Medicine (Austin & Northern Health) - Theses
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ItemNo Preview AvailableCardiovascular Disease in Patients with End-Stage Liver Disease undergoing Transplantation( 2021)It has been known for centuries that the heart and the liver are closely related. Galen suggested the body was controlled by the tripartite system of the liver, heart and brain, with the liver being the source of all veins and the principal instrument of sanguification. The complex interconnectedness of these organ systems is no more apparent than in patients with liver dysfunction. Liver cirrhosis leads to autonomic and neurohormonal dysregulation which can culminate in circulatory and cardiovascular dysfunction. These observations have been brought to the fore with advances in experimental techniques including biomarkers and structural imaging that have highlighted the manifestations of cirrhotic cardiomyopathy. However, the precise clinical consequences of these cardiac maladaptations have remained elusive. Liver transplantation (LT) is a valuable yet scarce resource with the ability to transform the lives of patients with advanced liver disease. Despite improvements in anaesthetic management and surgical techniques, patients undergoing LT are at a substantial risk of perioperative cardiovascular complications. This is pertinent as transplant candidates in the contemporary era are often older and have a higher proportion of vascular comorbidities. In addition, non-alcoholic fatty liver disease is becoming a major aetiology of liver disease and this condition shares similar risk factors to many cardiovascular disease states. As such, optimizing risk stratification of patients prior to LT is a priority to ensure optimal patient and graft outcomes. Moreover, whether transplantation itself confers risk of accelerated atherosclerosis is unclear. This dissertation work explores three key areas. First, it aims to provide an extensive review of the perioperative and long-term cardiovascular mortality of patients undergoing LT in Australia and New Zealand. Second, we investigate the pathophysiological connections that constitute the heart-liver axis in patients with end-stage liver disease undergoing LT. This covers both the structural and electrophysiological alterations that characterize cirrhotic cardiomyopathy with a translational focus. Third, we aimed to evaluate predictors of cardiovascular events in patients undergoing LT, including a prospective study evaluating whether LT leads to accelerated changes in coronary atherosclerosis. Collectively, this thesis explores key epidemiologic data relating to cardiovascular mortality in the LT population, and highlights key cardiac structural, electrophysiological and coronary disease manifestations in patients with end-stage liver disease undergoing transplantation.
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ItemThe role of the alternate renin angiotensin system in human portal hypertension( 2018)The vast majority of morbidity and mortality in human liver cirrhosis occurs due to portal hypertension. In advanced cirrhosis as resistance to intra-hepatic portal flow increases there is vasodilatation of the splanchnic vascular bed, which results in increased flow in the portal circulation thus contributing significantly to portal pressure. The pathophysiology underlying splanchnic vasodilatation in cirrhosis is not well understood. However, recent in-vivo and ex-vivo studies of experimental models of liver injury demonstrate that the novel ‘alternate arm of the renin angiotensin system’ is activated in cirrhosis and mediates vasodilatation through its effector peptide, angiotensin-(1-7). The aim of this thesis was thus to evaluate the role played by the alternate renin angiotensin system in human cirrhosis. The vasoactivity of renin angiotensin system mediators were studied in a myograph device using isolated vessels from animal models of cirrhosis and from human subjects undergoing liver transplantation surgery. Circulating components of both the classical and alternate renin angiotensin system were measured regionally in patients with cirrhosis undergoing liver transplantation or a portosystemic shunt procedure. Finally, the in-vivo response to angiotensin-(1-7) in an isolated peripheral vascular bed was compared between cirrhotic subjects and healthy controls. In-vitro studies showed contractile responses of isolated splanchnic vessels to be attenuated by angiotensin-(1-7) and levels of this peptide and its integral enzyme, angiotensin converting enzyme 2, were upregulated in human cirrhosis. Activation of the alternate renin angiotensin system in human cirrhosis was most marked in patients with clinical and laboratory features of advanced disease whilst deactivation of the system occurred post liver transplantation with restoration of normal circulatory function. Angiotensin-(1-7) elicited vasodilatation in the peripheral circulations of both cirrhotic and control subjects, however, this response was threefold higher among the cirrhotic group. In conclusion the data presented in this thesis provides evidence that the alternate renin angiotensin system is activated in human cirrhosis and through the action of the angiotensin-(1-7) peptide may contribute to pathological vasodilatation.
