepatorenal syndrome (HRS), ascites, systemic inflammatory response syndrome (SIRS), community-acquired infection (CAI), and fibrinogen. The diagnostic accuracy of the LIV-IN score, as well as Model for end-stage liver disease (MELD), Model for end-stage liver disease-Sodium (MELD-Na), albumin-bilirubin (ALBI), Neutrophil-to-lymphocyte ratio (NLR), Chronic Liver Failure Consortium-C acute decompensation (CLIF-C AD), Chronic Liver Failure Consortium- acute-on-chronic liver failure (CLIF-C ACLF) was tested. Results: Lethal outcome occurred in 46 (31.7%) patients. The mortality rate was higher in the ACLF group (n=22, 57.9%) compared to the AD group (n=24, 22.4%) (p<0.01). The highest predictive power for short-term mortality was observed for the LIV-IN score (AUC 73.4%, p<0.01). In patients with AD, the diagnostic accuracy of the CLIF-C AD score was better than for the LIV-IN score (AUC 0.699; p=0.004, AUC 0.686; p=0.007, respectively). In patients with ACLF, only the LIV-IN score had statistically significant discriminative power in predicting 28-day survival. Conclusion: LIVer mortality Inpatients prognostic score is a new, reliable prognostic model in predicting 28-day mortality.

Liver cancer imposes a pervasive global health challenge, ranking among the most prevalent cancers worldwide. Its prevalence and mortality rates are on a concerning upward trajectory and exacerbated by the dearth efficacious treatment options. The Hippo signaling pathway, originally discovered in Drosophila, comprises four core components: MST1/2, WW45, MOB1A/B, and LATS1/2. This pathway regulates the cellular localization of the transcriptional coactivator YAP/TAZ (Yes-associated protein/PDZ-binding motif) through a series of enzymatic reactions. The Hippo/YAP/TAZZ pathway maintains a balance between cell proliferation and apoptosis, regu-lates tissue and organ sizes, and stabilizes the internal environment. Abnormalities of any genes within the Hippo signaling pathway, such as deletion or mutation, disturb the delicate balance between cell proliferation and apoptosis, creating a favorable condition for tumor initiation and progression. Mutations or epigenetic alterations in the Hippo signaling pathway components can lead to its inactivation. Consequently, YAP/TAZ becomes overexpressed and activated, promoting excessive cell proliferation and inhibiting apoptosis. This dysregulation is closely associated with the development of liver cancer. This review discusses the pivotal role of the Hippo signaling pathway in the pathogenesis and progression of liver cancer. By elucidating its mechanisms, we aim to offer new insights into potential therapeutic targets for effectively combating liver cancer.

Background/Objectives: The increasing incidence and mortality rates of liver cancer have heightened the demand for the development of effective anticancer drugs with minimal side effects. In this study, the roles of exosomes derived from liver cancer stem cells (LCSCs) with PRELI (Protein of Relevant Evolutionary and Lymphoid Interest) modulation, and their miRNAs were investigated to explore the therapeutic for liver cancer. The purpose of this study is to identify a more effective and less toxic anticancer agent beyond the well-known Notch, p51, and Hippo signaling pathways, and to specifically propose the potential of PRELI-induced exosomes as an anticancer therapeutic candidate. Methods: Various techniques, such as miRNA profiling, flow cytometry, western blotting, and immunocytochemistry, were used to evaluate the effects of ex-osomes under PRELI up- and downregulation. Results: PRELI upregulation altered expression levels of miRNAs, including hsa-miR-378a-3p (involved in stem-like properties), hsa-miR-25-3p (contributing to cell proliferation), and hsa-miR-423-3p (driving invasiveness). Exosomes with downregulated PRELI inhibited AKT/mTORC1 signaling, while this signaling pathway was ac-tivated in LCSCs transfected with the candidate miRNAs. Under PRELI up-regulation, exosomes showed increased surface marker expression, promoting cancer progression. Conclusions: The modulation of PRELI in LCSCs affects miRNA expression significantly, revealing candidate miRNA targets for liver cancer treatment. Exosomes with PRELI down-regulation show potential as a novel therapeutic strategy.

LC-SPIK is a liver cancer-specific isoform of Serine Protease Inhibitor Kazal and has been proposed as a new biomarker for the detection of HCC given its unique 3-D structure which differs from normal pancreatic SPIK. An ELISA technology based on its unique structure was developed to use LC-SPIK as an effective biomarker for the clinical diagnosis of HCC. AFP, the most widely used biomarker for HCC surveillance currently, suffers from poor clinical performance, especially in the detection of early-stage HCC. In one case-control study, which included 164 HCC patients and 324 controls, LC-SPIK had an AUC of 0.87 compared to only 0.70 for AFP in distinguishing HCC from liver disease controls (cirrhosis, HBV/HCV). LC-SPIK also performed significantly better than AFP for the 81 patients with early-stage HCC (BCLC stage 0 and A), with an AUC of 0.85 compared to only 0.61 for AFP. Cirrhosis is the major risk factor for HCC, about 80% of patients with newly diagnosed HCC have preexisting cirrhosis. LC-SPIK’s clinical performance was also studied in HCC patients with viral and non-viral cirrhosis including cirrhosis caused by nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). In a total of 163 viral cirrhosis patients with 93 HCC patients (50 early-stage), LC-SPIK had an AUC of 0.85, while AFP had an AUC of 0.70. For patients with early-stage HCC, LC-SPIK had a similar AUC of 0.83, while AFP had an AUC of only 0.60. For 120 patients with nonviral cirrhosis, including 62 HCC (23 early-stage) patients, LC-SPIK had an AUC of 0.84 while AFP had an AUC of only 0.72. For the 23 patients with early-stage HCC, LC-SPIK had a similar AUC of 0.83, while the AUC for AFP decreased to 0.65. All these results suggest that LC-SPIK has significantly better performance in the detection of HCC than AFP in all etiologies of liver diseases. In addition, LC-SPIK accurately detected the presence of HCC in 71%-91% of HCC patients with false-negative AFP test results in viral associated HCC and non-viral associated HCC.

Portal myofibroblasts (PMF) are known to be critical in bile duct injury, but their role in liver fibrogenesis remains underexplored. Thy-1, an adhesion molecule integral to fibroblasts, relevant in fibrogenesis and detectable in serum as soluble Thy-1 (sThy-1), is expressed by PMF but not hepatic stellate cells in vitro. This study aimed to elucidate the correlation between Thy-1 expression in liver histology and sThy-1 levels in serum with the degree of liver fibrosis in patients with primary biliary cholangitis (PBC) and metabolic dysfunction associated steatotic liver disease (MASLD). Liver histology samples were stained for Thy-1 and sThy-1 was measured using an enzyme-linked immunosorbent assay (ELISA). In patients with PBC and MASLD, portal Thy-1 expression significantly correlated with increased fibrosis. The sinusoidal Thy-1 expression also significantly correlated with increased fibrosis in patients with PBC (p

Introduction: Despite its high prevalence and impact on health, metabolic dysfunction-associated steatotic liver disease (MASLD) is inadequately addressed in European primary care (PC), with a large proportion of cases going undiagnosed or diagnosed too late. A multi-country European re-search consortium led a project to design and evaluate a patient-centered, integrated model for MASLD screening, diagnosis and linkage to specialty care for European PC settings. Aim: Based on the lessons from this project, the latest research evidence and existing guidelines for the management of MASLD, we sought to develop a set of practice recommendations for screening, referral and management of MASLD in PC. Methods: The Rand/UCLA modified Delphi panel method, with two rounds, was used to reach consensus on practice recommendations. The international panel consisted of experts from six countries, representing family medicine, gastroenterology, hepatology, cardiology and public health. Initially, fifteen statements were drafted based on a synthesis of evidence from the literature and earlier findings from our consortium. Prior to the consensus meeting, the statements were rated by the experts in a first round. Then, in a hybrid meeting, the experts discussed findings of round one, adjusted the statements and reassessed the updated recommendations in a second round. Results: In round one, there was already a high level of consensus on 10 out of 15 statements. After round 2, there were fourteen statements with a high agreement (>90%). One statement was not endorsed. The approved recommendations addressed the following practice areas: risk screening and diagnosis, management of MASLD – Lifestyle interventions, pharmacological treatment of MASLD/MASH, pharmacological treatment for co-morbidity, integrated care, surgical management and other referrals to specialists. Conclusion: The final set of 14 recommendations focuses on increasing comprehensive care for MASLD in PC. The recommendations provide practical evidence-based guidance tailored to PC practitioners. We expect that these recommendations will contribute to the ongoing discussion on systematic approaches to tackle MASLD and support European PC providers by integrating the latest evidence into practice.

Background: Liver failure profoundly affects the immune system, leading to dysregulation of innate and adaptive immune responses. Body: This review explores the intricate relationship between liver function and immune homeostasis. The role of the liver as a central hub in immune response initiation is elucidated, emphasizing its involvement in hepatic inflammation induction and subsequent systemic inflammation. Cytokines, chemokines, growth factors, and lipid mediators orchestrate these immune processes, serving as both prognostic biomarkers and potential therapeutic targets in liver failure-associated immune dysregulation. Furthermore, the review delves into the mechanisms underlying immunosuppression in liver failure, encompassing alterations in innate immune cell functions such as neutrophils, macrophages, and natural killer cells (NK cells), as well as perturbations in adaptive immune responses mediated by B and T cells. Conclusion: Understanding the immunological consequences of liver failure is crucial for developing targeted therapeutic interventions and improving patient outcomes in liver disease management.

BackgroundLiving donor liver transplantation offers comparable long-term results to cadaveric donor transplantation. This study analyzes the selection process of living liver donors at a Western transplant center that utilizes both donation forms. MethodsThis retrospective analysis examined potential living donors, collecting medical data and reasons for refusal, and divided patients by indication and urgency for transplantation. ResultsFrom January 2013 to December 2023, 594 potential living donors were assessed at Jena University Hospital. Of these, 124 living donor transplants were performed. During outpatient evaluation, 357 potential donors were excluded. Subsequently, 238 individuals underwent inpatient assessment, with 100 more being excluded. Main reasons for donor refusal included medical or psychological issues (n=160), disease progression in recipients (n=90), and recipient refusal or donor withdrawal (n=54). The evaluation process showed a trend towards considering more distant relatives and acquaintances as donor candidates with increasing severity of the recipient's disease.

For esophageal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT), restaging using F-18-fluorodeoxyglucose (18F-FDG) positron emission tomography computed tomography (PET-CT) following nCRT can detect interval metastases, including liver metastases, in almost 10% of patients. However, in clinical practice, focal FDG liver uptake, unrelated to liver metastases, is observed after chemoradiotherapy. This radiation-induced liver injury (RILI) can potentially lead to overstaging. Liver radiation damage is also a concern during distal esophageal cancer radiotherapy due to proximity to the left liver lobe, typically included in the radiation field. Post-CRT, if FDG activity appears in the left or caudate liver lobes, thorough investigation is needed to confirm or rule out distant metastases. The increased FDG uptake in liver lobes post-CRT often presents a diagnostic dilemma. Distinguishing between radiation-induced liver disease and metastasis is vital for appropriate patient management, necessitating a combination of imaging techniques and an understanding of the factors influencing radiation response. Diagnosis involves identifying new foci of hepatic FDG avidity on PET/CT scans. Geographic regions of hypoattenuation on CT and well-demarcated regions with specific enhancement patterns on contrast-enhanced CT scan and MRI are characteristic of radiation-induced liver disease (RILD). Lack of mass effect on all three modalities (CT, MRI, PET) indicates RILD. Resolution of abnormalities on subsequent examinations also helps in diagnosing RILD. Moreover, it can also help to rule out occult metastases, thereby excluding those patients from further surgery who will not benefit from esophagectomy with curative intent.

