Chapter 77: Adrenal Insufficiency

• Adrenal insufficiency (AI) results from deficiency of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) secreted by the adrenal cortex.

• Glucocorticoid deficiency impairs gluconeogenesis and glycogenolysis, resulting in fasting hypoglycemia.

• Aldosterone deficiency results in decreased sodium retention by the kidney and distal renal tubular exchange of potassium and hydrogen ions for sodium, resulting in osmotic diuresis, hyponatremia, hypovolemia, hyperkalemia, acidosis, and prerenal azotemia.

• AI is classified into primary (adrenocortical failure itself), secondary (pituitary), or tertiary (hypothalamic) types. AI, because of withdrawal from exogenous steroid administration, is the most common cause of adrenal crisis.

• Symptoms of AI are usually nonspecific such as fatigue, anorexia, abdominal pain, nausea, or diarrhea but it can present as cardiovascular collapse or shock and hence a high index of suspicion is required.

• The most common cause of primary AI in infants is congenital adrenal hyperplasia (CAH).

• Acquired causes of primary AI in children are less common than congenital disorders.

• Acquired AI results from autoimmune, infectious, infiltrative, hemorrhagic, or toxic causes.

• Acute management consists of rapid fluid resuscitation, correction of hypoglycemia, hyperkalemia, and acidosis and stress doses of hydrocortisone (50–75 mg/m² IV).

The adrenal cortex produces two main hormones: glucocorticoid (cortisol) and mineralocorticoid (aldosterone). Adrenal insufficiency (AI) results from deficiency of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) secreted by the adrenal cortex.

Glucocorticoid deficiency impairs gluconeogenesis and glycogenolysis, resulting in fasting hypoglycemia.

Aldosterone deficiency results in decreased sodium retention by the kidney and distal renal tubular exchange of potassium and hydrogen ions for sodium, resulting in osmotic diuresis, hyponatremia, hypovolemia, hyperkalemia, acidosis, and prerenal azotemia.

AI is classified into primary (adrenocortical failure itself), secondary (pituitary), or tertiary (hypothalamic) types. AI, because of withdrawal from exogenous steroid administration, is the most common cause of adrenal crisis.

Symptoms of AI are usually nonspecific such as fatigue, anorexia, abdominal pain, nausea, or diarrhea but it can present as cardiovascular collapse or shock and hence a high index of suspicion is required.

The most common cause of primary AI in infants is congenital adrenal hyperplasia (CAH).

Acquired causes of primary AI in children are less common than congenital disorders.

Acquired AI results from autoimmune, infectious, infiltrative, hemorrhagic, or toxic causes.

Primary AI results from congenital or acquired adrenal gland dysfunction. Secondary and tertiary AI result from pituitary or hypothalamic underfunction, respectively. Glucocorticoid deficiency impairs gluconeogenesis and glycogenolysis, and decreases the sensitivity of the vascular system to angiotensin II and norepinephrine, resulting in hypoglycemia, tachycardia, and mild hypotension. Aldosterone deficiency causes decreased sodium retention by the kidney, osmotic diuresis, hyponatremia, hypovolemia, and dehydration. In addition, it causes a decreased distal renal tubular exchange of potassium and hydrogen ions for sodium ions, leading to hyperkalemia and acidosis. Androgen deficiency in primary AI leads to ambiguous genitalia and underdeveloped secondary sexual characteristics in prepubertal children. In addition, in primary AI, the lack of negative feedback from cortisol on the anterior pituitary causes oversecretion of ACTH and propiomelanocortin that in turn stimulate skin hyperpigmentation (Fig. 77-1).

Etiology and Epidemiology

One of the most common causes of AI in North America is the abrupt withdrawal of glucocorticoids while on chronic treatment.¹ Children, who have been on glucocorticoid therapy for 2 to 4 weeks, tend to have prolonged suppression of the hypothalamopituitary axis leading to secondary AI after treatment is stopped.² The most common cause of primary AI in children is CAH, with an incidence of 1 in 10,000 to 18,000 live births.³ In long-term studies of children with AI, most have primary AI and, of these, approximately 72% are found to have CAH.^4,5

CAH results from a deficiency in the enzymatic activity of one of the enzymes in the cortisol biosynthetic pathway, the commonest being 21-hydroxylase deficiency. Mortality for CAH is five times that of the general population. This has improved with the present recommendation for universal screening of newborns.^6,7 Other rarer forms of congenital primary AI are congenital adrenal hypoplasia, adrenal aplasia or hemorrhage associated with a traumatic delivery,⁸ familial isolated glucocorticoid deficiency, the “triple A syndrome,” consisting of AI, alacrima, and achalasia of the esophagus, and adrenoleukodystrophy (ALD) (Table 77-1).

