The adrenal gland is responsible for producing two kinds of signaling molecules: steroid hormones, produced in the outer adrenal cortex, and catecholamines, generated in the adrenal medulla. Steroids can further be divided into mineralocorticoid (aldosterone), glucocorticoid (cortisol) and androgen (dehydroepiandrosterone [DHEA] and dehydroepiandrosterone-sulfate [DHEA-S]) classes. Each of these steroids is stereotypically produced by histologically differentiable cells in a particular layer of the adrenal cortex—the outermost zona glomerulosa produces aldosterone, the middle zona fasciculata produces cortisol, and the innermost zona reticularis produces DHEA and DHEA-S. Control of steroid hormone production and release, however, occurs outside of the adrenal gland; aldosterone is primarily controlled by the renin-angiotensin system and cortisol is regulated by adrenocorticotropic hormone (ACTH) from the pituitary gland, which itself is regulated by hypothalamic secretion of corticotropin-releasing hormone (CRH). Although DHEA-S is the most abundant androgen in serum, the control and function of DHEA and DHEA-S are less well understood.

Similar to the rest of the endocrine system, each of the steroid hormones produced by the adrenal gland can be pathologically elevated or pathologically absent. Specific to steroid producing tissues, two additional types of pathologies occur in the adrenal gland. The first is a defect in enzymatic activity leading to the absence of one steroid and to overproduction of a precursor steroid, with predictable off-target effects (e.g. congenital adrenal hyperplasia). The second defect is an alteration of timing of steroid production/release (e.g. premature adrenarche).

HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

Hypothalamic CRH stimulates pituitary ACTH secretion. ACTH regulates adrenal glucocorticoid secretion and is secreted in a pulsatile fashion with amplitude that normally varies as a function of the time of day. This variation is the cause of the diurnal pattern of cortisol secretion. Cortisol secretion is highest early in the morning prior to waking, decreased in the afternoon to evening, and lowest at midnight, or 2 hours after sleep. Negative feedback on the synthesis and secretion of ACTH and CRH is provided by cortisol.¹ In addition to this seemingly simple feedback loop, inflammation, via interleukin-6, stimulates ACTH production leading to cortisol secretion.

ADRENAL CORTEX

Mineralocorticoids maintain electrolyte equilibrium, stabilizing blood volume and blood pressure. They control sodium reabsorption in exchange for potassium in the distal tubule of the kidney. Glucocorticoids are “stress hormones,” and thus they have metabolic activities increasing glucose availability in seemingly counterintuitive ways. They have catabolic effects—increasing protein degradation in muscle, skin, and peripheral adipose tissue, and anabolic effects—enhancing the ability for gluconeogenesis at the liver and increasing central fat storage. In addition, glucocorticoids are permissive for the vasoconstrictive actions of catecholamines.¹ Synthetic analogues of glucocorticoids demonstrate variable anti-inflammatory/gluconeogenic activity, and have variable salt-retaining properties. Androgens promote the growth of pubic and axillary hair.

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

Aldosterone production and secretion is regulated by renin, and to a lesser degree, serum potassium levels.² Renin is produced in the juxtaglomerular apparatus of the kidney and causes the production of angiotensin I. Angiotensin-converting enzyme converts angiotensin I to angiotensin II, which is cleaved to angiotensin III. Angiotensin II and III are potent stimulators of aldosterone synthesis and secretion. A decrease in sodium, blood volume, arterial pressure, and renal blood flow activates the juxtaglomerular apparatus and leads to an increase in renin and thus aldosterone. Increased potassium concentration directly increases aldosterone secretion by the adrenal cortex.

ADRENAL MEDULLA

The medulla produces catecholamines such as dopamine, norepinephrine, and epinephrine. Synthesis of catecholamines also occurs in the brain and sympathetic nerve endings and in chromaffin cells outside of the medulla. The catecholamine metabolites found in urine include vanillylmandelic acid (VMA) and metanephrine.

