Medicine (St Vincent's) - Theses
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ItemCoronary microcirculatory function in patients with ischaemic heart disease: a focus on novel assessment, management and outcomes of coronary microcirculatory function( 2015)Although there have been improvements in pharmacotherapy and percutaneous coronary intervention, patients with ischaemic heart disease, still pose a significant health burden. It has become increasingly evident that cardiovascular outcomes are impacted upon by dysfunction of the coronary microvasculature. Novel direct invasive measures, such as the index of microcirculatory resistance (IMR), have recently been developed. This index of microvascular function has been shown to have significant clinical utility in patients with ischaemic heart disease. However, to date, the body of knowledge on the state of the microcirculation as assessed by IMR in subsets of patients, such as thrombolysed ST-segment elevation myocardial infarction (STEMI) and Non-ST segment elevation myocardial infarction (NSTEMI), is lacking. Furthermore, in patients with NSTEMI, the effect of targeted therapies on IMR and hence microvascular function, is unknown. Finally, no test is perfect and the development of supplementary invasive measures of microvascular function may improve the management of patients with ischaemic heart disease and further enhance our understanding of microvascular dysfunction. The aim of this thesis was to examine microvascular function in patients with ischaemic heart disease. Specifically, I will examine and compare microvascular function, as assessed in particular by IMR, in patients presenting with thrombolysed ST-segment elevation myocardial infarction undergoing a pharmacoinvasive strategy and non-ST segment elevation myocardial infarction. I will examine the relationship between measures of microvascular function, including the IMR, and left ventricular recovery in patients presenting with ST-segment elevation myocardial infarction and undergoing a pharmacoinvasive strategy. I will also examine microvascular function, as assessed by IMR, and the role of the antiplatelet agent, abciximab, in patients presenting with Non-ST segment elevation myocardial infarction. Finally, I will examine and evaluate a novel measure of microvascular function, the coronary artery augmentation index, in patients with stable angina undergoing percutaneous coronary intervention. A full representation of patients with ischaemic heart disease undergoing percutaneous coronary intervention (PCI) were studied; 31 patients with STEMI, 36 patients with NSTEMI and 40 patients with stable angina. Invasive coronary physiological measurements in the culprit vessel were taken during the index procedure at varying times depending on the study protocol. Left ventricular function was assessed by either transthoracic echocardiography or cardiac MRI and compared with measures of microvascular function. Cardiac biomarker levels were taken pre-procedure, at the time of procedure and post procedure for up to 24 hours post intervention. In summary, the main findings of this thesis are: • Invasive measures of microvascular function, such as IMR, are significantly higher in a pharmacoinvasive STEMI population than in a clinically stable NSTEMI population. • In a STEMI population undergoing a pharmacoinvasive strategy, in contrast to other traditional markers of microvascular dysfunction, post PCI IMR correlates with left ventricular function and has the potential to predict left ventricular recovery at three months post STEMI. • In patients with NSTEMI undergoing PCI, a bolus dose of intracoronary abciximab improves coronary microvascular function as assessed by IMR. • Coronary augmentation index is a valid and reproducible measure of microvascular function in patients with stable angina undergoing PCI. • Coronary augmentation index is a predictor of periprocedural myocardial injury and may be able to identify those patients who are at greater risk of such injury following intervention. The findings of this Doctor of Medical Science are novel and have important clinical implications for the clinician. The work in this thesis supports the notion that it is important to consider microvascular dysfunction in patients with ischaemic heart disease undergoing PCI. With accurate assessment and appropriate management clinical outcomes may be improved. The work presented does warrant further investigation in larger multicentre trials. I anticipate that these will support the findings of this thesis and by measuring microvascular function will can aid risk-stratification and enable a more intensive therapeutic strategy not only within the catheterisation laboratory, but post procedure in the short and medium term.
