The Institute of Hepatology

London, United Kingdom

The Institute of Hepatology

London, United Kingdom

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PubMed | University of Calgary, University of the Basque Country, Vrije Universiteit Brussel, Loyola University Chicago and 6 more.
Type: Journal Article | Journal: Biochimica et biophysica acta | Year: 2015

Liver fibrosis develops when hepatic stellate cells (HSC) are activated into collagen-producing myofibroblasts. In non-alcoholic steatohepatitis (NASH), the adipokine leptin is upregulated, and promotes liver fibrosis by directly activating HSC via the hedgehog pathway. We reported that hedgehog-regulated osteopontin (OPN) plays a key role in promoting liver fibrosis. Herein, we evaluated if OPN mediates leptin-profibrogenic effects in NASH.Leptin-deficient (ob/ob) and wild-type (WT) mice were fed control or methionine-choline deficient (MCD) diet. Liver tissues were assessed by Sirius-red, OPN and SMA IHC, and qRT-PCR for fibrogenic genes. In vitro, HSC with stable OPN (or control) knockdown were treated with recombinant (r)leptin and OPN-neutralizing or sham-aptamers. HSC response to OPN loss was assessed by wound healing assay. OPN-aptamers were also added to precision-cut liver slices (PCLS), and administered to MCD-fed WT (leptin-intact) mice to determine if OPN neutralization abrogated fibrogenesis.MCD-fed WT mice developed NASH-fibrosis, upregulated OPN, and accumulated SMA+ cells. Conversely, MCD-fed ob/ob mice developed less fibrosis and accumulated fewer SMA+ and OPN+ cells. In vitro, leptin-treated HSC upregulated OPN, SMA, collagen 11 and TGF mRNA by nearly 3-fold, but this effect was blunted by OPN loss. Inhibition of PI3K and transduction of dominant negative-Akt abrogated leptin-mediated OPN induction, while constitutive active-Akt upregulated OPN. Finally, OPN neutralization reduced leptin-mediated fibrogenesis in both PCLS and MCD-fed mice.OPN overexpression in NASH enhances leptin-mediated fibrogenesis via PI3K/Akt. OPN neutralization significantly reduces NASH fibrosis, reinforcing the potential utility of targeting OPN in the treatment of patients with advanced NASH.


Manka P.,University of Duisburg - Essen | Bechmann L.P.,University of Duisburg - Essen | Coombes J.D.,The Institute of Hepatology | Thodou V.,University of Duisburg - Essen | And 10 more authors.
Clinical Gastroenterology and Hepatology | Year: 2015

In Western countries, infection with the hepatitis E virus (HEV) is considered to be rare and imported from endemic regions. However, the prevalence of HEV infection has increased among adults in central Europe. HEV infection can cause acute liver failure (ALF), but there have been only a few confirmed cases of HEV-associated ALF in Europe. We investigated the number of cases of indeterminate ALF associated with HEV infection. Methods: We performed a retrospective analysis of 80 patients diagnosed with ALF or acute hepatitis at the University Hospital Essen in Germany from November 2006 through December 2013. Clinical data were collected from the hospital databases; archived sera were tested for IgG and IgM against HEV, as well as HEV RNA. Results: Sera from 12 patients (15%) tested positive for IgG against HEV IgG; 7 of these samples did not test positive for HEV IgM or HEV RNA. Sera from 64 patients (80%) did not test positive for IgG or IgM against HEV or HEV RNA. Sera from 8 patients (10%) tested positive for HEV RNA (only 4 of these were positive for HEV IgG) and had clinical findings to support acute HEV infection. Conclusions: In a hospital in Germany, approximately 10% to 15% of patients with ALF had evidence for HEV infection. Serologic tests for IgG against HEV are insufficient to identify or exclude HEV infection; tests for HEV RNA also should be performed on patients with ALF of ambiguous etiology. © 2015 AGA Institute.


PubMed | The Institute of Hepatology and University of Duisburg - Essen
Type: Journal Article | Journal: PloS one | Year: 2014

Emerging data links different aspects of lipid metabolism to liver regeneration. In patients with acute liver failure (ALF), low levels of lipids may correlate with disease severity. Thus, we determined whether there is an etiology-specific link between lipid levels in patients suffering from ALF and aimed to investigate an effect of lipid levels on the prognosis of ALF.In this retrospective single center study, we reviewed 89 consecutive ALF patients, who met the criteria of the Acute Liver Failure Study Group. Patient characteristics, clinical data and laboratory parameters were individually analyzed at admission and correlated with the patients outcome after a four week follow up. Possible endpoints were either discharge, or death or liver transplantation.High-density lipoprotein (HDL), cholesterol and triglyceride levels were significantly lower in patients who died or required a liver transplant. HDL levels were significantly higher in patients with ALF caused by acetaminophen intoxication, compared to fulminant HBV infection or drug induced liver injury. HDL levels correlated with hepatic injury by ALT levels, and Albumin, and inversely correlated with the MELD score, INR, and bilirubin.In our cohort of patients with ALF, we could show that HDL and cholesterol are suppressed. In addition novel etiology specific patterns between acteminophen and non-acteminophen induced liver failure were detected for serum lipid components. Further studies are needed to address the role of cholesterol and lipid metabolism and the according pathways in different etiologies of ALF.


