Adrenocortical Insufficiency

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Chapter 569 Adrenocortical Insufficiency

In primary adrenal insufficiency, congenital or acquired lesions of the adrenal cortex prevent production of cortisol and often aldosterone (Table 569-1). Acquired primary adrenal insufficiency is termed Addison disease. Dysfunction of the hypothalamus or anterior pituitary gland can cause a deficiency of corticotropin (ACTH) and lead to hypofunction of the adrenal cortex; this is termed secondary adrenal insufficiency (Table 569-2).

Table 569-1 CAUSES OF PRIMARY ADRENAL INSUFFICIENCY

DIAGNOSIS	CLINICAL FEATURES IN ADDITION TO ADRENAL INSUFFICIENCY	PATHOGENESIS OR GENETICS
AUTOIMMUNE ADRENALITIS
Isolated autoimmune adrenalitis	No other features	Associations with HLA-DR, CTLA4
Autoimmune adrenalitis as part of APS
APS type 1 (APECED)	Hypoparathyroidism, chronic mucocutaneous candidiasis, other autoimmune disorders	Mutations in AIRE
APS type 2	Thyroid disease, type 1 diabetes mellitus, other autoimmune diseases (unusual in children)	Associations with HLA-DR, CTLA4
APS type 4	Other autoimmune diseases, excluding thyroid disease or diabetes (unusual in children)	Associations with HLA-DR, CTLA4
INFECTIOUS ADRENALITIS
Tuberculous adrenalitis	Other organ manifestations of tuberculosis	Tuberculosis
AIDS	Other AIDS-associated diseases	HIV-1, cytomegalovirus
Fungal adrenalitis	Mostly in immunosuppressed patients	Cryptococcosis, histoplasmosis, coccidioidomycosis
GENETIC DISORDERS LEADING TO ADRENAL INSUFFICIENCY
Adrenoleukodystrophy, adrenomyeloneuropathy	Demyelination of CNS (cerebral adrenoleukodystrophy), spinal cord, or peripheral nerves (adrenomyeloneuropathy)	Mutation in the ABCD1 gene encoding a peroxisomal fatty acid transport protein
Congenital lipoid adrenal hypoplasia	XY sex reversal	Mutations in the STAR gene encoding steroidogenic acute regulatory protein; rare mutations in CYP11A encoding P-450scc
CYP oxidoreductase deficiency	Antley-Bixler syndrome	Mutations in POR encoding CYP oxidoreductase
Smith-Lemli-Opitz syndrome	Mental retardation, craniofacial malformations, growth failure	Mutations in DHCR7 encoding 7-dehydrocholesterol reductase
Pallister-Hall syndrome	Hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, postaxial polydactyly	Mutations in GLI3
IMAGe syndrome	Intrauterine growth retardation, metaphyseal dysplasia, adrenal insufficiency, genital anomalies	Unknown
Kearns-Sayre syndrome	External ophthalmoplegia, retinal degeneration, and cardiac conduction defects; other endocrinopathies	Mitochondrial DNA deletions
ACTH insensitivity syndromes (familial glucocorticoid deficiency)	Glucocorticoid deficiency, but no impairment of mineralocorticoid synthesis
Type 1	Tall stature	Mutations in MC2R encoding the ACTH receptor
Type 2	No other features	Mutations in MRAP
Triple A syndrome (Allgrove’s syndrome)	Alacrimia, achalasia; additional symptoms, including neurologic impairment, deafness, mental retardation, hyperkeratosis	Mutations in AAAS
Congenital Adrenal Hyperplasia
21-Hydroxylase deficiency	Ambiguous genitalia in girls	Mutations in CYP21A2
11β-Hydroxylase deficiency	Ambiguous genitalia in girls and hypertension	Mutations in CYP11B1
3β-hydroxysteroid dehydrogenase deficiency	Ambiguous genitalia in boys, postnatal virilization in girls	Mutations in HSD3B2
17α-Hydroxylase deficiency	Ambiguous genitalia in boys, lack of puberty in both sexes, hypertension	Mutations in CYP17
Adrenal Hypoplasia Congenita
X-linked	Hypogonadotropic hypogonadism	Mutations in NR0B1 (DAX1)
Xp21 contiguous gene syndrome	Duchenne muscular dystrophy and glycerol kinase deficiency (psychomotor retardation)	Deletion of the Duchenne muscular dystrophy, glycerol kinase, and NR0B1 (DAX1) genes
SF-1 linked	XY sex reversal	Mutations in NR5A1 (SF1)
OTHER CAUSES
Bilateral adrenal hemorrhage	Symptoms of underlying disease	Septic shock, specifically meningococcal sepsis (Waterhouse-Friderichsen syndrome); primary antiphospholipid syndrome; anticoagulation
Adrenal infiltration	Symptoms of underlying disease	Adrenal metastases, primary adrenal lymphoma, sarcoidosis, amyloidosis, hemochromatosis
Bilateral adrenalectomy	Symptoms of underlying disease
Drug-induced adrenal insufficiency	No other symptoms	Treatment with mitotane, aminoglutethimide, etomidate, ketoconazole, suramin, mifepristone, etomidate