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ItemChronic hepatitis B in an Australian tertiary hospital cohort: natural history of disease and the association of viral markers with histological and serological outcomes( 2015)Chronic Hepatitis B (CHB) is a major worldwide public health problem with an estimated 240 million people chronically infected and at risk of the complications of liver cirrhosis and hepatocellular carcinoma. There are recognized phases of disease in CHB which are usually defined using a combination of HBeAg status, HBV DNA level and ALT level. These can provide a useful framework to conceptualise a patient’s risk of fibrosis and need for treatment. Using the large CHB cohort at our tertiary hospital in Melbourne, we described our patient group in terms of their phase of disease in a cross-sectional analysis in chapter 3. This analysis highlighted some of the limitations of tests used, eg the insensitivity of older generation HBV DNA. Histological liver injury due to hepatitis B virus (HBV) was also able to be examined in a large proportion of our cohort with liver biopsies and in chapter 4 we evaluated the effect of HBV DNA on liver fibrosis. We found that increasing HBV DNA was associated with increasing prevalence of significant fibrosis in HBeAg negative patients, however in HBeAg positive patients, the reverse was true. This once again leads back to the concept of phase of disease in which HBeAg positive patients in the immune tolerant phase have normal ALT and minimal fibrosis despite very high HBV DNA levels. Longitudinal analysis of untreated HBeAg negative patients in chapter 5 brought to light some of the weaknesses of current classification systems for phase of disease, since we showed that low level fluxes in viral load in HBeAg negative patients were common and strict thresholds for HBV DNA to define the immune control phase were often crossed. The effects of HBV genotype and viral variants (precore and basal core promoter) on liver histology were examined in chapter 6. No significant associations were found although there was a trend towards higher prevalence of significant fibrosis in patients with HBV genotype C. Furthermore we explored the role of the novel markers of quantitative HBeAg and HBsAg (qHBeAg and qHBsAg) for classification of patients into phases in the natural history of CHB and found significant differences in qHBsAg levels in patients in different phases of disease in chapter 7. Finally we evaluated the role of qHBeAg and qHBsAg in the setting of Nucleos(t)ide analogue treatment by comparing 2 groups of HBeAg positive patients, one of which was known to lose HBeAg during the 18 months of followup and the other group which did not. Differences in both baseline and on treatment levels of qHBeAg were found between the 2 groups, however no significant differences in qHBsAg levels were noted. Management of CHB frequently involves monitoring patients to decide on the need and optimal time for therapy. A better understanding of the tools used in evaluating patients and the performance of these in different phases of disease and on therapy helps to enhance the clinical care of CHB patients.
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ItemDetermining standards of care in the context of medical negligence, professional practice and informed consent in Victoria( 2014)The proposed Doctor of Medical Science by compilation seeks to describe recent medicolegal issues, with a focus on determination of standards of care with respect to clinical practice in Victoria in the context of professional negligence and informed consent. In the course of medical care, professional negligence can occur at any point during a doctor/patient relationship including assessment, diagnosis, advice and/or treatment. Integral to professional standards and negligence, and during any of these steps, lies the concept of informed consent and how information is communicated to patients in order to not only promote patient autonomy and beneficial outcomes, but also to protect medical practitioners from potential litigation. The proposed doctorate is comprised of 12 manuscripts and explores the question of by whom and how reasonable standards of care in clinical practice are determined in the context of professional negligence, and by virtue of this, who and how informed consent in clinical practice is determined. Causation, although a fundamental element in the tort of negligence, is excluded from this thesis. The doctorate commences with a general discussion around two of the fundamental elements in the tort of negligence in common law jurisdictions, the identification of a relationship which implies a duty of care, and the fundamental breach of that duty. Written for a medical audience, the doctorate discusses case law and legislation specific to medical professionals, and manuscripts will refer to practical and emerging issues for a medical readership such as interpretation of diagnostic tests, misdiagnosis, informed consent for procedures, standards of privacy and consent in the communication of information, the use of protocols to minimise breach of standards of care, refusal to treat and end-of-life decision making. In so doing, the doctorate explores specific clinical examples and situations which explore by whom and how professional negligence and informed consent are determined, whether it be by the medical practitioner, the courts or the patients themselves.
