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The basis of chronic infection following exposure to hepatitis C virus (HCV) infection is unexplained. One factor may be the low frequency and immature phenotype of virus-specific CD8+ T cells. The role of CD4+CD25+ T regulatory (Treg) cells in priming and expanding virus-specific CD8+ T cells was investigated. Twenty HLA-A2-positive patients with persistent HCV infection and 46 healthy controls were studied. Virus-specific CD8+ T-cell proliferation and gamma interferon (IFN-γ) frequency were analyzed with/without depletion of Treg cells, using peptides derived from HCV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). CD4+CD25+ Treg cells inhibited anti-CD3/CD28 CD8+ T-cell proliferation and perforin expression. Depletion of CD4+CD25+ Treg cells from chronic HCV patients in vitro increased HCV and EBV peptide-driven expansion (P = 0.0005 and P = 0.002, respectively) and also the number of HCV- and EBV-specific IFN-γ-expressing CD8+ T cells. Although stimulated CD8+ T cells expressed receptors for transforming growth factor beta and interleukin-10, the presence of antibody to transforming growth factor beta and interleukin-10 had no effect on the suppressive effect of CD4+CD25+ regulatory T cells on CD8+ T-cell proliferation. In conclusion, marked CD4+CD25+ regulatory T-cell activity is present in patients with chronic HCV infection, which may contribute to weak HCV-specific CD8+ T-cell responses and viral persistence. [ABSTRACT FROM AUTHOR]

See article in J. Gastroenterol. Hepatol. 2012; 27: 566-578. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults and at present no licensed medication has been approved. Despite its complex patho-physiology, dietary strategies aiming at delaying or preventing NAFLD have taken a reductionist approach, examining the impact of single components. Accumulating evidence suggests that n-3 LC-PUFAs are efficacious in regulating lipogenesis and fatty acid oxidation. In addition, plant derived flavonoids are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising and indirect antioxidant effects. Based on knowledge of their complementary molecular targets, we aimed to demonstrate that the combination of n-3 LC-PUFA (n-3) and flavan-3-ols (FLAV) prevents NAFLD. In a high-fat high-fructose (HF/HFr) fed C57Bl/6 J mouse model, the independent and interactive impact of n-3 and FLAV on histologically defined NAFLD, insulin sensitivity, weight gain, intestinal and hepatic gene expression, intestinal bile acids were examined. Only the combination of FLAV and n-3 (FLAVn-3) prevented steatosis as evidenced by a strong reduction in hepatocyte ballooning. While FLAV reduced body (− 28–30%), adipose tissue (− 45–50%) weights and serum insulin (− 22–25%) as observed following an intra-peritoneal glucose tolerance test, n-3 downregulated the expression of Srebf1 and the lipogenic genes ( Acaca , Fasn ). Significant impacts of interventions on intestinal bile acid metabolism, farnesoid X receptor ( Fxr ) signalling in the intestine and liver, and hepatic expression of fatty acid transporters ( Fabp4 , Vldlr , Cd36 ) were also evident. FLAVn-3 may be a novel intervention for NAFLD. Future research should aim to demonstrate its efficacy in the prevention and treatment of human NAFLD. [ABSTRACT FROM AUTHOR]

