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Title: The endocrine sequelae of intrahepatic cholestasis of pregnancy
Author: Martineau, Marcus
ISNI:       0000 0004 5353 3206
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder specific to pregnancy characterised by maternal pruritus, elevated maternal bile acids and adverse fetal outcomes. Although understanding of the condition has evolved, much remains unknown emphasising the need for further research. Using different approaches, this thesis will investigate the endocrine sequelae of ICP and its influence on fetal development. Bile acids have been shown to inhibit renal 11β-Hydroxysteroid dehydrogenase 2 (11β-HSD2), a protein responsible for attenuating the effect of cortisol on aldosterone-sensitive tissues. During pregnancy, cortisol levels increase and placental 11β- HSD2 acts to reduce the effect of maternal hypercortisolaemia on the developing fetus. Compromise in this placental barrier is therefore likely to increase fetal exposure to exogenous cortisol and potentially influence growth and development. This is the first study to look at the influence of cholestasis on placental 11β-HSD2 and cortisol metabolism. Through studying changes in gene expression, activity and paired maternal and fetal cord blood samples, ICP was associated with a significant reduction in placental 11β-HSD2 mRNA however fetal cortisol concentrations remain unchanged, suggestive of a concomitant attenuation of fetal adrenal function. Alterations in carbohydrate and lipid metabolism have been described in ICP. Although the aetiology underlying these findings is not yet not fully understood, the bile acid receptors Farnesoid-X receptor (FXR) and TGR5 have been shown to alter blood glucose and lipid concentrations suggesting that aberrant bile acid homeostasis is likely to influence maternal carbohydrate and lipid metabolism. Studied both retrospectively and prospectively, ICP is associated with impaired glucose tolerance; in conjunction with alterations in gut hormone signalling as well as a pro-atherogenic lipid profile. Elevated maternal blood glucose and lipids have been shown to promote fetal growth which is associated with an increased risk of maternal and fetal mortality and morbidity; furthermore this may have long term sequelae with regard to the future health of affected offspring.
Supervisor: Williamson, Catherine Sponsor: Genesis Research Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available