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ItemThe clinical utility of serum tumour markers prostate specific antigen and carcinoembryonic antigen in evaluating the effectiveness of chemotherapy for advanced prostate and colorectal cancers( 2014)Palliative chemotherapy for the treatment of metastatic castrate resistant prostate cancer (mCRPC) and metastatic colorectal cancer (mCRC) should only continue if the patient is deriving some benefit. Clinicians assess benefit using a variety of methods. The tumour markers, prostate specific antigen (PSA) and carcinoembryonic antigen (CEA) can be used as part of this assessment. I explored the clinical utility of using PSA and CEA to guide decisions on palliative chemotherapy for mCRPC and mCRC patients. I evaluated if falling levels of PSA predicted for a palliative response (decreasing pain and/or pain medication), and improved survival in 161 patients with mCRPC treated with mitoxantrone and prednisone in a randomised clinical trial. I also performed a phase IV analysis of 133 patients treated at Princess Margaret Hospital, Toronto, Canada to see how they compared with the clinical trial. Also, a retrospective cohort of 142 patients with mCRC treated with oxaliplatin-based chemotherapy at St Vincent’s Hospital Melbourne were evaluated to see if falling levels of CEA predicted survival and shrinkage of secondaries. A PSA response of 50% occurred in 34% of patients in the mitoxantrone and prednisone arm of the study and in 28% of the post trial cohort (P=0.36) A PSA response of 50% is predictive of a palliative response, although the strength of the association was relatively weak (phi coefficient =0.28, P = 0.001). The positive predictive value of a PSA response for a palliative response was 53%. Using a landmark analysis, PSA responders lived longer (P=0.0004). A CEA response of 50% occurred in 74% of the mCRC patients. Using a landmark analysis, CEA responders lived longer (P<0.0001). CEA response did correlate with radiological responses. Seventy per cent of the CEA responders had a complete or partial response on computed tomography (CT) scanning, but 42% of the CEA responders also had stable disease, and 36% of the CEA non-responders had a partial response. Both PSA and CEA responses yield useful adjunctive clinical information and should be part of the clinical assessment of the palliative benefit from chemotherapy for mCRPC and mCRC.
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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.
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ItemThe clinical and therapeutic significance of PI3K and MAPK signalling in epithelial ovarian cancer (EOC) and melanoma( 2012)A common goal in the genetic and molecular characterization of tumours is to identify oncogenic mutations that drive cancer growth and to identify clinical subsets of patients most likely to display these and other genetic aberrations that are of clinical and therapeutic significance. Improved understanding of the molecular circuitry of cancers and the biological consequences of their signals enables the rational application of targeted agents against key effector molecules. Two important examples of this include the successful clinical application of imatinib an inhibitor of the KIT receptor tyrosine kinase in the management of gastrointestinal stromal tumours (GISTs) with activating mutations in the KIT gene and trastuzumab, the monoclonal antibody to the HER2 receptor tyrosine kinase in HER2 over expressing breast cancer. It is also becoming more apparent that applying targeted agents to large undefined groups of cancer patients is an ineffective clinical strategy. An understanding of the role of these molecules in the non cancer state is also of importance as therapies will only be successful in clinical practice if undue toxicity is avoided. Understanding parameters for patient selection and developing pharmacodynamic markers of response will therefore assist in improving the therapeutic index of targeted agents. This thesis focuses on two important and inter-related cell signalling pathways in cancer, the PI3K and MAPK pathways and describes genetic aberrations of critical molecules within these pathways in epithelial ovarian cancer (EOC) and melanoma. In EOC, the molecular pathogenesis is less clearly defined compared with melanoma, but a body of evidence is building that broadly suggests that low grade and high grade cancers arise from distinct pathways of cancer pathogenesis. I hypothesize that these differences can arise from the genetic and molecular alterations of PI3K and MAPK pathway substrates within the histological subtypes of ovarian cancer. In chapter two, I will focus on PI3K pathway activation in these subtypes as a proposed mechanism in the pathogenesis and progression of this cancer and in the potential response to agents targeting key molecules within this pathway. As these interconnecting pathways are considered important in the response to conventional cytotoxics and in the mechanism of platinum resistance I hypothesize that in activated tumour subtypes pathway attenuation with molecular inhibitors would lead to reversal of platinum resistance. In melanoma, more recent advances have been made with respect to identifying distinct molecular subtypes and consequently patients that are highly likely to respond to targeted therapies. In chapter three it will be demonstrated that KIT mutant melanomas are clinically and pathologically distinct from BRAF mutant melanomas and that oncogene dependence represents the underlying biological mechanism for this. I will describe the clinic-pathological characteristics of patients with KIT mutant melanoma and their responses to KIT kinase inhibition using available small molecule inhibitors. I hypothesize that for patients with cutaneous melanoma, stratifying patients for KIT mutation testing based on the identification of solar elastosis can identify those most likely to harbour KIT mutations and therefore suitability for KIT directed therapy. Additionally the selection of specific therapy can be determined by the exonic location of KIT mutations in melanoma as has been proven to be the case in the management of gastrointestinal stromal tumours. The understanding of molecular or physical mechanisms of resistance to therapy can also help to direct targeted biological therapies to enhance patient management. The work in this thesis contributes to the body of data describing the clinical and molecular differences of EOC and melanoma. It will contribute to the understanding of the molecular mechanisms associated with these cancers which in turn will assist in guiding the selection of patients best suited to the growing list of molecular targeted therapies.