PubMed | University of Cologne, The Institute of Hepatology and University of Duisburg - Essen
Type: Journal Article | Journal: Gut | Year: 2015

Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity and constitutes part of the metabolic syndrome, which have been associated with low serum vitamin D (VD). Due to known crosstalk between VD and transforming growth factor (TGF)- signalling, VD has been proposed as an antifibrotic treatment.We evaluated the association between VD, the vitamin D receptor (VDR) and liver fibrosis in primary human hepatic stellate cells (phHSC) and 106 morbidly obese patients with NAFLD.Treating phHSC with VD ameliorated TGF--induced fibrogenesis via both VDR-dependent and VDR-independent mechanisms. Reduction of fibrogenic response was abolished in cells homozygous for GG at the A1012G single nucleotide polymorphisms within the VDR gene. Compared with healthy livers, NAFLD livers expressed higher levels of VDR mRNA and VDR fragments. VDR mRNA was lower in patients homozygous for GG at A1012G and expression of pro-fibrogenic genes was higher in patients carrying the G allele.VD may be an antifibrotic treatment option early in the onset of fibrosis in specific genotypes for VDR. Known polymorphisms of the VDR may influence the response to VD treatment.


PubMed | Heinrich Heine University Düsseldorf, The Institute of Hepatology and University of Duisburg - Essen
Type: Journal Article | Journal: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | Year: 2015

In Western countries, infection with the hepatitis E virus (HEV) is considered to be rare and imported from endemic regions. However, the prevalence of HEV infection has increased among adults in central Europe. HEV infection can cause acute liver failure (ALF), but there have been only a few confirmed cases of HEV-associated ALF in Europe. We investigated the number of cases of indeterminate ALF associated with HEV infection.We performed a retrospective analysis of 80 patients diagnosed with ALF or acute hepatitis at the University Hospital Essen in Germany from November 2006 through December 2013. Clinical data were collected from the hospital databases; archived sera were tested for IgG and IgM against HEV, as well as HEV RNA.Sera from 12 patients (15%) tested positive for IgG against HEV IgG; 7 of these samples did not test positive for HEV IgM or HEV RNA. Sera from 64 patients (80%) did not test positive for IgG or IgM against HEV or HEV RNA. Sera from 8 patients (10%) tested positive for HEV RNA (only 4 of these were positive for HEV IgG) and had clinical findings to support acute HEV infection.In a hospital in Germany, approximately 10% to 15% of patients with ALF had evidence for HEV infection. Serologic tests for IgG against HEV are insufficient to identify or exclude HEV infection; tests for HEV RNA also should be performed on patients with ALF of ambiguous etiology.


Syn W.-K.,The Institute of Hepatology
Clinical medicine (London, England) | Year: 2013

The mechanisms that drive non-alcoholic fatty liver disease (NAFLD) progression from simple steatosis to non-alcoholic steatohepatitis (NASH) and NASH-fibrosis and/or cirrhosis are complex. Recent studies suggest that the liver progenitor cell (ie liver stem cell) population expands during chronic liver injury, and is an essential component of the repair process. Hedgehog (Hh) is a developmental morphogen that has an important role in the adult tissue repair (and progenitor) response. Accumulating data in mice and human show that resurrection of the Hh pathway occurs during progressive NAFLD, and that activity of this pathway correlates with NASH-fibrosis stage. Importantly, Hh ligands secreted by dying (or stressed) hepatocytes, hepatic stellate cells (i.e. myofibroblasts), cholangiocytes and recruited immune cells can act on neighbouring cells to perpetuate the fibrogenic response. Intriguingly, Hh ligands can also stimulate cholangiocytes to secrete chemokines that recruit immune cell subsets (such as natural killer T cells), which could explain why fibrosis generally occurs in the context of chronic inflammation (i.e. fibrosis-associated inflammatory response). Finally, the administration of Hh inhibitors led to reduced fibrosis in a model of NASH. Future studies are needed to evaluate the utility of these inhibitors in other models of chronic liver disease. If successful, this could pave the way for the development of new therapy for patients with NASH, because Hh pathway inhibitors have now been licensed for use in patients with advanced basal cell carcinoma.


