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Dorin R.I.,Section of Endocrinology and Metabolism | Dorin R.I.,University of New Mexico | Qualls C.R.,University of New Mexico | Torpy D.J.,Endocrine and Metabolic Unit | And 2 more authors.
Critical Care Medicine | Year: 2015

Objective: Cortisol clearance is reduced in sepsis and may contribute to the development of impaired adrenocortical function that is thought to contribute to the pathophysiology of critical illness-related corticosteroid insufficiency. We sought to assess adrenocortical function using computer-assisted numerical modeling methodology to characterize and compare maximal cortisol secretion rate and free cortisol half-life in septic shock, sepsis, and healthy control subjects. Design: Post hoc analysis of previously published total cortisol, free cortisol, corticosteroid-binding globulin, and albumin concentration data. Setting: Single academic medical center. Patients: Subjects included septic shock (n = 45), sepsis (n = 25), and healthy controls (n = 10). Interventions: IV cosyntropin (250 μg). Measurements and Main Results: Solutions for maximal cortisol secretion rate and free cortisol half-life were obtained by least squares solution of simultaneous, nonlinear differential equations that account for free cortisol appearance and elimination as well as reversible binding to corticosteroid-binding globulin and albumin. Maximal cortisol secretion rate was significantly greater in septic shock (0.83 nM/s [0.44, 1.58 nM/s] reported as median [lower quartile, upper quartile]) compared with sepsis (0.51 nM/s [0.36, 0.62 nM/s]; p = 0.007) and controls (0.49 nM/s [0.42, 0.62 nM/s]; p = 0.04). The variance of maximal cortisol secretion rate in septic shock was also greater than that of sepsis or control groups (F test, p < 0.001). Free cortisol half-life was significantly increased in septic shock (4.6 min [2.2, 6.3 min]) and sepsis (3.0 min [2.3, 4.8 min] when compared with controls (2.0 min [1.2, 2.6 min]) (both p < 0.004). Conclusions: Results obtained by numerical modeling are consistent with comparable measures obtained by the gold standard stable isotope dilution method. Septic shock is associated with generally not only higher levels but also greater variance of maximal cortisol secretion rate when compared with control and sepsis groups. Additional studies would be needed to determine whether assessment of cortisol kinetic parameters such as maximal cortisol secretion rate and free cortisol half-life is useful in the diagnosis or management of critical illness-related corticosteroid insufficiency. Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Nordin B.E.C.,Endocrine and Metabolic Unit | Lewis J.R.,Sir Charles Gairdner Hospital | Daly R.M.,Deakin University | Horowitz J.,University of Adelaide | And 3 more authors.
Osteoporosis International | Year: 2011

Detailed consideration of the suggested association between calcium supplementation and heart attacks has revealed weakness in the evidence which make the hypothesis highly implausible. Introduction: The aim of this study was to evaluate the strength of the evidence that calcium supplementation increases the risk of myocardial infarction. Methods: This study used critical examination of a meta-analysis of the effects of calcium supplements on heart attacks in five prospective trials on 8,016 men and women, and consideration of related publications by the same author. Results: The meta-analysis was found to be subject to several limitations including non-adherence to the clinical protocol, multiple endpoint testing and failure to correctly adjust for endpoint ascertainment. The main risk factors for myocardial infarction were not available for 65% of the participants, and none of the trials had cardiovascular disease as its primary endpoint. There were more overweight participants, more subjects on thyroxine and more men on calcium than on placebo. In particular, over 65% of all the heart attacks were self-reported. When the evidence was considered in the light of Austin Bradford Hill's six main criteria for disease causation, it was found not to be biologically plausible or strong or to reflect a dose-response relationship or to be consistent or to reflect the relationship between the trends in calcium supplementation and heart attacks in the community or to have been confirmed by experiment. The addition of a more recent trial on 1,460 women over 5 years reduced the relative risk to 1.23 (P=0.0695). Conclusion: Present evidence that calcium supplementation increases heart attacks is too weak to justify a change in prescribing habits. © 2011 International Osteoporosis Foundation and National Osteoporosis Foundation.

