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Concept: Cirrhosis

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Alcoholic liver disease accounts for significant economic burden with second most common cause for liver transplantation in the US. Although alcohol abstinence is most crucial, morbidity and mortality occur amongst those with continuing alcohol intake and with established end stage liver disease due to lack of specific treatment modalities to manage this disease. Patients with severe acute alcoholic hepatitis, a distinct subset of alcoholic liver disease have a potential for mortality in about 25% within about 1 month despite treatment with available specific agents such as corticosteroids and /or pentoxifylline. Hence, there is clear need for newer and better treatment options to manage these patients. In this article, potential emerging newer targets to manage this disease are discussed including intestinal decontamination, caspase inhibitors, antioxidants, and interlukins. In the background of encouraging emerging data (retrospective data from the UNOS database and data from a case matched prospective French study ) on the beneficial effects of liver transplantation amongst patients with alcoholic hepatitis who are non-responders to current medical treatments, this article would also deal controversies surrounding the role and use of liver transplantation in patients with alcoholic hepatitis. Issues such as rule of 6 months of abstinence, ethical issues, and shortage of donor organs will be debated.

Concepts: Cirrhosis, Hepatitis, Alcoholism, Gastroenterology, Hepatology, Alcohol abuse, Alcoholic liver disease, Alcoholic hepatitis

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Currently, there are several drugs approved for the treatment of chronic hepatitis B including recombinant interferons, such as Interferon–α and its pegylated formulation, and the nucleos(t)ide analogues, such as Lamivudine, Adefovir, Telbivudine, Entecavir and Tenofovir. Pegylated–Interferon is an immune–modulatory agent that works mainly by enhancing the innate immune response while nucleos(t)ide analogues are oral drugs with direct inhibition of viral replication. Each agent has its own advantages and drawbacks. Pegylated–Interferon treatment has a finite duration without induction of drug resistance but only a limited number of patients achieve a sustained virological response to therapy. On the other hand, the care with nucleos(t)ide analogues requires a long–term treatment with a potential risk of induction of drug resistance, but higher rates of viral replication suppression are achieved. Nevertheless, second generation nucleos(t)ide analogues, such as Entecavir and Tenofovir, have both high genetic barrier to resistance and potent antiviral action. This review describes the mechanisms of antiviral activity and the efficacy of viral suppression of the different available drugs for chronic hepatitis B treatment, considering the recent clinical guidelines for an optimal management of chronic HBV infection.

Concepts: Immune system, Innate immune system, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Hepatitis C, Hepatitis B, Hepatitis A

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Intrahepatic T helper (Th)17 cytokine and serum interleukin (IL)‑17 levels in patients with hepatitis B are positively correlated with the progression of liver cirrhosis (LC). IL‑35 can significantly inhibit the differentiation of Th17 cells and the synthesis of IL‑17. The present study aimed to investigate the function and expression of IL‑17 and IL‑35 in the blood of patients with hepatitis B‑related LC. The levels of IL‑17 and IL‑35 in the peripheral blood of 30 patients with chronic hepatitis B (CHB), 79 with LC, 14 with chronic severe hepatitis B (CSHB), and 20 normal controls were detected by ELISA. Quantitative polymerase chain reaction was used to evaluate Epstein‑Barr virus‑induced gene 3 (EBI3), forkhead box (FOX)P3 and IL‑17 mRNA expression levels in peripheral blood mononuclear cells (PBMCs). Western blotting was used to determine protein expression. The liver function of patients and normal controls was measured. EBI3, IL‑17 and FOXP3 mRNA expression levels in PBMCs from patients with LC, CHB and CSHB were higher than those in cells from the controls. IL‑17 mRNA levels differed significantly according to the Child‑Pugh classification and exhibited an upward trend over time in contrast to a downward trend for EBI3 and FOXP3 mRNA. The changes in protein expression in the peripheral blood were consistent with the changes in mRNA expression. Serum IL‑17 levels were positively correlated with total bilirubin (TBIL), alanine aminotransferase (ALT) and Child‑Pugh grade, and were negatively correlated with albumin. These observed differences were significant. Serum IL‑35 levels were negatively correlated with albumin, but not with Child‑Pugh grade, ALT and TBIL. IL‑17 and IL‑35 may be critically involved in the pathogenesis of hepatitis B‑related LC.

Concepts: DNA, Gene expression, Molecular biology, Cirrhosis, Hepatitis, Liver, Bilirubin, Hepatitis C