The inclusion of spent hemp biomass (SHB), an extracted byproduct from industrial cannabidiol (CBD) production, in the diets of dairy cows and lambs appear to be safe with minor effects on the metabolism, including a decrease of circulating cholesterol and increase bilirubinemia, both associated with liver metabolism. Those effects could be consequence of the presence of cannabinoids, particularly Δ9-tetrahydrocannabinol (THC) and CBD in the SHB. This study aimed to study the transcriptional profile of the liver of dairy cows and lambs fed SHB. Dairy cows received SHB or alfalfa pellet for four weeks of intervention (IP) and four weeks of withdrawal periods (WP). Finishing lambs were fed a control diet (CON), 10% (LH2) or 20% (HH2) SHB for 2 months or 1 month followed by 1-month SHB withdrawal (LH1 and HH1, respectively). RNA sequencing was performed, and the mRNA was annotated using the latest reference genomes. The RNAseq data were filtered, normalized for library size and composition, and statistically analyzed by DESeq2. The bioinformatic analysis was performed by using DAVID, Gene Set Enrichment (GSE) analysis, and the Dynamic Impact Approach. Using a 0.2 FDR cut-off, we identified only ≤24 differentially expressed genes (DEG) in the liver by feeding SHB in dairy cows and a larger number of DEG in lambs (from 71 in HH1 vs. CON to 552 in LH1 vs. CON). The KEGG analysis demonstrated that feeding SHB in dairy cows and lambs had relatively minor to moderate metabolic alterations in dairy cows and lambs mainly associated with amino acids and lipid metabolism whereas cholesterol synthesis was overall activated in lambs. GSE analysis identified activation of PPAR signaling pathway only in dairy cows. We found an opposite effect on activation of metabolism of drug and xenobiotics by cytochrome P450 enzymes in dairy cows and lambs receiving less SHB but an inhibition in HH2 lambs. Immune system-related pathways were inhibited by feeding SHB in lambs, but the impact was minor. Cumulatively, inclusion of SHB containing cannabinoids in dairy and lambs demonstrate very little effects on the alteration of transcriptomic profile of the liver.

The formula Chong-Lou-Yao-Fang (CLYF) is an herbal medicinal formulation developed by the indigenous Naxi people for treating liver cancer. This study is to reveal the biological activity, potential targets, and molecular mechanisms of CLYF for cancer treatment through network pharmacology, molecular docking and in vitro experiments. 35 key compounds were screened from 176 active ingredients in CLYF, which played a vital role in the treatment of cancer, 20 core targets were filtered through protein–protein interaction (PPI) network analysis. The enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated that PI3K-Akt, MAPK, hepatitis B, hepatitis C might be effective in liver cancer treatment. Mo-lecular docking revealed stable binding between EGFR, TP53, and AKT1 with active ingredients. Experiments with cell cultures confirmed that CLYF-A suppressed the proliferation of HepG2 cells, which is consistent with the network pharmacology approach undertaken and the predictions of molecular docking. CLYF-A also induced significant apoptosis and cell cycle arrest in HepG2 cells, which was associated with the loss of mitochondrial membrane potential. This study explored the biological activity, potential targets, and molecular mechanisms of CLYF for cancer treatment. Our results may provide a scientific basis for the clinical use of CLYF for cancer treatment and have important implications for developing pharmaceutical preparations, which also need more phar-macological experiments.

Breast cancer, when advancing to a metastatic stage, involves the liver, impacting over 50% of cases and significantly diminishing survival rates. Presently, a lack of tailored therapeutic protocols for Breast Cancer Liver Metastasis (BCLM) underscores the need for a deeper understanding of molecular patterns governing this complication. Therefore, by analyzing differentially expressed genes (DEGs) between primary breast tumors and BCLM lesions, it aimed to shed light on the diversities of this process. This research investigates Breast cancer liver metastasis relapse by employing a comprehensive approach that integrates data filtering, Gene Ontology and KEGG Pathway Analysis, Overall Survival analysis, identification of the Alteration in the DEGs, Visualization of Protein-Protein Interaction Network, Signor 2.0, identification of positively correlated genes, screening results of the function of hub genes, immune cell infiltration analysis, genetic alternation analysis, Copy number variant analysis, Gene to mRNA interaction, transcription factor analysis , autodocking and identification of Potential Treatment Target. This study’s integrative approach unveils metabolic reprogramming, suggesting altered PCK1 and LPL expression as key in breast cancer metastasis recurrence.

Annually, more than 1.5 million preventable new hepatitis B (HBV) infections continue to occur, with an estimated global burden of 296 million individuals living with chronic hepatitis B infection. This substantial health challenge results in over 820,000 annual deaths attributed to complications such as liver cirrhosis and hepatocellular carcinoma (HCC). HBV vaccination remains the cornerstone of public health policy to prevent chronic hepatitis B and its related complications. It serves as a crucial element in the global effort to eliminate HBV, as established by the World Health Organization (WHO), with an ambitious 90% vaccination target by 2030. However, reports on global birth dose coverage reveal substantial variability, with an overall coverage rate of only 46%. This comprehensive review thoroughly examines global trends in HBV vaccination coverage, investigating the profound impact of vaccination on HBV prevalence and its consequences across diverse populations, including both high-risk and general demographics. Additionally, the review addresses the formidable challenges and facilitating factors essential for achieving WHO's HBV vaccination coverage objectives and elimination strategies in the coming decade and beyond.

The detection of Fasciola eggs in ruminant fecal samples typically occurs around 15 weeks post-infection during patent infections. The recent introduction of coproantigen ELISA (cELISA) diagnostics, which capture antigenic enzymes in fecal material, holds promise for monitoring Fasciola fecal egg count (FFEC) to implement control programs, particularly targeted treatments. This study compared two study groups, those with positive FFEC (FFEC+ve) and negative FFEC (FFEC-ve), to assess the sensitivity of Flukefinder sedimentation and a cELISA kit. This study reports that the coproantigen ELISA detection limit was 4.5 eggs per gram (epg) for a 100% positivity rate. Additionally, a moderate, statistically significant positive correlation (r²=0.716, p-value < 0.01) and an odds ratio of 1.96 (p-value < 0.01) were observed between FFEC and Fasciola coproantigen from cELISA. This implies that for every single unit increase in FFEC, there is a 96% likelihood of obtaining a higher optical density (OD) reading from the cELISA test. The results suggest that cELISA can complement fecal sedimentation tests, serving as a valuable tool for detecting cattle with high FFEC. This capability facilitates targeted treatment strategies, thereby aiding in the control and prevention of the spread of fasciolosis within the studied area.

Long-term safety of a nutraceutical combination based on agnus castus and magnolia extracts combined with soy isoflavones (SI) and lactobacilli, and effectiveness on vasomotor symptoms and sleep disorders in postmenopausal women, were assessed. A controlled study was carried-out in menopausal women comparing this nutraceutical combination (ESP group) with formulation containing isoflavones alone (C group), at the dosage recommended. Kuppermann index, PSQI, and SF-36 were determined at baseline, 3, 6 and 12 months. Endometrial thickness, mammary density and liver function were evaluated at baseline and after 12 months. 180 women (100 in ESP group and 80 in C group, mean age 55.5 years, in menopause for about 36 months) were enrolled in the study. At the treatment end, mammary density, endometrial thickness, and hepatic function did not show substantial differences between groups. Kuppermann index, and particularly hot flushes, were progressively and significantly decreased in frequency and severity during ESP versus C treatment. No adverse events were observed. Agnus castus and magnolia, combined with SI + lactobacilli, can effectively and safely be used in symptomatic postmenopausal women, mainly when quality of sleep is the most disturbing complaint. Endometrium, mammary glands and liver function, were unaffected after 12 months treatment.

The aim of our study was a comprehensive comparative assessment of the effect of consumption of 1 and 2% cholesterol as part of a standard diet with and without regular moderate physical activity on the main biomarkers of lipid and cholesterol metabolism, as well as the intestinal microbiota of male Wistar rats. The animals were randomly divided into 5 groups according to body weight and Open Field test results: Control (n=10), 1% Chol (n=10), 2% Chol (n=10), 1% Chol + RUN (n=10) and 2% Chol + RUN. The cholesterol was additionally added in the amount of 1g or 2g/100g, respectively, to the diet of animals. The rats of experimental groups 1% Chol + RUN and 2% Chol + RUN were subjected to regular (2 days a week) physical activity on a Treadmill. In rats of four experimental groups, when compared to the Control, a response of 39 indicators was revealed. The largest number of changes in biomarkers - 29 (statistically significant, p

A Clinical Prognostic Index (CPI) for improved patient selection for stereotactic liver-directed radiotherapy (SBRT) was developed. Using a large single-center database, 195 patients treated with SBRT for local control, including 66 with hepatocellular carcinoma (HCC) and 129 with metastatic liver disease, were analyzed. Only patients ineligible for alternative treatments were included. Overall survival was 11.9 months and 9.4 months in the HCC group and metastatic groups, respectively. In the combined dataset, Child-Pugh Score (CPS) (p=0.002), serum albumin (p=0.039) and presence of extrahepatic disease (p=0.012) were significant predictors of early death on multivariable analysis and were included in the CPI (total score 0 to 5). Median survival was 23.8, 9.1, 4.5 and 2.6 months for patients with 0, 1-2, 3 and 4-5 points, respectively. In the HCC dataset, CPS (p&lt;0.001) and gross tumor volume (p=0.013) were predictive of early death. In the metastatic dataset, serum albumin (p&lt;0.001) and primary disease site (p=0.003) were predictive of early death. The AUC for the combined, HCC, and metastatic datasets are 0.78, 0.84, 0.80 respectively. Poor liver function (defined by CPS and serum albumin) and extrahepatic disease were most predictive of early death, providing clinically important expected survival information for patients and caregivers.

Hepatic hemangiomas (HH) are the most frequent benign tumors of the liver. They are usually asymptomatic and small in size. However, others can present as large tumors and can be symptomatic. In this case surgical resection is recomemend. We present a case report for treatment in our hospital. A 48 years old male, who was brought to the emergency room complaining of vomiting and pain in the right upper quadrant that had been going on for 8 years. The examination showed a firm mass in the right hypochondrium that extended below the umbilicus. The ultrasound (US) reported severe hepatomegaly secondary to giant hypoechoic lesions. The study was completed with a computed tomography scan (CT-scan) or Magnetic resonance imaging (MRI). This case was evaluated by a multi - disciplinary team, who decided to do a liver transplant. After three months signed up on the waiting list,the patient finally received a new liver from a matched brain - dead organ donor. In this case the surgery was completed with caval - preserving Piggy - back implant technique, without the need of a classic technique nor a veno - venous bypass. He received a transfusion of 8 units of packed red blood cells during the operation. The postoperative time passed with good evaluation. Patient went back home after 14 days in the hospital. The pathology report showed a giant multifocal hemangioma, with a size of 28 x 19 x 15 cms. Some HH needs surgery, there are different options: simple enucleation to complete hepatectomy associating liver transplant as our case. The correct treatment is too important, and these case have to be tried with multi - disciplinary team. This group is composed of hepatobiliary surgeons, hepatologists and anesthetists. The bleeding massive risk is large, so it is necessary to know the clasic surgery technique.

Background: The purpuse was to investigate the influence induced by magnesium chloride (MgCl2) and zinc gluconate (ZnG) supplementation on liver and kidney injuries experimentally-induced with acetaminophen (AAPh) and potentiated by ciprofloxacin addition in rats. Material and methods: The experiment was performed on 5 animals groups: group 1 – control, treated for 6 weeks with normal saline, 1mL/kg; group 2 – AAPh, treated for 6 weeks with AAPh, 100 mg/ kg/day; group 3 – AAPh+C, treated AAPh 100 mg/kg/ day for 6 weeks and ciprofloxacin, 50mg /kg/day, only in the last 14 days of the experiment; group 4 – AAPh+C+Mg, with the same treatment as group 3, but, and in the last 14 days, MgCl2 10 mg/ kg/day was added; group 5 – AAPh+C+Zn, with the same treatment as group 3, but, and in the last 14 days, zinc gluconate (ZnG),10 mg/kg/day was added. All administrations were performed by oral gavage. At the end of the experiment, the animals were sacrificed and blood samples were collected for biochemistry examinations. Results: Treatment with AAPh for 6 weeks determined an alteration of the liver function (increases in alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase and, and gamma-glutamyl transferase) and of renal function (increases in serum urea and creatinine) (P < 0.001 group 2 vs. group 1 for all mentioned parameters). Also, the antioxidant defense capacity was impaired in group 2 vs. group 1 (superoxide dismutase and glutathione peroxidase activity decreased in group 2 vs. group 1, 0.001 < P < 0.01, respectively 0.01 < P < 0.05). The addition of ciprofloxacin, 50 mg/kg/day during the last 14 days resulted in further increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea and creatinine (0.01 < P < 0.05, group 3 vs. group 2). MgCl2 provided a slight protection against liver enzymes increase and a more pronounced protection against the increase in serum urea and creatinine (0.001 < P < 0.01 group 4 vs. group 3). MgCl2 provided a slight protection against the decrease in superoxide dismutase (0.01 < P < 0.05 group 4 vs. group 3), but not against decrease of glutathione peroxidase. The improvement of mentioned parameters could also be seen in case of ZnG, to a higher extent especially in the case of alanine aminotransferase and lactic dehydrogenase (0.01 < P < 0.05 group 5 vs. group 4). Conclusions: This study represents a furthermore proof for beneficial effect of magnesium and zinc salts against toxicity induced by different agents, including antibacterials added to the analgesic and antipyretic acetaminophen; the protection is proven on the liver and kidney’s function; the antioxidant profile improvement has a key role, especially in case of zinc gluconate.

