Disorders of the Adrenal Gland

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70 Disorders of the Adrenal Gland

The adrenal gland is really two separate organs: the adrenal medulla secretes epinephrine and norepinephrine, and the adrenal cortex secretes glucocorticosteroids, mineralocorticoids, and androgenic steroids. Glucocorticoids and mineralocorticoids are essential for maintaining metabolic homeostasis, particularly during times of stress; deficiency of these hormones can be life threatening if not recognized and treated. Conversely, excess of any of these hormones, although unusual, can lead to severe and permanent consequences. Accordingly, it is critically important to recognize disordered adrenal function and to institute treatment expediently. This chapter focuses on the physiology and pathology of the adrenal cortex.

Adrenal Gland Physiology

The adrenal cortex consists of three distinct zones, the glomerulosa, the fasciculata, and the reticularis. The fasciculata is the principal component of the hypothalamic–pituitary–adrenal axis. Glucocorticoid (cortisol) secretion from the fasciculata is regulated by adrenocorticotropic hormone (ACTH). ACTH is synthesized from pre-pro-opiomelanocortin (pre-POMC). The removal of the signal peptide during translation produces the 267 amino acid polypeptide POMC, which undergoes a series of posttranslational modifications to yield various polypeptide fragments with varying physiological activity. These fragments include the 39 amino acid polypeptide ACTH, as well as β-lipotropin, γ-lipotropin, melanocyte-stimulating hormone (α-MSH), and β-endorphin. POMC, ACTH and β-lipotropin are secreted from corticotropes in the anterior lobe of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH) released by the hypothalamus (Figure 70-1).

Figure 70-1 Regulation of adrenal hormones.

A reduction in circulating cortisol levels activates this axis, leading to increased secretion of ACTH; high levels of cortisol or exogenous steroids downregulate the axis and reduce secretion of adrenal cortisol. Aldosterone is produced in the zona glomerulosa under independent control through the renin–angiotensin system. Low blood pressure and intravascular volume contraction lead to renin release from the kidney, activating this system.

Functions of Adrenal Hormones

Cortisol plays important roles in cardiovascular stability (maintaining blood pressure by increasing the sensitivity of the vasculature to the vasoconstrictive effects of epinephrine and norepinephrine), metabolism (increasing gluconeogenesis to prevent hypoglycemia), and fluid and electrolyte balance (sodium retention and potassium excretion). It also inhibits bone formation and is a potent antiinflammatory agent (Figure 70-2).

Figure 70-2 Actions of cortisol.

Aldosterone acts on the distal tubules and collecting ducts of the kidney to increase conservation of sodium and water, secrete potassium, and increase blood pressure. Adrenal androgens produced in the zona reticularis play a role in pubarche and the development of secondary sexual characteristics (i.e., pubic hair) in both males and females during puberty (see Chapter 67).

Adrenal Insufficiency

Primary adrenal insufficiency is caused by congenital or acquired dysfunction of the adrenal cortex or the hormone-producing steroidogenic pathway (Table 70-1). The most common cause in the developed world is autoimmune adrenalitis, also known as Addison’s disease. In developing countries, tuberculosis remains the most prominent cause. Destruction of the gland leads to deficiencies in all adrenal cortex hormones, but this process may be metasynchronous, and not all hormones are lacking in all patients. Enzyme defects can cause cortisol deficiency with an excess of precursor hormones. Loss of negative feedback from low cortisol levels leads to high ACTH in these disorders.

