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Adrenocortical Stress Response during the Course of Critical Illness

Bram Peeters, Lies Langouche, Greet Van den Berghe

10.1002/cphy.c170022

Source: Volume 8, Issue 1, January 2018

Published online: December 2017

Full Article on Wiley Online Library



ABSTRACT

Critically ill patients have elevated plasma cortisol concentrations, in proportion to illness severity. This was traditionally attributed exclusively to a central activation of the hypothalamus‐pituitary axis. However, low rather than high plasma ACTH concentrations have been reported in critically ill patients, with loss of diurnal ACTH and cortisol rhythm. Low ACTH together with high cortisol is referred to as “ACTH‐cortisol dissociation.” Although cortisol production is somewhat increased with inflammation, a reduced cortisol breakdown explains to a larger extent the hypercortisolism during critical illness. Inflammation‐driven decrease in cortisol binding proteins further increase the active free cortisol fraction. Several drugs administered to ICU patients suppress plasma cortisol in a dose‐dependent manner.

Sustained low circulating ACTH might contribute to adrenal atrophy and dysfunction in the prolonged phase of critical illness. In the acute phase of sepsis or septic shock, a condition referred to as “relative adrenal insufficiency” has been suggested to ensue from glucocorticoid resistance and insufficiently elevated circulating cortisol to overcome such resistance, with pathological changes possibly occurring at every level of the HPA axis. However, it remains highly controversial whether tissue‐specific glucocorticoid resistance is adaptive or maladaptive, how to diagnose “relative” adrenal insufficiency, and how it should be treated. Large RCTs, investigating the effect of 200 mg/d hydrocortisone treatment for sepsis or septic shock have shown conflicting, mainly negative, results. Not taking into account the reduced cortisol breakdown, which increases the risk of overdosing hydrocortisone, might have played a role. Further research on diagnostic, therapeutic and dosing aspects is urgently warranted. Compr Physiol 8:283‐298, 2018.