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ItemEvaluating new technologies in the assessment and endoscopic management of Barrett’s oesophagus( 2012)The assessment and treatment of dysplastic Barrett’s oesophagus (BO) has evolved dramatically over the last decade. Recently, advances in endoscopic imaging techniques have enabled more accurate identification of subtle mucosal abnormalities and provide improved capacity to identify early cancers. This combined with advances in endoscopic resection and ablation techniques have resulted in excellent outcomes for individuals with high grade dysplasia (HGD) and intramucosal cancer (IMC) treated with endoscopic means alone. The aim of this work was to assess to efficacy and safety of these new technologies in the assessment and management of dysplastic BO. The first study assessed the accuracy of predicting HGD and IMC in mucosa predicted as being non dysplastic vs. dysplastic by high definition white light (HD WLE), Narrow band imaging (NBI) and confocal endomicroscopy (CEM). A prospective cohort study of 50 consecutive patients was performed. A prediction of likely histology was made for each biopsy point (4 quadrant every 1cm and any visible mucosal abnormality) firstly with HD WLE, then with NBI and finally CEM. 1190 individual biopsy points have been assessed (39 HGD and 52 IMC). For the detection of HGD/IMC the sensitivity, specificity and accuracy for HD WLE were 79.1%, 83.1% and 82.8%, for NBI were 89.0%, 80.1% and 81.4% and for CEM were 75.7%, 80.0% and 79.9% respectively. All mucosal points with IMC and all patients with HGD were detected by targeted biopsies guided by HD WLE and NBI without the need for random Seattle protocol biopsies. We then assessed the impact that endoscopic mucosal resection (EMR) had on the optimal staging and treatment of dysplastic BO. 71 consecutive patients referred for endoscopic management of dysplastic BO were included in the study. 48 patients had an EMR performed on a visible mucosal abnormality, resulting in upstaging in 20 patients (P= 0.0498). 33/48 patients had a lesion missed by their referring doctor, including 9 cancers. In 24/48 (50%) patients EMR was considered necessary for optimal treatment (12 patients with sub-mucosal invasion, were unsuitable for endoscopic therapy, 12 patients with IMC into the muscularis mucosa or lamina propria may not have been adequately treated by HALO radiofrequency ablation alone.) These results demonstrate the importance of EMR and secondly that a large proportion lesions are not identified by endoscopists in community practice. We finally assessed the rate of complete remission of intestinal metaplasia (CR-IM) at 12 months post commencement of HALO radiofrequency ablation (RFA) and secondly looked at factors that may predict resistance to HALO RFA. 92 patients at the time of analysis had been referred for endoscopic treatment of dysplastic BO of which 31 patients had reached the 12 month assessment. CR-IM was achieved in 25/31 patients (80%) within 12 months of the first HALO RFA treatment. A median of 3 therapeutic procedures (1 EMR and 2 HALO ablations sessions) were required to achieve CR-IM. Longer BO segments, median 9cm (range 5-14) predict failure to achieve CR-IM at 12 months (p = 0.04). Our study confirmed good success rates of combination endoscopic therapy comparable with other published studies.