Table 70-1 Causes of Primary Adrenal Insufficiency

Cause	Associations or Pathogenesis	Diagnosis
Acquired
Addison’s disease	Other autoimmune disease	Adrenal antibodies
Autoimmune polyglandular syndrome	Type 1: hypoparathyroidism and mucocutaneous candidiasis Type 2: type 1 diabetes, thyroiditis, other autoimmune	AIRE gene mutation in type 1
Infiltration or infection	TB, fungal, cancer, amyloidosis, sarcoid, hemochromatosis, CMV (HIV patients)	PPD, cultures, imaging, biopsy, ELISA or Western blot
Waterhouse-Friderichsen syndrome	Meningococcemia leading to adrenal hemorrhage	Cultures
Bilateral hemorrhage	Trauma, anticoagulants	Imaging
Medications: mitotane, ketoconazole	Destruction of gland, enzyme blockage	History
Congenital
CAH	Autosomal recessive; mutation of 21-hydroxylase and others	Adrenal steroid profiles, genetic testing CYP21
Adrenoleukodystrophy; adrenomyeloneuropathy	X-linked; buildup of VLCFAs in adrenals and cerebral or spinal cord involvement; neuromuscular disease	Serum VLCFAs; ALD gene
X-linked congenital adrenal hypoplasia	Delayed puberty, contiguous gene mutations (Duchenne’s muscular dystrophy, glycerol kinase)	DAX1 gene testing
Triple A syndrome	Autosomal recessive; achalasia, alacrima, adrenal insufficiency	AAAS gene at 12q13
Other syndromes: IMAGE, Smith-Lemli-Opitz	Vary	Genetic testing
ACTH resistance	ACTH receptor or melanocortin 2 receptor accessory protein (MRAP) gene mutations	Genotyping of receptor or MRAP genes

ACTH, adrenocorticotropic hormone; CAH, congenital adrenal hyper-plasia; CMV, cytomegalovirus; ELISA, enzyme-linked immunosorbent assay; HIV, human immunodeficiency virus; IMAGE, intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, genital abnormalities; PPD, purified protein derivative; TB, tuberculosis; VLCFA, very long chain fatty acid.

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency reflects a defect in the pituitary or hypothalamic (central) regions that impair secretion of ACTH. Central adrenal insufficiency most commonly occurs in patients with congenital or acquired pituitary defects that arise as a consequence of surgery, trauma, radiation, hemorrhage, infiltrative disease, genetic mutation, or structural defect. Patients may have isolated ACTH deficiency or multihormonal deficiency (panhypopituitarism). Although the adrenal gland is essentially normal, lack of appropriate stimulation for hormone synthesis and release can lead to atrophy of the zona fasciculata. Mineralocorticoid secretion remains intact.

Iatrogenic Adrenal Insufficiency

Long-term use of glucocorticoid steroids is a common cause of central adrenal insufficiency. Daily administration of glucocorticoids in doses that exceed normal adrenal production can cause prolonged suppression of the hypothalamic–pituitary–adrenal axis and ultimately atrophy of the adrenal cortex. This occurs most commonly from oral administration of potent glucocorticoids but can also occur from inhaled glucocorticoids or even injection of depot steroids. Slow tapering of the daily dosage over weeks to months may be required before adrenal function recovers; however, until normal function is proven, the patient remains at risk for consequences of adrenal insufficiency during times of stress.

Clinical Presentation

Chronic symptoms of adrenal insufficiency are vague and often unrecognized. Children experience fatigue, malaise, poor weight gain and growth, and anorexia. In primary adrenal insufficiency, pituitary secretion of ACTH is markedly increased and is often associated with hyperplasia of corticotrophic cells in the pituitary. Generalized hyperpigmentation of the skin and buccal mucosa may occur because of generation of α-MSH from ACTH (Figure 70-3).

Figure 70-3 Signs and symptoms of primary adrenal insufficiency and Cushing’s syndrome.

Physical stress can trigger acute adrenal crisis, the most severe manifestations of which are a shocklike syndrome with tachycardia, hypotension, dehydration, and acute abdominal pain that is often mistaken for appendicitis. A distinguishing feature of shock caused by primary adrenal insufficiency is the presence of both hyponatremia and hyperkalemia; in central adrenal insufficiency, aldosterone continues to be produced, and therefore serum levels of potassium remain normal. Other laboratory findings include hypoglycemia, hypercalcemia, acidosis, eosinophilia, and elevated blood urea nitrogen and creatinine.

Many associated signs and symptoms are unique to the specific etiology of adrenal insufficiency. For example, patients may exhibit evidence of autoimmune disease (thyroiditis, vitiligo, type 1 diabetes) with Addison’s disease; hypoparathyroidism and mucocutaneous candidiasis with autoimmune polyendocrinopathy syndromes; neuromuscular dysfunction with adrenoleukodystrophy; and weight loss, fever and pulmonary dysfunction with tuberculosis. In patients with central adrenal insufficiency, the presence of midline facial defects can suggest structural abnormalities of the pituitary, and poor growth or pubertal progression may reflect a more global disorder of the anterior pituitary gland.