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Figure 1. Figure 1. Shown are the biphasic neuroendocrine responses of the anterior pituitary hormones and their peripheral hormones to acute and chronic critical illness. In the acute phase of illness the growth hormone (GH) and thyrotrophin (TSH) secretory activity is amplified (red), and adrenocorticotropic hormone (ACTH) secretory activity is increased in some cases. Plasma concentrations of their anabolic peripheral hormones (insulin‐like growth factor‐I, triiodothyronine) are decreased (green), but cortisol levels are elevated (yellow). In prolonged critical illness, secretion of GH, TSH, and ACTH is consistently suppressed, with a further decrease of their peripheral hormones. Plasma cortisol levels remain high, but in some cases low plasma cortisol levels appear in the chronic phase of critical illness. (Figure was reproduced from Van den Berghe ( 160 ), with permission from The Journal of Clinical Endocrinology and Metabolism.)
Figure 2. Figure 2. Mean values and standard errors for plasma ACTH (Panel A), total cortisol (Panel B), and free cortisol (Panel C) in ICU patients from admission onward until day 3 of ICU stay. The blue shaded area represents the interquartile range of morning values in healthy control subjects. * P ≤ 0.05, ** P < 0.001, for the comparison with controls. § P ≤ 0.05, §§ P < 0.01, §§§ P < 0.0001, for the comparison of paired values of the consecutive days with the admission sample. For each day, the number of patients still in ICU is displayed below the figure. ICU denotes intensive care unit, adm denotes admission. (Figure was reproduced from Peeters ( 115 ), with permission from Clinical Endocrinology.)
Figure 3. Figure 3. Cortisol metabolism in humans. Cortisol and cortisone are mainly broken down via A‐ring reductases, 5α‐reductase and 5β‐reductase, in the liver to generate 5α‐ and 5β‐tetrahydrocortisol. In the kidney, cortisol is metabolized by 11β‐hydroxysteroid dehydrogenase (11β‐HSD) type 2, generating cortisone, which can further be broken down to tetra‐hydrocortisone (THE) by 5β‐reductase. 11β‐HSD type 1 can reconvert cortisone to cortisol.
Figure 4. Figure 4. Adrenocorticotropic hormone (ACTH) binds to its receptor, the melanocortin 2 receptor (MC2R), on the membrane of the adrenocortical cells, which increases cyclic AMP (cAMP) and stimulates protein kinase A (PKA). PKA causes the release of cholesterol from the lipid droplets into the cytoplasm and de novo production from acetyl coenzyme A (acetyl CoA). ACTH increases the expression of the steroidogenic acute regulatory protein (STAR) to transport cholesterol from the cytoplasm to the inner membrane of the mitochondria where steroidogenesis takes place. Cholesterol is converted into different steroid hormones. The long‐term impact of ACTH involves increased transcription of genes important for cholesterol uptake [scavenger‐receptor class B, member 1 (SCARB1), LDL receptor (LDLR)] and cholesterol synthesis [3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR)], and for steroidogenesis (STAR and CYP11A1). ACTH has a direct stimulatory effect on the expression of its own receptor (MC2R). Blue lines represent ACTH effects. (Figure was reproduced from Boonen ( 17 ), with permission from The Lancet Diabetes & Endocrinology.)
Figure 5. Figure 5. mRNA expression of ACTH‐regulated proteins in adrenal glands, harvested from individuals dying suddenly out of hospital (control subjects), from patients dying after short critical illness and from patients after prolonged critical illness. The mRNA data are expressed, normalized to RNA18S as a fold difference from the mean of the controls. Boxes represent medians and interquartile ranges and whiskers represent firstquartile‐1.5*IQR and thirdquartile+1.5*IQR. (Figure was reproduced from Boonen ( 18 ), with permission from The Journal of Clinical Endocrinology and Metabolism.)
Figure 6. Figure 6. Overview of the regulation of hypercortisolism during critical illness. ↑, elevated plasma concentrations; ↓, decreased plasma concentrations; ?, no univocal data available; +, stimulates; −, inhibits; PVN, paraventricular nucleus; ACTH, adrenocorticotropic hormone; CBG, corticosteroid‐binding globulin.


Figure 1. Shown are the biphasic neuroendocrine responses of the anterior pituitary hormones and their peripheral hormones to acute and chronic critical illness. In the acute phase of illness the growth hormone (GH) and thyrotrophin (TSH) secretory activity is amplified (red), and adrenocorticotropic hormone (ACTH) secretory activity is increased in some cases. Plasma concentrations of their anabolic peripheral hormones (insulin‐like growth factor‐I, triiodothyronine) are decreased (green), but cortisol levels are elevated (yellow). In prolonged critical illness, secretion of GH, TSH, and ACTH is consistently suppressed, with a further decrease of their peripheral hormones. Plasma cortisol levels remain high, but in some cases low plasma cortisol levels appear in the chronic phase of critical illness. (Figure was reproduced from Van den Berghe ( 160 ), with permission from The Journal of Clinical Endocrinology and Metabolism.)


Figure 2. Mean values and standard errors for plasma ACTH (Panel A), total cortisol (Panel B), and free cortisol (Panel C) in ICU patients from admission onward until day 3 of ICU stay. The blue shaded area represents the interquartile range of morning values in healthy control subjects. * P ≤ 0.05, ** P < 0.001, for the comparison with controls. § P ≤ 0.05, §§ P < 0.01, §§§ P < 0.0001, for the comparison of paired values of the consecutive days with the admission sample. For each day, the number of patients still in ICU is displayed below the figure. ICU denotes intensive care unit, adm denotes admission. (Figure was reproduced from Peeters ( 115 ), with permission from Clinical Endocrinology.)