Nguyen P.T.T.,Agresearch Ltd. | Lewis J.G.,Steroid and Immunobiochemistry Laboratory | Sneyd J.,University of Auckland | Lee R.S.F.,Agresearch Ltd. | And 3 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2014

Cortisol bound to corticosteroid binding globulin (CBG) contributes up to 90% of the total cortisol concentration in circulation. Therefore, changes in the binding kinetics of cortisol to CBG can potentially impact on the concentration of free cortisol, the only form that is responsible for the physiological function of the hormone. When CBG is cleaved into elastase-cleaved CBG (eCBG) by the activity of neutrophil elastase, its affinity for cortisol is reduced. Therefore, when eCBG coexists with intact CBG (iCBG) in plasma, the calculation of free cortisol concentration based on the formulae that considers only one CBG pool with the same affinity for cortisol may be inappropriate. In this study, we developed in vivo and in vitro models of cortisol partitioning which considers two CBG pools, iCBG and eCBG, with different affinities for cortisol, and deduce a new formula for calculating plasma free cortisol concentration. The formula provides better estimates of free cortisol concentration than previously used formulae when measurements of the concentrations of the two CBG forms are available. The model can also be used to estimate the affinity of CBG and albumin for cortisol in different clinical groups. We found no significant difference in the estimated affinity of CBG and albumin for cortisol in normal, sepsis and septic shock groups, although free cortisol was higher in sepsis and septic shock groups. The in vivo model also demonstrated that the concentration of interstitial free cortisol is increased locally at a site of inflammation where iCBG is cleaved to form eCBG by the activity of elastase released by neutrophils. This supports the argument that the cleavage of iCBG at sites of inflammation leads to more lower-affinity eCBG and may be a mechanism that permits the local concentration of free cortisol to increase at these sites, while allowing basal free cortisol concentrations at other sites to remain unaffected. © 2014 Elsevier Ltd.

Christopher Nordin B.E.,Endocrine and Metabolic Unit | Christopher Nordin B.E.,University of Adelaide
Nutrients | Year: 2010

Osteoporosis is the index disease for calcium deficiency, just as rickets/osteomalacia is the index disease for vitamin D deficiency, but there is considerable overlap between them. The common explanation for this overlap is that hypovitaminosis D causes malabsorption of calcium which then causes secondary hyperparathyroidism and is effectively the same thing as calcium deficiency. This paradigm is incorrect. Hypovitaminosis D causes secondary hyperparathyroidism at serum calcidiol levels lower than 60 nmol/L long before it causes malabsorption of calcium because serum calcitriol (which controls calcium absorption) is maintained until serum calcidiol falls below 20 nmol/L. This secondary hyperparathyroidism, probably due to loss of a "calcaemic" action of vitamin D on bone first described in 1957, destroys bone and explains why vitamin D insufficiency is a risk factor for osteoporosis. Vitamin D thus plays a central role in the maintenance of the serum (ionised) calcium, which is more important to the organism than the preservation of the skeleton. Bone is sacrificed when absorbed dietary calcium does not match excretion through the skin, kidneys and bowel which is why calcium deficiency causes osteoporosis in experimental animals and, by implication, in humans. © 2010 by the authors; licensee MDPI, Basel, Switzerland.

Thomas S.D.C.,Endocrine and Metabolic Unit
Australian Journal of Medical Science | Year: 2014

Refeeding syndrome is not uncommon in patients receiving parenteral or enteral nutrition in Intensive Care following chronic and serious illness, alcoholism, malnutrition and after major surgery. However refeeding syndrome remains underdiagnosed and therefore undertreated. Adequate nutrition after a period of starvation leads to hypophosphatemia as a consequence of a shift from fat to carbohydrate metabolism with phosphate moving into cells in response to insulin. This gives rise to low serum phosphate which can be fatal. Two cases of hypophosphatemia following oral feeding are presented. One case is of a man following major surgery and the other is a man who was fed after a period of malnutrition and alcoholism. These cases illustrate the biochemical changes seen with refeeding syndrome. © 2014, Australian Journal of Medical Science. All rights reserved.

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