The hypothalamus-pituitary-adrenal axis in sepsis- and hyperinflammation-induced critical illness: Gaps in current knowledge and future translational research directions

Abstract

The classical model of the vital increase in systemic glucocorticoid availability in response to sepsis- and hyperinflammation-induced critical illness is one of an activated hypothalamus-pituitary-adrenocortical axis. However, research performed in the last decade has challenged this rather simple model and has unveiled a more complex, time-dependent set of responses. ACTH-driven cortisol production is only briefly increased, rapidly followed by orchestrated peripheral adaptations that maintain increased cortisol availability for target tissues without continued need for increased cortisol production and by changes at the target tissues that guide and titrate cortisol action matched to tissue-specific needs. One can speculate that these acute changes are adaptive and that treatment with stress-doses of hydrocortisone may negatively interfere with these adaptive changes. These insights also suggest that prolonged critically ill patients, treated in the ICU for several weeks, may develop central adrenal insufficiency, although it remains unclear how to best diagnose and treat this condition.

Keywords: Adrenal; Corticosteroid; Critical-illness; Glucocorticoid-receptor; ICU; Sepsis.

Figure 1

Sepsis and hyperinflammation centrally activate the hypothalamus-pituitary-adrenocortical (HPA) axis. A variety of sepsis- or hyperinflammation-induced warning and alarm signals are integrated in the hypothalamic paraventricular nucleus, which in response releases CRH and AVP in the hypophyseal portal system. In turn, the corticotropes in the anterior pituitary are activated and start producing the precursor hormone POMC, which is cleaved by PC1/3 into ACTH, and release already produced and stored ACTH into the systemic circulation. ACTH stimulates the adrenal cortex to synthesize and secrete cortisol to initiate the hormonal ‘fight-or-flight’ response. Cortisol exerts a broad spectrum of effects in a variety of target cells and tissues, in order to cope with and overcome the illness-inducing insults. In addition, cortisol exerts suppressive effects at the hypothalamus and pituitary gland, the latter via suppressing PC1/3 processing of POMC into ACTH and via suppressing ACTH release through upregulation of Annexin A1, collectively designed to shut off the activated HPA-axis. ACTH: adrenocorticotropic hormone; AVP: vasopressin; CRH: corticotropin-releasing hormone; PC1/3: prohormone convertase 1; POMC: proopiomelanocortin. Created with Biorender.com.

Figure 2

HPA-axis function throughout the various phases of sepsis- and hyperinflammation-induced critical illness. In this framework, the sepsis and hyperinflammation-induced alterations within the HPA-axis are illustrated, in relation to the duration of illness (phases of critical illness). In the hyperacute phase, minutes to hours after the illness-inducing insult, the HPA-axis is centrally activated, resulting in a rapid and substantial increase in plasma total cortisol. A fast decline in plasma concentrations of cortisol carrier proteins, albumin and CBG, and of cortisol metabolism in liver and kidney, further increase the amount of free cortisol in the circulation. In the (sub)acute phase, the increase in systemic glucocorticoid availability exerts negative feedback at the hypothalamus and at the pituitary, the latter by suppressing PC1/3-mediated processing of POMC into ACTH and by increasing Annexin A1, a potent inhibitor of mature ACTH secretion from the pituitary. Meanwhile ongoing stress continues to stimulate pituitary POMC production via preserved CRH- and AVP-signaling, counteracting the negative feedback exerted by the increased systemic glucocorticoid availability. Plasma free cortisol concentrations remain high via the reduced carrier proteins and suppressed hepatic and renal breakdown and possibly also via (limited) POMC-mediated stimulation of the adrenal cortex. In the prolonged phase, the ongoing low circulating ACTH can result in deprivation of trophic signaling at the adrenal cortex, causing a dysfunction of the adrenal gland. As a results, plasma total and free cortisol start to decline, despite the ongoing severe illness. ACTH: adrenocorticotropic hormone; AVP: vasopressin; CBG: cortisol-binding globulin; CRH: corticotropin-releasing hormone; PC1/3: prohormone convertase 1; POMC: proopiomelanocortin. Created with Biorender.com.

Figure 3

Maintenance and guidance of the increased systemic glucocorticoid availability. A series of orchestrated peripheral adaptations maintain increased systemic cortisol availability for target tissues without (a continued need for) increased cortisol production. The actions of the increased circulating cortisol are selectively guided towards those tissue that may benefit from the immune or catabolic, fight-or-flight effects, while other tissues that may be harmed are, at least partially, protected. Created with Biorender.com.