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Concept: Cirrhosis

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Liver cancer is the third most common cancer, and the incidence as well as the mortality rate of liver cancer are on the increase. There are many signaling pathways that are involved in hepatic tumorigenesis. One of these pathways, the transforming growth factor-β (TGF-β)/Smad pathway with KLF10, has been reported to suppress cellular proliferation in most cases. However, the actual functions of KLF10 in various pathophysiological conditions are still fragmentary and unclear. In the present study, the practical role of KLF10 in DEN-induced hepatic carcinogenesis, was elucidated using KLF10 null mice. In the necropsy and histopathological analysis, KLF10 KO mice exhibited lower tumor incidence and PCNA labeling indices than these values in the wild-type mice. Additional analyses revealed that the mRNA and protein levels of Smad3, TGF-β1, TGF-β RI and p15 were increased in the tumor tissues of the KLF10 KO mice, while those of cMyc and cyclin D1 were downregulated. The level of phospho-Smad3 was also significantly higher in the tumor tissues of the KLF10 KO mice. All together, the KLF10 KO condition may reinforce the TGF-β‑Smad signaling pathway and confer tumor-suppressor effects against chemically induced liver tumorigenesis.

Concepts: Vitamin D, Epidemiology, Cancer, Oncology, Pathology, Medical statistics, Cirrhosis, Liver

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The main objective of our research was to examine the role and immunophenotypic characteristics of myofibroblasts in sheep liver naturally infected by the lancet liver fluke (Dicrocoelium dendriticum). In the reported study we analyzed liver samples from 20 adult sheep, 14 infected animals and 6 controls. The liver samples were fixed in 10% buffered formalin, and routinely processed and stained using hematoxylin eosin, the periodic acid-Schiff and Masson-Goldner trichrome methods. The immunohistochemical examination was carried out by the streptavidin biotin (LSAB2) method, using antibodies for α-smooth muscle actin (α-SMA), desmin and vimentin. The histopathological examination revealed liver fibrosis in 6 out of 14 (42.9%) analyzed samples, while different forms of cholangitis were observed in the remaining 8 out of 14 (57.1%). The expression of α-SMA was proven in perisinusoidal hepatic stellate cells, portal/septal myofibroblasts, and interface myofibroblasts. The degree of α-SMA expression and the number of α-SMA immunopositive cells were the most intensive in the liver with fibrosis. Desmin expression in all liver samples of infected sheep was confirmed in hepatic stellate cells and smooth muscle cells. The hepatic stellate cells, portal/septal myofibroblasts, and interface myofibroblasts reacted as vimentin positive cells. In the liver without fibrotic changes hepatic stellate cells and smooth muscle cells were desmin positive. The obtained results suggest that all populations of myofibroblasts, especially hepatic stellate cells, play an important role in the increased extracellular matrix formation during parasitic liver fibrosis in sheep naturally infected with D. dendriticum.

Concepts: Cirrhosis, Liver, Histology, Actin, Muscle contraction, Smooth muscle, Hepatic stellate cell, Liver fluke

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The prevalence of Type 2 diabetes is expected to increase in parallel with obesity rates and the ageing population. Recent studies show that Type 2 diabetes is associated with a twofold increase in the risk of non-alcoholic fatty liver disease, a leading cause of chronic liver disease. Individuals with non-alcoholic steatohepatitis, a more advanced stage of non-alcoholic fatty liver disease, are specifically at risk of developing fibrosis/cirrhosis (end-stage liver disease) and hepatocellular carcinoma; therefore, identifying individuals (with Type 2 diabetes) who are likely to develop hepatic complications is paramount. In the present clinical review, we discuss the potential impact of non-alcoholic fatty liver disease diagnosis on Type 2 diabetes, and the putative risk factors for developing non-alcoholic steatohepatitis and non-alcoholic steatohepatitis fibrosis. We highlight the limitations of currently used tools in non-alcoholic fatty liver disease diagnosis and staging, and provide an insight into future developments in the field. We present an example of a non-alcoholic fatty liver disease screening protocol and discuss the therapeutic options currently available to our patients. This article is protected by copyright. All rights reserved.

Concepts: Cancer, Obesity, Cirrhosis, Metabolic syndrome, Non-alcoholic fatty liver disease, Fatty liver, Steatosis, Steatohepatitis

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Nonalcoholic fatty liver disease is a common cause of chronic liver disease, including nonalcoholic steatohepatitis (NASH). Our aim was to investigate whether serum TLR2 and TLR4 levels are correlated with NASH and able to predict liver fibrosis, as well as to compare these markers with other non-invasive fibrosis scores (AAR, APRI, FI, FIB-4 and FCI).

