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Aims: Biliary atresia (BA) is characterized by intrahepatic inflammation and rapid progression of liver fibrosis. Galectin‐3, a beta‐galactoside binding protein, is a key regulator of inflammation and fibrosis. The aim of this study was to characterize circulating and hepatic Galectin‐3 levels in children with BA. Methods: Plasma and liver samples were obtained from children with early BA at time of Kasai hepatoportoenterostomy, late BA at time of transplant, early and late other cholestatic liver diseases (CLD), and controls. Plasma Galectin‐3 was measured using standard enzyme‐linked immunoassay. Liver tissue was analyzed with multiplex immunohistochemistry and quantified using whole slide analysis. Statistical comparisons were made using nonparametric testing. Results: Plasma Galectin‐3 in late BA was significantly higher than in early BA (20.82 [12.45–30.46] vs. 11.30 [8.74–16.83] ng/mL, p = 0.0096). Galectin‐3 levels correlated with markers of disease severity and interleukin‐6. There were significantly more Galectin‐3+ M2 macrophages in late BA in comparison to late other CLD (162 [157–233] vs. 49 [33–59] cells/mm2, p = 0.03). The number of Galectin‐3+ M2 macrophages correlated with the number of activated hepatic stellate cells and bile duct proliferation. Conclusions: Plasma Galectin‐3 is higher in late BA at time of transplant in comparison to early BA at time of Kasai. The number of Galectin‐3 expressing M2 macrophages in late BA is elevated relative to late other CLD and was associated with other prognostic histological findings. Galectin‐3 targeted therapy may be beneficial in slowing disease progression to cirrhosis in children with BA. [ABSTRACT FROM AUTHOR]

Background & Aims: Patients with advanced cirrhosis often have immune dysfunction and are more susceptible to infections. Galectin‐3 is a β‐galactoside‐binding lectin implicated in inflammation, immune regulation and liver fibrosis. We aim to investigate galectin‐3 expression in advanced cirrhosis and its ability to predict post‐transplant infectious complications. Methods: We collected sera and liver samples from 129 cirrhotic patients at the time of liver transplantation and from an external cohort of 37 patients with alcoholic liver disease including alcoholic hepatitis (AH) at the time of diagnosis. Galectin‐3 was assessed by ELISA, real‐time PCR, immunohistochemistry and RNA‐seq. Receiver operating characteristic curves and Cox proportional‐hazards regression analysis were performed to assess the predictive power of galectin‐3 for disease severity and post‐transplant infections. Results: Increased galectin‐3 levels were found in advanced cirrhosis. Galectin‐3 significantly correlated with disease severity parameters and inflammatory markers. Galectin‐3 had significant discriminating power for compensated and advanced cirrhosis (AUC = 0.78/0.84, circulating/liver galectin‐3; p <.01), and was even higher to discriminate severe AH (AUC = 0.95, p <.0001). Cox Proportional‐hazard model showed that galectin‐3, MELD‐Na and the presence of SIRS predict the development of post‐transplant infectious complications. Patients with circulating galectin‐3 (>16.58 ng/ml) were at 2.19‐fold 95% CI (1.12–4.29) increased risk, but when combined with MELD‐Na > 20.0 and SIRS, the risk to develop post‐transplant infectious complications, increased to 4.60, 95% CI (2.38–8.90). Conclusion: Galectin‐3 is a novel biological marker of active inflammation and disease severity that could be clinically useful alone or in combination with other scores to discriminate advanced cirrhosis and predict post‐transplant infectious complications. [ABSTRACT FROM AUTHOR]

Simple Summary: Several independent predictors of mortality for COVID-19 patients have been identified. However, those markers are usually parameters evaluated upon hospital admission, and clinical and biochemical parameters during the clinical course of the patients are usually neglected. To know the whole picture of COVID-19 patients it is important to evaluate the clinical course, as this will dictate how the patient progresses. We identify herein clinical and laboratory parameters from admission to discharge, or death, that distinguish between survivors and non-survivors of COVID-19, including those with independent ability to predict mortality. Independent predictors of mortality for COVID-19 patients have been identified upon hospital admission; however, how they behave after hospitalization remains unknown. The aim of this study is to identify clinical and laboratory parameters from admission to discharge or death that distinguish survivors and non-survivors of COVID-19, including those with independent ability to predict mortality. In a cohort of 266 adult patients, clinical and laboratory data were analyzed from admission and throughout hospital stay until discharge or death. Upon admission, non-survivors had significantly increased C reactive protein (CRP), neutrophil count, neutrophil to lymphocyte ratio (NLR) (p < 0.0001, each), ferritin (p < 0.001), and AST (aspartate transaminase) (p = 0.009) compared to survivors. During the hospital stay, deceased patients maintained elevated CRP (21.7 mg/dL [admission] vs. 19.3 [hospitalization], p = 0.060), ferritin, neutrophil count and NLR. Conversely, survivors showed significant reductions in CRP (15.8 mg/dL [admission] vs. 9.3 [hospitalization], p < 0.0001], ferritin, neutrophil count and NLR during hospital stay. Upon admission, elevated CRP, ferritin, and diabetes were independent predictors of mortality, as were persistently high CRP, neutrophilia, and the requirement of invasive mechanical ventilation during hospital stay. Inflammatory and clinical parameters distinguishing survivors from non-survivors upon admission changed significantly during hospital stay. These markers warrant close evaluation to monitor and predict patients' outcome once hospitalized. [ABSTRACT FROM AUTHOR]