Acquired causes of primary AI in children are less common than congenital disorders and result from autoimmune, infectious, infiltrative, hemorrhagic, or ablative disorders of the adrenal cortex. Granulomatous, degenerative, or storage diseases that involve the adrenal gland, such as tuberculosis, histoplasmosis, or lysosomal acid lipase deficiency (Wolman disease), also cause acquired primary AI. The most common cause of this is autoimmune adrenalitis, which accounts for 80% of all cases. Catecholamine resistant shock and low plasma cortisol levels may indicate acute AI in fulminating sepsis or meningococcemia.^9–11

Secondary AI that is not due to pharmacologic glucocorticoid withdrawal can result from any process that interferes with the pituitary's ability to secrete ACTH, such as tumors, craniopharyngioma, infections, infiltrative diseases of the pituitary, lymphocytic hypophysitis, head trauma, and intracranial aneurysms (Table 77-1). Most of these coexist with other pituitary hormone deficiencies and there is history of pituitary insult or abnormality of the hypothalamopituitary axis on MRI.¹²

AI can present with vague and nonspecific symptoms (Table 77-2) and the diagnosis is delayed in many cases.⁵ Acute insufficiency or Addison's crisis is typically encountered in a previously undiagnosed child who has been subjected to the stress of an acute illness, inadequate administration of stress steroid dosing in known cases, or abrupt withdrawal in the context of prolonged corticosteroid therapy. In all these clinical situations, the presentation is characterized by dehydration, hypotension, hypoglycemia, or altered sensorium. Hypoglycemia occurs most commonly in young children.

Physical clues to AI include hyperpigmentation of the face, neck, hands, areas subject to friction such as elbows, knees, and knuckles, the buccal mucosa, areolae, scars, and moles (Fig. 77-2).¹³ Other skin findings are vitiligo, secondary to autoimmune melanocyte destruction, and chronic mucocutaneous candidiasis, as part of autoimmune polyendocrinopathy type 1. In the absence of history of corticosteroid withdrawal, secondary AI is usually associated with signs of other pituitary hormone deficiencies such as growth failure, delayed puberty, secondary hypothyroidism, and diabetes insipidus.¹³ In the rare case of missed neonatal screening for CAH, ambiguous genitalia may be present (Fig. 77-3).

Laboratory findings and common abnormalities of AI are based on the pathophysiology (Fig. 77-1) and summarized in Table 77-2 above. The diagnosis of primary AI is confirmed by the documentation of an elevated plasma ACTH level (>100 pg/mL) and a low serum cortisol level (<10 μg/dL).¹³ Mineralocorticoid deficiency is confirmed by documentation of low aldosterone levels associated with hypereninemia with or without hyperkalemia and hyponatremia.¹³ Secondary AI is diagnosed by documenting simultaneously low blood ACTH and cortisol levels.

The differential diagnosis of acute AI must include all causes of hyponatremia, hyperkalemia, ketotic hypoglycemia, and shock and is summarized in Table 77-3.

Recognizing adrenal crisis immediately requires a high index of suspicion and is warranted in children presenting with unexplained shock and hypoglycemia. Stabilize the patient's airway, place on continuous cardiac monitoring, and start fluid resuscitation with 5% dextrose and normal saline. If sepsis is suspected, obtain appropriate culture samples and administer antibiotics. If there is no previous history of AI, prior to specific treatment, collect a critical blood sample for ACTH, cortisol, aldosterone, and plasma renin activity. If CAH is suspected, request 17-hydroxyprogesterone and androgen levels. Correction of specific disturbances such as hypoglycemia, hypokalemia, and the administration of stress doses of hydrocortisone are outlined in the clinical pathway in Figure 77-4.

Admit all patients presenting to an emergency department in acute adrenal crisis to the pediatric intensive care unit for continued parenteral fluid replacement and steroid maintenance therapy. Consult a pediatric endocrinologist for further inpatient evaluation, management, and continuity of care. Children with known AI and mild symptoms may be managed as an outpatient with consultation and close follow-up with their pediatric endocrinologist.