Liver cirrhosis is one of the most prevalent chronic liver diseases worldwide. In addition to viral hepatitis, genetic conditions such as steatohepatitis, autoimmune hepatitis, sclerosing cholangitis, and Wilson’s disease can also lead to cirrhosis. Moreover, alcohol can cause cirrhosis on its own and exacerbate chronic liver disease from other causes. The treatment of cirrhosis can be divided into addressing the cause of cirrhosis and reversing liver fibrosis. To this date, there is still no clear consensus on the treatment of cirrhosis. Recently, there has been a lot of interest in potential treatments that modulate the gut microbiota and gut-liver axis for the treatment of cirrhosis. According to recent studies, modulation of the gut microbiome by probiotics ameliorates the progression of liver disease. The precise mechanism for relieving cirrhosis via gut microbial modulation has not been identified. This paper summarizes the role and effects of the gut microbiome in cirrhosis based on experimental and clinical studies on absorbable antibiotics, probiotics, prebiotics, and synbiotics. Moreover, it provides evidence of a relationship between the gut microbiome and liver cirrhosis.

Introduction: Sarcopenia, muscle loss, often coexists with MASLD, a common liver disorder, which is more prevalent in those with sarcopenia. Sarcopenia also increases the risk of liver conditions like steatosis and fibrosis. Studies on sarcopenia in MASLD are common in developed countries, but fewer follow the EWGSOP2 guidelines in Brazil. Aim: to assess sarcopenia prevalence in MASLD patients. Methods: Cross-sectional study conducted at the Gastroen-terology/Hepatology Service of ISCMPA with patients diagnosed with MASLD. The EWGSOP2 criteria were used to evaluate sarcopenia. Categorical data presented as absolute and relative frequency; parametric continuous data ex-pressed as mean±standard deviation; non-parametric continuous data as me-dian and IQR. Gender differences in were analyzed using Fisher's Exact Test or Chi-squared tests, and for continuous variables, T Student tests (parametric) and Mann-Whitney U tests for independent samples (non-parametric). The significance level was set at 5% (p<0.05). Results: The study involved 103 MASLD patients with an average age of 60.39 years, comprising 48 (46.60%) adults and 55 (53.40%) older individuals. Concerning sarcopenia diagnosis, four individuals exhibited decreased muscle strength; two had reduced MME (sarcopenia); and one showed decreased walking speed (severe sarcopenia). Among the participants, 63 (60.6%) were physically active. 35 (62.5%) had mild to moderate steatosis, while 21 (37.5%) had severe steatosis. In terms of EHNA, 13 subjects (24.08%) had moderate to severe EHNA. Regarding fibrosis classi-fication, 68 (72.34%) individuals had undetermined or high probability based on the NAFLD score, with higher prevalence in males (n=23; 88.5%). Fibrosis assessment via liver biopsy revealed 27 (28.72%) in F1 and F2 and 15 (16.96%) in F3 and F4. Stratification of fibrosis into F3 and F4 was more com-mon among men (n=9; 47.4%). Conclusion: Most of the population was physi-cally active. The parameters indicating sarcopenia exceeded the thresholds recommended by EWGSOP2. The prevalence of sarcopenia was low in individuals with MASLD.

The hepatic sinusoids are lined by thin endothelium containing transcellular pores dubbed fenestra. These fenestrations are completely open channels connecting the sinusoidal lumen to the underlying Space of Disse (SoD) and the hepatocytes of the liver parenchyma. The fenestrations are in the size range 0.05-0.35µm in diameter and cover between 5-15% of the sinusoidal endothelial surface area depending on their location along the sinusoids. Motivation/Research Question: So far, the narrowness of the sinusoids prevented the direct measurement of hemodynamic features such as sinusoidal pressure and flow velocity. A better understanding of these parameters might help in better understanding the physiology of the hepatic niche and possible implications in liver diseases. Few simulations of liver blood flow focus on the level of the individual sinusoid, fewer still include the transcellular pores (fenestrations) of the sinusoidal endothelium, and none have included i) a porosity gradient along the sinusoid wall modelled with through-all pores rather than a porus medium, ii) the presence of the Space of Disse, iii) lymphatic drainage. Model: Computed fluid dynamic (CFD) simulations performed using a numerical model with relevant anatomical characteristics (length, diameter, porous size and porosity). Boundary conditions included physiological/pathological values of inlet/outlet pressure and lymphatic outflow from the portal region of the SoD. Results: The pressure and flow velocity of the sinusoidal lumen was entirely dependent on the shape, i.e. constant versus divergent radius and not dependent on porosity in the sinusoidal wall. The velocity through the space of Disse (SoD) was affected by the addition of lymphatic drainage and increases in porosity in the pericentral area of the model. Variations in porosity also affected flow velocity through the fenestrations. Conclusions: The flow velocity in the SoD was modified by differences in porosity, while the flow velocity in the lumen of the sinusoids was unaffected, even by the absence of fenestrations. The overall shape of the vessel is the singular most important factor in the pressure flow behavior of the sinusoidal lumen. The flow rate over the hepatocytes is the flow rate through the SoD, and is modestly affected by the distribution of porosity along the sinusoid, and by the addition of a lymphatic drainage, this parameter would be of interest for modelling blood exchange with the hepatic parenchyma, especially if accounting for zonation.

HCC is a highly aggressive malignancy with limited treatment options. In this study, novel conjugates, of NSAIDs - Ibuprofen and Ketoprofen with oleanolic acid oximes derivatives (OAO) were synthesized and their activity as modulators of signaling pathways involved in HCC pathogenesis was evaluated in normal THLE-2 liver cells and HCC derived HepG2 cells. The results demonstrated that conjugation with OAO derivatives reduces the cytotoxicity of parent compounds in both cell lines. In THLE-2 cells treatment with conjugates resulted in increased activation of the Nrf2-ARE pathway. An opposite effect was observed in HepG2 cells. In the later reduction of NF-κB was observed along with modulation of MAPK signaling pathways (AKT, ERK, p38, p70S6K, and JNK). Moreover, STAT3, STAT5, and CREB transcription factors on protein levels were significantly reduced as a result of treatment with IBU- and KET-OAO derivatives conjugates. The most active were conjugates with OAO-morpholide. Overall, the findings of this study demonstrate that IBU-OAO and KET-OAO derivatives conjugates modulate the key signaling pathways involved in hepatic cancer development. Their effect on specific signaling pathways varied depending on the structure of the conjugate. Since the conjugation of IBU and KET with OAO derivatives reduced their cytotoxicity, the conjugates may be considered good candidates for the prevention of liver cancer.

(1) Background: Although multiple studies have reported on the therapeutic effects of Atezo+Bev for the treatment of NASH-related liver cancer, few studies have focused on its effect on liver reserve. Here, we aimed to compare the changes in hepatic reserve during the Atezo+Bev treatment of NAFLD/NASH-related HCC and of non-NAFLD/non-NASH-related HCC. (2) Methods: We retrospectively compared the changes in ALBI score in 109 patients with NAFLD/NASH or non-NAFLD/non-NASH during 12 weeks of treatment with Atezo+Bev for advanced HCC between September 2019 and January 2022. PSM was performed, and the OS, PFS, and PPS of the two groups were compared. (3)Results: The ALBI after 12 weeks of Atezo+Bev treatment was significantly worse in the NAFLD/NASH group than in the non-NAFLD/non-NASH group. Analysis of the 24 propensity score-matched pairs of cases with NAFLD/NASH or non-NAFLD non-NASH yielded similar results. The prognoses of the two groups were similar with respect to OS and PFS, but the NAFLD/NASH group had a significantly shorter PPS. The 24 matched pairs had similar OS and PFS, but the PPS of the NAFLD/NASH group was shorter. (4)Conclusion: Atezo+Bev treatment may worsen hepatic reserve, and there-fore life expectancy, in patients with NAFLD/NASH-related liver cancer.

(1) Background: Endoscopic submucosal dissection (ESD) has been widely accepted as the standard method for treating early-stage cancer or precancerous lesions in the upper gastrointestinal tract, however it may be difficult in patients with liver cirrhosis due to coagulation dysfunction or presence of gastroesophageal varices. We aimed to demonstrate the safety and efficacy of ESD in these population. (2) Methods: We retrospectively collected the clinical data and analyzed. Patients inclusion criteria: 1) patients with liver cirrhosis; 2) patients who underwent ESD; 3) patients diagnosed of early-stage cancer or precancerous lesions in the upper gastrointestinal tract. (3) Results: Eight patients were enrolled from April 2019 to April 2023, of whom 3 were male and 5 female, with age ranging from 43 to 70 years old. Seven lesions were located in the stomach, and the other one lesion in the esophagus. ESD was performed successfully in all patients, and the resected lesion size ranged from 2 to 6 cm. Only one patient encountered postoperative complication, chest pain and fever. No recurrence of noticed during a follow-up of 6 to 36 months. (4) Conclusions: ESD is safe and effective for treating upper gastrointestinal early-stage cancer or precancerous lesions in patients with liver cirrhosis.

Background: RNA helicase DHX15 plays a significant role in vasculature development and lung metastasis in vertebrates. In addition, several studies have demonstrated the overexpression of DHX15 in the context of hepatocellular carcinoma. Therefore, we hypothesized that this helicase may play a significant role in liver regeneration, physiology and pathology. Methods: Dhx15 gene deficiency was generated by CRISPR/Cas9 in zebrafish and by TALEN-RNA in mice. FANA Antisense-Oligonucleotides were used to silence Dhx15 in wild-type mice. The hepatocellular carcinoma tumor induction model was generated by subcutaneous injection of Hepa 1-6 cells. Results: Homozygous Dhx15 gene deficiency was lethal in zebrafish and mouse embryos. Dhx15 gene deficiency impaired liver organogenesis in zebrafish embryos and liver regeneration after partial hepatectomy in mice. Also, heterozygous mice presented decreased number and size of liver metastasis after Hepa 1-6 cells injection compared to wild-type mice. Dhx15 gene silencing with FANA Antisense-Oligonucleotides in wild-type mice resulted in 80% reduced expression in the liver and a significant reduction in other major organs. In addition, Dhx15 gene silencing significantly hindered primary tumor growth in the hepatocellular carcinoma experimental model. Regarding the potential use of DHX15 as a diagnostic marker for liver disease, patients with hepatocellular carcinoma showed increased levels of DHX15 in blood samples compared with subjects without hepatic affectation. Conclusion: Dhx15 is a key regulator of liver physiology and organogenesis, is increased in the blood of cirrhotic and hepatocellular carcinoma patients and has a key role in controlling hepatocellular carcinoma tumor growth and expansion in experimental models.

Liver fibrosis is based on complex interactions between extracellular matrix-producing hepatic stellate cells and is defined as excessive matrix deposition and an abundance of infiltrating cells in the liver. Studying these processes requires in vitro and in vivo experimental work on animals. In fibrosis research, experimental work in rodents is currently the gold standard for confirming a proposed disease-associated mechanism. Bile duct ligation (BDL) induces obstructive jaundice resulting in cholestasis. BDL is useful for preclinical research studies of liver injury due to extrahepatic cholestasis such as apoptosis and fibrosis. Here we provide a stepwise surgical approach to resect the common bile duct and monitor in situ hepatic metabolism by microdialysis.

This study investigated the development of novel probiotic formulations specifically designed for rainbow trout aquaculture. The project evaluated the effects of two formulations containing potential probiotic strains isolated from rainbow trout itself. These effects were assessed on various parameters including growth performance, immune response, liver enzyme activity, gene expression related to immunity, and the composition of the bacterial gut microbiota in rainbow trout (Oncorhynchus mykiss). In a completely randomized experimental design, a total of 450 rainbow trout were randomly divided into 70-liter fiberglass tank. The study included six treatments of three replicates (n=18 tanks). Six dietary treatments were included (A) and (B) containing three strains of Pediococcus sp P15, Lactococcus lactis ml3, Weissella cibaria ml6 at two dosages (300 and 500 mg/kg), treatments (C) and (D) containing five strains of P. sp P15, L. lactis ml3, W. cibaria ml6, Enterococcus faecium E10 and Lactobacillus curvatus 13A at two dosages (300 and 500 mg/kg), a commercial probiotic (E) at 300 mg/kg, and a control group (F) without probiotics. Treatments of (A), (B) and (E) resulted in the highest final weights in compared to control group. Fish fed treatments (A) and (B) had the lowest FCR than other groups. Treatments (A) and (D) showed a significant increase in immunoglobulin M (IgM) concentration compared to other groups. The expression of tumor necrosis factor (TNF) was significantly lower in group (A) than the control. In contrast, the expression of interleukin 6 (IL6) and immunoglobulin T (IgT) was increased 4.4-fold and 41-fold, respectively, in group (A) compared to control group. Among the probiotic fed treatments, group (A) showed a significant higher number of lactic acid bacteria compared to other groups during the experiment. This study highlights the significant role of treatment (A) containing three strains of P. sp P15, L. lactis ml3, and W. cibaria ml6 at a dosage of 300 mg/kg as a potential probiotic product for the rainbow trout industry.

