Endocrinology of the Stress Response During Critical Illness

Objectives

This chapter will:

1.
Provide an overview of the stress response.
2.
Review changes in the hypothalamic-pituitary-adrenal axis during critical illness.
3.
Review stress hyperglycemia.
4.
Review stress hyperlactemia.
5.
Describe the sick euthyroid/low T3 syndrome.
6.
Describe changes in the hypothalamic-pituitary growth hormone axis during critical illness.

Stress Response

The stress system receives and integrates a diversity of cognitive, emotional, neurosensory, and peripheral somatic signals that arrive through distinct pathways. Activation of the stress system leads to behavioral and physical changes that are remarkably consistent in their qualitative presentation ( Box 76.1 ). This observation was first noted by Hans Selye, who in 1936 reported that biologic, physical, or psychologic stressors generally precipitate a similar response, which he named the “general adaption syndrome” or stress response. The stress response is normally adaptive and time limited and improves the chances of the individual for survival.

Box 76.1

Behavioral and Physical Adaptation During Acute Stress

Behavioral Adaptation

Increased arousal and alertness
Increased cognition, vigilance, and attention
Heightened analgesia
Suppression of reproductive axis

Physical Adaptation

Increased heart rate
Increased blood pressure
Increased cardiac output
Blood flow directed to brain and skeletal muscle
Increased temperature
Increased respiratory rate
Increased gluconeogenesis (stress hyperglycemia)
Increased lactate production (stress hyperlactemia)
Increased lipolysis
Inhibition of digestion
Stimulation of colonic motility
Containment of inflammatory/immune response

Behavioral adaptation during stress includes increased arousal, alertness, and vigilance; improved cognition; and inhibition of vegetative functions, such as appetite, feeding, and reproduction. A concomitant physical adaption also occurs mainly to promote an adaptive redirection of energy. Oxygen and nutrients are shunted to the central nervous system and the stressed body sites where they are most needed. Increases in cardiovascular tone, respiratory rate, and intermediate metabolism (gluconeogenesis, lipolysis) work in concert with these alterations to promote availability of vital substrates. The stress response evolved to be of short or limited duration. The time-limited nature of this process renders its accompanying antigrowth, antireproductive, catabolic, and immunosuppressive effects temporarily beneficial. Critical illness, however, is characterized by a pathologically prolonged stress response, which differs quantitatively and qualitatively from the acute stress response. Box 76.2 outlines the hormonal changes that occur with critical illness.

Box 76.2

“Typical” Hormonal Changes During Critical Illness

Hypothalamic-pituitary-adrenal (HPA) axis
- Initial increased corticotropin (ACTH) followed by low levels, which then normalize
- Decreased cortisol clearance
- Cortisol synthesis increased (may be followed by decreased synthesis)
- Decrease in circulating levels of cortisol-binding globulin (CBG)
- Increase in total and free cortisol (may be followed by decreased levels)
- Tissue glucocorticoid resistance
- Decrease in dehydroepiandrosterone
- Decreased androgen synthesis
- Decreased aldosterone synthesis
Sympathoadrenal system activation
- Increased epinephrine
- Increased norepinephrine
Growth hormone axis
- Increased growth hormone (GH)
- Decreased GH receptor synthesis
- Decreased insulin growth factor-1 (IGF-1)
Thyroid hormone axis
- Decreased triiodothyronine (T3)
- Increased reverse triiodothyronine (rT3)
Increased prolactin
Increased glucagon

The acute stress response is mediated primarily by the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathoadrenal system (SAS). Activation of the HPA axis results in increased secretion from the paraventricular nucleus of the hypothalamus of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). CRH plays a major role in orchestrating and coordinating the stress response ( Fig. 76.1 ). CRH stimulates the production of adrenocorticotrophic hormone (ACTH) by the anterior pituitary, causing the zona fasciculata of the adrenal cortex to produce more glucocorticoids (cortisol in humans). Activation of the SAS results in the secretion of epinephrine and norepinephrine from the adrenal medulla and sympathetic nerves and to an increased production of inflammatory cytokines such as interleukin-6 (IL-6).

FIGURE 76.1, Activation of the stress response. ACTH, Adrenocorticotrophic hormone; CRH, corticotrophin-releasing hormone; LC/NE, locus ceruleus norepinephrine system; PVN, paraventricular nucleus.

