• Eva Boonen, Lies Langouche, Thomas Janssens, Philippe Meersseman, Hilke Vervenne, Emilie De Samblanx, Zoë Pironet, Lisa Van Dijck, Sarah Vander Perre, Inge Derese, and Greet Van den Berghe.
• Clinical Division and Laboratory of Intensive Care Medicine (E.B., L.L., T.J., H.V., E.D.S., Z.P., L.V.D., S.V.P.I.D., G.V.d.B.), Department Cellular and Molecular Medicine, and Clinical Department of Internal Medicine (P.M.), University of Leuven (KU Leuven), B-3000 Leuven, Belgium.
• J. Clin. Endocrinol. Metab. 2014 Nov 1; 99 (11): 4214-22.

ContextAdrenal insufficiency is considered to be prevalent during critical illness, although the pathophysiology, diagnostic criteria, and optimal therapeutic strategy remain controversial. During critical illness, reduced cortisol breakdown contributes substantially to elevated plasma cortisol and low plasma ACTH concentrations.ObjectiveBecause ACTH has a trophic impact on the adrenal cortex, we hypothesized that with a longer duration of critical illness, subnormal ACTH adrenocortical stimulation predisposes to adrenal insufficiency.Design, Setting And ParticipantsAdrenal glands were harvested 24 hours or sooner after death from 13 long intensive care unit (ICU)-stay patients, 27 short ICU-stay patients, and 13 controls. Prior glucocorticoid treatment was excluded. MAIN OUTCOME AND MEASURE(S): Microscopic adrenocortical zonational structure was evaluated by hematoxylin and eosin staining. The amount of adrenal cholesterol esters was determined by Oil-Red-O staining, and mRNA expression of ACTH-regulated steroidogenic enzymes was quantified.ResultsThe adrenocortical zonational structure was disturbed in patients as compared with controls (P < .0001), with indistinguishable adrenocortical zones present only in long ICU-stay patients (P = .003 vs. controls). Adrenal glands from long ICU-stay patients, but not those of short ICU-stay patients, contained 21% less protein (P = .03) and 9% more fluid (P = .01) than those from controls, whereas they tended to weigh less for comparable adrenal surface area. There was 78% less Oil-Red-O staining in long ICU-stay patients than in controls and in short-stay patients (P = .03), the latter similar to controls (P = .31). The mRNA expression of melanocortin 2 receptor, scavenger-receptor class B, member 1, 3-hydroxy-3-methylglutaryl-CoA reductase, steroidogenic acute regulatory protein, and cytochrome P450 cholesterol side-chain cleavage enzyme was at least 58% lower in long ICU-stay patients than in controls (all P ≤ .03) and of melanocortin 2 receptor, scavenger-receptor class B, member 1, steroidogenic acute regulatory protein, and cytochrome P450 cholesterol side-chain cleavage enzyme at least 53% lower than in short ICU-stay patients (all P ≤ .04), whereas gene expression in short ICU-stay patients was similar to controls.Conclusion And RelevanceLipid depletion and reduced ACTH-regulated gene expression in prolonged critical illness suggest that sustained lack of ACTH may contribute to the risk of adrenal insufficiency in long-stay ICU patients.

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