Ferroptosis, a form of regulated cell death characterized by lipid peroxidation and iron accumulation, has been implicated in the progression of metabolic dysfunction-associated steatohepatitis (MASH) in obesity. This study investigated the role of ferroptosis in the development of hepatic steatosis and MASH in obese mice and assessed the therapeutic potential of ferrostatin-1, a ferroptosis inhibitor. C57BL/6J wild-type mice (n = 8) and ob/ob (n = 16) were maintained on a standard chow diet. Mice were divided into three groups that included C57BL/6 (n = 8), ob/ob (n = 8), and ob/ob + ferrostatin-1 (FER) (n = 8), with the latter group receiving an intraperitoneal injection of 5 μM/kg ferrostatin three times per week for eight weeks. Following treatment, serum and tissue samples were collected for analysis. Significant hepatic steatosis and increased lipogenesis markers were observed in ob/ob mice, and this was normalized in the ob/ob + FER group treated with ferrostatin-1. Elevated oxidative stress was indicated by increased reactive oxygen species (ROS) and Malondialdehyde (MDA) levels in the ob/ob group, while glutathione peroxidase 4 (GPX4) activity was significantly reduced. Ferrostatin-1 treatment decreases MDA levels and restores GPX4 activity. Additionally, ferrostatin mitigates iron overload and promotes macrophage polarization from M1 to M2, thereby reducing liver inflammation and fibrosis. Ferrostatin treatment reversed mitochondrial dysfunction in ob/ob mice Our findings revealed that ferroptosis plays a significant role in the progression of obesity to hepatic steatosis and MASH. Inhibiting ferroptosis using ferrostatin-1 effectively improves liver histology, reduces oxidative stress, normalizes lipogenesis, and modulates macrophage polarization. This study highlights the potential of targeting ferroptosis as a therapeutic strategy for obesity-related liver diseases, warranting further investigation in clinical settings.

Asians are known to more likely than Westerners develop fatty liver and lifestyle-related diseases despite their weight. However, the relationship between fat accumulation and lifestyle-related diseases in non-obese Asians is unknown. Therefore, this study aimed to analyze visceral fat and hepatic fat in participants with a normal body mass index (BMI) and examine their characteristics during a medical checkup. This cross-sectional study was conducted on 663 of 1,142 patients who underwent abdominal ultrasonography and who had an alcohol intake (converted to ethanol) of <30 g/day for males and <20 g/day for females and a BMI of <25 kg/m2 during a health checkup. Participants were classified into four groups: group A, visceral fat accumulation (VFA) (−) and fatty liver (FL) (−) (n = 549); group B, VFA (+) and FL(−) (n = 32); group C, VFA (−) and FL (+) (n = 58); and group D, VFA (+) and FL (+) (n = 24). The frequencies of lifestyle-related disease complications, liver function tests, and liver fibrosis were evaluated among the four groups. Compared with group A (control), groups B, C, and D had higher number of males; BMI; abdominal circumference, ALT, AST, γ-GTP, triglyceride, uric acid, fasting blood sugar levels; and incidence of hyperlipidemia. Groups C and D had higher ALT, HbA1c, cholinesterase, and triglyceride levels; FIB4 index; and number of patients with diabetes mellitus (DM) than groups A and B; however, there was no difference between groups A and B. FL is a risk factor of DM and liver fibrosis in non-obese Japanese individuals; however, VFA only is not a risk factor of DM and liver fibrosis.

The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here we show that despite obesity, mice with reduced neuronal LPL (NEXCreLPLflox [LPL KD]) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to WT controls (LPLflox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence Lifetime Imaging Microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of the free vs. bound Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in, or over-expressing, LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver–related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism.

Analysing the human body by direct observation can lead to misinterpretation of underlying trends, whereas in vitro organ models facilitate their understanding. Likewise, in vitro organ models serve as valuable tools for assessing the toxicity of compounds. However, none of the existing models had the features we considered critical for toxicity assessment, so we developed an in vitro liver model for toxicity assessment. We used four different types of primary liver cells: Hepatic sinusoidal endothelial cells, hepatic stellate cells, Kupffer cells and hepatocytes. We cultured them in different combinations of composition and volume of cell medium, hepatocyte proportion of total cells, and addition of extracellular matrix. We added rifampicin, ibuprofen and 5-fluorouracil to this model and observed the microanatomy and physiology changes for a week with preclinical and clinical instruments. Among the different model configurations, we selected the feature combination of the in vitro model that had similar biomarker values to those measured by the clinical instruments used in clinical diagnostics. When we exposed the selected model configuration to rifampicin, ibuprofen and 5-fluorouracil, the viability of Kupffer cells and liver sinusoidal endothelial cells was significantly lower than in the untreated samples. In contrast, we observed negligible viability of hepatocytes compared to the untreated samples. We have built an in vitro liver model that resembles the liver microenvironment and we have analysed it with clinical instrumentation to facilitate the data translation. In this sense, we have established that Kupffer and LSEC cells are suitable candidates for the search for clinical diagnostic markers of liver function.

Resistance to the existing drugs and increasing numbers of diseases result in identifying new drug candidates with new forms of activity. Marine sources of alkylglycerols such as the liver oil Shark (SLO) mixture of certain species or rat fish (elasmobranch fishes) contain high levels of these compounds as a mixture of few species varying by length and unsaturation or saturation of the alkyl chain. They have multiple biological activities such as hematopoiesis stimulation, lowering radiotherapy-induced injuries, reducing tumor growth and improving vaccination efficiency. The synthesis of two Alkylglycerols (AKGs) containing at least one alkyne moiety in the alkyl chain has been reported. In this work, we describe the synthesis of others unknown AKGs based alkyne 1-O-(hexadec-11’-ynyl)-sn-glycerol 4 and 1-O-(octadec-9’-ynyl)-sn-glycerol 5 as analogues of bioactive ether lipids found in the SLO mixture.

Background: COVID-19 infection has received the attention of the scientific community due its respiratory manifestations and association with evolution to severe acute respiratory syndrome (SARS-CoV-2). There are few studies characterizing SARS-CoV-2 in pediatric immunocompromised patients, such as liver transplanted (LT) patients.The aim of this study was to analyze the outcomes of the larger cohort of pediatric liver transplant recipients (PLTR) from a single center in Brazil who where contaminated with COVID-19 during the pandemic. Methods: Cross-sectional study. Primary outcomes: COVID-19 severity. The Cox regression method was used to determine independent predictors associated with the outcomes. Results: 74 PLTR were included. Patients were divided into two groups according to the severity of COVID-19 disease: moderate-severe COVID and asymptomatic-mild COVID. Patients categorized as moderate-severe COVID were younger (12.6 months vs. 82.1 months, p 0.03), higher prevalence of transplantation with deceased donor (50% vs. 4.3%, p 0.02) and with a higher prevalence of COVID-infected patients before 6 months after LT (75% vs. 5.7%, p 0.002). The independent predictor of COVID-19 severity identified in the multivariate analysis was COVID-19 infection < 6 months after LT (HR=0.001, 95% CI=0.001-0.67, p 0.03). Conclusion: The time interval of less than 6 months between COVID-19 infection and LT was the only predictor of disease severity in pediatric patients.

Drug-induced liver injury (DILI) stands as a significant cause of drug attrition. To mitigate clinical DILI risks, assessing drugs using human liver models is crucial since animal studies may fall short due to species-specific liver pathway variations. Cell-based preclinical hepatotoxicity testing is often pertinent. In the present study, cells from a human liver cancer line (HepG2, HepaRG) were cultured in both formats of 2D and 3D spheroids to explore their responses to drugs. Liver-specific marker expressions across cell lines and culture formats were also examined to assess disparities in drug-induced liver injury marker expressions. In cytotoxicity assays, HepG2 cells exhibited heightened sensitivity to amiodarone HCl, while HepaRG cells showed greater sensitivity to acetaminophen. Generally, 2D cultures were more responsive to drugs than 3D cultures. Consistency was observed between cytotoxicity assays and liver injury markers AST and ALT. Variations were also noted in liver cell marker secretion, with albumin and urea concentrations declining post-drug treatment, particularly with higher baseline expression in HepaRG cells and 3D cultures. Additionally, mRNA expression levels of CYP enzymes involved in hepatocellular drug metabolism were compared following treatment with enzyme inducers. CYP1A2 and CYP2C9 were not expressed in HepG2 cells. On the other hand, CYP3A4 was expressed higher in 3D culture than in 2D culture. HepaRG cells exhibited significantly increased expression of all three enzymes post-treatment. Notably, enzyme expression was notably higher in 3D cultures than in 2D cultures. Collectively, these findings suggest that HepaRG cells and 3D cultures hold promise for evaluating DILI during early-stage drug development.

Transplanted organs experience several episodes of ischemia and Ischemia-reperfusion. The graft injury resulting from ischemia-reperfusion (IRI) remains a significant obstacle to the successful survival of transplanted grafts. Temperature plays an important role in cellular metabolic rates since biochemical reactions are highly temperature dependent. Therefore, ischemia-triggered degradative reactions could be mitigated by lowering temperature. Whether a local hypothermia on liver before blockage of blood flow protects liver grafts against IRI has not been investigated. In this study, we applied local hypothermia to mouse donor livers for a specific duration before stopping blood flow to liver lobes, a procedure called "liver precooling." Mouse donor liver temperature in control groups was controlled at 37ºC. Subsequently, the liver donors were preserved in cold University of Wisconsin solution for various durations followed by orthotopic liver transplantation. Liver graft injury, function and inflammation were assessed at 1- and 2-days post-transplantation. Liver precooling exhibited a significant improvement in graft function, revealing more than a 47% decrease in plasma aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, coupled with a remarkable reduction of approximately 50% in liver graft histological damage compared to the control group. The protective effects of liver precooling were associated with the preservation of mitochondrial function, substantial reduction in hepatocyte cell death, and a significantly attenuated inflammatory response. A retrospective analysis of patient data revealed a close correlation between hypothermia and enhanced liver graft function. Taken together, reduction of the cellular metabolism and enzymatic activity to a minimum level before ischemia protects against IRI during transplantation.

The aim of this pilot study is to evaluate and compare the quality of the genomics and proteomics data obtained from paired formalin fixed paraffin embedded (FFPE) and frozen (FF) tissue percutaneous core biopsies of LIRADS 5 hepatocellular carcinoma (HCC) of varying histological grade. The preliminary data identified differentially expressed proteins and genes in poor, moderate and well differentiated HCC biopsies, with a greater efficacy in fresh frozen samples.

Methylmercury (MeHg) intoxication is a global health concern. Although MeHg neurotoxicity is well-recognized, less is known about MeHg's effects on metabolism. In this study, we evaluated MeHg intoxication (20mg/L in drinking water for 20 days) effects on liver and epididymal white fat (EWF) in young ApoE knockout (ko) and wild-type mice. The former is well-known to show spontaneous dyslipidemia. Hg levels in hair, liver, and EWF were measured to assess the degree of MeHg exposure. We also evaluated body weight gain, plasma triglycerides, total cholesterol levels, and liver injury by assessing steatosis score, AST, ALT, SOD, and TBAR levels. To evaluate EWF, we analyzed mean wet weight and adipocyte diameter, plasma leptin levels and metabolomics. Hg levels were markedly higher among intoxicated mice. ApoE ko mice showed higher Hg in the hair but lower levels in the liver and EWF than wild-type controls. Among wild-type mice, MeHg compromised weight gain and increased liver TBAR levels compared to non-challenged controls. Among non-intoxicated mice, ApoE deficiency significantly increased triglyceride, total cholesterol, and liver transaminases with reduced EWF wet weight, hepatic SOD, and plasma leptin levels. MeHg accumulation together with ApoE deficiency elevated total cholesterol, triglycerides, hepatic transaminases, and TBARS. We found distinct EWF metabolite activity in different scenarios of ApoE deficiency and MeHg intoxication, highlighting increased cardiovascular risk especially when both challenges occur. Further studies are required to elucidate the underlying mechanisms involved in these effects and the target nutritional interventions in most need to ameliorate them.

Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation; such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed cooperative effects of dual inhibition of the two pathways, in accordance with inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1-phase arrest, but not apoptosis (cleaved caspase-3, AIFM1 regulation, subG1-phase) or necroptosis (phospho-MLKL). We conclude that dual inhibition of MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block proliferation of ICC cell lines, but therapy must certainly be supplemented with standard therapies.

Background/aims: Prior research identified a significant association between heart disease and metabolic dysfunction-associated liver steatohepatitis (MASLD), but the mechanisms are unclear. This study aims to search predictive biomarkers for grade I left ventricular diastolic dysfunction (LVDD), an early stage of heart failure (HF), in type 2 diabetes mellitus (T2DM) patients. Methods: This single-center, prospective observational study screened 73 T2DM patients for grade 1 LVDD and MASLD using 2D echocardiography, tissue analysis, spectral color Doppler, and Fibromax. Results: The study analyzed 50 patients (mean age 58±11.3 years) with a median diabetes duration of 7 years, abdominal obesity (mean BMI 34.4±5.9 kg/m2), and a mean HbA1c of 7.9±1.5%. The prevalence of grade I LVDD, fibrosis, mild steatosis, moderate to severe liver steatosis, mild MASLD, and moderate MASLD was 54%, 44%, 14%, 80%, 43%, and 34%, respectively. Regression analysis revealed that grade 1 LVDD was positively associated with age, Fibrotest, ɑ2-macroglobulin, epicardiac adipose tissue (EAT), and negatively associated with lateral s`, E wave, E/e`, E/A, medium E`, and septal e` (p&lt; 0.05 for all). ɑ2-macroglobulin &gt; 1.92 g/L (AUROC= 0.782, sensitivity 70.4%, specificity 81.2%) and fibrotest score &gt; 0.11 (AUROC 0.766, sensitivity 92.6%, specificity 56.2%) were significant predictors of grade I LVDD. Conclusion: HF is a multifaceted disorder associated with multisystem organ damage, including nonalcoholic MASLD. Although the underlying mechanisms remain unclear, innovative non-invasive biomarkers, such as ɑ2-macroglobulin or fibrotest, could concurrently indicate liver stiffness and the likelihood of grade I LVDD, an early, asymptomatic HF stage in T2DM patients.

Background: Exposure to chronic low levels of aflatoxin B1 (AFB1) contamination can lead to immune suppression and nutritional consequences that might greatly contributed in the increase of hepatocellular carcinoma (HCC). The toxicity of AFB1 is greatly vary between different population, affected by age, gender, and environmental factors. Material and subjects: Aflatoxin B1 (AFB1) was measured in 50 blood samples collected from non B, C hepatitis viruses and non CMV-Ab liver disease patients from different general hospitals and polyclinic in KSA during period 01-2013 to 06-2014. All Patients demonstrate elevation of ALT and AST with unknown etiology. Serum samples were obtained and kept at −20 °C for AFB1detection. Results: Out of the 50 blood samples, 38 demonstrate a detectable serum level of AFB1 while the remaining 12 patients were AFB1 negative and used as control participants. While AST was non-significantly different in AFB1 exposed patients, ALT was significantly higher in AFB1 positive samples compared to control AFB1-negative. AFB1 was positively correlated with AST and ALT as liver function enzymes and with age as a risk factor of long duration of AFB1 chronic exposure. Multiple linear regression analysis ascertained the association between AFB1 chronic exposure and ALT increase in liver dysfunction Saudi patients. Conclusion: Measurement of elevated ALT as marker of liver injury in AFB1 chronically exposed Saudi patients can help to avoid the future development of HCC. Moreover, early detection of AFB1 exposure, together with early vaccination against HBV and HCV can remove the synergistic effects of these two etiological factors and thus decrease the risk of developing liver cancer.

Liver fibrosis, a consequence of chronic liver damage or inflammation, is characterized by the excessive buildup of extracellular matrix components. This progressive condition significantly raises the risk of severe liver diseases like cirrhosis and hepatocellular carcinoma. The lack of approved therapeutics underscores the urgent need for novel anti-fibrotic drugs. Hepatic stellate cells (HSCs), key players in fibrogenesis, are promising targets for drug discovery. This study investigated the anti-fibrotic potential of Citrus hystrix DC. (KL) and its bioactive compound, β-citronellol (β-CIT), in a human HSC cell line (LX-2). Cells exposed to TGF-β1 to induce fibrogenesis were co-treated with crude KL extract and β-CIT. Gene expression was analyzed by Real-Time qRT-PCR to assess fibrosis-associated genes (ACTA2, COL1A1, TIMP1, SMAD2). The releasing of matrix metalloproteinase 9 (MMP-9) was measured by ELISA. Proteomic analysis and molecular docking identified potential signaling proteins and modeled protein-ligand interactions. Results showed that both crude KL extract and β-CIT suppressed HSC activation genes and MMP-9 levels. The MAPK signaling pathway emerged as a potential target of β-CIT. This study demonstrates the ability of KL extract and β-CIT to inhibit HSC activation during TGF-β1-induced fibrogenesis, suggesting a promising role of β-CIT in anti-hepatic fibrosis therapies.

Zidovudine (AZT) has significantly reduced the mortality and morbidity rates among AIDS patients, but it has been associated with hepatotoxicity. AZT treatment has been linked to disrupted lipid and glucose metabolism, and the enhancement of pro-inflammatory chemokines and other mediators, which can lead to liver steatosis. In contrast, the administration of adenosine (ADO) has proven to be an effective hepatoprotector against both acute and chronic liver damage. Therefore, present study was aimed to investigate the harmful effects of chronic AZT administration and the beneficial effects of the co-administered ADO. Chronic oral AZT administration did not induce hyperglycemia or dyslipidemia, but serum liver marker enzyme activities were increased, as well as evidence of liver steatosis and inflammation. These findings were associated with low insulin and glucagon levels, elevated serum levels of pro-inflammatory cytokines and disruptions in cell redox states in these animals. ADO co-administration attenuated the deleterious effects induced by AZT: blocking the production of inflammatory molecules, increasing serum insulin and glucagon levels, and restoring liver cellular redox state. Then, blood insulin levels seemed to be greatly influenced by the cellular redox state, which was altered by AZT administration. This alteration is likely to be connected to mitochondrial integrity and metabolism.

Common genetic variants of the fat mass and obesity associated (FTO) gene are strongly associated with obesity and type 2 diabetes. FTO is ubiquitously expressed, but appears to have tissue-specific roles. Earlier studies have focused on the role of hypothlamic FTO in the regulation of metabolism. However, it appears that FTO plays a role in the regulation of metabolism in a tissue-specific manner. Recent studies suggest that expression of hepatic FTO is regulated by metabolic signals such as nutrients and hormones and altered FTO levels in liver affects glucose and lipid metabolism. This review outlines recent findings on hepatic FTO in the regulation of metabolism, with particular focus on hepatic glucose and lipid metabolism. It is proposed that abnormal activity of hepatic signaling pathways involving FTO links metabolic impairments such as obesity, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Therefore, a better understanding of these pathways may lead to therapeutic approaches to treat these metabolic diseases by targeting hepatic FTO. The overall goal of this review is to place FTO within the context of hepatic regulation of metabolism.

The relative paucity of donor livers suitable for transplantation has sparked innovations to preserve and recondition organs to expand the pool of transplantable organs. Currently, machine perfusion techniques have led to the improvement of the quality of marginal livers and to prolonged cold ischemia time and allowed for the prediction of graft function through analysis of the organ during perfusion, improving the rate of organ use. In the future, the implementation of organ modulation might expand the scope of machine perfusion beyond its current usage. The aim of this review was to provide an overview of the current clinical use of machine perfusion devices in liver transplantation and provide a perspective for future clinical use, including therapeutic interventions in perfused donor liver grafts.

The concept of Palliative Care (PC) is more and more known in medicine and the need for this type of approach is growing in a world with great longevity and exponentially increasing chronic diseases. More and more cases from internal medicine, gastroenterology or cardiology wards could benefit from a better care if their medical team would align with the PC concept and principles. In this sense we try to present the specifical needs for Romanian patients in accordance with the current standards of care and how they must be adapted to the reality of the medical system in which they are cared for. We consider also that for medical staff from chronic disease wards it may be necessary to recapitulate the most important principles that govern medical practice of palliation, emphasizing some important aspects of applicability in daily clinical activity.

We aimed to evaluate the magnesium content in human cirrhotic liver and its correlation with serum AST levels, expression of hepatocellular injury, and MELDNa prognostic score. In liver biopsies obtained at liver transplantation we measured the magnesium content in liver tissue in 27 cirrhotic patients (CIRs) and 16 deceased donors with healthy liver (CTRLs) by atomic absorption spectrometry and within hepatocytes in 15 CIRs using synchrotron-based X-ray Fluorescence Microscopy. In 31 CIRs and 10 CTRLs we evaluated the immunohistochemical expression in hepatocytes of the transient receptor potential melastatin 7 (TRPM7), a magnesium influx chanzyme also involved in inflammation. CIRs showed a lower hepatic magnesium content [117.2 (IQR 110.5-132.9) vs 162.8 (IQR 155.9-169.8) μg/g; p&lt;0.001] and a higher percentage of TRPM7 positive hepatocytes [53.0 (IQR 36.8-62.0) vs 20.7 (10.7-32.8) %; p&lt;0.001) than CTRLs. In CIRs, MELDNa and serum AST at transplant correlated: a) inversely with the magnesium content both in liver tissue and hepatocytes; b) directly with the percentage of hepatocytes stained intensely for TRPM7. The latter also directly correlated with worsening of MELDNa at transplant compared to waitlisting. Magnesium depletion and overexpression of its influx chanzyme TRPM7 in hepatocytes are associated with severity of hepatocyte injury and prognosis in cirrhosis. These data represent the pathophysiological basis for a possible beneficial effect of magnesium supplementation in cirrhotic patients.

Background and objective: Iliopsoas abscess (IPA) is a rare condition with varied symptomology and etiology. Less than one-third of patients with IPA present on the emergency department (ED) admission with the traditional triad of fever, back pain, and restricted hip motion (or limp), leading to delays in diagnosis and management. This case report aims to bring awareness among healthcare professionals regarding the atypical presentation and introduce a potential differential diagnosis when evaluating patients with fever and back pain. The intention is to provide insights into the signs and symptoms that may indicate the presence of an iliopsoas abscess and prompt additional investigations. Case report: Here, we describe a case of primary iliopsoas abscess associated with drug-induced acute liver failure in our ED. The patient complained of pain in the left lumbar region and fatigue that started two weeks before this presentation, claiming that, during the previous night, the pain suddenly worsened. She had a fever, pain at palpation in the right hypochondriac and left lumbar regions, accompanied by fever and vomiting, jaundiced skin, and sclera at the examination in ED. On abdominal ultrasonography, the diagnosis of acute cholangitis was suspected. The laboratory test shows leukocytosis with neutrophilia, thrombocytosis, hepatocytolysis syndrome, and hyperbilirubinemia with the predominance of indirect bilirubin. We performed then abdominal and pelvic computed tomography, which confirmed the diagnosis of cholelithiasis observed with the diameter of the bile duct within normal limits but also showed an abscess-like collection fused to the interfibrillar level of the left iliopsoas muscle; a diagnosis we most likely would have been missed. After that, the patient was hospitalized in the General Surgery Department, and surgery drainage of the abscess was performed. The patient's evolution was excellent; she was discharged after 11 days. Conclusions: The case presented here exemplifies how iliopsoas abscess, a rare cause of back pain, can quickly go unrecognized, especially in the emergency department. Our experiences will raise awareness among doctors in emergency departments about this uncommon but essential diagnosis. With advancements in diagnostic tools and techniques, we aspire that more cases of iliopsoas abscess will be accurately diagnosed.

Background: Nonalcoholic fatty liver disease (NAFLD) is regarded as a component of metabolic syndrome, which has insulin resistance (IR) as the primary physiopathological event. The aim of study was to establish the association between IR, assessed using triglyceride and glucose index (TyG), and histopathological features of NAFLD lesions. Methods: The study included patients with metabolic syndrome. Fasting plasma glucose (FPG), fasting lipid profiles and liver enzymes were measured. IR was assessed by TyG index. Liver biopsy was performed for assessment steatosis and fibrosis. Results: TyG index had a mean value of 8.93 ± 1.45, with a higher value in the patients with overweight (p=0.002) and obesity (p=0.004) than in the patients with normal weight. TyG index mean value of 8.78 ± 0.65 in subjects without NASH, 8.91 ± 0.57 in patients with borderline NASH and 9.13 ± 0.55 in patients with definite NASH. Significant difference was found between subjects without NASH and the ones with definite NASH (p=0.004). The analysis of the area under the ROC curve proved that TyG index is a predictor for NASH (p=0.043). Conclusion: TyG index is a facile tool used to identify individuals at risk for NAFLD, but not for the progression of liver lesions.