Evaluation and Management

Laboratory Studies

In the setting of acute adrenal crisis, evaluation must be performed rapidly so as not to delay administration of life-saving glucocorticoid steroids. An elevated serum level of ACTH and low serum level of cortisol, along with the classic electrolyte abnormalities of hyponatremia and hyperkalemia, are diagnostic of primary adrenal insufficiency. An elevated plasma renin activity level and low aldosterone in the presence of hyponatremia or shock indicate concomitant mineralocorticoid deficiency. Because it takes considerable time to obtain the results of these specialized endocrine tests, it is prudent to draw blood for these hormones and to treat patients for suspected adrenal insufficiency until laboratory studies prove otherwise.

If the test results are equivocal or a patient does not have clinical signs of an acute crisis, it may be necessary to perform stimulation tests with ACTH or CRH. In general, the standard ACTH simulation test is performed with the 23-amino acid synthetic corticotropin (Cortrosyn, 15 µg/kg not to exceed 250 µg) to identify primary adrenal insufficiency, and low-dose Cortrosyn testing (1 µg) is used to diagnose secondary adrenal insufficiency or recovery from adrenal suppression. Serum samples are collected at baseline and 60 minutes after stimulation for measurement of cortisol. CRH stimulation testing can be used to identify adrenal insufficiency caused by a pituitary lesion. Serum cortisol levels have a diurnal variation, with peak levels in the early morning; thus, the basal serum cortisol level at 8 AM is often checked as a screening test for adrenal insufficiency; a level greater than 12 µg/dL suggests normal cortisol production. In interpreting these tests, it is important to remember that the circadian rhythm for cortisol secretion is not established until a few months of life. After serum samples have been obtained, patients with suspected adrenal insufficiency should be treated without waiting for results.

Comprehensive analyses to determine the underlying cause of adrenal insufficiency should be pursued after treatment is initiated and the child is stabilized. Common tests include very long chain fatty acids (for adrenoleukodystrophy), adrenal antibodies (for Addison’s disease), genetic testing, purified protein derivative (PPD) placement (for tuberculosis), and HIV testing (for AIDS). For secondary adrenal insufficiency, pituitary imaging and testing for other pituitary deficiencies (growth hormone, thyroid-stimulating hormone, and gonadotropins) is indicated.

Treatment and Prognosis

Treatment of adrenal insufficiency should be pursued in consultation with a pediatric endocrinologist and centers on appropriate replacement of cortisol and aldosterone, when necessary. Treatment is divided into maintenance (daily needs) and stress coverage (for times of illness or other physical stress). Maintenance doses of hydrocortisone are adjusted to provide 8 to 10 mg/m². Tablets should be used and can be crushed and mixed with liquids immediately before administration because commercial suspensions of hydrocortisone are unreliable. In secondary and iatrogenic adrenal insufficiency, the adrenal glands continue to be able to produce modest amounts of hormone; maintenance corticosteroids may not be needed. Symptoms such as abnormal fatigue and lethargy may suggest underdosing, and increased weight gain and decreased height velocity may suggest overdosage. Hydrocortisone is the preferred glucocorticoid because use of apparently equivalent doses of other more potent steroids is often associated with excessive steroid effects.

All patients with proven or assumed adrenal insufficiency should be instructed in the use of stress dose steroids for illness, injury, or other physical stress. Instructions for both oral and intramuscular stress dosing should be given and reviewed at regular intervals. During stress, such as a high fever, triple the maintenance dosage (i.e., 25 mg/m²/d) can be given orally in three divided doses. In the event of vomiting, lethargy, or other conditions precluding oral intake, one recommendation is an intramuscular injection of hydrocortisone at a dose of 100 mg/m². In these cases, the child should be brought to the hospital for evaluation. In hospital settings, stress coverage for surgery or critical illness consists of 100 mg/m² of hydrocortisone intravenously or intramuscularly and then 100 mg/m²/d intravenously divided every 6 hours until recovery, at which time maintenance doses can be resumed. For a child presenting in extremis with suspected adrenal insufficiency, baseline diagnostic laboratory studies should be obtained immediately and resuscitation initiated with isotonic fluids and glucocorticoid steroids.

