Medicine (St Vincent's) - Theses
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ItemNovel biomarkers in the early detection of pulmonary arterial hypertension in systemic sclerosis( 2013)Systemic sclerosis (SSc) is a complex disease characterised by extensive fibrosis, vascular abnormalities and autoantibodies. Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in SSc, and the early detection of PAH has emerged as an essential component of disease management. The hypothesis for this thesis is that biomarkers, either alone or in combination with other non-invasive screening investigations, may improve screening in patients with SSc-PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. To begin, I present a comprehensive review of SSc-PAH focusing on the rationale and methods used to facilitate the early detection of SSc-PAH. Next, I present a systematic review highlighting some of the limitations in current screening practices, demonstrating the clinical need to further evaluate and refine current screening before making recommendations regarding the nature and frequency of screening. I then evaluate the screening utility of N-terminal-pro brain natriuretic peptide (NT-proBNP) in SSc-PAH, first proposing, and later validating a novel screening strategy combining NT-proBNP with pulmonary function tests (PFT) in a high-risk group of patients for SSc-PAH. Using this strategy, only patients who screen ‘positive’ to the proposed screening algorithm undergo echocardiography and further confirmatory testing for PAH. I show that asymmetric dimethylarginine, a novel biomarker of endothelial dysfunction involved in nitric oxide metabolism, may be an important screening and diagnostic biomarker for SSc-PAH, especially when combined with NT-proBNP. I also evaluate various other cytokines, chemokines and growth factors, previously suggested to play a role in SSc-PAH, and show in a well-characterised population of SSc-PAH patients that serum levels of interleukin-6 (IL-6), interleukin-13 (IL-13), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), fractalkine (FKN), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are not specific biomarkers of SSc-PAH. However, VEGF and ICAM-1 levels appeared to correlate with markers of PAH severity and deserve further study. I showed the wide variability of measured levels of these cytokines, chemokines and growth factors in SSc patients, possibly reflecting the heterogeneity of this complex disease. Overall, I demonstrate that biomarkers, particularly when combined with other non-invasive screening investigations such as PFT, may identify patients with SSc-PAH.
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ItemAssessment of inflammatory bowel disease epidemiology in Barwon, Victoria: an observational prospective population based study( 2013)Background: The Inflammatory bowel diseases (IBD) Crohn’s disease (CD), ulcerative colitis (UC), and IBD unspecified (IBDU), are chronic conditions with significant health-related disability and potentially expensive therapies. Recent research locally suggests high IBD incidence rates. However, no Australian population-based prevalence data is available, nor has the natural history of newly diagnosed community-based IBD patients been studied. Aims: To estimate current IBD burden by calculating incidence and prevalence rates in an Australian population, and to assess for recent changes in IBD incidence. We also aimed to form a pilot IBD registry, allowing longitudinal observations of natural history in newly diagnosed community-based patients. Methods: The study region of Barwon, Victoria (population 293,426) was studied from July 1st 2010 to June 30th 2011. Capture-recapture methodology was used, with cases identified from multiple overlapping sources including clinicians (gastroenterologists, surgeons and paediatricians), histopathology databases, endoscopy records, hospital coding and medication dispensing records. Strict internationally recognised diagnostic criteria were used to define incident cases. All incident cases were individually verified by 2 clinicians and phenotypes defined by Montreal criteria. Incident cases were enrolled in a registry with opt-out consent. Prevalent case ascertainment required extension of data collection into General Practices across the region. Three-month clinical outcomes were assessed for incident cases, including surgical rates, hospitalisation and medication use. Results: 71 incident IBD cases were identified (incident rate 24.2 per 100,000). This was stable compared to local data from 2007/08. Incidence rates for CD, UC and IBDU were 14.7, 7.5 and 2.0 per 100,000 respectively. 1011 prevalent IBD cases were recorded (point prevalence rate on June 30th 2011 344.6 per 100,000). Prevalence rates for CD, UC and IBDU were 197.3, 136.0 and 8.5 per 100,000 respectively. All incident cases were enrolled in the registry. Within three months of diagnosis 28% had been hospitalised, and 11% required surgery (all with CD). Peri-anal disease was present in 14% of CD cases. 55% were under 40 years of age. Corticosteroids were prescribed in 59% and immunosuppression in 11%. None received biological therapy within three months of diagnosis. Conclusion: This study has produced Australia's first epidemiologically sound population-based IBD prevalence data, demonstrating a large burden of disease. Stable high IBD incidence rates were reconfirmed. Three month outcome data from the incident inception cohort shows a high proportion have aggressive disease, defined by age less than 40 at onset, hospitalisation and surgery rates, steroid use, and the presence of peri-anal disease. This inception cohort will be followed longitudinally to further define the natural history of IBD.