Background: Advances in medicine and public health mean that people are living longer; however, a significant proportion of that increased lifespan is spent in a prolonged state of declining health and wellbeing which places increasing pressure on medical, health and social services. There is a social and economic need to develop strategies to prevent or delay age-related disease and maintain lifelong health. Several studies have suggested links between the gut microbiome and age-related disease, which if confirmed would present a modifiable target for intervention development. The MOTION study aims to determine whether and how changes in the gut microbiome are associated with physical and mental capacity. A comprehensive longitudinal multiparameter study such as this has not been previously undertaken. Methods: MOTION is a longitudinal prospective cohort study with a focus on gut health and cognitive function. 360 healthy individuals aged 60 years and older, living in East Anglia, UK will be recruited to the study, stratified into one of three risk groups (cohorts) for developing dementia based on their cognitive function. Participants will attend study appointments every six months over four years, providing stool and blood samples and a health questionnaire. Participants will also undergo physical measurements and cognitive tests at alternating appointments, and undergo Optical Coherence Tomography scans at 3 timepoints. Two subgroups of participants in the study will provide colonic tissue biopsies (n = ≥30 from each cohort), and brain imaging (n = 30) at two timepoints. Discussion: This study will provide new insights into the gut-(microbiota)-brain axis and the relationship between age-associated changes in gut microbe populations and cognitive health. Such insights could help develop new microbe-based strategies to improve lifelong health and wellbeing. Trial registration: This study is registered in the ClinicalTrials.gov Database with ID: NCT04199195 Registered: May 14, 2019. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5–3.0 mg, or OCA 5–10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety. The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5–3.0 mg (n = 25), and OCA 5–10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5–10 mg vs. placebo (least-square [LS] mean difference = −83.4 [SE = 40.3] U/L; 95% CI −164.28 to −2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5–3.0 mg vs. placebo at week 24 (LS mean [SE] difference = −78.29 [41.81] U/L; 95% CI −162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5–3.0 mg 60%; OCA 5–10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged. Treatment with OCA 5–10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event. ClinicalTrials.gov : NCT02177136 ; EudraCT: 2014-002205-38. Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies. • Novel treatments for PSC are an urgent unmet need. • This phase II study evaluated OCA in patients with PSC. • OCA 5–10 mg significantly reduced serum ALP levels at 24 weeks. • The safety profile of OCA was consistent with previous studies. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Background & Aims: Age is the dominant prognostic factor influencing the natural history of hepatitis C virus (HCV) infection and treatment response. Accelerated lymphocyte telomere shortening in HCV infection correlates with adverse clinical outcomes. Critical telomere shortening generates double-stranded DNA breaks (DSB) inducing the DNA damage response, leading to replicative senescence. The phenotype and function of CD8+ T lymphocytes and the in vitro response to IFN-α in relation to the DNA damage response were investigated in patients with chronic HCV infection. Methods: CD8+ T lymphocytes with DSB were identified by expression of γ-H2AX (Ser-139) in 134 HCV-exposed subjects and 27 controls. Telomere length was determined by flow-FISH; cytokine expression by intracellular cytokine staining; in vitro responses to IFN-α, IL-2 or IL-6 by phospho-STAT1 (Y701) or phospho-STAT5 (Y694) expression. Results: The proportion of circulating CD8+γ-H2AX+ T lymphocytes rose with increasing fibrosis stage (p= 0.0023). CD8+γ-H2AX+ T lymphocytes were enriched in liver compared to blood (p= 0.03). CD8+γ-H2AX+ T lymphocytes demonstrated increased IFN-γ (p= 0.02) and reduced IL-2 expression (p= 0.02). CD8+γ-H2AX+ T lymphocytes failed to phosphorylate STAT1 in response to IFN-α compared to unfractionated CD8+ T lymphocytes (p <0.0001). More widespread failure of Jak/Stat signalling in CD8+γ-H2AX+ T lymphocytes was suggested by impaired phosphorylation of STAT1 with IL-6 (p= 0.002) and STAT5 with IL-2 (p= 0.0039) compared to unfractionated CD8+ T-lymphocytes. Conclusions: In chronic HCV infection, CD8+γ-H2AX+ T lymphocytes are highly differentiated with shortened telomeres, are more frequent within the liver, are associated with severe fibrosis and fail to activate Jak/Stat pathways in response to IFN-α, IL-2 or IL-6, perhaps explaining treatment failure in those with severe fibrosis. [Copyright &y& Elsevier]

Background. Studies have suggested that albumin has a value in cirrhotic patients undergoing paracentesis but its value in infection and sepsis is less clear. We planned to perform a meta-analysis of the risk of adverse outcomes in cirrhotic patients with and without albumin use. Methods. We searched MEDLINE and EMBASE in January 2013 for randomized studies of cirrhotic patients that reported the risk of adverse events and mortality with albumin and no albumin exposure. We performed random effects meta-analysis and assessed heterogeneity using the I² statistic. Results. Our review included 16 studies covering 1,518 patients. The use of albumin in paracentesis was associated with significantly reduced risk of paracentesis-induced circulatory dysfunction (OR 0.2695%, CI 0.08-0.93) and there was a nonsignificant difference in death, encephalopathy, hyponatraemia, readmission, and renal impairment. Compared to the other volume expanders, albumin use showed no difference in clinical outcomes. In cirrhotic patients with any infection, there was a significant reduction in mortality (OR 0.4695%, CI 0.25-0.86) and renal impairment (OR 0.3495%, CI 0.15-0.75) when albumin was used. Conclusion. The use of albumin in cirrhotic patients is valuable in patients with any infection and it reduces the risk of circulatory dysfunction among patients undergoing paracentesis. [ABSTRACT FROM AUTHOR]