ACTH, adrenocorticotropin hormone; APS, autoimmune polyendocrinopathy; CYP, cytochrome P-450; P-450scc, cytochrome P-450 side chain cleavage enzyme.

Adapted from Arlt W, Allolio B: Adrenal insufficiency, Lancet 361:1881–1892, 2003.

Table 569-2 CAUSES OF SECONDARY ADRENAL INSUFFICIENCY

DIAGNOSIS	COMMENT
Pituitary tumors	Secondary adrenal insufficiency mostly as part of panhypopituitarism; additional symptoms (visual-field impairment): generally adenomas, carcinoma is a rarity; consequence of tumor growth, surgical treatment, or both
Other tumors of the hypothalamic-pituitary region	Craniopharyngioma, meningioma, ependymoma, germinoma, and intrasellar or suprasellar metastases
Pituitary irradiation	Craniospinal irradiation in leukemia, irradiation for tumors outside the hypothalamic-pituitary axis, irradiation of pituitary tumors
Lymphocytic hypophysitis
Isolated	Autoimmune hypophysitis; most often in relation to pregnancy (80%); mostly hypopituitarism, but also isolated adrenocorticotropic hormone deficiency
As part of APS	Associated with autoimmune thyroid disease and, less often, with vitiligo, primary gonadal failure, type 1 diabetes, and pernicious anemia
Isolated congenital ACTH deficiency	Pro-opiomelanocortin cleavage enzyme defect?
Pro-opiomelanocortin-deficiency syndrome	Pro-opiomelanocortin gene mutations; clinical triad of adrenal insufficiency, early-onset obesity, and red hair pigmentation
Combined pituitary-hormone deficiency	Mutations in the gene encoding the pituitary transcription factor PROP1 (Prophet of Pit1), progressive development of panhypopituitarism in the order GH, PRL, TSH, LH/FSH, (ACTH) Mutations in the homeobox gene HESX1, combined pituitary hormone deficiency, optic-nerve hypoplasia, and midline brain defects (septo-optic dysplasia)
Pituitary apoplexy (Sheehan’s syndrome)	Onset mainly with abrupt severe headache, visual disturbance, and nausea or vomiting Histiocytosis syndromes, pituitary apoplexy or necrosis with peripartal onset, e.g., due to high blood loss or hypotension
Pituitary infiltration or granuloma	Tuberculosis, actinomycosis, sarcoidosis, Wegener granulomatosis
Head trauma	For example, pituitary stalk lesions
Previous chronic glucocorticoid excess	Exogenous glucocorticoid administration for >2 wk, endogenous glucocorticoid hypersecretion due to Cushing syndrome

ACTH, adrenocorticotropin hormone; APS, autoimmune polyendocrinopathy; FSH, follicle stimulating hormone; GH, growth hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyrotropin.

Adapted from Arlt W, Allolio B: Adrenal insufficiency, Lancet 361:1881–1892, 2003.

569.1 Primary Adrenal Insufficiency

Perrin C. White

Primary adrenal insufficiency may be caused by genetic conditions that are not always manifested in infancy and by acquired problems such as autoimmune conditions. Susceptibility to autoimmune conditions often has a genetic basis, and so these distinctions are not absolute.

Inherited Etiologies

Inborn Defects of Steroidogenesis

The most common causes of adrenocortical insufficiency in infancy are the salt-losing forms of congenital adrenal hyperplasia (Chapter 570). Approximately 75% of infants with 21-hydroxylase deficiency, almost all infants with lipoid adrenal hyperplasia, and most infants with a deficiency of 3β-hydroxysteroid dehydrogenase manifest salt-losing symptoms in the newborn period because they are unable to synthesize either cortisol or aldosterone.

