Medicine (RMH) - Theses
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ItemLiver-bone relationships: integrative pathophysiology, diagnostic, prognostic, preventive and therapeutic considerations( 2019)Over the last 10 years we examined complex multidirectional interactions between the digestive system and osteoporotic fractures focusing on pathophysiological and clinical issues of liver-bone relationships. These included: vitamin D, vitamin K and parathyroid hormone in chronic liver and pancreatic diseases (2 papers: [1, 2]); associations between liver function, bone-mineral biomarkers, indices of iron metabolism and adipokines (leptin, adiponectin, resistin) in orthogeriatric patients (3 papers: [3-5]); diagnostic and prognostic indicators of osteoporosis, fractures, and in- hospital outcomes (5 papers: [6-10]). A shortened overview of our main findings is presented.
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ItemNovel markers in chronic liver disease and hepatocellular carcinoma( 2013)Chronic liver disease is associated with a number of metabolic changes and nutritional deficiencies, and these may have important consequences on the natural history of liver disease. Chronic liver disease is a continuum of progressive liver fibrosis with replacement of injured tissue by a collagenous scar. Fibrosis is a multi-step process and progresses at variable rates depending on the cause of the liver disease, environmental factors, and host factors. Cirrhosis is an advanced stage of liver fibrosis, and is a common cause of morbidity and mortality worldwide, including a predisposition to hepatocellular carcinoma of 2–7% per year. Hepatocellular carcinoma is one of the most common malignant tumours in the world accounting for 500,000 deaths per year, making it the 3rd most common cause of cancer death worldwide. In this thesis, I have reviewed the epidemiology, natural history and current investigations used in chronic liver disease and hepatocellular carcinoma. The progression of liver disease to cirrhosis, and hepatocellular carcinoma, are multi-step pathways. The poor outcomes highlight the need for novel factors to be explored to determine if they can predict and/or alter the natural history. In this thesis, I review the previous literature on CD163, CD147 and 25(OH)D as novel markers in liver disease assessment, to determine their relationship to liver disease severity and outcome. CD163 is a marker of activated macrophages and sCD163 is found in normal plasma. Upregulation of sCD163 occurs during inflammation and increased levels are seen in acute and chronic liver disease. Routine biochemistry and imaging are often insensitive for complications of chronic liver disease, and in this thesis we demonstrate that sCD163 levels predict chronic liver disease progression and portal hypertension. sCD163 is a good marker of chronic liver disease patients who have developed cirrhosis, stratifying patients based on the degree of liver impairment. High sCD163 levels may be used for screening purposes and in the early identification of the need for interventions, such as starting anti-viral treatment in patients with chronic viral hepatitis, or in screening for oesophageal varices. CD147 is a cell surface transmembrane protein that regulates tumour-stromal interactions, and induces the secretion of MMP in the tumor local environment, thus promoting tumor invasion and metastasis. CD147 is highly expressed on hepatocellular carcinoma cells and is associated with a poor prognosis. Soluble CD147 is released by shedding, and in this thesis, we demonstrate that increased sCD147 levels predict patients with more advanced hepatocellular carcinoma and a high likelihood of death within 90 days. This may assist in the identification of HCC patients with a poor prognosis and help clinician’s define patients unsuitable for ongoing active treatment. 1,25-dihydroxyvitamin D3 has been shown to exert potent immunoregulatory effects that are mediated through binding to an intracellular receptor protein, the vitamin D receptor. In this thesis, we demonstrate that vitamin D deficiency is more common in chronic liver disease and hepatocellular carcinoma compared to the Australian population. Higher serum 25(OH)D concentrations were demonstrated to be associated with a reduced risk of disease progression and death due to liver disease in both the chronic liver disease and hepatocellular carcinoma cohorts. Vitamin D deficiency is a common problem in the Australian population.