Howarth M.,The Institute of Hepatology | Riva A.,The Institute of Hepatology | Marks P.,The Institute of Hepatology | Williams R.,The Institute of Hepatology
Alcohol and Alcoholism | Year: 2012

Aims: To test the hypothesis that regional variations in the prevalence of alcoholic liver disease are contributed to by regional variations in 'softness' of drinking water, i.e. its mineral content. Methods: Annual hospital admission rates for alcoholic liver disease per 100,000 population in the 28 Strategic Health Authorities (SHAs) existing in England over the period 2003-2006 were compared with regional measures of water hardness, alcohol consumption and social deprivation. As corroborative evidence, the same relations were examined for hospital admission rates for osteoporosis, a disorder with an already established link with calcium deficiency in drinking water (as well as with heavy drinking). Results: Hospital admissions rates for alcoholic liver disease were higher in predominant-soft-water SHAs than with hard water SHAs. These areas, with one exception, were also associated with high alcohol consumption, but not with greater social deprivation. Hospital admission rates for osteoporosis were found to vary in a way similar to that for alcoholic liver disease, with significant correlations with soft water and alcohol consumption. Conclusion: Given experimental evidence that magnesium deficiency can aggravate liver damage from alcohol, soft water with its low magnesium concentration may be a factor additional to alcohol consumption in the development of liver damage. The parallel findings with osteoporosis admissions, explainable by low calcium and magnesium levels present in soft water, along with the known effect of heavy drinking on bone metabolism, provide corollary support for the hypothesis linking soft water with the pathogenesis of these two diseases. © The Author 2012. Medical Council on Alcohol and Oxford University Press. All rights reserved.


PubMed | Institute of Liver Studies and The Institute of Hepatology
Type: Journal Article | Journal: Results in immunology | Year: 2013

Cirrhotic patients (CPs) are susceptible to spontaneous bacterial peritonitis (SBP). Aim of this study was to examine if this susceptibility was related to peritoneal macrophages (PMs) altered host defence. Absorbance of phagocytosed particles by PMs from CPs was lower than that of control (31.88% vs. 77.2%). Particle opsonisation increased the absorbance to 41% in CPs PMs, and this value remains lower than the control; 77.2%. Respiratory burst (RB) was expressed as fluorescence index values, and these were higher in PMs from CPs than in controls (82 vs. 41, 73 vs. 26 and 71 vs. 26). IFN- made no further increase of RB values in PMs from CPs. CD14 expression was also higher in CPs PMs. IFN- significantly downregulated CD14 expression in both CPs PMs and control. Reduced phagocytosis by predominantly CD14-positive PMs from CPs could be related to intense RB. Findings suggest altered host defence that could contribute to susceptibility to SBP.


PubMed | The Institute of Hepatology
Type: | Journal: Clinical medicine (London, England) | Year: 2013

The mechanisms that drive non-alcoholic fatty liver disease (NAFLD) progression from simple steatosis to non-alcoholic steatohepatitis (NASH) and NASH-fibrosis and/or cirrhosis are complex. Recent studies suggest that the liver progenitor cell (ie liver stem cell) population expands during chronic liver injury, and is an essential component of the repair process. Hedgehog (Hh) is a developmental morphogen that has an important role in the adult tissue repair (and progenitor) response. Accumulating data in mice and human show that resurrection of the Hh pathway occurs during progressive NAFLD, and that activity of this pathway correlates with NASH-fibrosis stage. Importantly, Hh ligands secreted by dying (or stressed) hepatocytes, hepatic stellate cells (i.e. myofibroblasts), cholangiocytes and recruited immune cells can act on neighbouring cells to perpetuate the fibrogenic response. Intriguingly, Hh ligands can also stimulate cholangiocytes to secrete chemokines that recruit immune cell subsets (such as natural killer T cells), which could explain why fibrosis generally occurs in the context of chronic inflammation (i.e. fibrosis-associated inflammatory response). Finally, the administration of Hh inhibitors led to reduced fibrosis in a model of NASH. Future studies are needed to evaluate the utility of these inhibitors in other models of chronic liver disease. If successful, this could pave the way for the development of new therapy for patients with NASH, because Hh pathway inhibitors have now been licensed for use in patients with advanced basal cell carcinoma.


PubMed | The Institute of Hepatology
Type: Journal Article | Journal: Alcohol and alcoholism (Oxford, Oxfordshire) | Year: 2012

To test the hypothesis that regional variations in the prevalence of alcoholic liver disease are contributed to by regional variations in softness of drinking water, i.e. its mineral content.Annual hospital admission rates for alcoholic liver disease per 100,000 population in the 28 Strategic Health Authorities (SHAs) existing in England over the period 2003-2006 were compared with regional measures of water hardness, alcohol consumption and social deprivation. As corroborative evidence, the same relations were examined for hospital admission rates for osteoporosis, a disorder with an already established link with calcium deficiency in drinking water (as well as with heavy drinking).Hospital admissions rates for alcoholic liver disease were higher in predominant-soft-water SHAs than with hard water SHAs. These areas, with one exception, were also associated with high alcohol consumption, but not with greater social deprivation. Hospital admission rates for osteoporosis were found to vary in a way similar to that for alcoholic liver disease, with significant correlations with soft water and alcohol consumption.Given experimental evidence that magnesium deficiency can aggravate liver damage from alcohol, soft water with its low magnesium concentration may be a factor additional to alcohol consumption in the development of liver damage. The parallel findings with osteoporosis admissions, explainable by low calcium and magnesium levels present in soft water, along with the known effect of heavy drinking on bone metabolism, provide corollary support for the hypothesis linking soft water with the pathogenesis of these two diseases.

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