There have been numerous reports of cardiovascular and pulmonary abnormalities in patients with cirrhosis and portal hypertension. The role of portal hypertension in the pathogenesis of pulmonary abnormalities in patients with liver disease has not been defined. The present study was therefore undertaken to clarify this. Pulmonary function, including exercise testing, was evaluated in two groups of patients, 11 with portal hypertension due to cirrhosis and 10 with extrahepatic portal vein thrombosis and normal liver histology. Carbon monoxide gas transfer (TLCOsb) was less than 75% of predicted values in four patients from each group. One patient from each group had clinical and catheter confirmed evidence of pulmonary hypertension. Abnormal cardiorespiratory responses to exercise occurred in three patients in the extrahepatic group. Two had associated low TLCOsb and one developed arterial desaturation on exercise. A similar pattern was seen in three patients with cirrhosis. All had low TLCOsb and one developed arterial desaturation during exercise. In the cirrhotic group however three additional patients showed reduction in Pa02 unassociated with elevated heart rate response on exercise. There was no significant correlation with the presence of autoimmune antibodies which appear to be a secondary phenomenon. Our results suggest that pulmonary hypertension is linked to the presence of portal hypertension. Reduction in arterial P02, appears to occur only in patients with liver disease, presumably on the basis of intrapulmonary shunting.

No description available.

Persistent elevation of portal venous pressure (portal hypertension- PH), is linked to chronic liver disease and invariably leads to multi-organ circulatory complications. Hallmarks of PH are renal dysfunction and a characteristic hemodynamic profile (hyperdynamic circulation), which synergistically cause the development of the fatal sequelae of PH. Despite extensive research, PH remains a serious clinical problem, with no effective treatment. In large part, this is due to lack of comprehensive knowledge regarding the initiation and early progression of renal dysfunction and the hyperdynamic circulation. The spleen, which is actively engaged in cardiovascular regulation, is intimately connected with the portal venous system such that splenic venous pressure (SVP) is also elevated in PH. We therefore investigated the contribution of the spleen to PH-related cardiovascular dysregulation. Specifically, we employed an acute rat model to elucidate the existence of neurohormonal pathways activated in early PH. It was known that PH-related renal dysfunction is functional and neurally mediated (via the hepato-renal reflex). We hypothesized that, in addition, selective elevation of splenic venous pressure (SVP) also increases renal vascular resistance and modulates renal vascular function, through reflex activation of splenic afferent and renal sympathetic nerves. Indeed, acutely elevated SVP by partial splenic vein occlusion (SVO) did increase splenic afferent nerve activity and reflexly increased renal sympathetic nerve activity (RSNA). Simultaneously, renal blood flow (RBF) and renal arterial conductance fell; this was α1 adrenergic receptor-mediated and dependent on intact splenic and renal nerves. Moreover, our data showed that, in the absence of increased SVP, PH did not affect RSNA or renal vascular function. Although splanchnic vasodilation is characteristic of the hyperdynamic circulation in PH, its development is thought to be contingent upon an initial transient mesenteric vasoconstriction. Our data revealed that increased SVP reflexly activates mesenteric efferent nerves, and reduces mesenteric arterial blood flow, vascular conductance and resistance artery diameter; this was primarily mediated through angiotensin II release (spleno-renal reflex-, renal baroreceptor-, and mesenteric angiotensinergic nerve-mediated). In conclusion, the spleen neurohormonally modulates renal and mesenteric circulations, thus contributing to the initiation of renal dysfunction and hyperdynamic circulation of PH.

Thesis (PhD) - Swinburne University of Technology, 2008. / Submitted for the degree of Doctor of Philosophy, Swinburne University of Technology - 2008. Typescript. Includes bibliographical references (p.271-304).

Introduction: Hepatorenal syndrome (HRS) is a common complication of advanced cirrhosis with a high mortality rate and limited treatment options. Central to its pathogenesis is severe, but potentially reversible, renal vasoconstriction leading to functional renal failure. Current pharmacological treatment using splanchnic vasoconstrictors is suboptimal and prognosis without liver transplantation is dismal. The peptide hormone relaxin (RLN) mediates haemodynamic adaptations to pregnancy including increased renal blood flow (RBF) and glomerular filtration rate (GFR). I hypothesised that exogenous RLN could be used therapeutically to improve RBF and renal function in the context of experimental cirrhosis and HRS. Methods: To address this I generated pathologically distinct rat models of liver cirrhosis with features of human HRS including renal vasoconstriction and renal failure. Compensated cirrhosis was induced in male rats by 16 weeks of i.p. carbon tetrachloride (CCl4) and decompensated cirrhosis by bile duct ligation (BDL). I studied the effects of acute i.v. or sustained (72 hr) s.c. infusion of RLN compared with vehicle on systemic haemodynamics, RBF, GFR and kidney histology. I used blood oxygen dependent-magnetic resonance imaging (BOLD-MRI) to detect changes in kidney parenchymal oxygenation and Doppler ultrasound to monitor changes in RBF (velocity time integral, VTI) and renal arterial resistance (resistive index, RI). Hepatic and renal expression of the relaxin receptor RXFP1 was determined by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Vascular functional responses in isolated renal arteries were assessed by wire myography. Relaxin mediated changes in key vaso-regulatory signalling pathways in the kidney and renal vessels were analysed by qPCR, IHC and ELISA. Results: I showed using in vitro myography that the pathophysiological mechanism that underlies renal vasoconstriction in experimental cirrhosis models is an impairment of endothelium-dependent vasodilatation. Selective targeting of renal vasoconstriction using relaxin improved renal blood flow, tissue oxygenation, and normalized glomerular filtration rate in both compensated and decompensated rat cirrhosis. Furthermore, relaxin treatment restored endothelium-dependent vasodilation in isolated renal vessels from CCl4 cirrhotic rats. Relaxin-induced effects on renal blood flow and glomerular filtration rate were mediated though activation of the AKT/eNOS/nitric oxide signalling pathway in kidney, though systemic nitric oxide levels were unaffected. Crucially for human translation, relaxin did not reduce mean arterial blood pressure even in advanced cirrhosis. Conclusion: My findings identify relaxin as the first potential targeted treatment reversing the vascular dysfunction which causes HRS and directly improving renal function in HRS. Clinical translation in carefully selected populations is warranted.