Cushing’s Syndrome

Etiology and Pathogenesis

Glucocorticoid excess caused by oversecretion of ACTH from a pituitary corticotrope adenoma is called Cushing’s disease. Cushing’s syndrome is a general term for glucocorticoid excess of any nonpituitary cause, including ectopic ACTH production, adrenal disease, and exogenous glucocorticoid use.

Clinical Presentation

The signs and symptoms of Cushing’s syndrome include weight gain, growth failure, fatigue, hypertension, glucose intolerance, and delayed puberty (see Figure 70-3). Osteopenia, acne, plethora, hirsutism, a dorsocervical fat pad (“buffalo hump”), and striae can occur. Hyperandrogenism and virilization can indicate an adrenal carcinoma.

A diagnosis of exogenous Cushing’s syndrome may be obvious in a patient with a long history of glucocorticoid use. Exogenous obesity and monogenic or syndromic obesity must sometimes be differentiated from Cushing’s disease.

Evaluation and Management

Documenting a loss of diurnal rhythm of cortisol secretion or excessive production of cortisol supports the diagnosis of Cushing’s syndrome. This can be documented through a 24-hour urine collection and measurement of free cortisol (reference range, <40-50 µg/d), an 11 PM salivary cortisol determination (reference range, <4.2 nmol/L), or measurement of serum cortisol before 9 AM after administration of 1 mg of dexamethasone at 11 PM the evening before (reference range, <1.8 µg/dL). Abnormal results should be confirmed by repeating one or more of these tests. ACTH measurements should be performed, and a high dose dexamethasone test can be used to distinguish between ACTH-dependent and ACTH-independent Cushing’s syndrome. Pituitary magnetic resonance imaging (MRI) with gadolinium can be used to visualize small adenomas. Adrenal masses can be identified using ultrasonography or abdominal computed tomography (CT). In some cases, ectopic secretion of ACTH can mimic a pituitary adenoma, and additional testing may be required. When an unequivocal pituitary tumor (>5 mm) is identified with MRI, further diagnostic evaluation may not be needed depending on the clinical presentation. In such a case, referral to an experienced pituitary neurosurgeon is recommended. It is worth noting that at least 10% of the population have incidental tumors in the pituitary gland demonstrated on MRI. This means that at least 10% to 15% of patients with the ectopic ACTH syndrome also have an abnormal MRI of the pituitary gland. In patients in whom the diagnosis is not certain based on pituitary imaging, the single best test to confirm the presence or absence of an ACTH-secreting pituitary tumor is a procedure in which the inferior petrosal sinuses are catheterized with blood sampled for ACTH before and after the administration of CRH (which stimulates ACTH) and at 2, 5, and 10 minutes. This invasive study should be performed at a center with extensive experience in the procedure and has a diagnostic accuracy of 95% to 98%. Pituitary-dependent Cushing’s disease is treated by transsphenoidal surgery. Adrenal adenomas and ACTH-independent micronodular or macronodular hyperplasia may be treated with surgery, but surgery and chemotherapy for adrenal carcinoma are not highly successful.

Congenital Adrenal Hyperplasia

Etiology and Pathogenesis

Congenital adrenal hyperplasia (CAH) is a group of disorders characterized by defective adrenal steroid synthesis; accumulation of androgenic steroid intermediates; and variably, cortisol and mineralocorticoid deficiency. The most common form of CAH is caused by homozygous mutation of the CYP21 gene that encodes 21-hydroxylase, the enzyme that catalyzes the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and the conversion of progesterone to deoxycorticosterone (see Figure 70-1). The absence (or severe deficiency) of 21-hydroxylase results in a deficiency of cortisol and aldosterone.

Clinical Presentation

Deficiency of 21-hydroxylase activity classically presents as a salt-wasting adrenal crisis during the second week of life; 46 XX females can have varying degrees of virilization with genital ambiguity (Figure 70-4). Affected children can also present later in childhood with premature development of pubic hair, penile enlargement in boys, or as infertility or a polycystic ovary syndrome– (PCOS-) like syndrome in women. Newborn screening programs now include measurement of 17-hydroxyprogesterone as a screen for 21-hydroxylase deficiency, as well as less common 11-hydroxylase deficiency. Both conditions are virilizing, but 21-hydroxylase deficiency is associated with salt wasting and low blood pressure, and 11-β-hydroxylase deficiency (CYP11 gene) is associated with hypertension.