PATHOPHYSIOLOGY

Adrenal steroid hormones are classically thought to mediate their effects via their respective nuclear-receptor family receptors, with aldosterone acting through the mineralocorticoid receptor (MR) and cortisol acting through the glucocorticoid receptor. As noted above, aldosterone has a critical role in salt and water balance, while glucocorticoids have critical roles in metabolism and maintenance of vascular tone. Absence of each or both of these hormones therefore has predictable effects. Isolated absence of aldosterone leads to sodium wasting and hyperkalemia. Similarly, isolated cortisol deficiency (e.g. central adrenal insufficiency) leads to hypotension and risk for hypoglycemia. The context of this simple picture of adrenal insufficiency complicates its pathology in two ways: first, the context can add other non-adrenal problems (e.g. hypothyroidism in panhypopituitarism) and second, if adrenal insufficiency is due to absence of a steroidogenic enzyme, overproduction of cortisol precursors can lead to increases in androgen activity or mineralocorticoid activity. The most common form of congenital adrenal hyperplasia (CAH), 21-hydroxylase deficiency, is characterized by salt-wasting in its severe form. However, in 11-β-hydroxylase deficiency, initial salt wasting is usually mild. Lack of negative feedback through the glucocorticoid receptor at the levels of the hypothalamus and pituitary by cortisol paradoxically leads to excess mineralocorticoid activity and consequent elevation in sodium and hypertension. Thus different forms of CAH exert their effects variably due to altered androgen (usually increased) and mineralocorticoid (sometimes increased, and in other cases decreased) activity. There are not as of yet clinically described deficiencies in DHEA, DHEA-S, or adrenal catecholamines.

CLINICAL PRESENTATION

The clinical manifestations and age at onset of adrenal insufficiency depend on its cause. Presentation at birth or soon after is seen with adrenal hypoplasia, defects in steroidogenesis, and pseudohypoaldosteronism. In these diseases, patients present with symptoms of salt wasting and failure to thrive, vomiting, lethargy, anorexia, and dehydration. In older children, adrenal insufficiency caused by Addison disease presents with muscle weakness, lassitude, anorexia, weight loss, wasting, hypotension, and abdominal pain.

An adrenal crisis may present with hypoglycemia, hypotension, cyanosis, cold skin, and/or a weak, rapid pulse. In disorders associated with excess ACTH (e.g. congenital adrenal hypoplasia, CAH, Addison disease, adrenoleukodystrophy, and ACTH resistance), there can be hyperpigmentation of the skin and oral mucosa as a result of increased melanocyte-stimulating hormone (MSH) levels.

Because cortisol signaling is permissive for catecholamine action, the hypotension is particularly challenging to manage as it is classically nonresponsive to catecholamines or fluid resuscitation, and can be fatal.

The clinical features of CAH are determined by the specific enzyme deficiency and include virilized female for deficiencies in 21-hydroxylase and 3β-hydroxysteroid dehydrogenase (3β-HSD) and undervirilized males as seen in cholesterol desmolase and 3β-HSD deficiencies. Deficiencies of either 11-hydroxylase or 17-hydroxylase deficiencies may present with ambiguous genitalia but not with symptoms of adrenal insufficiency.

DIFFERENTIAL DIAGNOSIS

Because adrenal insufficiency presents primarily with lethargy, hypotension, dehydration, or hypoglycemia, the differential diagnosis is broad for these patients. Other diseases that may present acutely with these symptoms include sepsis, severe or longstanding diarrhea, or hyperinsulinism. Classically, we think of hyperinsulinism and diarrhea resulting in severe dehydration presenting in infancy. In the absence of crisis, adrenal insufficiency may present as decreased exercise tolerance or lethargy, particularly in the afternoon, and/or muscle aches or nonspecific complaints. The differential for this presentation is broad, but also includes, notably, hypothyroidism as well as depression.

Once the diagnosis of adrenal insufficiency is made, the specific cause needs to be established. Adrenal insufficiency can be due to abnormalities of the hypothalamus, pituitary, and adrenal cortex (Table 72-1). Hypothalamic and pituitary deficiencies are discussed in a separate chapter. Familial glucocorticoid deficiency, or ACTH resistance, is an autosomal recessive disorder in which there is an isolated deficiency of glucocorticoid. In this disease aldosterone production is normal and there is no salt wasting. In Allgrove syndrome (triple A syndrome), ACTH resistance may occur in association with achalasia and alacrima.

The most common cause of adrenocortical insufficiency is salt-losing CAH, or 21-hydroxylase deficiency, it accounts for 90% to 95% of CAH and occurs in roughly 1 in 13,000 live births. Lipoid adrenal hyperplasia and 3β-HSD deficiency are less common forms of CAH, in which both cortisol and aldosterone are deficient.

Isolated deficiency of aldosterone is a rare autosomal recessive disorder. Pseudohypoaldosteronism occurs when there is target organ unresponsiveness to aldosterone. It can be limited to the kidney or may involve multiple target organs (sweat glands, salivary glands, and colon). Both autosomal dominant and autosomal recessive inheritance has been reported.