A Systematic Approach to the Treatment of Hyponatraemia.

The work in this thesis was designed to develop an evidence base for the mainstays of treatment of acute and chronic hyponatraemia, and to contribute to our understanding of the morbidity and mortality associated with hyponatraemia. The work provides the first head to head comparison of bolus and slow infusion of 3% saline in acute syndrome of inappropriate antidiuresis (SIAD), and demonstrates bolus administration of 3% saline is associated with faster initial elevation of plasma sodium concentration and improvement in GCS, thus supporting the switch to bolus treatment of symptomatic acute SIAD. We present the first prospective randomised controlled trial data for fluid restriction in chronic SIAD, using prospective data in a well-defined cohort of patients. The results highlight the suboptimal efficacy of fluid restriction in a significant proportion of patients with chronic SIAD. The thesis also illustrates how improvements in the management approach to hyponatraemia in our hospital have led to a reduction in mortality in patients with severe hyponatraemia over time. While hyponatraemia-treatment rates are higher in elderly patients than their younger counterparts with hyponatraemia, plasma sodium is more often uncorrected at discharge. Hyponatraemia in both age groups is associated with increased mortality compared with eunatraemic controls, but the impact is greater in younger patients. The data produced from these studies emphasise the clinical need for other treatment strategies for chronic SIAD, particularly if a clinically significant reduction in morbidity is to be targeted, both in clinical practice and in future research studies.</p

How should we interrogate the hypothalamic-pituitary-adrenal axis in patients with suspected hypopituitarism?

Hypopituitarism is deficiency of one or more pituitary hormones, of which adrenocorticotrophic hormone (ACTH) deficiency is the most serious and potentially life-threatening. It may occur in isolation or, more commonly as part of more widespread pituitary failure. Diagnosis requires demonstration of subnormal cortisol rise in response to stimulation with hypoglycemia, glucagon, ACTH(1-24) or in the setting of acute illness. The choice of diagnostic test should be individualised for the patient and clinical scenario. A random cortisol and ACTH level may be adequate in making a diagnosis in an acutely ill patient with a suspected adrenal crisis e.g. pituitary apoplexy. Often however, dynamic assessment of cortisol reserve is needed. The cortisol response is both stimulus and assay- dependent and normative values should be derived locally. Results must be interpreted within clinical context and with understanding of potential pitfalls of the test used. </p

Outcomes of endoscopic transsphenoidal surgery for Cushing's disease

Background: Transsphenoidal surgery (TSS) to resect an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment for Cushing's disease (CD), with increasing usage of endoscopic transsphenoidal (ETSS) technique. The aim of this study was to assess remission rates and postoperative complications following ETSS for CD. Methods: A retrospective analysis of a prospective single-surgeon database of consecutive patients with CD who underwent ETSS between January 2012-February 2020. Post-operative remission was defined, according to Endocrine Society Guidelines, as a morning serum cortisol Results: A single surgeon (MJ) performed 43 ETSS in 39 patients. Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). IPSS was carried out in 33 (85%) patients. The remission rates for initial surgery were 87% using standard criteria, 58% using the strict criteria (day 3 cortisol Conclusion: Endoscopic transsphenoidal surgery produces satisfactory remission rates for the primary treatment of CD, with higher remission rates for microadenomas. A longer follow-up period is required to assess recurrence rates. Patients should be counselled regarding risk of postoperative diabetes insipidus.</p

The modulation of platelet function by growth hormone in growth hormone deficient Hypopituitary patients

Background: Growth hormone deficiency (GHD) has been implicated in increased cardiovascular and cerebrovascular disease risk seen in hypopituitarism, however the mechanism remains speculative. We hypothesise that platelet abnormalities may play a contributory role. Herein we examined platelet behaviour in GHD hypopituitary patients, pre- and post-growth hormone (GH) replacement. Methods: This study utilizes a physiological flow-based assay to quantify platelet function in whole blood from patient cohorts under arterial shear. Thirteen GH Naïve hypopituitary adults with GHD and thirteen healthy matched controls were studied. Patients were assessed before and after GH treatment. All other pituitary replacements were optimised before the study. In addition to a full endocrine profile, whole blood was labelled and perfused over immobilised von Willibrand factor (vWF). Seven parameters of dynamic platelet-vWF interactions were recorded using digital image microscopy and analysed by customised platelet tracking software. Results: We found a significantly altered profile of platelet-vWF interactions in GHD individuals compared to healthy controls. Specifically, we observed a marked increase in platelets shown to form associations such as tethering, rolling and adherence to immobilized vWF, which were reduced post GH treatment. Speed and distance platelets travelled across vWF was similar between controls and pre-therapy GHD patients, however, this was considerably increased post treatment. This may indicate reduced platelet signaling resulting in less stable adhesion of platelets post GH treatment. Conclusions: Taken together observed differences in platelet behaviour may contribute to an increased risk of thrombosis in GHD which can in part be reversed by GH therapy.</p

The modulation of platelet function by growth hormone in growth hormone deficient Hypopituitary patients

Background: Growth hormone deficiency (GHD) has been implicated in increased cardiovascular and cerebrovascular disease risk seen in hypopituitarism, however the mechanism remains speculative. We hypothesise that platelet abnormalities may play a contributory role. Herein we examined platelet behaviour in GHD hypopituitary patients, pre- and post-growth hormone (GH) replacement. Methods: This study utilizes a physiological flow-based assay to quantify platelet function in whole blood from patient cohorts under arterial shear. Thirteen GH Naïve hypopituitary adults with GHD and thirteen healthy matched controls were studied. Patients were assessed before and after GH treatment. All other pituitary replacements were optimised before the study. In addition to a full endocrine profile, whole blood was labelled and perfused over immobilised von Willibrand factor (vWF). Seven parameters of dynamic platelet-vWF interactions were recorded using digital image microscopy and analysed by customised platelet tracking software. Results: We found a significantly altered profile of platelet-vWF interactions in GHD individuals compared to healthy controls. Specifically, we observed a marked increase in platelets shown to form associations such as tethering, rolling and adherence to immobilized vWF, which were reduced post GH treatment. Speed and distance platelets travelled across vWF was similar between controls and pre-therapy GHD patients, however, this was considerably increased post treatment. This may indicate reduced platelet signaling resulting in less stable adhesion of platelets post GH treatment. Conclusions: Taken together observed differences in platelet behaviour may contribute to an increased risk of thrombosis in GHD which can in part be reversed by GH therapy.</p