Liver injury can result from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with more than one-third of COVID-19 patients exhibiting elevated liver enzymes. Microvesicular steatosis, inflammation, vascular congestion, and thrombosis in the liver have been described in autopsy samples from COVID-19 patients. Several factors, including direct cytopathic effect of the virus, immune-mediated collateral damage, or an exacerbation of preexisting liver disease may contribute to liver pathology in COVID-19. Due to its immunological functions, the liver is an organ likely to participate in the viral response against SARS-CoV-2 and this may predispose it to injury. A better understanding of the mechanism contributing to liver injury is needed to develop and implement early measures to prevent serious liver damage in patients suffering from COVID-19. This review summarizes current reports of SARS-CoV-2 with an emphasis on how direct infection and subsequent severe inflammatory response may contribute to liver injury in patients with and without preexisting liver disease. [ABSTRACT FROM AUTHOR]

The mechanisms by which the liver fails in end‐stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver‐enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4α, HNF1α, forkhead box protein A2 (FOXA2), CCAAT/enhancer‐binding protein (CEBP)α, and CEBPβ. We then selected downstream genes responsible for some hepatic functions (ornithine transcarbamylase [OTC], cytochrome P450 3A4 [CYP3A4], coagulation factor VII [F7], cadherin 1 [CDH1], phospho‐ezrin (Thr567)/radixin (Thr564)/moesin (Thr558) [p‐ERM], phospho‐myosin light chain [p‐MLC], low‐density lipoprotein receptor‐related protein 1 [LRP1]) in liver tissue from patients at different stages of decompensated liver function based upon Child‐Pugh classification, Model for End‐Stage Liver Disease score, and degree of inflammatory activity/fibrosis. We first examined differential expression of LETF and determined whether a relationship exists between transcript and protein expression, and liver function. We found HNF4α expression was down‐regulated and correlated well with the extent of liver dysfunction (P = 0.001), stage of fibrosis (P = 0.0005), and serum levels of total bilirubin (P = 0.009; r = 0.35), albumin (P < 0.001; r = 0.52), and prothrombin time activity (P = 0.002; r = 0.41). HNF4α expression also correlated with CYP3A4, OTC, and F7 as well as CDH1 RNA levels. The Rho/Rho‐associated protein kinase pathways, which have been implicated in the regulation of HNF4α, were also differentially expressed, in concert with LRP1, a reported upstream regulator of RhoA function. Conclusion: HNF4α and other members of the LETFs appear to be important regulators of hepatocyte function in patients with chronic hepatic failure. (Hepatology Communications 2018;2:582‐594) [ABSTRACT FROM AUTHOR]

Organ-like microenviroment and 3-dimensional (3D) cell culture conformations have been suggested as promising approaches to mimic in a micro-scale a whole organ cellular functions and interactions present in vivo. We have used this approach to examine biologic features of hepatocellular carcinoma (HCC) cells. In this study, we demonstrate that hepatocellular carcinoma (HCC) cells, fibroblasts, endothelial cells and extracellular matrix can generate organoid-like spheroids that enhanced numerous features of human HCC observed in vivo. We show that the addition of non-parenchymal cells such as fibroblast and endothelial cells is required for spheroid formation as well as the maintenance of the tissue-like structure. Furthermore, HCC cells cultured as spheroids with non-parenchymal cells express more neo-angiogenesis-related markers (VEGFR2, VEGF, HIF-α), tumor-related inflammatory factors (CXCR4, CXCL12, TNF-α) and molecules-related to induced epithelial-mesenchymal transition (TGFβ, Vimentin, MMP9) compared with organoids containing only HCC cells. These results demonstrate the importance of non-parenchymal cells in the cellular composition of HCC organoids. The novelty of the multicellular-based organotypic culture system strongly supports the integration of this approach in a high throughput approach to identified patient-specific HCC malignancy and accurate anti-tumor therapy screening after surgery. [ABSTRACT FROM PUBLISHER]