Concepts: Toll-like receptor, Cirrhosis, Hepatitis, Non-alcoholic fatty liver disease, Fatty liver, Steatosis, Steatohepatitis

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Existing predictive models of risk of disease progression in chronic hepatitis C (CHC) have limited accuracy. The aim of this study was to improve upon existing models by applying novel statistical methods that incorporate longitudinal data. Patients in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial were analyzed. Outcomes of interest were: 1) fibrosis progression (increase of ≥2 Ishak stages) and 2) liver-related clinical outcomes (liver-related death, hepatic decompensation, hepatocellular carcinoma, liver transplant, or increase in Child-Turcotte-Pugh score to ≥7). Predictors included longitudinal clinical, laboratory, and histologic data. Models were constructed using logistic regression (LR), and two machine learning (ML) methods [random forest (RF) and boosting] to predict an outcome in the next 12 months. The control arm was used as the training dataset (n= 349 clinical; n=184 fibrosis) and the interferon arm for internal validation. The area under the receiver operating characteristic curve (AUROC) for longitudinal models of fibrosis progression was: 0.78 (95%CI 0.74-0.83) using LR, 0.79 (95%CI 0.77-0.81) using RF, and 0.79 (95%CI 0.77-0.82) using boosting. The AUROC for longitudinal models of clinical progression was: 0.79 (95%CI 0.77-0.82) using LR, 0.86 (95%CI 0.85-0.87) using RF, and 0.84 (95%CI 0.82-0.86) using boosting. Longitudinal models outperformed baseline models for both outcomes (p<0.0001). Longitudinal ML models had negative predictive values of 94% for both outcomes. Conclusions: Prediction models that incorporate longitudinal data can capture the non-linear disease progression in CHC and thus outperform baseline models. ML methods can capture complex relationships between predictors and outcomes, yielding more accurate predictions. Our models can help target costly therapies to patients with most urgent need, guide intensity of clinical monitoring required, and provide prognostic information to patients. This article is protected by copyright. All rights reserved.

Concepts: Regression analysis, Prediction, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Hepatitis C, Hepatitis B, Receiver operating characteristic

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Several studies revealed that gut microbiota are associated with various human diseases, e.g., metabolic diseases, allergies, gastroenterological diseases, and liver diseases. The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein, and the liver-gut axis is important to understand the pathophysiology of several liver diseases, especially non-alcoholic fatty liver disease and hepatic encephalopathy. Moreover, gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis. Based on these previous findings, trials using probiotics have been performed for the prevention or treatment of liver diseases. In this review, we summarize the current understanding of the changes in gut microbiota associated with various liver diseases, and we describe the therapeutic trials of probiotics for those diseases.

Concepts: Cancer, Bacteria, Gut flora, Metabolism, Cirrhosis, Liver, Hepatology, Liver biopsy

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The development of effective nucleos(t)ide analogs (NAs) against hepatitis B virus (HBV) has improved the outcome of patients with chronic hepatitis B (CHB). This review updates issues related to the management of CHB patients included in special populations. Entecavir (ETV) and tenofovir (TDF) represent the currently recommended first-line NAs in patients with HBV decompensated cirrhosis. The combination of HBV immunoglobulin (usually for a finite duration) and NA is considered the standard of care for prophylaxis against HBV recurrence after liver transplantation. TDF is the best choice for hemodialysis patients and in patients with chronic kidney disease with nucleoside resistance. ETV and telbivudine are the preferred options in naïve renal transplant recipients and with low viremia levels, respectively. All hepatitis B surface antigen (HBsAg)-positive candidates should be treated with NAs before renal transplantation to achieve undetectable HBV DNA at the time of transplantation. Conventional interferon or NAs can also be used in children, on the basis of well-established therapeutic indication. Pregnant women at high risk of perinatal transmission could be treated with lamivudine, telbivudine or TDF in the last trimester of pregnancy. HBsAg-positive patients under immunosuppression should receive NA pre-emptively (regardless of HBV DNA levels) up to 12 mo after its cessation. In HBsAg negative, anti-HBc positive patients under immunosuppression, further studies are needed to form a final conclusion; however, it seems that anti-HBV prophylaxis is justified in such patients with hematological diseases and/or for those receiving rituximab-containing regimens, regardless of their anti-HBs or serum HBV DNA status.

Concepts: Chronic kidney disease, Kidney, Pregnancy, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Hepatitis B, Hepatitis B virus

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To investigate the possible involvement of Sirtuin 1 (SIRT1) in rat orthotopic liver transplantation (OLT), when Institute Georges Lopez 1 (IGL-1) preservation solution is enriched with trimetazidine (TMZ).

Concepts: Cirrhosis, Liver, Organ transplant, Enzymes, Sir2, Liver transplantation, Liver dialysis, Sirtuin 1

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To elucidate the molecular mechanisms underlying hepatitis B virus (HBV) occult infection of genotype C.

Concepts: DNA, Bacteria, Cirrhosis, Hepatitis, Hepatitis B, Viruses, Hepatitis B virus, Hepadnaviridae

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