Thesis (M.D.)--Boston University

No description available.

Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Department of Physiology. Title from pdf file main screen (viewed on August 16, 2009). Includes bibliographical references.

Acute variceal bleeding (AVB) is the most dramatic complication of portalhypertension. It occurs in one-third of cirrhotic patients with varices and causes70% of all upper gastrointestinal (GI) bleeding episodes in cirrhotic patientsresulting in major morbidity and mortality despite improvements in primaryprophylaxis and management of acute bleeding episodes over the past threedecades. The best strategies for management of AVB have been investigated innumerous clinical trials and this has led to multiple guidelines. Endoscopicmanagement combined with pharmacotherapy is the ideal strategy to controlvariceal bleeding, but this can be challenging. Bleeding may be difficult to identifyor may occur from sites that are difficult to approach. A trained multidisciplinaryteam consisting of endoscopists, hepatologists, and specialized nurses as well asinterventional radiologists is required to administer the ideal treatment for AVB.However, this setup is not available everywhere. Early management of AVB ismandatory within 24 hours of admission and better outcomes are reported in thosepatients who receive endoscopic therapy within 12 hours. Although this is stillcontroversial, it seems to be increasingly obvious that earlier hemostasis leads tobetter outcomes.In practice, treatment for AVB is often delayed by a lack of expert endoscopists.Therefore, having a simple endoscopic hemostatic technique that does not requirean experienced team could have a major impact on AVB management.Hemospray powder (Hemospray, TC-325; Cook Medical Inc. Winston-Salem, NC,USA) is an FDA-approved organic powder made from a proprietary mineral blend.The material works in two different ways: as a mechanical barrier and byabsorption. When in contact with the bleeding site, the powder forms a barrier over6the vessel wall, quickly stopping the bleeding. In addition, the absorbent powderincreases the local concentration of clotting factors and enhances clot formation.Previous studies described Hemospray as a simple and feasible new modality forobtaining rapid hemostasis of peptic ulcer bleeding during gastrointestinalendoscopy, either as primary treatment or as a salvage indication.The work presented here evaluated the safety, feasibility, clinical efficacy, andpotential outcome benefits of applying this hemostatic powder early in themanagement of AVB, as a potential new clinical indication. We have performedour research in three phases, starting with a safety study on AVB that originatedfrom esophageal varices and two case reports on portal hypertension-relatedbleeding. This was followed by an efficacy study and then we confirmed our datain a randomized controlled study where we observed a potential impact on survival,opening the door to additional clinical investigations.The aim of the research was to investigate the concept of treating portalhypertension-related AVB with early endoscopic hemostasis using a novelhemostatic powder which can be applied without the need for a skilled team.We showed that this easy-to-perform technique, in a novel indication, is indeed safeand effective when added to the gold standard of care for AVB and can improveendoscopic and clinical hemostasis, providing easier elective treatment with lessneed for experienced teams. An effect on mortality was also observed in therandomized controlled study as a secondary outcome measure.The next step is to design a study focused on survival, perhaps with a simplifieddesign in which the spraying catheter can be used without the need for endoscopyor sedation. Another interesting future investigation will be to design a study thatcompares two groups with early powder application that are randomized within 247to 48 hours either to elective endoscopic treatment or a transjugular intrahepaticportosystemic shunt (TIPS) procedure. This would allow us to learn whether thisnew therapeutic approach impacts the need for early TIPS placement in severe casesof AVB. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

Goals: The purpose of our study was to evaluate trends of hospitalization, acute kidney injury (AKI) and mortality in cirrhotic patients with spontaneous bacterial peritonitis (SBP). Background: SBP is a frequent bacterial infection in cirrhotic patients leading to increased morbidity and mortality. Materials and Methods: A total of 4,840,643 patients hospitalized with cirrhosis from 2005 to 2014 were identified using the Nationwide Inpatient Sample database, of which 115,359 (2.4%) had SBP. We examined annual trends and used multivariable mixed-effects logistic regression analyses to obtain adjusted odds ratios by accounting for hospital level and patient level variables. Results: We identified a striking increase in hospitalizations for SBP in cirrhotic patients (0.45% to 3.12%) and AKI in SBP patients (25.6% to 46.7%) from 2005 to 2014. Inpatient mortality decreased over the study period in patients with SBP (19.1% to 16.1%) and in patients with SBP plus AKI (40.9% to 27.6%). Patients with SBP had a higher inpatient mortality rate than those without SBP [15.5% vs. 6%, adjusted odd ratio (aOR): 2.02, P<0.001]. AKI was 2-fold more prevalent in cirrhotics with SBP than those without SBP (42.8% vs. 17.2%, aOR: 1.91, P<0.001) and concomitant AKI was associated with a 6-fold mortality increase (aOR: 5.84, P<0.001). Cirrhotic patients with SBP had higher hospitalization costs and longer length of stays than patients without SBP. Conclusions: Despite a higher hospitalization rate and prevalence of concomitant AKI, mortality in patients with SBP decreased during the study period. SBP is associated with high likelihood of development of AKI, which in turn, increases mortality.