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Itemβ-cell function, insulin sensitivity and non-esterified fatty acid (NEFA) dynamics after intra-portal allogeneic islet transplantation( 2010)BACKGROUND: Intra-portal allogeneic islet-transplantation is an effective means of biologic insulin-therapy in T1DM with debilitating hypoglycemia. While whole-pancreas-transplantation is known to restore normal biphasic, pulsatile insulin secretion and the incretin-response; little is known of islet-function and the metabolic milieu post-islet-transplantation. Few studies have compared recipients with T2DM subjects. AIMS: We aimed to evaluate Si pre- and post-transplantation as well as biphasic secretion, the incretin-response, glucose-sensitivity and NEFA suppression during an OGTT; comparing these results with controls and type 2 diabetics. METHODS: 3 islet-recipients in their 1st year of insulin-independence, 10 non-diabetic controls and 4 T2DM patients (requiring OHAs) each underwent 3 different glucose challenges on 3 separate days over 3-4 months, 4-6 weeks apart. The 3 procedures were a 4hr 75g-OGTT, an isoglycemic IVGTT and an FSIGT. Plasma glucose, insulin, C-peptide and NEFA were assayed. The islet-recipients underwent a non-insulin-modified FSIGT (enabling estimation of 2nd phase), the results of which were compared with historical controls similarly assessed. The rest underwent an insulin-modified-FSIGT. 2-step hyperinsulinemic-euglycemic-clamps were performed pre-transplantation and post-insulin-independence. RESULTS: Although recipients maintain an HbA1c ≤ 6% post-transplant without exogenous insulin, mean 2hr-glucose post-OGTT was 13 mmol/L. Clamp Si was unimpaired post-transplantation despite use of tacrolimus/mycophenolate. Post-transplantation, FSIGT second-phase secretion was restored to a greater extent than first (87% vs 46% normal). AIRg post-transplant was diminished compared with controls but ~8.5 times better than that in T2DM. During the OGTT while both early (0-30min) and late (30-240min) phase secretion were significantly and similarly reduced in recipients and T2DM compared with controls, more insulin was secreted per mmol glucose during late phase than early phase in recipients but not in type 2 diabetics. Islet-recipients had an oral DI ~26% of normal (4-fold higher thanT2DM). The incretin-response was reduced post-transplant and in T2DM (recipients 49%, T2DM 47%, controls 80%). Glucose-sensitivity was 26.3% of normal in recipients. NEFA suppression was unexpectedly normal and better than that in T2DM. Insulin secretion in recipients was worse during the OGTT (21% of normal) than the FSIGT (77% of normal). CONCLUSIONS: Our findings indicate that islet-recipients have a hybrid form of diabetes with features in common with T1DM (unimpaired Si) and T2DM (metabolic stability without exogenous insulin), and features unique to the post-transplant state (normal NEFA dynamics).Post-transplant diabetes is characterized by quantitative and qualitative β-cell secretory defects classically associated with the T2DM phenotype–reduced first-phase, incretin-response and glucose-sensitivity with preserved second-phase. Islet-recipients however have greater functional β-cell secretory-capacity and better insulin-sensitivity than OHA-requiring T2DM subjects. The presence of these secretory defects in recipients infused with healthy donor beta-cells indicate these are acquired functional β-cell defects common to all forms of dysglycemia resulting from a final common pathway of β-cell dysfunction/apoptosis. Despite these severe defects, insulin-independence is preserved - indicating that an oral DI 1/4th normal, in these highly insulin-sensitive subjects is sufficient for normoglycemia under free-living conditions. The impaired insulin response during the oral challenge compared with the intravenous challenge may be secondary to defects in incretin mechanisms and/or secretion of anti-incretin factors during the OGTT. Normal NEFA levels early post-transplant imply reduced risk of glucolipotoxicity and its deleterious effects on Si and graft-function. Our work highlights the important contribution of insulin-sensitivity and second-phase secretion towards maintaining normoglycemia post-transplant and hence the need to monitor these parameters. Abbreviations: type 1 diabetes (T1DM), type 2 diabetes (T2DM), oral hypoglycaemic agents (OHAs), oral glucose tolerance test (OGTT), isoglycemic intravenous glucose tolerance test (IVGTT), frequently-sampled intravenous glucose tolerance test (FSIGT), non-esterified fatty acids (NEFA), HbA1c (glycated hemoglobin), disposition index (DI), AIRg (acute insulin response to glucose), insulin-sensitivity (Si)