Adrenal Hypoplasia Congenita

Adrenal hypoplasia congenita (AHC) represents approximately half of cases of adrenal failure in boys that are not caused by congenital adrenal hyperplasia, autoimmune disease, or adrenoleukodystrophy. Hypoadrenalism usually occurs acutely in the neonatal period but may be delayed until later childhood or even adulthood with a more insidious onset. Histologic examination of the hypoplastic adrenal cortex reveals disorganization and cytomegaly. The disorder is caused by mutation of the DAX1 (NR0B1) gene, a member of the nuclear hormone receptor family, located on Xp21. Boys with AHC often do not undergo puberty owing to hypogonadotropic hypogonadism; both AHC and hypogonadotropic hypogonadism are caused by the same mutated DAX1 gene. Cryptorchidism, often noted in these boys, is probably an early manifestation of hypogonadotropic hypogonadism.

AHC also occurs as part of a contiguous gene deletion syndrome together with Duchenne muscular dystrophy, glycerol kinase deficiency, mental retardation, or a combination of these conditions.

Other Genetic Causes of Adrenal Hypoplasia

The transcription factor SF-1 is required for adrenal and gonadal development (Chapter 568). Males with a heterozygous mutation in SF-1 (NR5A1) have impaired development of the testes despite the presence of a normal copy of the gene on the other chromosome and can appear to be female, similar to patients with lipoid adrenal hyperplasia (Chapter 570). Rarely, such patients have adrenal insufficiency as well.

Adrenal hypoplasia is also occasionally seen in patients with Palister-Hall syndrome caused by mutations in the GLI3 oncogene (Chapter 568).

Adrenoleukodystrophy

In adrenoleukodystrophy (ALD), adrenocortical deficiency is associated with demyelination in the central nervous system (Chapters 80 and 592.3). High levels of very long chain fatty acids are found in tissues and body fluids, resulting from their impaired β-oxidation in the peroxisomes.

The most common form of ALD is an X-linked disorder with various presentations. The most common clinical picture is of a degenerative neurologic disorder appearing in childhood or adolescence and progressing to severe dementia and deterioration of vision, hearing, speech, and gait, with death occurring within a few years. A milder form of X-linked ALD is adrenomyeloneuropathy (ALM), which begins in later adolescence or early adulthood. Many patients have evidence of adrenal insufficiency at the time of neurologic presentation, but Addison disease may be present without neurologic symptoms or can precede them by many years. X-linked adrenal leukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene located on Xq28. The gene encodes a transmembrane transporter involved in the importation of very long chain fatty acids into peroxisomes. More than 400 mutations have been described in patients with X-ALD; the majority of X-ALD families have a unique mutation. Clinical phenotypes can vary even within families, perhaps owing to modifier genes or other unknown factors. There is no correlation between the degree of neurologic impairment and severity of adrenal insufficiency. Prenatal diagnosis by DNA analysis and family screening by very long chain fatty acid assays and mutation analysis are available. Women who are heterozygous carriers of the X-ALD gene can develop symptoms in midlife or later; adrenal insufficiency is rare.

Neonatal ALD is a rare autosomal recessive disorder. Infants have neurologic deterioration and have or acquire evidence of adrenocortical dysfunction. Most patients have severe mental retardation and die before 5 yr of age. This disorder is a subset of Zellweger (cerebrohepatorenal) syndrome, in which peroxisomes do not develop at all owing to mutations in any of several genes controlling the development of this organelle.

Familial Glucocorticoid Deficiency

Familial glucocorticoid deficiency is a form of chronic adrenal insufficiency characterized by isolated deficiency of glucocorticoids, elevated levels of ACTH, and generally normal aldosterone production, although salt-losing manifestations as are present in most other forms of adrenal insufficiency occasionally occur. Patients mainly have hypoglycemia, seizures, and increased pigmentation during the 1st decade of life. The disorder affects both sexes equally and is inherited in an autosomal recessive manner. There is marked adrenocortical atrophy with relative sparing of the zona glomerulosa. Mutations in the gene for the ACTH receptor (MCR2) have been described in approximately 25% of these patients, most of which affect trafficking of receptor molecules from the endoplasmic reticulum to the cell surface. Another 20% of cases are caused by mutations in MRAP, which encodes a melanocyte receptor accessory protein required for this trafficking.

