HPA axis in critical illness: cause and consequence of altered cortisol metabolism

The hormone cortisol is an essential component of the response to stress to provide energy, reduce inflammation and ensure hemodynamic stability. Increased production and release of cortisol is normally driven by an activated hypothalamic-pituitary-adrenal (HPA) axis. However, our research group recently demonstrated low plasma ACTH concentrations and high plasma cortisol concentrations during critical illness. This is known as the ‘ACTH-cortisol dissociation’. Furthermore, the research group showed that these elevated plasma cortisol concentrations are only to a limited extent explained by increased cortisol production. Instead, increased cortisol availability during critical illness is largely brought about via suppressed cortisol breakdown 

My project aims at unravelling the cause and consequence of the reduced cortisol breakdown during critical illness. Four hypotheses will be investigated. First, we hypothesized that the pharmacological effects of drugs used during surgery or the acute phase of critical illness prior to ICU admission may partly explain the acute ‘ACTH-cortisol dissociation’, as observed already upon admission to the ICU. Second, we hypothesized that the dissociation between ACTH and cortisol during critical illness is at least in part the result of bile acid-driven reduced cortisol metabolism. Third, the impact of sustained high circulating cortisol levels on the central components of the HPA axis and the impact of prolonged high ACTH on the structure and function of the adrenal cortex will be elucidated. Fourth, I will determine regulation of tissue specific cortisol action during critical illness, as some tissues might suffer from prolonged exposure to high cortisol, while other organs might benefit. For this translational project, I will combine molecular studies on human biopsies, in vivo animal work and human clinical studies. I expect that this project will provide important novel insights in the HPA response to severe stress of which the relevance extends beyond the domain of intensive care medicine.