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ItemSerological studies into the natural history of chronic hepatitis B( 2011)Chronic hepatitis B (CHB) infection represents a global health problem, with an estimated 400 million people affected worldwide. The potential long term sequelae includes cirrhosis, hepatic decompensation and hepatocellular carcinoma. The paradigm for treatment of chronic hepatitis B virus (HBV) is evolving with the advent of newer medications, improved laboratory assay sensitivity and an increased understanding of the natural history of chronic infection. The natural history of CHB is typically regarded as consisting of four phases which are classified by specific biochemical, serological and virological characteristics, including serum ALT levels, HBeAg serostatus and HBV DNA titre. Whilst serum HBsAg is the serological hallmark of HBV infection, measurement of the serum HBsAg titre is currently not required for the distinction between the different phases of CHB, and is also not routinely assessed during antiviral therapy. The first aim of this thesis was to perform a detailed cross-sectional examination of the baseline HBsAg titres in the different phases of the natural history of CHB. The cohort of patients with CHB that were evaluated included adult patients attending a tertiary centre, pregnant women and a paediatric group. This study demonstrated that median baseline HBsAg titres differed between the four phases of CHB, with higher titres in HBeAg positive compared to HBeAg negative patients. Furthermore there was an apparent “disconnect” between HBsAg titres and HBV DNA in the different phases of CHB. It was hypothesized that these findings may be due to the expression of HBsAg from integrated viral envelope sequences instead of HBsAg production off mRNA derived from the HBV cccDNA template, or due to differences in the immune regulation of viral replication during different phases of infection. The second aim of this thesis was to evaluate the changes in serum HBsAg titres during long term therapy with oral nucleos(t)ide agents (NA). HBsAg clearance and seroconversion represent the ultimate endpoint in antiviral in CHB. Although clinical trials have suggested a benefit in monitoring baseline and on-treatment serum HBsAg titres during Peg-IFN therapy in predicting virological responses, there is little data on the effect of oral NA on HBsAg titres. In this thesis, different patterns of HBsAg decline during oral NA therapy were observed, although overall the on- treatment reduction in HBsAg titres were modest in comparison to that previously described in the literature with Peg-IFN therapy. This was attributed to the indirect affect of oral NAs on HBsAg synthesis via inhibition of the intracellular cccDNA conversion pathway, with a subsequent decline in pre-existing cccDNA molecules over time. Serum anti-HBs is usually only detectable on current commercial assays once HBsAg seroclearance has occurred, and is thought to be due anti-HBs complexing into immune aggregates with the excess envelope proteins. The third aim of this thesis was to test the serum and the B-cell component of peripheral blood mononuclear cells (PBMCs) for anti-HBs in patients who also test positive for serum HBsAg. A minority of patients had detectable anti-HBs by the commercial immunoassay. It was hypothesized that there would be a higher proportion of patients with detectable anti-HBs in the B-cell component of PBMCs. Unfortunately, anti-HBs was not detected in the lysate of B-cells using two commercial immunoassays, and an in-house enzyme linked immunosorbent assay (ELISA) could not be optimised for technical reasons. In conclusion, the measurement of baseline and on-treatment HBsAg titres has the potential to become the next focus of translational and clinical research in CHB. In the context of the natural history of CHB, monitoring of baseline HBsAg titres may facilitate an improved understanding of the interplay between HBV with the innate and adaptive immune response. Finally, monitoring of HBsAg titres may allow the development of new algorithms to individualise patient therapy, and also encourage further study of novel therapeutic strategies which more directly affect HBsAg levels.