Another syndrome of ACTH resistance occurs in association with achalasia of the gastric cardia and alacrima (triple A or Allgrove syndrome). These patients often have a progressive neurologic disorder that includes autonomic dysfunction, mental retardation, deafness, and motor neuropathy. This syndrome is also inherited in an autosomal recessive fashion, and the AAAS gene has been mapped to chromosome 12q13. The encoded protein, aladin, might help regulate nucleocytoplasmic transport of other proteins.

Type I Autoimmune Polyendocrinopathy

Although autoimmune Addison disease most often occurs sporadically (see later), it can occur as a component of 2 syndromes, each consisting of a constellation of autoimmune disorders (Chapter 560). Type I autoimmune polyendocrinopathy (APS-1), also known as autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome, is inherited in mendelian autosomal recessive manner, whereas APS-2 (described later) has complex inheritance. Chronic mucocutaneous candidiasis is most often the first manifestation of APS-1, followed by hypoparathyroidism and then by Addison disease, which typically develops in early adolescence. Other closely associated autoimmune disorders include gonadal failure, alopecia, vitiligo, keratopathy, enamel hypoplasia, nail dystrophy, intestinal malabsorption, and chronic active hepatitis. Hypothyroidism and type 1 diabetes mellitus occur in less than 10% of affected patients. Some components of the syndrome continue to develop as late as the 5th decade. The presence of antiadrenal antibodies and steroidal cell antibodies in these patients usually indicates a high likelihood of the development of Addison disease or, in female patients, ovarian failure. Adrenal failure can evolve rapidly in APS-1; death in patients with a previous diagnosis and unexplained deaths in siblings of patients with APS-1 have been reported, indicating the need to closely monitor patients with APS-1 and to thoroughly evaluate apparently unaffected siblings of patients with this disorder.

Autoantibodies to the cytochrome P-450 21 (CYP21), CYP17, and CYP11A1 enzymes have been reported in patients with APS-1. The gene affected in APS-1 is designated autoimmune regulator-1 (AIRE1); it has been mapped to chromosome 21q22.3. The AIRE1 gene encodes a protein that appears to be a transcription factor having an important role in immune response. Approximately 40 different mutations in the AIRE1 gene have been described in patients with APS-1, with 2 mutations (R257X and a 3-bp deletion) being most common. There has been autosomal dominant transmission in 1 kindred owing to a specific missense mutation (G228W).

Disorders of Cholesterol Synthesis and Metabolism

Patients with disorders of cholesterol synthesis or metabolism, including abetalipoproteinemia with deficient lipoprotein B-containing lipoproteins, and familial hypercholesterolemia, with decreased or impaired LDL receptors, have been demonstrated to have limited adrenocortical function. Adrenal insufficiency has been reported in patients with Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive disorder manifesting with facial anomalies, microcephaly, limb anomalies, and developmental delay (Chapter 80.3). Mutations in the gene coding for sterol Δ⁷-reductase, mapped to 11q12-q13, resulting in impairment of the final step in cholesterol synthesis with marked elevation of 7-dehydrocholesterol, abnormally low cholesterol, and adrenal insufficiency, have been identified in SLOS. Wolman disease is a rare autosomal recessive disorder caused by mutations in the gene encoding human lysosomal acid lipase on chromosome 10q23.2-23.3. Cholesteryl esters accumulate in lysosomes in most organ systems, leading to organ failure. Infants during the 1st or 2nd mo of life have hepatosplenomegaly, steatorrhea, abdominal distention, and failure to thrive. Adrenal insufficiency and bilateral adrenal calcification are present, and death usually occurs in the first year of life.

Corticosteroid-Binding Globulin Deficiency and Decreased Cortisol-Binding Affinity

Corticosteroid-binding globulin deficiency (CBG) and decreased cortisol-binding affinity result in low levels of plasma cortisol but normal urinary free cortisol and normal plasma ACTH levels. A high prevalence of hypotension and fatigue has been reported in some adults with abnormalities of CBG.

Acquired Etiologies

Autoimmune Addison Disease

The most common cause of Addison disease is autoimmune destruction of the glands. The glands may be so small that they are not visible at autopsy, and only remnants of tissue are found in microscopic sections. Usually, the medulla is not destroyed, and there is marked lymphocytic infiltration in the area of the former cortex. In advanced disease, all adrenocortical function is lost, but early in the clinical course, isolated cortisol deficiency can occur. Most patients have antiadrenal cytoplasmic antibodies in their plasma; 21-hydroxylase (CYP 21) is the most commonly occurring autoantigen.