Figure 3. Cortisol metabolism in humans. Cortisol and cortisone are mainly broken down via A‐ring reductases, 5α‐reductase and 5β‐reductase, in the liver to generate 5α‐ and 5β‐tetrahydrocortisol. In the kidney, cortisol is metabolized by 11β‐hydroxysteroid dehydrogenase (11β‐HSD) type 2, generating cortisone, which can further be broken down to tetra‐hydrocortisone (THE) by 5β‐reductase. 11β‐HSD type 1 can reconvert cortisone to cortisol.


Figure 4. Adrenocorticotropic hormone (ACTH) binds to its receptor, the melanocortin 2 receptor (MC2R), on the membrane of the adrenocortical cells, which increases cyclic AMP (cAMP) and stimulates protein kinase A (PKA). PKA causes the release of cholesterol from the lipid droplets into the cytoplasm and de novo production from acetyl coenzyme A (acetyl CoA). ACTH increases the expression of the steroidogenic acute regulatory protein (STAR) to transport cholesterol from the cytoplasm to the inner membrane of the mitochondria where steroidogenesis takes place. Cholesterol is converted into different steroid hormones. The long‐term impact of ACTH involves increased transcription of genes important for cholesterol uptake [scavenger‐receptor class B, member 1 (SCARB1), LDL receptor (LDLR)] and cholesterol synthesis [3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR)], and for steroidogenesis (STAR and CYP11A1). ACTH has a direct stimulatory effect on the expression of its own receptor (MC2R). Blue lines represent ACTH effects. (Figure was reproduced from Boonen ( 17 ), with permission from The Lancet Diabetes & Endocrinology.)


Figure 5. mRNA expression of ACTH‐regulated proteins in adrenal glands, harvested from individuals dying suddenly out of hospital (control subjects), from patients dying after short critical illness and from patients after prolonged critical illness. The mRNA data are expressed, normalized to RNA18S as a fold difference from the mean of the controls. Boxes represent medians and interquartile ranges and whiskers represent firstquartile‐1.5*IQR and thirdquartile+1.5*IQR. (Figure was reproduced from Boonen ( 18 ), with permission from The Journal of Clinical Endocrinology and Metabolism.)


Figure 6. Overview of the regulation of hypercortisolism during critical illness. ↑, elevated plasma concentrations; ↓, decreased plasma concentrations; ?, no univocal data available; +, stimulates; −, inhibits; PVN, paraventricular nucleus; ACTH, adrenocorticotropic hormone; CBG, corticosteroid‐binding globulin.
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Teaching Material

B. Peeters, L. Langouche, G. Van den Berghe. Adrenocortical Stress Response during the Course of Critical Illness. Compr Physiol. 8: 2018, 283-298.

Didactic Synopsis

Major Teaching Points:

  • Unlike the hypothalamus-pituitary-adrenal axis response to stress outside the context of intensive care, the stress response to critical illness is hallmarked by low rather than high plasma ACTH in the face of high plasma cortisol.
  • During critical illness, the diurnal rhythm of ACTH and cortisol secretion is absent.
  • A normal or only slightly increased cortisol production and a consistently reduced cortisol breakdown determine the degree of hypercortisolism during critical illness.
  • Sustained suppressed circulating ACTH can contribute to risk of adrenal atrophy specifically in prolonged critically ill patients
  • Drugs often given to critically ill patients such as etomidate, opioids and propofol can suppress plasma cortisol. One should consider omitting these before initiating treatment with hydrocortisone for low plasma cortisol.
  • It remains controversial whether “relative” adrenal insufficiency is a clinical entity ensuing from glucocorticoid resistance with cortisol availability that is insufficiently elevated to overcome such resistance.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Shown are the biphasic neuroendocrine responses of the anterior pituitary hormones and their peripheral hormones to acute and chronic critical illness. In the acute phase of illness the growth hormone (GH) and thyrotrophin (TSH) secretory activity is amplified (red), and adrenocorticotropic hormone (ACTH) secretory activity is increased in some cases. Plasma concentrations of their anabolic peripheral hormones (insulin-like growth factor-I, triiodothyronine) are decreased (green), but cortisol levels are elevated (yellow). In prolonged critical illness, secretion of GH, TSH and ACTH is consistently suppressed, with a further decrease of their peripheral hormones. Plasma cortisol levels remain high, but in some cases low plasma cortisol levels appear in the chronic phase of critical illness. [Figure was reproduced from Van den Berghe (160), with permission from The Journal of Clinical Endocrinology and Metabolism.]