Background and aims. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts eventually leading to biliary cirrhosis. Recent genetic studies in PSC have identified associations at 2q13, 2q35, 3p21, 4q27, 13q31 and suggestive association at 10p15. The aim of this study was to further characterize and refine the genetic architecture of PSC. Methods. We analyzed previously reported associated SNPs at four of these non-HLA loci and 59 SNPs tagging the IL-2/IL-21 (4q27) and IL2RA (10p15) loci in 992 UK PSC cases and 5162 healthy UK controls. Results. The most associated SNPs identified were rs3197999 (3p21 ( MST1), p = 1.9 × 10-6, ORA vs G = 1.28, 95% CI (1.16-1.42)); rs4147359 (10p15 ( IL2RA), p = 2.6 × 10-4, ORA vs G = 1.20, 95% CI (1.09-1.33)) and rs12511287 (4q27 ( IL-2/IL-21), p = 3.0 × 10-4, ORA vs T = 1.21, 95% CI (1.09-1.35)). In addition, we performed a meta-analysis for selected SNPs using published summary statistics from recent studies. We observed genome-wide significance for rs3197999 (3p21 ( MST1), Pcombined = 3.8 × 10-12) and rs4147359 (10p15 ( IL2RA), Pcombined = 1.5 × 10-8). Conclusion. We have for the first time confirmed the association of PSC with genetic variants at 10p15 ( IL2RA) locus at genome-wide significance and replicated the associations at MST1 and IL-2/IL-21 loci in a large homogeneous UK population. These results strongly implicate the role of IL-2/IL2RA pathway in PSC and provide further confirmation of MST1 association. [ABSTRACT FROM AUTHOR]

Background/Aims: Liver transplantation is an effective treatment for highly selected patients with hepatocellular carcinoma (HCC), but tumour recurrence remains an important cause of mortality. There are few data on the relation between the recurrence of HCC and lymphocytic infiltration following liver transplantation. Methods: The tumour CD4 + , CD8 + , CD25 + and Foxp3 + lymphocyte infiltrate was assessed by immunohistochemistry in explant tissue of 69 patients who underwent liver transplantation for HCC between 1985 and 2001. The data were analysed according to HCC recurrence and factors known to be associated with outcome. Results: Tumour size (Hazard ratio (95% CI: 1.19 (1.02, 1.39), P =0.03)), vascular invasion (P =0.02), lymphocyte infiltration (P =0.02) and CD4:CD8 ratio (P =0.001) were identified as significant univariate predictors of tumour recurrence. On multivariate analysis CD4:8 ratio (P =0.001), vascular invasion (P =0.01), tumour size (P =0.06) and reduced lymphocyte infiltration (P =0.03) were significant independent predictors of recurrence. The presence of Foxp3 + T-lymphocytes was not predictive of recurrence, but was associated with vascular invasion (FE=9.02, P =0.04). Conclusions: The data support the hypothesis that immune responses are important in HCC and that the phenotype of infiltrating lymphocytes is informative regarding prognosis. [Copyright &y& Elsevier]

The article describes the case of a 54-year-old Caucasian man who had biliary sepsis and Sweet's syndrome. The patient also suffered from several conditions such as pyrexia, leukocytosis with neutrophilia and raised C-reactive protein following transhepatic biliary stent insertion. Among the successful treatments received by the patient were potassium iodide, dapsone, and colchicine.

Background. Studies have suggested that albumin has a value in cirrhotic patients undergoing paracentesis but its value in infection and sepsis is less clear. We planned to perform a meta-analysis of the risk of adverse outcomes in cirrhotic patients with and without albumin use. Methods. We searched MEDLINE and EMBASE in January 2013 for randomized studies of cirrhotic patients that reported the risk of adverse events and mortality with albumin and no albumin exposure. We performed random effects meta-analysis and assessed heterogeneity using the I² statistic. Results. Our review included 16 studies covering 1,518 patients. The use of albumin in paracentesis was associated with significantly reduced risk of paracentesis-induced circulatory dysfunction (OR 0.2695%, CI 0.08-0.93) and there was a nonsignificant difference in death, encephalopathy, hyponatraemia, readmission, and renal impairment. Compared to the other volume expanders, albumin use showed no difference in clinical outcomes. In cirrhotic patients with any infection, there was a significant reduction in mortality (OR 0.4695%, CI 0.25-0.86) and renal impairment (OR 0.3495%, CI 0.15-0.75) when albumin was used. Conclusion. The use of albumin in cirrhotic patients is valuable in patients with any infection and it reduces the risk of circulatory dysfunction among patients undergoing paracentesis. [ABSTRACT FROM AUTHOR]