Background/Objectives: The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Cardiovascular disease (CVD) is the leading cause of mortality in MASLD patients, therefore, the therapeutic interventions for MASLD should improve coronary risk factors such as obesity, diabetes and dyslipidemia, in addition to improving liver function. The evidence on effect of sodium-glucose cotransporter 2 inhibitors (SGLT2is) which have beneficial pharmacological properties for MASLD, especially the long-term effects, on the progression of MASLD in Asian population is very limited. Methods: The retrospective longitudinal study was performed by using the medical records at the National Center for Global Health and Medicine, Kohnodai Hospital, Japan. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between April 1, 2014 and March 31, 2018. We collected the data on metabolic parameters, including blood tests and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results: During the observation period, 324 patients had taken SGLT2is for 3 years. The 3-year-SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein-cholesterol, triglyceride and non-high-density lipoprotein-cholesterol (HDL-C) and significantly increased HDL-C. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions: Considering that the development of CVD determines the prognosis of MASLD patients, the long-term SGLT2is treatment may be an ideal therapy for MASLD patients.

Liver disease can significantly impact life expectancy, making early diagnosis and therapeutic intervention critical challenges in medical care. Imaging diagnostics play a crucial role in diagnosing and managing liver diseases. Recently, the application of artificial intelligence (AI) in medical imaging analysis has become indispensable for healthcare. AI, trained on vast datasets of medical images, has sometimes demonstrated diagnostic accuracy that surpasses human experts. AI-assisted imaging diagnostics are expected to contribute significantly to the standardization of diagnostic quality. Furthermore, AI has the potential to identify image features imperceptible to humans, thereby playing an essential role in clinical decision-making. This capability enables physicians to formulate more accurate diagnoses and develop effective treatment strategies, ultimately improving patient outcomes. Additionally, AI is anticipated to become a powerful tool in personalized medicine. By integrating individual patient imaging data with clinical information, AI can propose optimal treatment plans, making it an essential component in providing the most appropriate care for each patient. Current reports highlight the advantages of AI in managing liver diseases. As AI technology continues to evolve, it is expected to further advance personalized diagnostics and treatments, contributing to overall improvements in healthcare quality.

Altered amino acid levels have been found in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, it is not clear whether this alteration is due to altered hepatic metabolism or insulin resistance. The aim of this study was to clarify the association among amino acid levels, fatty liver, and liver fibrosis while eliminating the influence of insulin resistance. NAFLD and liver fibrosis were diagnosed using transient elastography and subjects were divided in three groups: normal, NAFLD, and liver fibrosis. To exclude the influence of insulin resistance, the subjects were matched using the homeostasis model assessment of insulin resistance (HOMA-IR). The amino acid serum levels were compared among the groups. Of 731 enrolled subjects, 251 and 33 were diagnosed with NAFLD and liver fibrosis. Although significant differences were observed among the groups in the serum levels of most amino acids, all but those of glutamate and glycine disappeared after matching for HOMA-IR. The multivariate logistic regression revealed that glutamate, glycine, and HOMA-IR were independent risk factors for liver fibrosis. The altered serum levels of most amino acids were associated with insulin resistance, while the increase in glutamate and the decrease in glycine levels were strongly associated not only with insulin resistance, but also with altered liver metabolism in patients with liver fibrosis.

This study evaluated the effects of replacing zinc bacitracin with a symbiotic diet on the biochemical profile, liver development, and Clostridium perfringens presence in laying hens at 90 weeks of age. A total of 198 Dekalb–White hens were assigned to six experimental diets: MBM (corn, soybean meal, and meat and bone meal), BAC (MBM + 0.05% zinc bacitracin), and SIMC (MBM + 0.1% symbiotic), provided from day 1 to 90 weeks. Additional treatments, SIMR and SIMP, received symbiotics from weeks 6 and 17, re-spectively. At 90 weeks, blood and tissue samples were analyzed. Results showed that symbiotic-treated hens had 20% heavier livers (P < 0.01) and lower concentrations of uric acid, total proteins, AST, ALT, and LDH (P < 0.01) compared to BAC-treated birds. Phosphorus, triglycerides, and HDL levels were better in symbiotic groups. C. perfringens counts and antibiotic resistance (ampicillin, erythromycin, aminoglyco-sides, lincomycin, tetracycline, bacitracin) were significantly higher in BAC groups (P < 0.01). Symbiotic supplementation improved intestinal health, reduced pathogenic bacterial colonization, and enhanced liver function compared to continuous antibiotic use, especially when administered from early life stages.

The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts, lose their vitamin A, upregulate -smooth muscle actin, and produce pro-inflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.

Necroptosis is a regulated form of cell death implicated in several pathological conditions, in-cluding viral infections. In this study, we investigated the expression and correlation of necroptosis markers, MLKL, RIP1 and RIP3, in human liver tissue from fatal cases of yellow fever (YF) using immunohistochemistry (IHC). Liver samples were obtained from 21 YF-positive individuals and five flavivirus-negative controls with preserved liver parenchymal architecture. The cases un-derwent histopathological analysis, followed by tissue immunostaining with the immuno-histochemical method of streptavidin-biotin peroxidase. Using the in situ method, we evaluated the centrilobular (Z3), midzonal (Z2), periportal zone and portal tract (PT) zones of human liver parenchyma with markers for necroptosis, RIPK1, RIPK3 and MLKL. Quantitative analysis re-vealed significantly higher expression of MLKL, RIP1 and RIP3 in the liver parenchyma of YF cases compared to controls in different zones (Z3, Z2, Z1) and portal tracts (PT) of the liver, especially in zone 2. Immunostaining confirmed the localization of MLKL, RIP1 and RIP3 in hepatocytes and inflammatory infiltrates, highlighting their involvement in the pathogenesis of YF. Pearson's correlation analysis demonstrated significant correlations between necroptosis markers which indicate their coordinated regulation during YF-induced liver injury.

This study investigated the influence of single nucleotide polymorphisms (SNPs) in genes asso-ciated with the interferon pathway (IFNAR2 rs2236757), antiviral response (OAS1 rs10774671, OAS3 rs10735079), and viral entry (ACE2 rs2074192) on COVID-19 severity and their association with non-alcoholic fatty liver disease (MAFLD). We did not observe a significant association between the investigated SNPs and COVID-19 severity. While the IFNAR2 rs2236757 A allele correlated with higher creatinine levels upon admission and the G allele with lower band neu-trophils upon discharge, these findings require further investigation. The distribution of OAS gene polymorphisms (rs10774671, rs10735079 did not differ between MAFLD and non-MAFLD patients. Our study population's distribution of ACE2 rs2074192 genotypes and alleles differed from the European reference population. Overall, our findings suggest that these specific SNPs may not be major contributors to COVID-19 severity in our patient population, highlighting the potential role of other genetic factors and environmental influences.

Introduction: Levosimendan is a positive inotropic molecule that does not reduce splanchnic circulation and has anti ischemic properties by opening mito KATP channels. Cirrhosis is a chronic and diffuse process characterized by fibrosis and the conversion of typical liver architecture into structurally abnormal nodules. In the late stages of the disease, cirrhosis is responsible for organ failure and complications such as cirrhotic cardiomyopathy and hepatic encephalopathy. Material and methods: We examined the effect of levosimendan in rat models of liver cirrhosis. Male Wistar rats were divided into four groups: Group A: cirrhotic rats 14 days after bile duct ligation (BDL); Group B: control (intact rats); Group A1: BDL and levosimendan (liver cirrhosis induced by bile duct ligation plus intraperitoneal administration of levosimendan); Group B1: control and levosimendan (intact animals with normal liver function treated with an intraperitoneal injection of levosimendan). Each group was subjected to blood sampling to determine GOT, GPT, and bilirubin at baseline, two weeks after surgery, and four days after treatment. In addition, echocardiography was performed in all the groups simultaneously. At the end of the experiments, the rats were subjected to cerebral and hepatic microdialysis and sacrificed. Results: Serum GOT, GPT, and bilirubin in Group A1 (GOT 304 UI/L, GPT 60 UI/L, BIL 3,9 mg/dl) were considerably lower than in Group A (GOT 320 UI/L, GPT 67,16 UI/L, BIL 6,4 mg/dl). The Ejection fraction value decreased significantly postoperatively in Group A (preop 55,66%, BDL 38,85%) and was highest after treatment with levosimendan (Group A1 48,38%). Significant histological differences were detected between the experimental groups (Group A Sheuer staging 3, severe fibrosis, Group A1 Sheuer staging 0-2 no, mild and moderate fibrosis). Group A had a higher value of Lactate, Pyruvate, Glycerol, and Glutamate cerebral microdialysate concentrations (Lac 0.37mM, Pyr 16.25 mcM, Glyc 15.72 mcM, Glut 15.8 mcM) in comparison with BDL rats treated with levosimendan (Group A1 - Lac 0.31 mM, Pyr 6.3 mcM, Glyc 13.66 mcM, Glut 11.15 mcM). Glucose concentrations in cerebral dialysate from Group A were significantly lower (0.13 mM) than in Group A1 (0.25 mM). Glucose and Glycerol concentrations in liver microdialysate from Group A were significantly lower (Gluc 0.95 mM, Glyc 1 mcM) than in Group A1 (Gluc 1.6 mM, Glyc 3.4 mcM). Conversely, in liver dialysate from Group A (0.52 mM), lactate was significantly higher than in Group A1 (0.35 mM). Conclusions: Our results suggest that levosimendan can be potentially protective for fibrotic liver and probably can prevent cirrhosis complication as cirrhotic cardiomyopathy and hepatic encephalopathy.

Medicinal mushrooms, especially Ganoderma species hold immense promise for production of a wide range of bioactive compounds with various effects. The biochemical potential of indigenous fungal strains, specific to a region, could play a critical role in the continuous search for novel strains with superior activities on a global scale. This research focused on the ethanolic (EtOH) and hot-water (H2O) extracts of fruiting bodies of two wild-growing Ganoderma species: G. pfeifferi and G. resinaceum with an aim to assess its nutritional (total carbohydrate content-TCC), and mineral composition in relation to bioactive properties: antioxidant, antiproliferative and lipid-lowering. Atomic absorption spectrophotometry (AAS) revealed that G. pfeifferi is a promising source of minerals that are essential for numerous physiological functions in the human body like bone health and muscle and nerve function, with calcium (Ca 4.55 ± 0.41 mg/g d.w.) and magnesium (Mg 1.33 ± 0.09 mg/g d.w.), being the most abundant macro element present. Zinc (Zn), manganese (Mn), and chromium (Cr) were particularly notable, with concentrations ranging from 21.49 to 41.70 mg/kg d.w. The EtOH extract of G. pfeifferi demonstrated significantly elevated levels of TCC, essential macromolecules for energy and structural functions in the body, with higher quantities of all three standard carbohydrates detected in this type of extract. Similar to revealed composition the same species, G. pfeifferi stood out as the most prominent antioxidant agent, with H2O extract being stronger than EtOH in ABTS assay (86.85 ± 0.67 mg TE/g d.w.), while EtOH extract displayed the highest anti OH• radical scavenging ability (IC50 = 0.18 ± 0.05 μg/mL) as well as the most notable reducing potential among all. The highest antiproliferative effect against the breast cancer cell line (MCF-7), demonstrated the H2O extracts from G. resinaceum with the most pronounced activity after 24 hours (IC50 = 4.88 ± 0.50 μg/mL) which surpasses that of the standard compound, ellagic acid (IC50 = 33.94 ± 3.69 μg/mL). Administration of both Ganoderma extracts mitigated diabetic lipid disturbances and exhibited potential renal and hepatic protection in vivo on white Wistar rats by preservation of kidney function parameters in G. resinaceum H2O pre-treatment (urea: 6.27 ± 0.64 mmol/L, creatinine: 50.00 ± 6.45 mmol/L) and the reduction of ALT levels (17.83 ± 3.25 U/L) com-pared to diabetic control groups treated with saline (urea: 46.98 ± 6.01 mmol/L, creatinine: 289.25 ± 73.87 mmol/L, and ALT: 60.17 ± 9.64 U/L). These results suggest that pre-treatment with G. resinaceum H2O extracts may have potential antidiabetic properties. In summary, detected microelements are vital for maintaining overall health, supporting metabolic processes, and protecting against various chronic diseases. Further research and dietary assessments could help determine the full potential and applications of two underexplored Ganoderma species native to Serbia in nutrition and health supplements.