Addison disease can occur as a component of 2 autoimmune polyendocrinopathy syndromes. Type I (APS-1) was discussed previously. Type II autoimmune polyendocrinopathy (APS-2) consists of Addison disease associated with autoimmune thyroid disease (Schmidt syndrome) or type 1 diabetes (Carpenter syndrome). Gonadal failure, vitiligo, alopecia, and chronic atrophic gastritis, with or without pernicious anemia, can occur. HLA-D3 and HLA-D4 are increased in these patients and appear to confer an increased risk for development of this disease; alleles at the major histocompatibility complex class I chain-related genes A and B (MICA and MICB) also have been associated with this disorder. The disorder is most common in middle-aged women and can occur in many generations of the same family. Antiadrenal antibodies, specifically antibodies to the CYP 21, CYP 17, and CYP 11A1 enzymes, are also found in these patients. Autoimmune adrenal insufficiency may also be seen in celiac disease (Chapter 330.2).

Infection

Tuberculosis was a common cause of adrenal destruction in the past but is much less prevalent now. The most common infectious etiology for adrenal insufficiency is meningococcemia (Chapter 184); adrenal crisis from this cause is referred to as the Waterhouse-Friderichsen syndrome. Patients with AIDS can have a variety of subclinical abnormalities in the hypothalamic-pituitary-adrenal axis, but frank adrenal insufficiency is rare. However, drugs used in the treatment of AIDS can affect adrenal hormone homeostasis.

Drugs

Ketoconazole, an antifungal drug, can cause adrenal insufficiency by inhibiting adrenal enzymes. Rifampicin and anticonvulsive drugs such as phenytoin and phenobarbital reduce the effectiveness and bioavailability of corticosteroid replacement therapy by inducing steroid-metabolizing enzymes in the liver. Mitotane (o,p′-DDD), used in the treatment of adrenal carcinoma and refractory Cushing syndrome (Chapters 571 and 574), is cytotoxic to the adrenal cortex and can also alter extra-adrenal cortisol metabolism. Signs of adrenal insufficiency occur in a substantial percentage of patients treated with mitotane. Etomidate, used in the induction and maintenance of general anesthesia, inhibits 11β-hydroxylase (CYP 11B1), and a single induction dose can block cortisol synthesis for 4-8 hr or longer. This may be problematic in severely stressed patients, particularly if repeated doses are used in a critical care setting.

Hemorrhage into Adrenal Glands

Hemorrhage into adrenal glands can occur in the neonatal period as a consequence of a difficult labor (especially breech presentation), or its etiology might not be apparent. An incidence rate of 3/100,000 live births has been suggested. The hemorrhage may be sufficiently extensive to result in death from exsanguination or hypoadrenalism. An abdominal mass, anemia, unexplained jaundice, or scrotal hematoma may be the presenting sign. Often, the hemorrhage is asymptomatic initially and is identified later by calcification of the adrenal gland. Fetal adrenal hemorrhage has also been reported. Postnatally, adrenal hemorrhage most often occurs in patients being treated with anticoagulants. It can also occur as a result of child abuse.

Clinical Manifestations

Primary adrenal insufficiency leads to cortisol and often aldosterone deficiency. The signs and symptoms of adrenal insufficiency are most easily understood in the context of the normal actions of these hormones, which were discussed in Chapter 568.

Hypoglycemia is a prominent feature of adrenal insufficiency. It is often accompanied by ketosis as the body attempts to use fatty acids as an alternative energy source. Ketosis is aggravated by anorexia, nausea, and vomiting, all of which occur frequently.

Cortisol deficiency decreases cardiac output and vascular tone; moreover, catecholamines such as epinephrine have decreased inotropic and pressor effects in the absence of cortisol. These problems are initially manifested as orthostatic hypotension in older children and can progress to frank shock in patients of any age. They are exacerbated by aldosterone deficiency, which results in hypovolemia owing to decreased resorption of sodium in the distal nephron.

Hypotension and decreased cardiac output decrease glomerular filtration and thus decrease the ability of the kidney to excrete free water. Vasopressin (AVP) is secreted by the posterior pituitary in response to hypotension and also as a direct consequence of lack of inhibition by cortisol. These factors decrease plasma osmolality and lead in particular to hyponatremia. Hyponatremia is also caused by aldosterone deficiency and may be much worse when both cortisol and aldosterone are deficient.

