Reduced Glucocorticoid Receptor Protein Expression in Children with Critical Illness

Abstract

Background/Aims: The diagnostic criteria for critical illness-related corticoid insufficiency (CIRCI) are not well established, particularly for children. In addition to alterations in adrenal function, cellular resistance to glucocorticoid action could contribute to CIRCI due to alterations in the functioning of the intracellular receptor protein for corticosteroids, the glucocorticoid receptor (GR). Methods: We have therefore undertaken a pilot, prospective study to assess whether cellular GR activity can be measured in peripheral blood mononuclear cells (PBMCs) from critically ill children. Results: Total and cytoplasmic, but not nuclear GR levels were significantly lower in PBMCs from critically ill children (i.e. sepsis/septic shock and traumatic brain injury) compared to healthy controls. While total cortisol concentrations did not differ between test groups, salivary and serum-free cortisol concentrations were significantly greater in both groups of children with critical illness. Cortisol-binding globulin levels were significantly lower in patients with sepsis/septic shock. Conclusions: The lower total and cytoplasmic receptor levels in critically ill children suggest that the GR-mediated response to exogenous glucocorticoid therapy may be limited. However, the nuclear transport of GR in critically ill patients suggests that residual receptors in these patients retain functionality and may be accessible to therapeutic treatments that maximize their activity.

Evaluation of adrenal function in critically ill children

“…We also found higher basal and post‐ACTH salivary cortisol levels in critically ill children than in healthy controls, in accordance with published data in adults . A recent publication reported higher basal levels of salivary cortisol in children with septic shock compared with controls with congenital hypothyroidism, but concentrations of salivary cortisol were much lower in both groups compared with those found in our study . Basal salivary cortisol concentrations in our control group were similar to those previously reported for healthy children .…”

Decreased glucocorticoid receptor expression during critical illness

“…38 Another study showed that total and cytoplasmic, but not nuclear GCR levels, were significantly lower in critically ill children compared to healthy controls. 39 Other studies have also found reduced levels of GCR-α in sepsis, 40,41 while reduced GCR protein levels have been reported in various organs (liver, brain and muscle) during sepsis. 42 A link found between induction of miR124 and reduced GCR expression in septic patients 37 suggested that steroid treatment might aggravate GCR resistance in patients with high GCR-β levels, while evidence that GCR expression increased during septic shock, while GCR binding capacity decreased, proposed that it is the decreased GCR binding capacity that blocks the response to exogenous or endogenous glucocorticoids, rather than the number of receptors.…”

“…Results of these studies have shown lower GCR‐α and increased GCR‐β expression levels in septic patients compared to healthy subjects, and decreased α:β GCR ratio and increased GCR‐β expression were shown to be related to illness severity in infants with bronchiolitis . Another study showed that total and cytoplasmic, but not nuclear GCR levels, were significantly lower in critically ill children compared to healthy controls . Other studies have also found reduced levels of GCR‐α in sepsis, while reduced GCR protein levels have been reported in various organs (liver, brain and muscle) during sepsis .…”

Critical Illness-Related Corticosteroid Insufficiency in Children

“…Different, and probably interacting, mechanisms account for the decreased activity of glucocorticoids. Two of them are a reduction of glucocorticoid receptors [31] and an increase in the conversion of cortisol to inactive cortisone by enhanced activity of 11-β-hydroxysteroid dehydrogenase stimulated by IL-2, IL-4, and IL-13 [15]. …”