Center for Liver Research

Kolkata, India

Center for Liver Research

Kolkata, India
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Das K.,Gastroenterology | Datta S.,Center for Liver Research | Hembram J.R.,Gastroenterology | Dhali G.K.,Gastroenterology | Santra A.,Center for Liver Research
Liver International | Year: 2010

Background: Data regarding the outcome of hepatitis B virus (HBV)-related cirrhosis after the onset of decompensation is scanty. Method: From January 1998 to December 2008, a retrospective-prospective inception cohort study involving HBV-related decompensated cirrhotics was performed. Predictors of death and clinical events after the onset of decompensation were evaluated. Patients with co-infection with hepatitis C virus and/or human immunodeficiency virus, alcohol consumption to any degree and diabetes diagnosed before the detection of liver disease were excluded. Result and analysis: Two hundred and fifty-three patients (231 males, 139 e-negative), including 102 untreated patients, were analysed. The mean (±SD) age was 43.0 (±12.0) years. The mean (±SD) follow-up period was 47 (±47) months. Decompensation was the first presentation of liver disease in 210 (83%) patients. Ascites (70%) and variceal bleed (28%) were predominant modes of decompensation. Forty-three (17%) patients died (22 vs 14% in untreated and treated cohort, respectively; P=0.002). Type 2 hepato-renal syndrome was the commonest cause of death (32%). Survival was independent of e-antigen status. In the total cohorts, predictors of death were occurrence of sepsis with systemic inflammatory response (SIRS), ascites as the initial mode of decompensation, absence of antiviral therapy and events of high-grade hepatic encephalopathy [hazards ratios (HR) of 4.4, 3.6, 2.2 and 1.7 respectively]. In the untreated cohort, initial decompensation with ascites and development of sepsis with SIRS were independent predictors of death (HR 8.5 and 2.3 respectively), while 5-year survival was higher in patients having initial decompensation with variceal bleed vs ascites (29 vs 16%, respectively, P=0.002). Conclusion: Decompensation with ascites and sepsis with SIRS predict reduced survival. Antiviral therapy beyond 6 months improves outcome. © 2010 John Wiley & Sons A/S.

Svegliati-Baroni G.,Marche Polytechnic University | Faraci G.,Marche Polytechnic University | Fabris L.,University of Padua | Fabris L.,Center for Liver Research | And 12 more authors.
Gut | Year: 2011

Objective: To study the mechanism(s) linking insulin resistance (IR) to hepatic fibrosis and the role of the epithelial component in tissue repair and fibrosis in chronic hepatitis C (CHC). Design: Prospective observational study. Setting: Tertiary care academic centre. Patients: 78 consecutive patients with CHC. Main outcome measures: IR, calculated by the oral glucose insulin sensitivity during oral glucose tolerance test; necroinflammatory activity and fibrosis, defined according to Ishak's score; steatosis, graded as 0 (<5% of hepatocytes), 1 (5-33%), 2 (33-66%) and 3 (>66%). To evaluate the role of the epithelial component in tissue repair and fibrosis, the expansion of the ductular reaction (DR) was calculated by keratin-7 (CK7) morphometry. Nuclear expression of Snail, downregulation of E-cadherin and expression of fibroblast specific protein-1 (FSP1) and vimentin by CK7-positive cells were used as markers of epithelial-mesenchymal transition in DR elements. Results: IR, the degree of necroinflammation and expansion of the DR (stratified as reactive ductular cells (RDCs), hepatic progenitor cells and intermediate hepatobiliary cells according to morphological criteria) were all associated with the stage of fibrosis. Nuclear Snail expression, E-cadherin downregulation and vimentin upregulation were observed in RDCs. By dual immunofluorescence for CK7 and FSP1, the number of RDCs undergoing epithelial-mesenchymal transition progressively increased together with the necroinflammatory score. By multivariate analysis, total inflammation and insulin resistance were the only factors significantly predicting the presence of advanced fibrosis (Ishak score ≥3) and the expansion of RDCs. Conclusion: This study indicates that IR is associated with the degree of necroinflammatory injury in CHC and contributes to hepatic fibrosis by stimulating the expansion of RDCs that express epithelial- mesenchymal transition markers.

Fiorotto R.,Yale University | Fiorotto R.,Center for Liver Research | Scirpo R.,Yale University | Scirpo R.,University of Milan Bicocca | And 9 more authors.
Gastroenterology | Year: 2011

Background & Aims: Loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) in the biliary epithelium reduces bile flow and alkalinization in patients with cystic fibrosis (CF). Liver damage is believed to result from ductal cholestasis, but only 30% of patients with CF develop liver defects, indicating that another factor is involved. We studied the effects of CFTR deficiency on Toll-like receptor 4 (TLR4)-mediated responses of the biliary epithelium to endotoxins. Methods: Dextran sodium sulfate (DSS) was used to induce colitis in C57BL/6J-Cftr tm1Unc (Cftr-KO) mice and their wild-type littermates. Ductular reaction and portal inflammation were quantified by keratin-19 and CD45 immunolabeling. Cholangiocytes isolated from wild-type and Cftr-KO mice were challenged with lipopolysaccharide (LPS); cytokine secretion was quantified. Activation of nuclear factor κB (NF-κB), phosphorylation of TLR4, and activity of Src were determined. HEK-293 that expressed the secreted alkaline phosphatase reporter and human TLR4 were transfected with CFTR complementary DNAs. Results: DSS-induced colitis caused biliary damage and portal inflammation only in Cftr-KO mice. Biliary damage and inflammation were not attenuated by restoring biliary secretion with 24-nor-ursodeoxycholic acid but were significantly reduced by oral neomycin and polymyxin B, indicating a pathogenetic role of gut-derived bacterial products. Cftr-KO cholangiocytes incubated with LPS secreted significantly higher levels of cytokines regulated by TLR4 and NF-κB. LPS-mediated activation of NF-κB was blocked by the TLR4 inhibitor TAK-242. TLR4 phosphorylation by Src was significantly increased in Cftr-KO cholangiocytes. Expression of wild-type CFTR in the HEK293 cells stimulated with LPS reduced activation of NF-κB. Conclusions: CFTR deficiency alters the innate immunity of the biliary epithelium and reduces its tolerance to endotoxin, resulting in an Src-dependent inflammatory response mediated by TLR4 and NF-κB. These findings might be used to develop therapies for CF-associated cholangiopathy. © 2011 AGA Institute.

