Gastrointestinal Motility Disorders and Their Clinical Implications in Cirrhosis

Gastrointestinal motility is impaired in a substantial proportion of patients with cirrhosis. Cirrhosis-related autonomic neuropathy, increased nitric oxide production, and gut hormonal changes have been implicated. Oesophageal dysmotility has been associated with increased frequency of abnormal gastro-oesophageal reflux. Impaired gastric emptying and accommodation may result in early satiety and may have an impact on the nutritional status of these patients. Small intestinal dysmotility might be implicated in small intestinal bacterial overgrowth and increased bacterial translocation. The latter has been implicated in the pathophysiology of hepatic encephalopathy and spontaneous bacterial peritonitis. Enhanced colonic motility is usually associated with the use of lactulose. Pharmacological interventions aiming to alter gastrointestinal motility in cirrhosis could potentially have a beneficial effect reducing the risk of hepatic decompensation and improving prognosis

The role of the coagulation system in the pathogenesis of liver injury

There is a growing body of evidence that suggests a role for the coagulation cascade in promoting liver injury, in particular fibrosis. With the exception of thrombin, the expression and role of individual coagulation proteins in liver injury is poorly understood. The aim of this body of work was to further our understanding of the role of specific coagulation proteins in liver injury and consider viable targets as anti-fibrotic therapies. We examined these concepts using immunohistochemical, cell line, and animal based studies as well as translational studies in human subjects. Using immunohistochemical techniques, upregulation of coagulation proteins in both acute and chronic liver injury in mice and humans was demonstrated and correlated with severity of injury. Data from cell line studies demonstrated stellate cells, the principal cell involved in hepatic fibrosis, were sensitive to both thrombin and Factor Xa. Furthermore the direct inhibition of both thrombin and Factor Xa using novel anticoagulants in cell line studies and chemical induced murine models of liver fibrosis exhibited anti-fibrotic effects. Two unique translational studies were undertaken to determine the applicability of these findings in humans. A pilot study demonstrated that warfarin anticoagulation resulted in a significant reduction in liver stiffness measurements, a surrogate marker of liver fibrosis, in patients with pre-existing hepatitis C related liver fibrosis, and the interim results of a larger study, performed in the setting of hepatitis C post liver transplantation, has shown a reduction in fibrosis scores. The studies presented in this thesis add to the growing body of evidence suggesting a role for coagulation proteins in the pathogenesis of liver injury and are the first to show the potential anti-fibrotic benefits of both novel anticoagulants in murine models of liver fibrosis and warfarin anticoagulation in patients with hepatitis C related liver fibrosis pre and post transplantation

The role of the coagulation system in the pathogenesis of liver injury

There is a growing body of evidence that suggests a role for the coagulation cascade in promoting liver injury, in particular fibrosis. With the exception of thrombin, the expression and role of individual coagulation proteins in liver injury is poorly understood. The aim of this body of work was to further our understanding of the role of specific coagulation proteins in liver injury and consider viable targets as anti-fibrotic therapies. We examined these concepts using immunohistochemical, cell line, and animal based studies as well as translational studies in human subjects. Using immunohistochemical techniques, upregulation of coagulation proteins in both acute and chronic liver injury in mice and humans was demonstrated and correlated with severity of injury. Data from cell line studies demonstrated stellate cells, the principal cell involved in hepatic fibrosis, were sensitive to both thrombin and Factor Xa. Furthermore the direct inhibition of both thrombin and Factor Xa using novel anticoagulants in cell line studies and chemical induced murine models of liver fibrosis exhibited anti-fibrotic effects. Two unique translational studies were undertaken to determine the applicability of these findings in humans. A pilot study demonstrated that warfarin anticoagulation resulted in a significant reduction in liver stiffness measurements, a surrogate marker of liver fibrosis, in patients with pre-existing hepatitis C related liver fibrosis, and the interim results of a larger study, performed in the setting of hepatitis C post liver transplantation, has shown a reduction in fibrosis scores. The studies presented in this thesis add to the growing body of evidence suggesting a role for coagulation proteins in the pathogenesis of liver injury and are the first to show the potential anti-fibrotic benefits of both novel anticoagulants in murine models of liver fibrosis and warfarin anticoagulation in patients with hepatitis C related liver fibrosis pre and post transplantation.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Proteomic analysis of extracellular matrix from the hepatic stellate cell line LX-2 identifies CYR61 and Wnt-5a as novel constituents of fibrotic liver

[Image: see text] Activation of hepatic stellate cells (HSCs) and subsequent uncontrolled accumulation of altered extracellular matrix (ECM) underpin liver fibrosis, a wound healing response to chronic injury, which can lead to organ failure and death. We sought to catalogue the components of fibrotic liver ECM to obtain insights into disease etiology and aid identification of new biomarkers. Cell-derived ECM was isolated from the HSC line LX-2, an in vitro model of liver fibrosis, and compared to ECM from human foreskin fibroblasts (HFFs) as a control. Mass spectrometry analyses of cell-derived ECMs identified, with ≥99% confidence, 61 structural ECM or secreted proteins (48 and 31 proteins for LX-2 and HFF, respectively). Gene ontology enrichment analysis confirmed the enrichment of ECM proteins, and hierarchical clustering coupled with protein–protein interaction network analysis revealed a subset of proteins enriched to fibrotic ECM, highlighting the existence of cell type-specific ECM niches. Thirty-six proteins were enriched to LX-2 ECM as compared to HFF ECM, of which Wnt-5a and CYR61 were validated by immunohistochemistry in human and murine fibrotic liver tissue. Future studies will determine if these and other components may play a role in the etiology of hepatic fibrosis, serve as novel disease biomarkers, or open up new avenues for drug discovery