In addition to hypovolemia and hyponatremia, aldosterone deficiency causes hyperkalemia by decreasing potassium excretion in the distal nephron. Cortisol deficiency alone does not cause hyperkalemia.

Cortisol deficiency decreases negative feedback on the hypothalamus and pituitary, leading to increased secretion of ACTH. Hyperpigmentation is caused by ACTH and other peptide hormones (γ-melanocyte-stimulating hormone) arising from the ACTH precursor pro-opiomelanocortin. In patients with a fair complexion, the skin can have a bronze cast. Pigmentation may be more prominent in skin creases, mucosa, and scars. In dark-skinned patients, it may be most readily appreciated in the gingival and buccal mucosa.

The clinical presentation of adrenal insufficiency depends on the age of the patient, whether both cortisol and aldosterone secretion are affected, and to some extent on the underlying etiology. The most common causes in early infancy are inborn errors of steroid biosynthesis, sepsis, adrenal hypoplasia congenita, and adrenal hemorrhage. Infants have a relatively greater requirement for aldosterone than do older children, possibly owing to immaturity of the kidney and also to the low sodium content of human breast milk and infant formula. Hyperkalemia, hyponatremia, and hypoglycemia are prominent presenting signs of adrenal insufficiency in infants. Ketosis is not consistently present because infants generate ketones less well than do older children. Hyperpigmentation is not usually seen because this takes weeks or months to develop, and orthostatic hypotension is obviously difficult to demonstrate in infants.

Infants can become ill very quickly. There may be only a few days of decreased activity, anorexia, and vomiting before critical electrolyte abnormalities develop.

In older children with Addison disease, symptoms include muscle weakness, malaise, anorexia, vomiting, weight loss, and orthostatic hypotension. These may be of insidious onset. It is not unusual to elicit, in retrospect, an episodic history spanning years with symptoms being noticeable only during intercurrent illnesses. Such patients can present with acute decompensation (adrenal crisis) during relatively minor infectious illnesses.

Hyperpigmentation is often but not necessarily present. Hypoglycemia and ketosis are common, as is hyponatremia. Hyperkalemia tends to occur later in the course of the disease in older children than in infants. Thus, the clinical presentation can be easily confused with gastroenteritis or other acute infections. Chronicity of symptoms can alert the clinician to the possibility of Addison disease, but this diagnosis should be considered in any child with orthostatic hypotension, hyponatremia, hypoglycemia, and ketosis.

Salt craving is seen in primary adrenal insufficiency with mineralocorticoid deficiency. Fatigue, myalgias, fever, eosinophilia, lymphocytosis, hypercalcemia, and anemia may be noted with glucocorticoid deficiency.

Laboratory Findings

Hypoglycemia, ketosis, hyponatremia, and hyperkalemia have been discussed. An electrocardiogram is useful for quickly detecting hyperkalemia in a critically ill child. Acidosis is often present, and the blood urea nitrogen level is elevated if the patient is dehydrated.

Cortisol levels are sometimes at the low end of the normal range but are invariably low when the patient’s degree of illness is considered. ACTH levels are high in primary adrenal insufficiency but can take time to be reported by the laboratory. Similarly, aldosterone levels may be within the normal range but inappropriately low considering the patient’s hyponatremia, hyperkalemia, and hypovolemia. Plasma renin activity is elevated. Blood eosinophils may be increased in number, but this is rarely useful diagnostically.

Urinary excretion of sodium and chloride are increased and urinary potassium is decreased, but these are difficult to assess on random urine samples. Accurate interpretation of urinary electrolytes requires more-prolonged (24 hr) urine collections and knowledge of the patient’s sodium and potassium intake.

The most definitive test for adrenal insufficiency is measurement of serum levels of cortisol before and after administration of ACTH; resting levels are low and do not increase normally after administration of ACTH. Occasionally, normal resting levels that do not increase after administration of ACTH indicate an absence of adrenocortical reserve. A low initial level followed by a significant response to ACTH can indicate secondary adrenal insufficiency. Traditionally, this test has been performed by measuring cortisol levels before and 30 or 60 min after giving 0.250 mg of cosyntropin (ACTH 1-24) by rapid intravenous infusion. Aldosterone will transiently increase in response to this dose of ACTH and may also be measured. A low-dose test (1 µg ACTH 1-24/1.73 m²) is a more sensitive test of pituitary-adrenal reserve but has somewhat lower specificity (more false-positive tests).

