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Concept: Cirrhosis

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Background and objective: Among the indigenous population of India, Primitive Tribal Groups (PTGs) are vulnerable to various health related events and some of the PTGs are showing a decline in population associated with high mortality rates. The present study was undertaken to define the prevalence of Hepatitis B Virus (HBV) infection, its genetic characterization and possible risk factors for transmission in five PTGs in Odisha, India. Methods: Cross-sectional observational studies were carried out in the Lodha, Saora, Khadia, Mankidia, and Juanga tribes residing in different parts of Odisha between 2006 and 2010. Results: Hepatitis B surface antigen (HBsAg) prevalence was 0·8%, 0·9%, 0·9%, 3·7%, and 1·7% in Lodha, Saora, Khadia, Mankidia, and Juanga tribes, respectively. While 54·8% of seropositive (HBsAg) cases demonstrated HBV DNA, occult HBV infection was observed in 19·48% of cases. High viral load with detectable ‘e’ antigen was found in 29% of HBsAg-positive individuals. All HBV isolates (n = 17) were genotype D without pre-core mutants. Only 15·6% of HBV positive individuals had symptoms of hepatic disease, though none had severe manifestations. Multivariate analysis of the prevailing risk factors indicated that shaving by the village barber was significantly associated with HBV transmission in males. Tattooing was found to be significantly associated with females. Interpretation and conclusion: This is the first report on HBV infection in PTGs of Odisha that suggests a high potential for transmission of HBV infection in two PTGs (Mankidia and Juanga). It warrants early public health attention in tribal populations vulnerable to HBV infection.

Concepts: Epidemiology, Virus, Cirrhosis, Hepatitis B, Hepatitis B virus, Indigenous peoples, Indigenous peoples of the Americas, Adivasi

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BackgroundVisceral obesity is often accompanied by non-alcoholic fatty liver disease (NAFLD). Activation of NACHT, LRR and PYD domains-containing proteins (NALPs) may contribute to the release of pro-inflammatory cytokines by adipose and the obesity-associated progression of NAFLD to non-alcoholic steatohepatitis (NASH).MethodsWe analyzed visceral adipose expression of various NALPs and its downstream effectors caspase-1, ASC (Apoptosis-associated speck-like protein containing a CARD), IL-18 (Interleukin-18) and IL-1ß (Interleukin- 1Beta) in obese subjects (BMI¿¿¿35) with biopsy proven NAFLD.ResultsIn adipose samples collected from NASH and pericellular fibrosis patients cohorts, expression levels of NALPs and IL-1ß were lower than that in non-NASH patients. In portal fibrosis, the levels of mRNA encoding anti-inflammatory NALP6 were upregulated. The expression levels of all NALPs were significantly co-correlated. Circulating IL-18 levels were associated with increased liver injury markers AST and ALT and portal fibrosis.ConclusionOur observations point at a possible shift in inflammation and fibrotic response from adipose tissue to liver and a possible negative feedback regulation of tissue inflammation that may instigate NAFLD severity.

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

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Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the non-nucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naïve patients with HCV genotype-1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (N=362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W; BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0-F2 vs F3-F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3-F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in SVR12 rates between patients with mild to moderate fibrosis (F0-F2) vs F3-F4 did not show a consistent pattern and were not statistically significant (63% vs 47% for TID16W; 53% vs 76% for TID28W; 48% vs 67% for TID40W; 70% vs 67% for BID28W; and 40% vs 36% for TID28W-NR, respectively; p>0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. Conclusion: The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (ClinicalTrials.gov NCT01132313).

Concepts: Cirrhosis, Hepatitis, Liver, Hepatocellular carcinoma, Bilirubin, Hepatitis C, Hepatitis B, Hepatitis A

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Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of our study is to identify small molecular agonists of pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in hepatocyte-derived stable cell line supporting HBV replication in a tetracycline inducible manner. An agonist of the mouse stimulator of interferon genes (STING), 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages, which efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative toll-like receptors (TLRs) in mouse macrophages revealed that unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I interferons (IFN). Moreover, as demonstrated in a HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of STING pathway induces an antiviral cytokine response against HBV and the development of small molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted.

