Obesity in adults and children is associated with increased cardiovascular mortality and morbidity. This is forecast to increase markedly in the next decade as childhood obesity is a burgeoning epidemic. Excess weight is clearly associated with insulin resistance, increased circulating triglycerides, and hypertension, all of these are related to progressive heart and liver disease. Ectopic fat deposition within organs is reported to cause lipotoxicity, which may lead to dysfunction and disease, but there have been few human studies to confirm this. This doctoral thesis set out to study the early pathophysiology of obesity in adults and children using in vivo magnetic resonance (MR) imaging and spectroscopy to assess the composition and function of the heart and liver in lean and obese individuals. The central tenet of this project was to establish and validate a clinically viable method for measuring the fat content of viscera safely and accurately, and to determine a normal range for the triglyceride content of the heart and liver. The initial study demonstrated that the heart remodels in response to weight loss, with over 20% reduction in LV mass, confirming that excess weight is genuinely a modifiable risk factor. Then, using spectroscopy, it was established that the healthy myocardium has a median triglyceride content of 0.37% (IQR 0.24% - 0.47%), which increases linearly in overweight and obese adults. Obesity, in the absence of any confounders, was also associated with a 10% reduction in cardiac contractile function. In comparison, healthy liver median lipid content was 0.67% (IQR 0.44% – 0.88%), which increased in obese adults to 2.9% (IQR 1.6% - 7.6%). There was a graded association between ectopic fat deposition in the liver and dyslipidaemia in adults, characterised by increased circulating triglycerides and reduced high-density lipoprotein. This dyslipidaemia may impair reverse cholesterol transport, and thus could be expected to exacerbate weight gain. Among obese and overweight subjects, there were some with severe steatosis and evidence of coexistent hepatic inflammation and fibrosis. To verify the accuracy of these spectroscopic measures for ectopic fat, a blinded, prospective comparison of non-invasive assessment of unselected liver disease in liver biopsy patients was completed. Liver disease presents with one or more of steatosis, fibrosis and haemosiderosis, all of which are associated with adverse cardiovascular outcomes. Fifty patients were recruited, and interobserver variability among pathologists was measured for histological reference standards for fat, fibrosis and iron deposition. MR measures of each of these metrics predicted the fibrosis, steatosis and haemosiderosis scores accurately. This enabled precise tissue characterisation of all forms of liver disease, including steatohepatitis, with one non-invasive test, to allow the diagnosis and monitoring of hepatic conditions. Lastly, all these new biomarkers of early cardiac and liver disease associated with excess weight were applied to obese and lean children, to understand whether ectopic fat played a substantial role in early life. Obese children had increased ectopic fat in their hearts and livers, as well as impaired strain, evidence of dyslipidaemia, and in some cases evidence of active steatohepatitis, comparable to adults with severe disease. The thesis therefore demonstrates that in vivo magnetic resonance techniques can be used for accurate measurement of visceral lipid content. Furthermore, there is evidence of significant ectopic fat deposition in both adults and children, with evidence of organ dysfunction, which raises the possibility that cardiovascular magnetic resonance may be of value to risk stratify obese individuals based on organ involvement. Finally, the developed methods may have broader applicability and offer a promising new method for the non-invasive diagnosis of chronic liver disease in other clinical settings.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:684938 |
| Date | January 2013 |
| Creators | Banerjee, Rajarshi |
| Contributors | Neubauer, Stefan ; Leeson, Paul |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:652e90cd-1f11-4fb6-8a4b-4ce649f72ee5 |
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