Introduction: Liver cirrhosis develops in about 10% of alcohol abusers. To date, a number of cells and cytokines have been identified, which are involved in induction of liver fibrotic processes. Nevertheless, the pathogenesis of liver cirrhosis has not been fully elucidated. The aim of the present study was to determine serum concentrations of afamin and adropin in patients with alcoholic liver cirrhosis and to define their correlation with the stage of disease. Materials and methods: The study included 99 patients with alcoholic cirrhosis from the region of Lublin, (Eastern Poland). Liver cirrhosis was diagnosed based on clinical features, history of heavy alcohol consumption, laboratory tests and abdominal ultrasonography. The control group consisted of 20 healthy individuals without liver disease who did not abuse alcohol. The serum afamin and adropin concentrations were determined using ELISA kits. Results: The concentration of afamin was found to be significantly lower in patients with compensated alcoholic liver cirrhosis, i.e. P-Ch B (85.1±40.6 μg/ml) and P-Ch C (56.4±32.3 μg/ml) individuals, as compared to the control group (135.9±43.6 μg/ml); p-value was <0.01 and <0.001, respectively. As far as adropin is concerned, a reverse relationship was demonstrated: the highest concentration was found in patients with P-Ch C (11.7±5.7 ng/ml) cirrhosis. Furthermore, the above concentration was significantly higher compared to patients with P-Ch A cirrhosis (7.2±2.8 ng/ml; p<0.05) and controls (7.5±2.6 ng/ml; p<0.05). Conclusions: The concentration of afamin decreases with the severity of alcoholic liver cirrhosis, which most likely results from impaired hepatic synthesis. Otherwise, the higher the stage of disease according to the Child-Pugh score, the higher the concentration of adropin.

The body of evidence available in paediatrics population is limited for making clinical decisions regarding pharmacotherapy optimization of tacrolimus. The objective of this study was to estimate the frequency of CYP3A5 genetic polymorphisms and their relationship with tacrolimus requirements in paediatric population. This was a longitudinal cohort study, with two-year follow-up of 77 patients under 18 who had liver transplant over the period 2009-2012 at the Paediatric Hospital J. P Garrahan. Tacrolimus levels from day 5 to 2-year post-transplant were obtained from hospital records of routine therapeutic drug monitoring. The genotyping of CYP3A5 (CYP3A5*1/*3 or *3/*3) were performed in liver biopsies of both the donor and the recipient. Recipients frequency of CYP3A5 *1 expression was 37.1% and 32.2% for Donors. Patient who received an organ expresser showed lower Co/dose especially after 90 days post-surgery. The role of each polymorphism is different according to days after transplantation proceeds and it must be taken into account to optimize the benefits of TAC therapy during the post-transplant induction and maintenance phase.

Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, has potency to prevent pathological mitochondrial fission by inhibiting protein-protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel blocking action of cilnidipine, prevent the palmitic ac-id-induced Drp1-filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high fat diet-fed mouse livers. These results propose that targeting Drp1-filimin interaction becomes a new strategy for the prevention or treatment of fatty liver disease.

Colonization of distant organs by tumor cells is a critical step of cancer progression. The initial avascular stage of this process (micrometastasis) remains almost inaccessible to study due to the lack of relevant experimental approaches. Here, we introduce an in vitro/in vivo model of organ-specific micrometastases of triple-negative breast cancer (TNBC) that is fully implemented in a cost-efficient chick embryo (CE) experimental platform. The model is built as three-dimensional (3D) tissue engineering constructs (TECs) combining human MDA-MB-231 cells and decellular-ized CE organ-specific scaffolds. TNBC cells colonized CE organ-specific scaffolds in 2-3 weeks, forming tissue-like structures. The feasibility of this methodology for basic cancer research, drug development and nanomedicine was demonstrated on a model of hepatic micrometastasis of TNBC. We revealed that MDA-MB-231 differentially colonize parenchymal and stromal com-partments of the liver-specific extracellular matrix (LS-ECM) and become more resistant to the treatment with molecular Doxorubicin (Dox) and Dox-loaded mesoporous silica nanoparticles than in monolayer cultures. When grafted on CE chorioallantoic membrane, LS-ECM-based TECs induced angiogenic switch. These findings may have important implications for the diag-nosis and treatment of TNBC. The methodology established here is scalable and adaptable for pharmacological testing and cancer biology research of various metastatic and primary tumors.

The gut-liver axis plays a pivotal role in the development of liver diseases, necessitating exploration into substances capable of modulating the microbiota to prevent dysbiosis. Over the past decade, diverse therapeutic approaches have emerged to target pathogenic factors involved in the hepatic gut microbiota axis. This study investigated the impact of a supplement with hepatoprotective activity, containing extracts of Silybum marianum, prebiotics, probiotics, n-3 polyunsaturated fatty acids, minerals, and vitamins on hematological markers of liver functions and on the intestinal microbiota of 10 adult dogs with metabolic liver disease over a 35-day time span. Animals underwent clinical and laboratory evaluations every 7 days, before administration of the supplement (T0) and after 7, 14, 21, 28 and 35 days (T1, T2, T3, T4 and T5). In comparison to T0, a significant (P&lt;0.05) decrease of AST activity was measured at T2, T3, T4 and T5. The activity of ALP, glucose and CRP significantly decreased (P&lt;0.05) at T3, T4, and T5. The alpha diversity of the fecal microbiota significantly decreased (P&lt;0.05) only at T1, a high variability was observed between dogs. The total short-chain fatty acid and lactic acid were also lower at T1 (P&lt;0.05) in comparison to the other times of sampling. The beta diversity of fecal microbiota failed to find a clear pattern in relation to the sampling times. These results underscore the usefulness of the supplement on liver function and highlight high individual variability in its interaction with the fecal microbiome.

Crigler-Najjar Syndrome (CNS) is a rare genetic disorder caused by mutations in the UGT1A1 gene, leading to impaired bilirubin conjugation and severe unconjugated hyperbilirubinemia. CNS presents in two forms: CNS type 1 (CNS1), the more severe form with a complete absence of UGT1A1 activity, and CNS type 2 (CNS2), with partial enzyme activity. CNS1 requires aggressive management, including phototherapy and plasmapheresis, but liver transplantation (LT) remains the only definitive cure. The timing of LT is critical, as it must be performed before the onset of irreversible brain damage (kernicterus), making early intervention essential. However, LT poses risks such as graft rejection and lifelong immunosuppression. CNS2 is milder, with patients re-sponding well to phenobarbital and having a lower risk of kernicterus. Recent advancements in gene therapy and autologous hepatocyte transplantation offer promising alternatives to LT. Gene therapy using adeno-associated virus (AAV) vectors has shown potential in preclinical studies, though challenges remain in pediatric applications due to liver growth and pre-existing immunity. Autologous hepatocyte transplantation avoids the risks of rejection but requires further research. These emerging therapies provide hope for more effective and less invasive treatment options, aiming to improve the quality of life for CNS patients and reduce reliance on lifelong interven-tions.

Toll-like receptor 5 ligand, flagellin, and Vascular Adhesion Protein-1 (VAP-1) are involved in non-alcoholic fatty liver disease (NAFLD). This study aimed to determine whether VAP-1 mediates flagellin-induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected to C57BL/6J WT and C57BL/6-Aoc3^-/- (VAP-1 KO) mice on high-fat diet twice a week every two weeks for 10-weeks. After that, the effects on inflammation, insulin signaling, and metabolism were studied in liver and adipose tissues. Hepatic fat was quantified histologically and biochemically. Because flagellin challenge increased VAP-1 expression in human adipocytes, we used VAP-1 KO mice to determine whether VAP-1 regulates the inflammatory and metabolic effects of flagellin in vivo. In mice, VAP-1 mediated flagellin-induced inflammation, leukocyte infiltration and lipolysis in visceral adipose tissue. Consequently, increased release of glycerol led to hepatic steatosis in WT but not KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT, while flagellin did not affect the gut microbiota. Our results suggest that by acting on visceral adipose tissue, flagellin increased leukocyte infiltration that induced lipolysis. Further, the released glycerol participated in hepatic fat accumulation. In conclusion, the results describe that gut microbial flagellin through VAP-1 induced hepatic steatosis.

Patients with predominantly antibody deficiencies (PAD) display hypogammaglobulinemia with a high prevalence of infections, along with autoimmune manifestations, benign and malignant lymphoproliferation and granulomatous disease. It is noteworthy that PAD patients, even those with defects in the same causative genes display a variable clinical phenotype, suggesting that additional genetic polymorphisms, located in either immune-related or non-immune-related genes, may affect their clinical and laboratory phenotype. In this context, we analyzed 80 PAD patients, including 70 with common variable immunodeficiency (CVID) for SERPINA1 defects, in order to investigate their possible contribution to PAD clinical phenotype. Eight CVID patients carried heterozygous pathogenic SERPINA1 defects with normal alpha-1 antitrypsin levels. Interestingly, the presence of the Z allele (rs28929474) which was found in three patients, was significantly associated with liver disease; hepatic complications were also observed in patients carrying the p.Leu23Gln (rs1379209512) and the p.Phe76del (rs775982338) alleles. Conversely, no correlation of SERPINA1 defective variants with respiratory complications was observed, although patients with pathogenic variants exhibit a reduced probability of developing autoimmune diseases. Therefore, we recommend SERPINA1 genetic analysis in PAD, in order to identify patients with a higher risk for liver disease.

Background and Objective: In the present study, the purpose was to compare the demographic, clinical and laboratory results of pediatric brucella cases who had liver involvement and who had no specific organ involvement. Material and Methods: The data of 248 patients between 2 and 18 years of age diagnosed with Brucellosis between July 2017 and August 2018 were analyzed retrospectively. The patients who had liver involvement and who did not have other specific organ involvement were compared in terms of presentation, physical examination findings, age, gender, hemogram, AST, ALT, GGT, ALP, bilirubines, sedimentation, CRP, clinical and laboratory findings, and culture and relapse rates. Results: No significant differences were detected between the patients who had liver involvement (n=92) and who did not have specific organ involvement (n=156) in terms of diagnosis age and gender. Loss of appetite, nausea and sensitive stomach were higher in the patients who had hepatic involvement, and weariness was determined to be more in the control group patients. In the patients who had hepatic involvement, the hemoglobin and platelet values were lower, and the sedimentation, CRP and blood culture growth were higher. The relapse rates were lower in patients who had liver involvement. Conclusion: In patients who have liver involvement, in addition to elevated hepatomegaly and transaminase levels, the growth rate of the acute-phase reactants and brucella is higher in blood culture; and the relapse rate is lower after treatment. Brucellosis must be considered in the differential diagnosis of hepatomegaly and transaminase elevation where brucellosis is seen endemically. We believe that early diagnosis of brucellosis is important in treatment response.

A high intake of carbohydrates, associated with obesity, is one of the major causes of fatty liver disease in humans. This study investigated how high carbohydrate intake induces fatty liver disease in Blunt snout bream (Megalobrama amblycephala). Blunt snout bream were fed a high-carbohydrate diet (HCBD) for 60 days. Their growth indices were evaluated, and the transcriptomes, metabolites, biochemistry, and histology of their blood and livers were analyzed. The final weight, weight gain, specific growth rate, and feed conversion ratio were all higher in the HCBD group than in the control group, but not significantly so (P > 0.05). The hepatosomatic index (HSI) differed significantly in the two groups (P < 0.05), and the metabolomics results showed that a high carbohydrate intake induced significant increases in plasma α/β-glucose, succinate, and tyrosine, which could increase hepatic glycogen and triglyceride. Low levels of betaine were also found in the livers of the HCBD group. The histology and blood biochemistry results suggested abnormal liver, with excessive lipid accumulation and liver damage. A transcriptome analysis and quantitative reverse transcription–PCR (RT–qPCR) indicated that the expression of the factors INSR, IRS, PI3K, PDK, AKT, ACC, IL6, AP1, ChREBP-MLX, PEPCK, and FBP in the insulin signaling pathway was significantly upregulated and that of SOCS3, GSK3β, and AMPK significantly downregulated in the HCBD. This pattern is associated with the nonalcoholic fatty liver disease (NAFLD) pathway. This study extends our understanding of how high carbohydrate causes increased fat deposition in the liver, enhanced glycolysis (α/β-glucose) in the plasma, and reduced betaine in the liver. This leads to activation of hepatocyte insulin resistance and lipogenesis by regulating the expression of genes related to fatty liver disease.