The acute stress response results in increased circulating levels of cortisol, epinephrine, and norepinephrine. The combined effects of these hormones increase cardiac output blood, blood pressure, and blood flow to vital organs with an increase in circulating levels of glucose (stress hyperglycemia) and lactate levels (stress hyperlactemia). In general, there is a graded response to the degree of stress with cortisol and catecholamine levels correlating with the intensity of the stressor. An intact HPA axis is required to protect the host against diverse stressors (fight-and-flight response) and to ensure survival.

Cortisol Physiology

ACTH stimulates steroidogenesis by binding to the melanocortin-2 receptor on adrenocortical cells. ACTH upregulates expression of this receptor and mediates cholesterol release from lipid droplets. In addition, ACTH activates the expression of genes encoding cholesterol uptake and synthesis as well as key enzymes responsible for cortisol synthesis. Cortisol (hydrocortisone) is the major endogenous glucocorticoid secreted by the adrenal cortex. More than 90% of circulating cortisol is bound to corticosteroid-binding globulin (CBG) with less than 10% in the free, biologically active form. CBG is the predominant binding protein with albumin binding a lesser amount. The adrenal gland does not store cortisol; increased secretion arises because of increased synthesis under the control of ACTH. Cholesterol is the principal precursor for steroid biosynthesis in steroidogenic tissue. In a series of sequential enzymatic steps, cholesterol is converted to pregnenolone and then to the end products of adrenal biosynthesis, namely, aldosterone, dehydroepiandrostenedione, and cortisol. At rest and during stress about 80% of circulating cortisol is derived from plasma cholesterol, the remaining 20% synthesized in situ from acetate and other precursors. High-density lipoprotein (HDL) is the preferred cholesterol source of steroidogenic substrate in the adrenal gland. In healthy individuals the circulating half-life of cortisol varies from 70 to 120 minutes, with a biologic half-life of about 6 to 8 hours. The principal route of cortisol clearance occurs in the liver (through A-ring reductases) and the kidney, where 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts cortisol to cortisone.

The activities of glucocorticoids are mediated by the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). The GR and MR share functional and structural homology. Aldosterone and glucocorticoid hormones bind to the GR and MR. At low basal levels cortisol binds to the high-affinity, low-capacity MR. However, with increased cortisol secretion the MRs are saturated and cortisol then binds to the low-affinity, high-capacity GR. In addition, the 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes play an important role in preventing glucocorticoid access to cells that express the MR. This enzyme has two isoforms, a NAD+-dependent form (11β-HSD-2) and a NADP+ dependent form (11β-HSD-1). 11β-HSD-2 is found in tissues with high levels of MR activity such as the kidney, sweat and salivary glands, placenta, and colon. 11β-HSD-2 converts cortisol to cortisone, its inactive reduced metabolite, which is unable to bind to the GR and MR. 11β-HSD-1, which is found in glucocorticoid target tissues, catalyzes the conversion of cortisone to the active glucocorticoid cortisol.

Cortisol diffuses rapidly across cell membranes binding to the GR. Two isoforms of the GR have been isolated, namely GR-α and GR-β. The GR-β isoform fails to bind cortisol and activate gene expression and thus functions as a negative inhibitor of GR-α. Seven isoforms of GR-α have been reported; these isoforms may be selectively expressed by different tissues with each isoform eliciting a distinct response. Through the association and disassociation of chaperone molecules the glucocorticoid-GR-α complex moves into the nucleus, where it binds as a homodimer to DNA sequences called glucocorticoid-responsive elements (GREs) located in the promoter regions of target genes, which then activate or repress transcription of the associated genes. In addition, the cortisol-GR complex may affect cellular function indirectly by binding to and modulating the transcriptional activity of other nuclear transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). Overall, glucocorticoids affect the transcription of thousands of genes in every cell of the body. It has been estimated that glucocorticoids affect 20% of the genome of mononuclear blood cells.

Cortisol has several important physiologic actions on metabolism, cardiovascular function, and the immune system. Cortisol increases the synthesis of catecholamines and catecholamine receptors, which are partially responsible for its positive inotropic effects. In addition, cortisol has potent antiinflammatory actions, including the reduction in number and function of various immune cells, such as T and B lymphocytes, monocytes, neutrophils, and eosinophils at sites of inflammation. Cortisol is the most important inhibitor of the transcription of proinflammatory mediators (inhibits NF-κB and AP-1 by multiple mechanisms).