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Chronic hepatitis B (CHB) is one of the most common infectious disease worldwide and a leading cause of death. Hepatitis B surface antigen (HBsAg) has previously been proven to be a steady biomarker that may be used to predict clinical outcomes. The amount of circulating HBsAg has been reported to reflect the number of infected hepatocytes. An advantage of pegylated interferon alpha (peg‑IFN‑α) is that as a finite course of therapy, it can potentially lead to sustained disease remission in subsequent decades. HBsAg seroclearance can reportedly be achieved in some hepatitis B patients treated with peg‑IFN‑α; this is a major advantage of IFN‑α, as compared with nucleoside analogue treatment. In the present study, a random phage display peptide library was used to screen for potential serum peptide biomarkers in predicting which patients with CHB would exhibit HBsAg seroclearance, following 48 weeks of peg‑IFN‑α therapy. A total of 30 patients with CHB who achieved HBsAg seroclearance following peg‑IFN‑α therapy and an additional 30 age‑, gender‑, hepatitis B e antigen (HBeAg) status‑ and hepatitis B virus genotype‑matched patients with CHB without HBsAg seroclearance following peg‑IFN‑α therapy, were enrolled as a discovery cohort. In the discovery/screening phase, 17/20 of the randomly selected phage clones, exhibited a specific reaction with purified sera immunoglobulin G from the HBsAg clearance group, and 13/17 positive phage clones came from the same phage clone, with the inserted peptide sequence ETCRASCINESA (named IFNC1). In the validation phase, phage‑ELISA results showed that the positive reaction rate of the IFNC1 peptide phage clone was 92.0% with the HBsAg seroclearance group (n=50), which was significantly higher, as compared with the randomly selected HBsAg non‑clearance group (12.0%, n=50) and the healthy control group (8.0%, n=50). In conclusion, the newly identified mimic peptide IFNC1 showed a high predictive validity HBsAg seroclearance in patients with CHB, following peg‑IFN‑α therapy. Therefore IFNC1 may be a potential serum biomarker, which could be used to predict the treatment outcomes of peg‑IFN‑α therapy.

Concepts: Immune system, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Interferon, Hepatitis C, Hepatitis B, Hepatitis A

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Hepatitis B virus (HBV) infection represents a serious global health problem and persistent HBV infection is associated with an increased risk of cirrhosis, hepatocellular carcinoma and liver failure. Recently, the study of the role of microRNA (miRNA) in the pathogenesis of HBV has gained considerable interest as well as new treatments against this pathogen have been approved. A few studies have investigated the antiviral activity of vitamin E (VE) in chronic HBV carriers. Herein, we review the possible role of tocopherols in the modulation of host miRNA with potential anti-HBV activity. A systematic research of the scientific literature was performed by searching the MEDLINE, Cochrane Library and EMBASE databases. The keywords used were ‘HBV therapy’, ‘HBV treatment’, ’VE antiviral effects', ‘tocopherol antiviral activity’, ‘miRNA antiviral activity’ and ’VE microRNA'. Reports describing the role of miRNA in the regulation of HBV life cycle, in vitro and in vivo available studies reporting the effects of VE on miRNA expression profiles and epigenetic networks, and clinical trials reporting the use of VE in patients with HBV-related chronic hepatitis were identified and examined. Based on the clinical results obtained in VE-treated chronic HBV carriers, we provide a reliable hypothesis for the possible role of this vitamin in the modulation of host miRNA profiles perturbed by this viral pathogen and in the regulation of some cellular miRNA with a suggested potential anti-HBV activity. This approach may contribute to the improvement of our understanding of pathogenetic mechanisms involved in HBV infection and increase the possibility of its management and treatment.

Concepts: Immune system, RNA, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Hepatitis C, Hepatitis B, Hepatitis B virus

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Objective: This study sought to use a meta-analysis approach to comprehensively evaluate correlations between the human leukocyte antigen-DR beta 1 (HLA-DRB1)*03 allele and chronic hepatitis B (CHB) in the Han Chinese population. Methods: The China Biomedical Literature database (CBMdisc), the Chongqing VIP database (VIP), and the PubMed database were searched. Using the inclusion and exclusion criteria of this study, all relevant case-control studies retrieved in these searches that satisfied the conditions of this investigation were collected. Review Manager (RevMan) 5.2 software was used to conduct a meta-analysis on the results of these studies. Results: There were 9 publications that satisfied the inclusion criteria. These publications included a total of 970 cases in the CHB group and 1185 cases in the normal control group. Egger’s test revealed no significant publication bias. A comprehensive analysis indicated that the pooled odds ratio (OR) value was 1.94 with a 95% confidence interval (CI) of 1.23-3.06 (Z=2.84, p=0.004); these findings suggested that in the Han Chinese population, the HLA-DRB1*03 allele is a susceptibility allele related to the occurrence of CHB. Conclusion: There is a statistically significant correlation between the HLA-DRB1*03 allele and the occurrence of CHB in the Han Chinese population, and the HLA-DRB1*03 allele may be a susceptibility allele for this disease.