Stem cell research has significantly evolved over the last few years, allowing the differentiation of pluripotent cells into almost any kind of lineage possible. Studies that focus on the liver have considerably taken a leap into this novel technology, and hepatocyte-like cells are being generated that are close to resembling actual hepatocytes both genotypically and phenotypically. The potential of this extends from disease models to bioengineering, and even also innovative therapies for end-stage liver disease. Nonetheless, too few attention has been given to the non-parenchymal cells which are also fundamental for normal liver function. This includes cholangiocytes, the cells of the biliary epithelium, without whose role in bile modification and metabolism would impair hepatocyte survival. Such can be observed in diseases that target them, so called cholangiopathies, for which there is much yet to study so as to improve therapeutical options. Protocols that describe the induction of human induced pluripotent stem cells into cholangiocytes are scarce, although progress is being achieved in this area as well. In order to give the current view on this emerging research field, and in hopes to motivate further advances, we present here a review on the known differentiation strategies with sight into future applications. [ABSTRACT FROM PUBLISHER]

Background: Liver transplantation for the most critically ill remains controversial; however, it is currently the only curative treatment option., Aim: To assess immediate posttransplant outcomes and compare the short (1 year) and long-term (6 years) posttransplant survival among cirrhotic patients stratified by disease severity., Methods: We included cirrhotic patients undergoing liver transplantation between 2015 and 2019 and categorized them into compensated cirrhosis (CC), decompensated cirrhosis (DC), and acute-on-chronic liver failure (ACLF). ACLF was further divided into severity grades. Our primary outcomes of interest were total days of intensive care unit (ICU) and hospital stay, development of complications and posttransplant survival at 1 and 6 years., Results: 235 patients underwent liver transplantation (CC = 11, DC = 129 and ACLF = 95). Patients with ACLF had a significantly longer hospital stay [8.0 (6.0-13.0) vs CC, 6.0 (3.0-7.0), and DC 7.0 (4.5-10.0); P = 0.01] and developed more infection-related complications [47 (49.5%), vs CC, 1 (9.1%) and DC, 38 (29.5%); P < 0.01]. Posttransplant survival at 1- and 6-years was similar among groups ( P = 0.60 and P = 0.90, respectively). ACLF patients stratified according to ACLF grade [ACLF-1 n = 40 (42.1%), ACLF-2 n = 33 (34.7%) and ACLF-3 n = 22 (23.2%)], had similar ICU and hospital stay length ( P = 0.68, P = 0.54), as well as comparable frequencies of overall and infectious post-transplant complications ( P = 0.58, P = 0.80). There was no survival difference between ACLF grades at 1 year and 6 years ( P = 0.40 and P = 0.15)., Conclusion: Patients may benefit from liver transplantation regardless of the cirrhosis stage. ACLF patients have a longer hospital stay and frequency of infectious complications; however, excellent, and comparable 1 and 6-year survival rates support their enlisting and transplantation including those with ACLF-3., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aim: To describe our experience concerning the surgical treatment of Strasberg E-4 (Bismuth IV) bile duct injuries., Methods: In an 18-year period, among 603 patients referred to our hospital for surgical treatment of complex bile duct injuries, 53 presented involvement of the hilar confluence classified as Strasberg E4 injuries. Imagenological studies, mainly magnetic resonance imaging showed a loss of confluence. The files of these patients were analyzed and general data were recorded, including type of operation and postoperative outcome with emphasis on postoperative cholangitis, liver function test and quality of life. The mean time of follow-up was of 55.9 ± 52.9 mo (median = 38.5, minimum = 2, maximum = 181.2). All other patients with Strasberg A, B, C, D, E1, E2, E3, or E5 biliary injuries were excluded from this study., Results: Patients were divided in three groups: G1 (n = 21): Construction of neoconfluence + Roux-en-Y hepatojejunostomy. G2 (n = 26): Roux-en-Y portoenterostomy. G3 (n = 6): Double (right and left) Roux-en-Y hepatojejunostomy. Cholangitis was recorded in two patients in group 1, in 14 patients in group 2, and in one patient in group 3. All of them required transhepatic instrumentation of the anastomosis and six patients needed live transplantation., Conclusion: Loss of confluence represents a surgical challenge. There are several treatment options at different stages. Roux-en-Y bilioenteric anastomosis (neoconfluence, double-barrel anastomosis, portoenterostomy) is the treatment of choice, and when it is technically possible, building of a neoconfluence has better outcomes. When liver cirrhosis is shown, liver transplantation is the best choice.