Differential Diagnosis

Upon presentation, Addison disease often needs to be distinguished from more acute illnesses such as gastroenteritis with dehydration or sepsis. Additional testing is directed at identifying the specific cause for adrenal insufficiency. When congenital adrenal hyperplasia is suspected, serum levels of cortisol precursors (17-hydroxyprogesterone) should be measured along with cortisol in an ACTH stimulation test (Chapter 570). Elevated levels of very long chain fatty acids are diagnostic of adrenoleukodystrophy. The presence of antiadrenal antibodies suggests an autoimmune pathogenesis. Patients with autoimmune Addison disease must be closely observed for the development of other autoimmune disorders. In children, hypoparathyroidism is the most commonly associated disorder, and it is suspected if hypocalcemia and elevated phosphate levels are present.

Ultrasonography, CT, or MRI can help define the size of the adrenal glands.

Treatment

Treatment of acute adrenal insufficiency must be immediate and vigorous. If the diagnosis of adrenal insufficiency has not been established, a blood sample should be obtained before therapy to determine electrolytes, glucose, ACTH, cortisol, aldosterone, and plasma renin activity. If the patient’s condition permits, an ACTH stimulation test can be performed while initial fluid resuscitation is under way. An intravenous solution of 5% glucose in 0.9% saline should be administered to correct hypoglycemia, hypovolemia, and hyponatremia. Hypotonic fluids (e.g., 5% glucose in water or 0.2% saline) must be avoided because they can precipitate or exacerbate hyponatremia. If hyperkalemia is severe, it can require treatment with intravenous calcium and/or bicarbonate, intrarectal potassium-binding resin (Kayexalate), or intravenous infusion of glucose and insulin. A water-soluble form of hydrocortisone, such as hydrocortisone sodium succinate, should be given intravenously. As much as 10 mg for infants, 25 mg for toddlers, 50 mg for older children, and 100 mg for adolescents should be administered as a bolus and a similar total amount given in divided doses at 6-hr intervals for the first 24 hr. These doses may be reduced during the next 24 hr if progress is satisfactory. Adequate fluid and sodium repletion is achieved by intravenous saline administration, aided by the mineralocorticoid effect of high doses of hydrocortisone.

Particular caution should be exercised in the rare patient with concomitant adrenal insufficiency and hypothyroidism, because thyroxine can increase cortisol clearance. Thus, an adrenal crisis may be precipitated if hypothyroidism is treated without first ensuring adequate glucocorticoid replacement.

After the acute manifestations are under control, most patients require chronic replacement therapy for their cortisol and aldosterone deficiencies. Hydrocortisone (cortisol) may be given orally in daily doses of 10 mg/m²/24 hr in 3 divided doses; some patients require 15 mg/m²/24 hr to minimize fatigue, especially in the morning. Timed-release preparations of hydrocortisone are undergoing clinical trials but are not yet generally available. Equivalent doses (20-25% of the hydrocortisone dose) of prednisone or prednisolone may be used and divided and given twice daily. ACTH levels may be used to monitor adequacy of glucocorticoid replacement in primary adrenal insufficiency; in congenital adrenal hyperplasia, levels of precursor hormones are used instead (Chapter 570). Blood samples for monitoring should be obtained at a consistent time of day and in a consistent relation to (i.e., before or after) the hydrocortisone dose. Normalizing ACTH levels is unnecessary and can require excessive doses of hydrocortisone; generally morning ACTH levels high in the normal range to 2-3 times normal are satisfactory. Because untreated or severely undertreated patients can acutely decompensate during relatively minor illnesses, assessment of symptoms (or lack thereof) must not be used as a substitute for biochemical monitoring. During situations of stress, such as periods of infection or minor operative procedures, the dose of hydrocortisone should be increased 2- to 3-fold. Major surgery under general anesthesia requires high intravenous doses of hydrocortisone similar to those used for acute adrenal insufficiency.

If aldosterone deficiency is present, fludrocortisone (Florinef), a synthetic mineralocorticoid, is given orally in doses of 0.05-0.2 mg daily. Measurements of plasma renin activity are useful in monitoring the adequacy of mineralocorticoid replacement. Chronic overdosage with glucocorticoids leads to obesity, short stature, and osteoporosis, whereas overdosage with fludrocortisone results in tachycardia, hypertension, and occasionally hypokalemia.

