Obesity, 11β-hydroxysteroid dehydrogenase and metabolic changes in the pathogenesis of idiopathic intracranial hypertension

R Medicine > RE Ophthalmology

Sinclair, Alexandra ; Rauz, Saaeha,Walker, Elizabeth,Stewart, Paul M,Burdon, Michael

University:University of Birmingham

Department:School of Immunity and Infection

关键词: R Medicine;    RE Ophthalmology;   

Others  :  http://etheses.bham.ac.uk//id/eprint/1013/1/Sinclair10PhD.pdf

来源: University of Birmingham eTheses Repository

【 摘 要 】

Idiopathic intracranial hypertension (IIH) is a blinding condition amongst the young obese female population characterised by elevated intracranial pressure (ICP). The aetiology of IIH is not known and, as highlighted in the 2005 Cochrane review, an evidence base for treatment has not been established, although weight loss is frequently advocated. Obesity is associated with dysregulation of cortisol metabolism by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Additionally, 11β-HSD1 has a role in the regulation of intraocular pressure. This thesis hypothesised that 11β-HSD1 is involved in the aetiology of IIH and examined the roles of obesity, 11β-HSD1 and metabolic changes in the pathogenesis and treatment of IIH. We demonstrated that ICP regulating structures (choroid plexus and arachnoid granulation tissue), are potential glucocorticoid target tissues expressing 11β-HSD1. Metabolomic analysis identified a unique biofluid metabolite biomarker profile, with potential implications for IIH pathogenesis. We established the therapeutic efficacy of weight loss in IIH (improving headaches, papilloedema and ICP) and provided evidence that the beneficial effects may relate to alterations in the glucocorticoid profile driving 11β-HSD1 and potentially, 5α reductase. These studies have started to address the important issues of causation and treatment in IIH and provide avenues for future research into this complex condition.