Spirli C.,Yale University | Spirli C.,Center for Liver Research | Okolicsanyi S.,Yale University | Okolicsanyi S.,Center for Liver Research | And 13 more authors.
Hepatology | Year: 2010

Polycystic liver disease may complicate autosomal dominant polycystic kidney disease (ADPKD), a disease caused by mutations in polycystins, which are proteins that regulate signaling, morphogenesis, and differentiation in epithelial cells. The cystic biliary epithelium [liver cystic epithelium (LCE)] secretes vascular endothelial growth factor (VEGF), which promotes liver cyst growth via autocrine and paracrine mechanisms. The expression of insulin-like growth factor 1 (IGF1), insulin-like growth factor 1 receptor (IGF1R), and phosphorylated mammalian target of rapamycin (p-mTOR) and the protein kinase A (PKA)-dependent phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) are also up-regulated in LCE. We have hypothesized that mammalian target of rapamycin (mTOR) represents a common pathway for the regulation of hypoxia-inducible factor 1 alpha (HIF1α)-dependent VEGF secretion by IGF1 and ERK1/2. Conditional polycystin-2-knockout (Pkd2KO) mice were used for in vivo studies and to isolate cystic cholangiocytes [liver cystic epithelial cells (LCECs)]. The expression of p-mTOR, VEGF, cleaved caspase 3 (CC3), proliferating cell nuclear antigen (PCNA), IGF1, IGF1R, phosphorylated extracellular signal-regulated kinase, p-P70S6K, HIF1α, and VEGF in LCE, LCECs, and wild-type cholangiocytes was studied with immunohistochemistry, western blotting, or enzyme-linked immunosorbent assays. The cystic area was measured by computerassisted morphometry of pancytokeratin-stained sections. Cell proliferation in vitro was studied with 3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and bromodeoxyuridine assays. The treatment of Pkd2KO mice with the mTOR inhibitor rapamycin significantly reduced the liver cyst area, liver/body weight ratio, pericystic microvascular density, and PCNA expression while increasing expression of CC3. Rapamycin inhibited IGF1-stimulated HIF1α accumulation and VEGF secretion in LCECs. IGF1-stimulated LCEC proliferation was inhibited by rapamycin and SU5416 (a vascular endothelial growth factor receptor 2 inhibitor). Phosphorylation of the mTOR-dependent kinase P70S6K was significantly reduced by PKA inhibitor 14-22 amide and by the mitogen signal-regulated kinase inhibitor U1026. Conclusion: These data demonstrate that PKA-dependent up-regulation of mTOR has a central role in the proliferative, antiapoptotic, and pro-angiogenic effects of IGF1 and VEGF in polycystin-2-defective mice. This study also highlights a mechanistic link between PKA, ERK, mTOR, and HIF1α-mediated VEGF secretion and provides a proof of concept for the potential use of mTOR inhibitors in ADPKD and conditions with aberrant cholangiocyte proliferation. Copyright © 2009 by the American Association for the Study of Liver Diseases.

Strazzabosco M.,Yale University | Strazzabosco M.,Center for Liver Research | Strazzabosco M.,University of Milan Bicocca | Somlo S.,Yale University
Gastroenterology | Year: 2011

Polycystic liver diseases (PLD) are inherited disorders of the biliary epithelium, caused by genetic defects in proteins associated with intracellular organelles, mainly the endoplasmic reticulum and the cilium. PLD are characterized by the formation and progressive enlargement of multiple cysts scattered throughout the liver parenchyma, and include different entities, classified based on their pathology, inheritance pattern, involvement of the kidney and clinical features. PLD should be considered as congenital diseases of cholangiocyte signaling. Here, we will review the changes in signaling pathways involved in liver cyst formation and progression, and their impact on cholangiocyte physiology. Each pathway represents a potential target for therapies aimed at reducing disease progression. © 2011 AGA Institute.

Ghosh S.,Center for Liver Research | Banerjee P.,Post Graduate Institute of Medical Education and Research | Sarkar A.,Center for Liver Research | Datta S.,Post Graduate Institute of Medical Education and Research | Chatterjee M.,Center for Liver Research
Journal of Clinical Microbiology | Year: 2012

Leishmania donovani is considered the causative organism of visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). Testing of 4/29 DNA samples from VL and PKDL patients as well as 2/7 field isolates showed an aberrant internal transcribed spacer 1 (ITS1) restriction fragment length polymorphism (RFLP) pattern, which upon sequencing strongly matched Leptomonas seymouri, thus confirming its presence in Indian leishmaniasis. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

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