Impact of duration of critical illness and level of systemic glucocorticoid availability on tissue-specific glucocorticoid receptor expression and actions: A prospective, observational, cross-sectional human and two translational mouse studies

Téblick, Arno; Dyck, Lisa Van; Aerde, Nathalie Van; Perre, S Van der; Pauwels, Lies; Derese, Inge; Debaveye, Yves; Wouters, Pieter; Vanhorebeek, Ilse; Langouche, Lies; Berghe, Greet Van den

doi:10.1016/j.ebiom.2022.104057

Cited by 14 publications

(25 citation statements)

References 48 publications

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“…A recent set of studies, performed in human critically ill patients with sepsis and in a clinically relevant mouse model of sepsis-induced critical illness have revealed that a “generalized resistance” to glucocorticoids is in fact not present. 5 In contrast, these studies have shown that in sepsis, certain cells and tissues downregulate GRα action whereas others upregulate GRα action. Most strikingly, it was shown that in neutrophils gene expression of the GRα as well as GRα action, reflected by suppressed expression of glucocorticoid-induced leucine zipper (GILZ), were suppressed throughout critical illness.…”

Section: Introductionmentioning

confidence: 96%

“… 2 , 3 DAMPs are also induced by extensive or complicated surgery and by trauma, triggering hyper-inflammation quite similar as in sepsis. 2 , 4 , 5 , 6 Hence, we here discuss sepsis-induced as well as hyperinflammation-induced critical illness as one entity.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, increased GRα action was present in monocytes - shown to be an essential response for effective bacterial killing 27 - as well as in all other (vital) target tissues not in the least the lungs. 5 It was also shown that local GRα action was not only determined by the level of receptor expression but also by the degree of local cortisol production via 11β-hydroxysteroid dehydrogenase 1 (11bHSD1) and by the expression of the GRα-ligand binding induced FK506 binding protein 5 (FKBP51), an inhibitor of GRα sensitivity. These recent studies also showed that further increasing glucocorticoid availability, such as by infusion of high doses of hydrocortisone, (a) did not overcome the glucocorticoid resistance in neutrophils (GRα expression and action was substantially suppressed and stayed suppressed upon treatment), (b) triggered adaptive responses to prevent a rise in GRα action in other tissues such as skeletal muscle and (c) only in the lung and the diaphragm resulted in a further rise of GRα action.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Berghe¹,

Berghe²,

Langouche³

et al. 2022

eBioMedicine

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Berghe¹,

Berghe²,

Langouche³

et al. 2022

eBioMedicine

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“…However, glucocorticoid-induced leucine zipper, which is the marker of the action of GR is reported to be upregulated in the diaphragm. Thus, the steroid excess could cause the abnormalities of the diaphragm ( 11 ). On the other hand, there are little reports in which the lack of steroid in diaphragm are discussed.…”

Section: Discussionmentioning

confidence: 99%

Hiccups as the first presentation of secondary adrenal insufficiency associated with advanced cervical cancer

Sawamura

Ohmori

Sawada

et al. 2022

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary Hiccups are a common symptom characterized by intermittent spasmodic contraction of the diaphragm. Most hiccups are transient, but some are refractory. Patients with intractable hiccups often have abnormalities of the diaphragm, medulla oblongata, and lesions affecting nerve fibers connecting them. Moreover, electrolyte abnormalities, including hyponatremia, are frequently observed in patients with intractable hiccups. Adrenal insufficiency (AI) is one of the causes of hyponatremia. However, hiccups are not commonly the first presentation. Herein, we describe a case of a 45-year-old woman complaining of refractory hiccups. The patient was initially diagnosed with hiccups associated with cervical cancer metastasis to the liver and peritoneum. The administration of chlorpromazine did not have a beneficial effect on her hiccup. Fasting hypoglycemia and hyponatremia were later found. Her serum cortisol level was low without an elevation of adrenocorticotropic hormone level. MRI of the pituitary gland showed metastatic lesion in the pituitary gland and stalk. Thus, the patient was diagnosed with secondary AI due to cervical cancer metastasis to the pituitary gland and stalk. Administration of hydrocortisone improved her hiccups with the normalization of serum sodium level. Therefore, differential diagnosis in advanced cancer patients with hiccups should include AI-induced hyponatremia. Learning points Hiccups could be the first manifestation of adrenal insufficiency (AI). Hiccups in patients with AI are often mediated by hyponatremia. Hyponatremia is less frequent in secondary AI than in primary AI. However, hyponatremia can result from increased antidiuretic hormone due to loss of cortisol. The differential diagnosis should include AI-induced hyponatremia if hiccups occur in patients with advanced cancer, as metastasis to adrenal gland or pituitary gland could cause AI.

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“…These complex changes have been summarized under the term critical illness-related glucocorticoid insu ciency (CIRCI) (8). The exact prevalence of CIRCI is unknown, and recent studies argue against CIRCI being a common syndrome in the acute phase, but rather occurring in the prolonged phase of critical illness (9,10).…”

Section: Introductionmentioning

confidence: 99%

Corticotropin stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study

Briegel

Möhnle

Keh

et al. 2022

Preprint

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Rationale: Steroid profiles combined with the corticotropin stimulation test can be used to obtain a more complete picture of adrenocortical function in critically ill patients. Objectives: Our objective was to investigate whether steroid profiles before and after corticotropin stimulation predict shock development and mortality in human sepsis. Methods: An exploratory data analysis of a double-blind, randomized trial in sepsis (HYPRESS [Hydrocortisone for the PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment (200 mg for 5 days). Corticotropin tests were performed in 206 patients before randomization and in 20 healthy subjects. Samples were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS) for steroid profiling. Steroid profiles of healthy subjects undergoing corticotropin tests served as controls to determine reference ranges. Measurements and Main Results: Corticotropin test samples from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways before stimulation. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. A predominance of glucocorticoids over mineralocorticoids after corticotropin stimulation (cortisol-corticosterone ratio > 32.2) predicted the development of shock within 14 days and death within 90 days in the placebo group. Conclusions: In this exploratory data analysis, corticotropin stimulated cortisol-to-corticosterone ratio served as a criterion to predict shock development and mortality in sepsis. Clinical trial registered with www.clinicaltrials.gov Identifier: NCT00670254. Registered 1 May 2008.

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Impact of duration of critical illness and level of systemic glucocorticoid availability on tissue-specific glucocorticoid receptor expression and actions: A prospective, observational, cross-sectional human and two translational mouse studies

Cited by 14 publications

References 48 publications

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

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

Hiccups as the first presentation of secondary adrenal insufficiency associated with advanced cervical cancer

Corticotropin stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study

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