Concepts: Epidemiology, Statistics, Cirrhosis, Hepatitis, Han Chinese, People's Republic of China, Hepatitis B, Hepatitis A

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Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells (MSCs) are multipotent adult progenitor cells being used as vehicles of therapeutic genes. Insulin Growth Factor like-I (IGF-I) was shown to counteract liver fibrosis. We aimed at analyzing the effect of applying IGF-I overexpressing mouse bone marrow-derived MSCs on hepatic fibrosis. Fibrosis was induced by chronic thioacetamide application or bile duct ligation. MSCs engineered to produce GFP (AdGFP-MSCs) or IGF-I (AdIGF-I-MSCs) were applied systemically and changes in collagen deposition and in the expression of key pro-fibrogenic and pro-regenerative genes/proteins were assessed. In addition, immunogenicity of transduced cells was analyzed. Liver fibrosis was further ameliorated after single dose application of AdIGF-I-MSCs when compared to AdGFP-MSCs and/or recombinant IGF-I treatments. Interestingly, an early and transitory upregulation in IGF-I and HGF mRNA expression was found in the liver of MSC-treated animals which was more pronounced in AdIGF-I-MSCs condition. A reduction in hepatic stellate cells activation status was found after incubation with MSCs conditioned media. In addition, the AdIGF-I-MSCs cell-free supernatant induced the expression of IGF-I and HGF in primary cultured hepatocytes. From day 1 after transplantation, the proliferation marker PCNA was upregulated in the liver of AdIGF-I-MSCs group, mainly in hepatocytes. MSCs were in vivo traced up to day 14 after injection. In addition, multiple doses of Ad-IGF-I-MSCs likely suppressed antiviral immune response and it further reduced collagen deposition. Our results uncover early events likely involved in the anti-fibrogenic effect of genetically modified MSCs and overall would support the use of AdIGF-I-MSCs in treatment of liver fibrosis.

Concepts: DNA, Scar, Mesenchymal stem cell, Cirrhosis, Liver, Bilirubin, Bile, Hepatic stellate cell

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Chronic hepatitis B virus (HBV) infection can cause hepatocellular carcinoma (HCC). Several hypotheses have been proposed to explain the mechanisms of HBV tumorigenesis, including inflammation and liver regeneration associated with cytotoxic immune injuries and transcriptional activators of mutant HBV gene products. The mutant viral oncoprotein-driven tumorigenesis is prevailed at the advanced stage or anti-HBe-positive phase of chronic HBV infection. Besides HBx, the pre-S2 (deletion) mutant protein represents a newly recognized oncoprotein that is accumulated in the endoplasmic reticulum (ER) and manifests as type II ground glass hepatocytes (GGH). The retention of pre-S2 mutant protein in ER can induce ER stress and initiate an ER stress-dependent VEGF/Akt/mTOR and NF¿B/COX-2 signal pathway. Additionally, the pre-S2 mutant protein can induce an ER stress-independent pathway to transactivate JAB-1/p27/RB/cyclin A,D pathway, leading to growth advantage of type II GGH. The pre-S2 mutant protein-induced ER stress can also cause DNA damage, centrosome overduplication, and genomic instability. In 5-10% of type II GGHs, there is co-expression of pre-S2 mutant protein and HBx antigen which exhibited enhanced oncogenic effects in transgenic mice. The mTOR signal cascade is consistently activated throughout the course of pre-S2 mutant transgenic livers and in human HCC tissues, leading to metabolic disorders and HCC tumorigenesis. Clinically, the presence of pre-S2 deletion mutants in sera frequently develop resistance to nucleoside analogues anti-virals and predict HCC development. The pre-S2 deletion mutants and type II GGHs therefore represent novel biomarkers of HBV-related HCCs. A versatile DNA array chip has been developed to detect pre-S2 mutants in serum. Overall, the presence of pre-S2 mutants in serum has implications for anti-viral treatment and can predict HCC development. Targeting at pre-S2 mutant protein-induced, ER stress-dependent, mTOR signal cascade and metabolic disorders may offer potential strategy for chemoprevention or therapy in high risk chronic HBV carriers.

Concepts: Immune system, DNA, Protein, Gene, DNA repair, Cirrhosis, Hepatitis, Hepatitis B

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Pulmonary gas exchange abnormalities and refractory hypoxemia cause myriad difficulties in patients with chronic liver disease. In addition to intrinsic cardiopulmonary diseases and hepatopulmonary syndrome, some unusual pathophysiological mechanisms in patients with portosystemic collaterals might contribute to hypoxemia. We report the clinical presentation of an unusual portosystemic anatomic shunt that permits venous admixture with oxygenated blood, causing hypoxemia that is refractory to the administration of supplemental oxygen, and recurrent hepatic encephalopathy. There has been no such report in the published literature. This case highlights the importance of keeping direct portopulmonary venous anastomosis in the differential diagnosis of oxygen-refractory hypoxemia and recurrent hepatic encephalopathy in patients with cirrhosis in the appropriate clinical context.

Concepts: Hemoglobin, Oxygen, Medical terms, Red blood cell, Heart, Cirrhosis, Medical diagnosis, Hepatic encephalopathy

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Ipilimumab is a fully human, monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma. Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis. Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection, there is a paucity of data on the safety of ipilimumab administration to that patient population. Here, we report the largest case series to date of patients with hepatitis B or C who received ipilimumab for advanced melanoma. Two of the nine patients described in this case series experienced fluctuations in their liver function tests (LFTs) and were subsequently treated with corticosteroids. Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection. The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options.

Concepts: Immune system, White blood cell, Clinical trial, Cirrhosis, Natural killer cell, Liver function tests, Gastroenterology, Cytotoxic T cell