Measurement of Adrenal Function in Critical Illness: The Role of Tissue Glucocorticoid Activity

Jeremy Cohen (2011). Measurement of Adrenal Function in Critical Illness: The Role of Tissue Glucocorticoid Activity PhD Thesis, School of Medicine, The University of Queensland.

       
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Author Jeremy Cohen
Thesis Title Measurement of Adrenal Function in Critical Illness: The Role of Tissue Glucocorticoid Activity
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2011-12
Thesis type PhD Thesis
Supervisor Professor Bala Venkatesh
Professor Jon Prins
Total pages 138
Language eng
Subjects 110310 Intensive Care
Abstract/Summary Abstract Background The concept of relative adrenal insufficiency in patients with severe sepsis continues to be controversial. This arises in part from the lack of an accepted “gold standard” for the diagnosis of adrenal insufficiency in the critically ill. Historically, assessment of adrenal function in this population has relied on measurement of plasma total cortisol level, in a blood sample taken either at random or as part of a corticotrophin stimulation test. However, an alternative is to focus on the site of glucocorticoid activity within the tissues as a potentially more useful index of functional adrenal status. Tissue glucocorticoid activity has now been given a central role in modern concepts of adrenal function in critical illness, yet its mechanisms and importance remain elusive. The purpose of this thesis is to examine the measurement of adrenal function in the critically ill, in particular the role of total and free plasma cortisol concentrations, indices of tissue glucocorticoid function, and their interrelationship. Clinical Studies Initially the interassay variability of total plasma cortisol concentrations in a critically ill population was examined. A literature review had indicated that commercially available assays are subject to cross reactivity with steroids other than cortisol. It was hypothesised that this cross reactivity may be exaggerated in a population that was expressing high concentrations of these molecules. A comparison study of four different assays indicated a high degree of observed variability such that concordance in diagnosing adrenal insufficiency occurred in less than 50% of patients. Subsequent studies investigated the role of plasma free cortisol concentrations in describing adrenal function in the critically ill. The majority of circulating plasma cortisol is bound to corticosteroid binding globulin but only the smaller fraction of free cortisol possesses biological activity. Measurement techniques that do not distinguish between the bound and free fractions may therefore be unreliable in estimating adrenal activity in circumstances where plasma corticosteroid binding protein levels are abnormal, as is the case in critical illness. Serial free cortisol concentrations were studied using an ultra high performance mass spectrometry technique in patients with septic shock. This investigation demonstrated dissociation between the total and free cortisol concentrations over time, and in response to exogenous corticotrophin. Free cortisol exhibited a significantly greater response to a low dose corticotrophin test than did total cortisol, and free cortisol levels fell over an observed 10 day period while total cortisol levels remained static. Additionally, it was observed that the mass spectrometry technique employed gave a substantially lower range of values than those previously observed in the literature using less accurate assays. Additionally this study reported the first documented association between low plasma free cortisol concentrations at baseline and subsequent 28 day mortality. To investigate the role of tissue glucocorticoid activity several techniques were employed. Microdialysis catheters allow the sampling of interstitial cortisol concentrations, which represent the available glucocorticoid pool for diffusion into the cell. Comparing plasma total, plasma free, and interstitial cortisol concentrations a significant elevation of interstitial cortisol concentrations in patients with severe burns compared to controls was observed. However, there was no correlation between the interstitial and plasma concentrations. Following its passage into the cell, cortisol is subject to the actions of the 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme system. This widely distributed intracellular system exists as two isomers; 11β-HSD1 is primarily reductase, and generates cortisol from inactive cortisone, whereas 11β-HSD2 is a dehydrogenase and inactivates cortisol by converting it to cortisone. The relative activity of these isomers thus has a profound effect upon intracellular cortisol levels, which will be tissue specific. Overall body 11β-HSD can be estimated by measurement of the total plasma cortisol: cortisone (F:E) ratio, while urinary F:E ratios indicate the activity of 11β-HSD2. In critically ill patients over a 7 day period there was a significant increase in plasma F:E ratio, but an elevation followed by a fall in urinary F:E ratio, implying reduced 11β-HSD2 activity. A rodent septic shock model was employed to further examine the role of 11β-HSD1. Rats exposed to a sub-acute caecal ligation and perforation model of sepsis exhibited a significant increase in 11β-HSD1 gene expression in hepatic, but not adipose tissue. Rats that underwent an acute endotoxic insult did not manifest any observable increase in gene expression over controls. Conclusions These observations suggest that in critical illness there appear to be substantial alterations in glucocorticoid physiology such that total plasma cortisol concentrations may not provide a valid indication of adrenal status. The interassay variability in sepsis appears to be increased for the available assays for total cortisol. This results in significant discrepancies in classification, making comparisons without standardised assays between populations difficult. Additionally, there appear to be significant dissociations between total cortisol measurements and those of free cortisol. The significant increase in free cortisol response to corticotrophin compared to total cortisol casts some doubt upon total cortisol response as a valid index of adrenal function. Changes in F:E ratios and in rodent gene expression studies indicate an increase in activity of 11β-HSD1, leading to an increase in intracellular cortisol concentrations that will not be reflected in plasma measurements. These results suggest that further work is needed to accurately measure functional adrenal status in critically ill patients. Studies investigating either glucocorticoid target gene expression or in vitro suppression of cytokine production methods may prove to be fruitful.
Keyword Cortisol
Adrenal Function
Adrenal Insufficiency
Sepsis
Septic Shock
11β-hydroxysteroid dehydrogenase
Microdialysis

 
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Created: Fri, 04 May 2012, 13:32:53 EST by Jeremy Cohen on behalf of Library - Information Access Service