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ItemThe impact of low testosterone and the effect of testosterone therapy in men with advanced liver disease( 2017)Background: Cirrhosis is increasing in prevalence, and disproportionately affects men. Sarcopenia is one of commonest clinical sequelae of cirrhosis, with a reported prevalence of up to 70%. Sarcopenia has been associated with increased mortality across multiple studies, independently of the established prognostic tool the Model for End-stage Liver Disease (MELD). This association appears to be attributable to an increase in infection-related deaths. Serum testosterone is reduced in up to 90% of men with cirrhosis, and has also been independently associated with increased mortality in a single-centre cohort of men waitlisted for liver transplantation. Serum testosterone and muscle mass are closely related in non-liver populations, but the relationship between low testosterone and sarcopenia has not been investigated in cirrhosis. Testosterone therapy increases muscle mass in non-cirrhotic men with hypogonadism, but the impact of testosterone therapy on body composition in cirrhotic men is not known. Aims: This work aims to explore the interaction between low testosterone and sarcopenia and their relative impact on outcome in men with cirrhosis, and prospectively validate the prognostic value of low testosterone. The potential therapeutic application of testosterone as a means of ameliorating sarcopenia in cirrhotic men is assessed in addition to its impact on other outcomes. Methods: A retrospective analysis of 145 patients from a single centre liver transplant database was conducted to correlate muscle mass (as measured by height-adjusted muscle area at the transverse CT scan slice of the 4th lumbar vertebrae) with testosterone levels, and to investigate their respective impact on outcomes including mortality. A prospective cohort study followed 268 consecutive men with cirrhosis reviewed in the hepatology ambulatory care setting for a 12 month period after quantifying baseline circulating testosterone to evaluate the association between testosterone levels and infection, mortality and transplantation. A 12 month, randomised, placebo-controlled trial of testosterone undecanoate in 101 men with cirrhosis with low baseline testosterone levels (total testosterone <12nmol/L or free testosterone <230pmol/L) evaluated the effect of testosterone on body composition (as measured by dual energy x-ray absorptiometry) and other outcomes including mortality, infection, bone density and haematology and biochemistry. Results: In a pre-transplant cohort of cirrhotic men, low testosterone correlates modestly with sarcopenia (tau=0.132, p=0.019) and appeared to be a better predictor of mortality than sarcopenia in a multivariable analysis incorporating the MELD score (HR 1.07, p=0.02 for low testosterone vs HR 1.04, p=0.09 for sarcopenia). In a general hepatology setting, there is an increased risk of mortality or transplantation (OR 2.36, p=0.018) when total testosterone fell below the threshold of 8.3nmol/L, independent of the MELD score. Similarly, the low testosterone group conferred an independent increase in the risk of major infection (HR 3.61, p<0.001). Administration of intramuscular testosterone undecanoate to this population resulted in a significant increase in both appendicular lean mass (mean adjusted difference (MAD) 1.69kg, p=0.021), and total lean mass (MAD 4.74kg, p=0.008) as compared to placebo. In addition, testosteronetreated patients had a reduction in fat mass (MAD -4.34kg, p<0.001) and HbA1c (MAD -0.35%, p=0.024) as well as increased bone mass (MAD 0.08kg, p=0.009) and haemoglobin (MAD 10.2g/L, p=0.041). There was no increase in adverse events in testosterone-treated subjects. Conclusion Low testosterone in men with cirrhosis is associated with increased risk for mortality or transplantation as well as major infection. It may be a better prognostic marker than sarcopenia, which may relate to its non-muscle effects. Testosterone therapy in men with cirrhosis selected for low baseline testosterone levels increases muscle mass as well as increases bone mass and haematocrit, and reduces fat mass and HbA1ct. Testosterone is the first therapy with randomised controlled data to support its use in the treatment of sarcopenia in cirrhosis. Larger-scale studies are required to assess for an effect on clinically meaningful endpoints such as infection risk, hospitalisation and mortality.