Concepts: Immune system, Virus, Innate immune system, Cirrhosis, Hepatitis, Interferon, Hepatitis C, Hepatitis B

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Various pathological conditions can cause fatty liver in children. Nonalcoholic steatohepatitis (NASH) in children has been known since 1983. However, NASH diagnosed in childhood does not have a favorable outcome. The pathological characteristics of NASH are significantly different between children and adults. Nonalcoholic fatty liver disease (NAFLD)/NASH is accompanied by insulin resistance, which plays a pivotal role in its pathophysiology in both children and adults. In NASH, a “two-hit” model involving triglyceride accumulation (first hit) and liver damage (second hit) has been accepted. Insulin resistance was found to correlate with changes in fat levels; however, it did not correlate with fibrosis or NAFLD activity score in children. Therefore, insulin resistance may be important in the first hit. Because there is obvious familial clustering in NASH, genetic predisposition as well as environmental factors including diet might be the second hit of NAFLD/NASH.

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

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This study aimed to investigate the effects of Se-enriched probiotics (SP) on the liver fibrosis induced by CCl4 in rats. The results showed that SP significantly decreased serum alanine aminotransferase (48.2%), aspartate aminotransferase (26.8%), hepatic hydroxyproline (29.3%) and malondialdehyde (30.1%) levels, but increased glutathione peroxidase (47.2%) and superoxide dismutase (39.4%) activites and glutathione levels (43.7%) (P < 0.05) in rats treated by CCl4. SP could alleviate hepatic inflammation and necrosis induced by CCl4. Moreover, SP significantly reversed up-regulation of inflammation-related gene expression induced by CCl4 (P < 0.05). SP also significantly reduced the expression of collagen, α-smooth muscle actin, TGF-β1 and TIMP-1 gene and induced apoptosis of activated hepatic stellate cells in rats treated by CCl4 (P < 0.05). Our results suggest that SP could protect the liver fibrosis by attenuating hepatic oxidative stress, suppressing hepatic inflammation and inducing apoptosis of hepatic stellate cells.

Concepts: DNA, Gene, Amino acid, Oxidative stress, Superoxide dismutase, Cirrhosis, Liver, Alanine transaminase

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This study aims to investigate the prevalence of nonalcoholic fatty liver disease (NAFLD), to determine the metabolic risk factors of this disease, and to predict nonalcoholic steatohepatitis (NASH) with liver fibrosis in women of different ages and body mass index (BMI).

Concepts: Obesity, Cirrhosis, Hepatitis, Body mass index, Metabolic syndrome, Non-alcoholic fatty liver disease, Fatty liver, Steatosis

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Previous studies about the association of the interleukin-10 (IL-10) polymorphisms with the progression of liver fibrosis or cirrhosis susceptibility in chronic hepatitis B/C (CHB/C) disease were inconsistent. The aim of this meta-analysis was to derive a more precise estimation of the association.

Concepts: Cirrhosis, Bilirubin, Hepatitis C

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Anthocyanins may have beneficial effects on lipid metabolism and inflammation and are demonstrated to have hepatoprotective properties in models of restraint-stress- and chemically-induced liver damage. However, their potential to protect against non-alcoholic steatohepatitis (NASH) under conditions relevant for human pathogenesis remains unclear. Therefore, we studied the effects of the standardized anthocyanin-rich extract Mirtoselect on diet-induced NASH in a translational model of disease.

Concepts: Metabolism, Cirrhosis, Model, Liver disease, Non-alcoholic fatty liver disease, Bilberry

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HBsAg loss is a desired, but rare, treatment-induced clinical endpoint in chronic hepatitis B (CHB). Few studies have evaluated viral factors contributing to HBsAg loss.

Concepts: Antiretroviral drug, Cirrhosis, Hepatitis, Hepatitis C, Hepatitis B, Tenofovir, Hepatitis A