Figure 2. Teaching points: Mean values and standard errors for plasma ACTH (Panel A), total cortisol (Panel B), and free cortisol (Panel C) in ICU patients from admission onward until day 3 of ICU stay. The blue shaded area represents the interquartile range of morning values in healthy control subjects. *P ≤ 0.05, **P < 0.001, for the comparison with controls. §P ≤ 0.05, §§P < 0.01, §§§P < 0.0001, for the comparison of paired values of the consecutive days with the admission sample. For each day, the number of patients still in ICU is displayed below the figure. ICU denotes intensive care unit, adm denotes admission. [Figure was reproduced from Peeters (115), with permission from Clinical Endocrinology.]

Figure 3. Teaching points: Cortisol metabolism in humans. Cortisol and cortisone are mainly broken down via A-ring reductases, 5α-reductase and 5β-reductase, in the liver to generate 5α- and 5β-tetrahydrocortisol. In the kidney, cortisol is metabolized by 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, generating cortisone, which can further be broken down to tetra-hydrocortisone (THE) by 5β-reductase. 11β-HSD type 1 can reconvert cortisone to cortisol.

Figure 4. Teaching points: Adrenocorticotropic hormone (ACTH) binds to its receptor, the melanocortin 2 receptor (MC2R), on the membrane of the adrenocortical cells, which increases cyclic AMP (cAMP) and stimulates protein kinase A (PKA). PKA causes the release of cholesterol from the lipid droplets into the cytoplasm and de novo production from acetyl coenzyme A (acetyl CoA). ACTH increases the expression of the steroidogenic acute regulatory protein (STAR) to transport cholesterol from the cytoplasm to the inner membrane of the mitochondria where steroidogenesis takes place. Cholesterol is converted into different steroid hormones. The long-term impact of ACTH involves increased transcription of genes important for cholesterol uptake [scavenger-receptor class B, member 1 (SCARB1), LDL receptor (LDLR)] and cholesterol synthesis [3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)], and for steroidogenesis (STAR and CYP11A1). ACTH has a direct stimulatory effect on the expression of its own receptor (MC2R). Blue lines represent ACTH effects. [Figure was reproduced from Boonen (17), with permission from The Lancet Diabetes & Endocrinology.]

Figure 5. Teaching points: mRNA expression of ACTH-regulated proteins in adrenal glands, harvested from individuals dying suddenly out of hospital (control subjects), from patients dying after short critical illness and from patients after prolonged critical illness. The mRNA data are expressed, normalized to RNA18S as a fold difference from the mean of the controls. Boxes represent medians and interquartile ranges and whiskers represent firstquartile-1.5*IQR and thirdquartile + 1.5*IQR. [Figure was reproduced from Boonen (18), with permission from The Journal of Clinical Endocrinology and Metabolism.]

Figure 6. Teaching points: Overview of the regulation of hypercortisolism during critical illness. ↑, elevated plasma concentrations; ↓, decreased plasma concentrations; ?, no univocal data available; + , stimulates; -, inhibits; PVN, paraventricular nucleus; ACTH, adrenocorticotropic hormone; CBG, corticosteroid-binding globulin.

 


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Article Title: Adrenocortical Stress Response during the Course of Critical Illness
 

How to Cite

Bram Peeters, Lies Langouche, Greet Van den Berghe. Adrenocortical Stress Response during the Course of Critical Illness. Compr Physiol 2017, 8: 283-298. doi: 10.1002/cphy.c170022