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ItemThe utility of immune function monitoring in predicting clinical outcomes in cirrhosis and following liver transplantation( 2015)Background: Transplantation is a life-saving procedure offered to thousands of people around the world each year. In most cases, lifelong suppression of the recipient’s immune system is required to prevent allorecognition and organ rejection. However, immunosuppressive medications have significant side effects that are now responsible for much of the post-transplant morbidity and mortality. Balancing the risks of over and under immunosuppression is key to patient management, but without an objective marker of immune function, clinical events remain common. QuantiFERON-Monitor (QFM) is a net immune function biomarker that measures IFNγ after stimulation of whole blood with an innate and adaptive immune stimulant. It is potentially accessible as it is based on the same laboratory platform as the readily available QuantiFERON-gold assay. The studies within this thesis represent the first translational clinical studies evaluating this assay. Methods: A cross-sectional pilot study compared QFM in healthy controls with patients before and after liver transplantation. Subsequent studies focused on immune function biomarkers and correlation with clinical events both before and after transplantation. In a cirrhotic transplant-waitlisted population, the QFM assay was performed and patients prospectively monitored for infection prior to transplant. This was followed by a prospective observational post-transplant cohort study in which QFM was taken longitudinally to assess for clinical events including infection and rejection based on pre-defined criteria. The same cohort was monitored for cytomegalovirus (CMV) reactivation with a CMV-specific T-cell assay, to evaluate the potential for more specialised immune monitoring. A small subgroup of controls and rejectors were compared for pre-transplant cytokine production using an enhanced sensitivity bead array and flow cytometry. Results: The pilot study confirmed that QFM could discriminate between populations known to be immunosuppressed. Compared with healthy controls, lower QFM was seen in patients following transplantation when on immunosuppression. QFM did not vary by age, gender or disease aetiology. In the cohort of cirrhotic patients, low QFM was associated with the risk of infection prior to transplant. This risk was also demonstrated after transplantation, where a low QFM at one week was significantly associated with risk of infection, but not rejection. Conversely, a high week 1 QFM was significantly associated with rejection, but not infection. Based on the selected optimal cut-offs, approximately 70% of all transplant patients were identified as being over- or under-suppressed. The risk of post-transplant rejection was further heightened in patients who had lower pre-transplant baseline pro-inflammatory cytokine production. QFM was not associated with risk of CMV reactivation. However, a CMV-specific immune function assay was significantly associated with CMV in patients inappropriately classified as low-risk based on current standard of care. Conclusions: Without an objective marker of immune function, clinical events remain exceedingly common following liver transplantation. The studies within this thesis represent the first translational studies involving QFM - a net immune function biomarker which benefits from being accessible, rapid and comprising both innate and adaptive immune stimulants. Future individualisation and optimisation of immunosuppression based on immune monitoring could fundamentally alter the way patients are monitored and treated following transplantation.
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ItemThe role of the alternate renin-angiotensin system in the pathogenesis of splanchnic vasodilatation in cirrhosis( 2012)The classic renin-angiotensin system (RAS), mediated by angiotensin II, contributes towards the pathophysiology of fibrogenesis and elevated hepatic resistance in cirrhosis, and the alternate axis of the RAS, comprising angiotensin-converting enzyme-2 (ACE2), angiotensin-(1-7) and the Mas receptor, may have opposing effects. Splanchnic vasodilatation, with consequent increased portal venous inflow, is a key factor in the pathogenesis of portal hypertension in cirrhosis. There is splanchnic vascular hypocontractility to angiotensin II in cirrhosis, but the role of the alternate axis of the RAS in the splanchnic circulation is unknown. The aim of this thesis was to determine whether the alternate axis of the RAS is implicated in the pathophysiology of splanchnic vasodilatation in experimental cirrhosis. Expression of the splanchnic vascular RAS was characterised in rats with portal hypertension induced by chronic biliary cirrhosis. In-vivo levels of angiotensin-(1-7) and angiotensin II, and ex-vivo metabolism of angiotensin peptides was examined in the portal circulation in cirrhosis. Finally, the effect of angiotensin-(1-7) on splanchnic vascular contractility was studied ex-vivo in two models of portal hypertension, that due to chronic biliary cirrhosis, and that due to partial portal vein ligation, where liver injury is absent. In experimental cirrhosis, there was upregulation of ACE2 in the splanchnic vasculature, and portal levels of angiotensin-(1-7) were increased, whereas expression of the classic arm of the RAS was unchanged from controls. There was increased, ACE2-mediated, formation of angiotensin-(1-7), both from angiotensin I and from angiotensin II, in cirrhotic vessels. Angiotensin-(1-7) mediated splanchnic vascular hypocontractility in both portal hypertension due to experimental cirrhosis and that due to partial portal vein ligation. These effects of angiotensin-(1-7) occurred via the Mas receptor and the angiotensin II type 2 receptor, both of which were also upregulated in cirrhotic vessels. In conclusion, the data presented in this thesis provide evidence of a shift towards increased activity and expression of the ACE2/angiotensin-(1-7)/MasR axis in the splanchnic vessels as a novel causal mechanism for vascular hypocontractility in cirrhosis, and identify potential therapeutic targets in portal hypertension.