Hypothalamic-Pituitary-Adrenal Axis in Critical Illness

Classically the stress response is short lived, allowing the host to successfully deal with the acute threat, after which the stress response rapidly dissipates with cortisol and catecholamine levels returning to baseline. Critically ill and injured patients, however, have a prolonged stress response that may last for weeks. It previously has been assumed that the stress response of critical illness was an extension of the acute stress response. However, recent data suggest that the chronic stress response differs qualitatively and quantitatively from the acute stress response. Although the changes of the hypothalamic-pituitary-thyroid axis with critical illness have been well characterized (euthyroid sick syndrome), the changes of the HPA axis have been less well studied. Furthermore, although a number of studies have evaluated the HPA axis early in the course of critical illness (i.e., on ICU admission), very few studies have investigated the temporal trends of CRH, ACTH, and cortisol over time. These studies have demonstrated that the pattern of the HPA activation during critical illness differs considerably from the classic short-lived acute stress response. Most strikingly there appears to be a dissociation between the serum cortisol and ACTH levels, known as the “cortisol-ACTH dissociation.” In addition, there is a marked hourly variability in plasma cortisol levels with loss of the circadian rhythm. Annane et al. performed a cosyntropin stimulation and metyrapone test within 24 hours of ICU admission in critically ill patients with sepsis, critically ill patients without sepsis, and healthy volunteers. In this study the mean basal cortisol was 17.8 ug/dL, 27.8 ug/dL, and 12.6 ug/dL, respectively, whereas the simultaneous ACTH levels were 8 pg/mL, 6 pg/mL and 33 pg/mL, respectively. This study demonstrated that, although the basal cortisol was elevated in the majority of critically ill patients, the ACTH levels were subnormal. In addition, the basal cortisol levels were lower in the critically ill septic as compared with nonseptic patients.

Only a few studies have evaluated the course of serum cortisol and ACTH levels over time. Vermes et al. measured the cortisol and ACTH levels daily for 8 days in 30 critically ill patients and 15 matched hospitalized controls. The plasma cortisol levels were elevated in the critically ill patients and remained high during the whole observation period. In contrast, plasma ACTH levels decreased between days 3 and 5, reaching significantly lower levels on day 5 compared with those in the control group. Vassiliadi et al. measured cortisol, ACTH, and stimulated cortisol levels every 3 to 4 days until day 30, recovery, or death in 51 critically ill patients with sepsis. In this study basal cortisol was elevated and remained elevated throughout the duration of the study. The ACTH levels, however, were low on presentation and normalized after day 10. In the most comprehensive study to date, Boonen et al. evaluated the time course of the HPA axis and cortisol metabolism over 7 days in 158 ICU patients. Similar to the study of Vassiliadi et al., plasma cortisol levels were elevated on presentation and remained elevated over the 7 days of the study; however, ACTH levels were reduced on presentation (lower than controls) and tended to increase over the next 6 days. This dissociation between ACTH and cortisol suggested that non–ACTH-mediated mechanisms regulate cortisol availability during critical illness. The authors of this study quantified cortisol production with the use of the deuterated cortisol tracer technique in addition to evaluating cortisol metabolism. This analysis demonstrated that daytime cortisol production was only twice that of healthy subjects, whereas cortisol breakdown was reduced substantially, which resulted in a fivefold longer half-life of cortisol.

The calculated plasma clearance after the administration of 100 mg of hydrocortisone was 60% lower in patients than in controls. Furthermore, patients with a cortisol response to corticotropin less than 21ug/dL had a substantially reduced plasma clearance of cortisol than patients with a normal response to corticotrophin. The reduced cortisol breakdown was explained by suppressed expression and activity of A-ring reductases in the liver and by suppressed activity of 11β-HSD2 in the kidney. The results of this study suggest that impaired cortisol clearance contributes to the increased cortisol levels found during critical illness. It is postulated further that the increased cortisol levels via negative feedback inhibit ACTH release accounting for the low ACTH levels. The increased cortisol levels do not appear to be due to increased adrenocortical sensitivity to ACTH. In addition, these authors have demonstrated that pulsatile ACTH secretion was 31% lower in critically ill patients than controls, largely because of decreased ACTH burst mass.

ACTH levels are subnormal during critical illness and ACTH plays an important role in steroidogenesis and has tropic effects on the adrenal cortex. Therefore it has been postulated that the low ACTH levels would lead to atrophy of the adrenal gland and decreased ACTH responsiveness. Boonen et al. harvested the adrenal glands from long-stay ICU patients, short-stay ICU patients, and controls within 24 hours of their death. These authors demonstrated 78% less cholesterol ester and at least 58% less mRNA expression of ACTH-regulated steroidogenic enzymes in the long-stay ICU patients as compared with the controls and short-stay patients. This finding may contribute to “relative adrenal insufficiency,” which may occur in chronically critically ill patients.

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