Aim. The purpose of the work was the development of a machine learning model for diagnosing the stage of liver fibrosis in patients with chronic viral hepatitis C according to the data of routine clinical examination. Materials and methods. A total of 1240 patients with chronic viral hepatitis C was examined. A set of data obtained from 689 patients balancing by the stage of liver fibrosis was used for developing and testing machine learning models. 9 routine clinical parameters were selected as the most important predictors for determining the likelihood of liver fibrosis the 3–4 stages presence: age, height, weight and body mass index of the patient, the number of platelets in the clinical blood test, levels of alanine transaminase, aspartate transaminase, gamma-glutamyltransferase, and total bilirubin in a biochemical blood test. Results. The accuracy of the developed method for determining the 3–4 stages of liver fibrosis in patients with chronic viral hepatitis C in comparison with the «gold standard» of diagnosis (liver biopsy) was 80.56% (95% CI: 69.53–88.94%), sensitivity — 66.67%, specificity — 94.44%. Conclusion. The developed method is an alternative to more expensive and geographically inaccessible studies. The method does not require the purchase of additional equipment or software, as well as additional laboratory tests, when used in real clinical practice. The introduction of the method into clinical practice can help to solve the problem of low material and territorial availability of diagnostic tests and allow determining the stage of liver fibrosis in patients with chronic viral hepatitis C.

COVID-19 breakout in Italy has caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection very few information are available about liver involvement in COVID-19 infection, that could possibly evocate a systemic disease targeting a lot of organs. Since now there are no reports of large series of histological evaluation of liver morphology in this setting. Knowledge of histological liver findings connected to clinical data is crucial in management of this disease.Post-mortem wedge liver biopsies from 48 patients died for COVID-19 infection were available from two main hospitals located in northern Italy, Lombardy; all sample were obtained during autopsies. No patient has a significant clinical complain of liver disease or signs of liver failure before and during hospitalization; for each of them laboratory data focused on liver were available. All liver samples showed minimal inflammation features; on the other side, many histological pictures compatible with vascular alterations were observed, characterized by portal vein braches number increase associated with lumen massive dilatation, partial or complete recent luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally severely enlarged and fibrotic. Our preliminary results concerning histological liver involvement in COVID-19 infection confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage; histopatological findings are highly suggestive for marked alteration of intrahepatic blood vessel network secondary to systemic alterations induced by virus that could target, besides lung parenchyma, cardiovascular system, coagulation cascade or endothelial layer of blood vessels.

Background Systemic sclerosis (SSc) is a rare, multisystemic disorder of connective tissue, characterized by widespread inflammation, vascular abnormalities, and both skin and visceral organ fibrosis. Tissue fibrosis is the final phase of a complex biological process of immune activation and vascular damage. Objectives The aim of study was to assess hepatic fibrosis and steatosis in SSc patients by transient elastography (TE). Methods Fifty-nine SSc patients, satisfying the 2013 ACR/EULAR classification criteria, were recruited. Clinical and laboratory findings, modified Rodnan skin score (mRSS), ac-tivity index, video-capillaroscopy, echocardiography, and lung function data were ana-lyzed. Liver stiffness (LS) was measured by transient elastography (TE), with 7 kPa used as the cut-off value for significant liver fibrosis and steatosis. Specifically, values ≥ 238 CAP ≤ 259 dB/m were considered consistent with mild steatosis (S1), 260 ≥ CAP ≤ 290 dB/m with moderate steatosis (S2) and ≥291 dB/m with severe steatosis (S3) Results The median age of patients was 51 years, with a median disease duration of 6 years. Median LS was 4.5 (2.9–8.3) kPa; 41 patients (69.5%) had no evidence of fibrosis (F=0), 16 (27.1%) displayed LS values between 5.2 and 7 kPa; only 2 patients (3.4%) had LS values >7 kPa (F3). The median CAP value for liver steatosis was 223 dB/m (IQR: 164–343). Overall, 39 patients (66.1%) did not show evidence of steatosis (CAP values <238 dB/m); 9 patients (15.2%) showed values consistent with mild (S1) steatosis (CAP value ≥238 ≤259 dB/m); 8 patients (13.5%) had moderate (S2) steatosis (CAP value ≥260 ≤290 dB/m); 3 patients (5.1%) were deemed to have severe steatosis (S3) due to CAP values ≥291 dB/m. Conclusions Only 3.4% of our patient population showed evidence of marked liver fibrosis, which is the same prevalence as that expected in the general population. Likewise, the prevalence of significant steatosis was low (5.1%) and depending on the same variables associated with fatty liver in the general population. TE was shown to be an easy and valuable method for detection and screening of liver fibrosis in SSc patients with no additional risk factors for liver disease.

Objectives: To compare the volumes and shapes of the coagulation zone (CZ) of a multi-probe RFA system (three RFA electrodes) and a single-probe MWA system from the same vendor in an ex-vivo bovine liver model. Material &amp; Methods: A total of 48 CZs were obtained in bovine liver specimens with three different ablation system configurations (single-probe MWA vs. multi-probe RFA with 20 mm inter-probe distance [confluent CZ] vs. multi-probe RFA with 50 mm inter-probe distance [three individual CZ]) at 4-, 6-, 8-, and 10-min ablation time using a fixed ablation protocol. Ablation diameters were measured and ellipticity indices (EI) and volumes calculated. Calculations for all systems/configurations were compared. Results: Volumes and diameters increased with ablation time for all configurations. At 4- and 6-min ablation time volumes obtained with the RFA 50 mm setup, and at 8 and 10 min with the RFA 20 mm setup were the largest with 26.5 ± 4.1 mL, 38.1 ± 5.8 mL, 46.3 ± 4.9 mL, 48.4 ± 7.3 mL, respectively. The single-probe MWA could not reach the volumes of the RFA setups for any of the ablation times evaluated. EI were very similar and almost round for RFA 20 mm and single-probe MWA and differed significantly to the more ovoid ones for the RFA 50 mm configuration. Conclusion: The multi-probe RFA system employing three electrodes achieved significantly larger ablation volumes in both configurations (confluent CZ and three individual CZ) per time as compared to a single-probe MWA system in this ex-vivo bovine liver model.

Background The distinctive feature of liver fibrosis is the progressive replacement of healthy hepatic cells by extracellular matrix protein, which is abundant in collagen I and III with impaired matrix remodelling. The activation of myofibroblastic cells enhances a fibrogenic response of complex interactions of hepatic stellate cells, fibroblasts and inflammatory cells to produce excessive deposition of extracellular protein matrix. This process is activated by multiple fibrogenic mediators and cytokines such as TNF-α and IL-1ß with decrease in the anti-fibrogenic factor NF-ҡß. Mesenchymal stem cells (MSCs) represent a promising therapy for liver fibrosis giving more advanced regenerative influence when cultured with extrinsic or intrinsic proliferative factors, cytokines, anti-oxidants, growth factors, and hormones such as Melatonin (MT). However, previous studies showed conflicted findings concerning the therapeutic effects of adipose (AD) and bone marrow (BM)-MSCs, therefore, the present work aimed to accomplish a comparative and comprehensive study investigating the impact of MT pre-treatment on the immunomodulatory, anti-inflammatory and anti-apoptotic effects of AD and BM-MSCs and to critically analyse whether MT pre-treated both AD-MSCs and BM-MSCs reveal equal or different therapeutic and regenerative potentials in CCl4-injured liver of experimental rat models. Materials and methods Six groups of experimental rats were used with ten rats in each group; group I (control group), group II (CCl4-treated group), group III (CCl4 and BM-MSCs treated group), group IV (CCl4 and MT pre-treated BM-MSCs group), group V (CCl4 and AD-MSCs treated group) and group VI (CCl4 and MT pre-treated AD-MSCs group). Liver function tests, gene expression of inflammatory, fibrogenic, apoptotic and proliferative factors were analysed. Histological and immunohistochemical changes were assessed. Results The present study compared the capability of AD and BM-MSCs, with and without the pre-treatment of MT, to reduce hepatic fibrosis. Both types of MSCs improved hepatocyte function by reducing the serum levels of (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), and total bilirubin (TBIL). In addition, the changes in the hepatocellular architecture including the hepatocytes, liver sinusoids, central veins, portal veins, biliary ducts and hepatic arteries showed decrease hepatocyte injury and cholestasis with reduction of inflammation, apoptosis and necrosis of the hepatic cells together with inhibition of liver tissue fibrosis. These results were augmented by the analysis of the expression of the anti-inflammatory cytokines TNFα and IL-1β, the anti-fibrogenic factor NF-ҡß, the apoptotic factor caspase-3 and the proliferative indicators antigen Ki-67 and proliferating cell nuclear antigen (PCNA). These findings were found statistically significant, with the best results in the rats received AD-MSCs pre-treated with MT, denoting better regenerative and therapeutic effects. Conclusion AD-MSCs, pre-treated with MT, are superior to BM-MSCs due to their better efficacy in improving hepatic fibrosis and promoting the therapeutic and regenerative capability of liver tissue. They represent a very significant tool for future stem cell use in tissue regeneration strategy for the treatment of liver diseases.

Liver is structurally organized into zonation where LSECs endothelial cells play a crucial role during chronic liver injury and early stages of fibrosis. Fibrosis can be reversed if diagnosed early at molecular level in zonation before progressing to advanced stages like bridging fibrosis. This study identified zonation marker genes using scRNA-seq and spatial transcriptomics molecular profiling technologies in normal and diseased fibrotic human liver. DEG analysis is performed over LSECs and identified the top 20 expressed genes in periportal, perivenous, and intermediate acinar zones. Multi-omics and scRNA-seq analysis over Visium images and ECs liver cells figured out OIT3, DNASE1L3, CLEC4G, LYVE1, FCN2, CRHBP as commonly expressed mid-lobular zonation-specific genes. Also, this study detected STAB2, F8, AQP1, TEK, TIMP3, TIE1, CTSL genes as expressed in DILI and NASH ECs populations. The connection between LSECs marker genes in zone 2 and liver fibrosis holds significant promise for advancing our understanding in developing new therapeutic strategies for fibrosis reversal and designing computational molecular biomarkers in NASH and DILI fibrotic liver diseases.

Hepatocellular carcinoma is the most common primary malignant hepatic tumor and occurs most often in the setting of chronic liver disease. Liver transplantation is a curative treatment option and is an ideal solution because it solves the chronic underlying liver disorder while removing the malignant lesion. Because of organ shortages this treatment can only be applied to carefully selected patients according to clinical guidelines to minimize risk of recurrence. Artificial intelligence is an emerging technology with multiple applications in medicine with a predilection for domains that work with medical imaging like radiology. With the help of these technologies laborious tasks like segmentation can be automated and workflow in radiology departments can be improved. Other roles include in depth pixel-wise analysis of lesions by radiomics or deep learning in order to find new imaging criteria that allow better prediction of treatment response or risk of recurrence. Liver transplant is an ideal treatment for patients with hepatocellular carcinoma in the setting of chronic liver disease and artificial intelligence could provide solutions for improving the management of liver transplant candidates to improve survival.

Transplant oncology is a relatively new field in which transplantation is used to treat patients who would otherwise be unresectable. New anticancer treatment paradigms using tumor and transplant immunology and cancer immunogenomics are emerging. In turn, liver transplantation (LT) has become a potential therapy for certain patients with colorectal cancer (CRC) with liver metastasis, hepatocellular (HCC), cholangiocarcinoma (CCA), and metastatic neuroendocrine tumor (NET) to the liver. Although there are established criteria for LT in HCC, the evidence regarding LT as a treatment modality for certain gastrointestinal malignancies is still debated. The aim of this review is to highlight updates in the role of LT for certain malignancies, including HCC, metastatic CRC, hilar CCA, and neuroendocrine tumor (NET), as well as contextualize LT use and discuss controversies in transplant oncology.

To clarify the risk factors for aggravation of esophagogastric varices (EGV) after hepatitis C virus (HCV) eradication with direct-acting antiviral (DAA) therapy, we enrolled 167 consecutive patients with HCV-related compensated cirrhosis who achieved a sustained virological response (SVR) after DAA therapy. During a median of 69 months, EGV was aggravated in 42 (25%) patients despite SVR. The cumulative 1, 3, 5, and 10-year aggravated EGV rates were 7%, 23%, 25%, and 27%, respectively. Multivariate analysis identified platelet count <11.0×10⁴/μL, LSM ≥18.0 kPa, total bile acid ≥33.0 μmol/L, and diameter of left gastric vein (LGV) ≥5.0 mm at HCV eradication as independent risk factors for EGV aggravation post-SVR. In groups that meet all of these risks, the cumulative EGV aggravation rates at 1, 3, and 5 years were 27%, 87%, and 91%, respectively. However, none of the patients who had only one or none of the risk factors experienced EGV aggravation. Platelet count, LSM, total bile acid, and diameter of LGV at HCV eradication were associated with aggravated EGV post-SVR. EGV tends to worsen as two or more of these risk factors increase.