PHYSIOLOGY

The adrenal glands are functionally divided into medulla and cortex; the cortex is responsible for the secretion of three major classes of hormones: glucocorticoids, mineralocorticoids and sex hormones. The major pathogenic effects of disease result from cortisol and aldosterone deficiency.

Cortisol, the major glucocorticoid synthesised by the adrenal cortex, plays a pivotal role in normal metabolism. It is necessary for the synthesis of adrenergic receptors, normal immune function, wound healing and vascular tone. These actions are mediated by the glucocorticoid receptor, a member of the nuclear hormone receptor superfamily. The activated receptor migrates to the nucleus and binds to specific recognition sequences within target genes, but also interacts with numerous transcription factors and cytosolic proteins. Numerous isoforms of the glucocorticoids receptor have now been described; the alpha subtype, a 777-amino-acid polypeptide chain, was initially felt to be the primary mediator of glucocorticoid action. In contrast the beta isoform, a 742-amino-acid chain was felt to have no physiological activity. More recently it appears that the beta subtype has a negative effect on alpha-mediated gene transactivation, the physiological relevance of which remains controversial. Furthermore, additional isoforms have now been described, suggesting that glucocorticoid receptor diversity may be an important factor in understanding the complex effects of corticosteroid action.¹

Under normal circumstances, cortisol is secreted in pulses, and in a diurnal pattern.² The normal basal output of cortisol is estimated to be 15–30 mg/day, producing a peak plasma cortisol concentration of 110–520 nmol/l (4–19 μµg/dl) at 8–9 a.m., and a minimal cortisol level of < 140 nmol/l (< 5 μµg/dl) after midnight. The daily output of aldosterone is estimated to be 100–150 μg/day.

Secretion is under the control of the hypothalamic–pituitary axis. There are a variety of stimuli to secretion, including stress, tissue damage, cytokine release, hypoxia, hypotension and hypoglycaemia. These factors act upon the hypothalamus to favour the release of corticotrophin-releasing hormone (CRH) and vasopressin. CRH is synthesised in the hypothalamus and carried to the anterior pituitary in portal blood, where it stimulates the secretion of adrenocorticotrophic hormone (ACTH), which in turn stimulates the release of cortisol, mineralocorticoids (principally aldosterone) and androgens from the adrenal cortex. CRH is the major (but not the only) regulator of ACTH release and is secreted in response to a normal hypothalamic circadian regulation and various forms of ‘stress’. Vasopressin, oxytocin, angiotensin II and β-adrenergic agents also stimulate ACTH release while somatostatin, β-endorphin and enkephalin reduce it. Cortisol has a negative feedback on the hypothalamus and pituitary, inhibiting hypothalamic CRH release induced by stress, and pituitary ACTH release induced by CRH. During periods of stress, trauma or infection, there is an increase in CRH and ACTH secretion and a reduction in the negative-feedback effect, resulting in increased cortisol levels, in amounts roughly proportional to the severity of the illness.³^–⁵

The majority of circulating cortisol is bound to an α-globulin called transcortin (corticosteroid-binding globulin, CBG). At normal levels of total plasma cortisol (e.g. 375 nmol/l or 13.5 μµg/dl) less than 5% exists as free cortisol in the plasma; however it is this free fraction that is biologically active. Circulating CBG concentrations are approximately 700 nmol/l. In normal subjects CBG can bind approximately 700 nmol/l (i.e. 25 µg/dl).⁶ At levels greater than this, the increase in plasma cortisol is largelyin the unbound fraction. The affinity of CBG for synthetic corticosteroids, with the exception of prednisolone, is negligible. CBG is a substrate for elastase, a polymorphonuclear enzyme that cleaves CBG, markedly decreasing its affinity for cortisol.⁷ This enzymatic cleavage results in the liberation of free cortisol at sites of inflammation. CBG levels have been documented to fall during critical illness,⁸^–¹⁰ and these changes are postulated to increase the amount of circulating free cortisol.

Cortisol has a half-life of 70–120 minutes. It is primarily eliminated by hepatic metabolism and glomerular filtration. The excretion of free cortisol through the kidney represents 1% of the total secretion rate. Currently, available routine assays measure only total cortisol levels – bound and free.

The metabolic effects of cortisol are complex and varied. In the liver, cortisol stimulates glycogen deposition by increasing glycogen synthase and inhibiting the glycogen-mobilising enzyme glycogen phosphorylase.¹¹ Hepatic gluconeogenesis is stimulated, leading to increased blood glucose levels. Concurrently, glucose uptake by peripheral tissues is inhibited.¹² Free fatty acid release into the circulation is increased, and triglyceride levels rise.

In the circulatory system, cortisol increases blood pressure both by direct actions upon smooth muscle, and via renal mechanisms. The actions of pressor agents such as catecholamines are potentiated, whilst nitric oxide-mediated vasodilation is reduced.^13,¹⁴ Renal effects include an increase in glomerular filtration rate, and sodium transport in the proximal tubule, and sodium retention and potassium loss in the distal tubule.¹⁵

The primary effects of cortisol upon the immune system are anti-inflammatory and immunosuppressive. Lymphocyte cell counts decrease, whilst neutrophil counts rise.¹⁵ Accumulation of immunologically active cells at inflammatory sites is decreased. The production of cytokines is inhibited, an effect that is mediated via nuclear factor (NF)-κB. This occurs both by induction of NF-κB inhibitor and by direct binding of cortisol to NF-κB, thus preventing its translocation to the nucleus. Whilst the well-defined effects of cortisol upon the immune system are primarily inhibitory, it is also suggested that normal host defence function requires some cortisol secretion. Cortisol has been described as having a positive effect upon immunoglobulin synthesis, potentiation of the acute-phase response, wound healing and opsonisation.¹⁶

CLASSIFICATION

AI may be considered to be primary, secondary or relative. Primary AI, otherwise known as Addison’s disease, results from hypofunction of the adrenal cortex. Secondary AI occurs when there is suppression or absence of ACTH secretion from the anterior pituitary. RAI describes a situation of inadequate cortisol response to stress in the setting of critical illness.

PRIMARY ADRENAL INSUFFICIENCY

Primary AI or Addison’s disease is a rare disorder. In the western world its estimated prevalence is 120 per million.¹⁷ In adulthood, the commonest cause is autoimmune, but in the intensive care setting, consideration should be given to other causes of adrenal gland destruction (Table 53.1). These include infection, haemorrhage and infiltration. Tuberculosis is the commonest infective cause worldwide, but rarer infections such as histoplasmosis, coccidiomycosis and cytomegalovirus (especially in patients with human immunodeficiency virus (HIV)) have also been implicated. Haemorrhage into the glands is associated with septicaemias, particularly meningococcal (Waterhouse–Friedrichsen syndrome). Asplenia and the antiphospholipid syndrome may also be associated with adrenal haemorrhage. Adrenal gland destruction may also be secondary to infiltration with tumour, or amyloid.

Table 53.1 Causes of primary adrenal insufficiency