Abstract
BackgroundSepsis is typically hallmarked by high plasma (free) cortisol and suppressed cortisol breakdown, while plasma adrenocorticotropic hormone (ACTH) is not increased, referred to as ‘ACTH–cortisol dissociation.’ We hypothesized that sepsis acutely activates the hypothalamus to generate, via corticotropin-releasing hormone (CRH) and vasopressin (AVP), ACTH-induced hypercortisolemia. Thereafter, via increased availability of free cortisol, of which breakdown is reduced, feedback inhibition at the pituitary level interferes with normal processing of pro-opiomelanocortin (POMC) into ACTH, explaining the ACTH–cortisol dissociation. We further hypothesized that, in this constellation, POMC leaches into the circulation and can contribute to adrenocortical steroidogenesis.MethodsIn two human studies of acute (ICU admission to day 7, N = 71) and prolonged (from ICU day 7 until recovery; N = 65) sepsis-induced critical illness, POMC plasma concentrations were quantified in relation to plasma ACTH and cortisol. In a mouse study of acute (1 day), subacute (3 and 5 days) and prolonged (7 days) fluid-resuscitated, antibiotic-treated sepsis (N = 123), we further documented alterations in hypothalamic CRH and AVP, plasma and pituitary POMC and its glucocorticoid-receptor-regulated processing into ACTH, as well as adrenal cortex integrity and steroidogenesis markers.ResultsThe two human studies revealed several-fold elevated plasma concentrations of the ACTH precursor POMC from the acute to the prolonged phase of sepsis and upon recovery (all p < 0.0001), coinciding with the known ACTH–cortisol dissociation. Elevated plasma POMC and ACTH–corticosterone dissociation were confirmed in the mouse model. In mice, sepsis acutely increased hypothalamic mRNA of CRH (p = 0.04) and AVP (p = 0.03) which subsequently normalized. From 3 days onward, pituitary expression of CRH receptor and AVP receptor was increased. From acute throughout prolonged sepsis, pituitary POMC mRNA was always elevated (all p < 0.05). In contrast, markers of POMC processing into ACTH and of ACTH secretion, negatively regulated by glucocorticoid receptor ligand binding, were suppressed at all time points (all p ≤ 0.05). Distorted adrenocortical structure (p < 0.05) and lipid depletion (p < 0.05) were present, while most markers of adrenocortical steroidogenic activity were increased at all time points (all p < 0.05).ConclusionTogether, these findings suggest that increased circulating POMC, through CRH/AVP-driven POMC expression and impaired processing into ACTH, could represent a new piece in the puzzling ACTH–cortisol dissociation.
Highlights
Patients suffering from critical illnesses, which can be evoked by sepsis, major trauma, extensive burn injuries or surgery, typically present with high plasma concentrations of total and even more so of free cortisol [1, 2]
Human studies of critically ill patients suffering from sepsis During the first week in Intensive care unit (ICU), plasma concentrations of adrenocorticotropic hormone (ACTH) in patients were always lower than those of healthy controls (p < 0.0001 for each time point, median across all time points: 3.26 pg/ml (IQR 1.57–5.87) versus 30.04 pg/ml (IQR 24.52–48.92)), whereas plasma concentrations of total cortisol were always higher in patients than normal (p < 0.01 for each time point, median across all time points: 14.65 μg/dl (IQR 10.67–19.09) versus 11.22 μg/dl (IQR 8.99–12.04)) (Fig. 1a)
The two studies of human patients suffering from sepsis revealed that, in the face of the known ACTH–cortisol dissociation, plasma concentrations of the ACTH precursor POMC were substantially elevated from the acute into the prolonged phase of sepsis-induced critical illness
Summary
Patients suffering from critical illnesses, which can be evoked by sepsis, major trauma, extensive burn injuries or surgery, typically present with high plasma concentrations of total and even more so of free cortisol [1, 2]. The increased systemic cortisol availability during critical illness is crucial for survival as it plays a key role in providing essential energy substrates and in regulating the immune and hemodynamic responses necessary for restoring homeostasis [3,4,5]. Both very high and very low levels of systemic cortisol have been associated with poor outcome, underlining the importance of a thorough understanding of this response [2]. In this constellation, POMC leaches into the circulation and can contribute to adrenocortical steroidogenesis
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