Replacement of dehydroepiandrosterone (DHEA) in adults remains controversial; prepubertal children do not normally secrete large amounts of DHEA. Many adults with Addison disease complain of having decreased energy, and replacing DHEA can improve this problem, particularly in women in whom adrenal androgens represent approximately 50% of total androgen secretion.

Additional therapy might need to be directed at the underlying cause of the adrenal insufficiency in regard to infections and certain metabolic defects. Therapeutic approaches to adrenoleukodystrophy include administration of glycerol trioleate and glycerol trierucate (Lorenzo’s oil), bone marrow transplantation, and lovastatin (Chapter 592.3).

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569.2 Secondary Adrenal Insufficiency

Perrin C. White

Etiology

Abrupt Cessation of Administration of Corticosteroids

Secondary adrenal insufficiency most commonly occurs when the hypothalamic-pituitary-adrenal axis is suppressed by prolonged administration of high doses of a potent glucocorticoid and that agent is suddenly withdrawn or the dose is tapered too quickly. Patients at risk for this problem include those with leukemia, asthma (particularly when patients are transitioned from oral to inhaled corticosteroids), and collagen vascular disease or other autoimmune conditions and those who have undergone tissue transplants or neurosurgical procedures. The maximal duration and dosage of glucocorticoid that can be administered before encountering this problem is not known, but it is assumed that high-dose glucocorticoids (the equivalent of >10 times physiologic cortisol secretion) can be administered for at least 1 wk without requiring a subsequent taper of dose. On the other hand, when high doses of dexamethasone are given to children with leukemia, it can take up to 2 mo or longer after therapy is stopped before tests of adrenal function return to normal. Signs and symptoms of adrenal insufficiency are most likely in patients who are subsequently subjected to stresses such as severe infections or additional surgical procedures.

Corticotropin Deficiency

Pituitary or hypothalamic dysfunction can cause corticotropin deficiency (Chapter 551), usually associated with deficiencies of other pituitary hormones such as growth hormone and thyrotropin. Destructive lesions in the area of the pituitary, such as craniopharyngioma and germinoma, are the most common causes of corticotropin deficiency. In many cases the pituitary or hypothalamus is further damaged during surgical removal or radiotherapy of tumors in the midline of the brain. In rare instances, autoimmune hypophysitis is the cause of corticotropin deficiency.

Congenital lesions of the pituitary also occur. The pituitary alone may be affected, or additional midline structures may be involved, such as the optic nerves or septum pellucidum. The latter type of abnormality is termed septo-optic dysplasia, or de Morsier syndrome (Chapter 585.9). More-severe developmental anomalies of the brain, such as anencephaly and holoprosencephaly, can also affect the pituitary. These disorders are usually sporadic, although a few cases of autosomal recessive inheritance have occurred. Isolated deficiency of corticotropin has been reported, including in several sets of siblings. Patients with multiple pituitary hormone deficiencies caused by mutations in the PROP1 gene have been described with progressive ACTH/cortisol deficiency. Isolated deficiency of corticotropin-releasing hormone has been documented in an Arab kindred as an autosomal recessive trait.

It has recently been recognized that up to 60% of children with Prader-Willi syndrome (Chapter 76) have some degree of secondary adrenal insufficiency as assessed by provocative testing with metyrapone (see later), although diurnal cortisol levels are normal. The clinical significance of this finding is uncertain, but it can contribute to the relatively high incidence of sudden death with infectious illness that occurs in this population. Although it is not yet a standard of care, some endocrinologists advocate treating patients who have Prader-Willi syndrome with hydrocortisone during febrile illness.

Clinical Presentation

Aldosterone secretion is unaffected in secondary adrenal insufficiency because the adrenal gland is, by definition, intact and the renin-angiotensin system is not involved. Thus, signs and symptoms are those of cortisol deficiency. Newborns often have hypoglycemia. Older children can have orthostatic hypotension or weakness. Hyponatremia may be present.

When secondary adrenal insufficiency is due to an inborn or acquired anatomic defect involving the pituitary, there may be signs of associated deficiencies of other pituitary hormones. The penis may be small in male infants if gonadotropins are also deficient. Infants with secondary hypothyroidism are often jaundiced. Children with associated growth hormone deficiency grow poorly after the 1st yr of life.

Some children with pituitary abnormalities have hypoplasia of the midface. Children with optic nerve hypoplasia can have obvious visual impairment. They usually have a characteristic wandering nystagmus, but this is often not apparent until several months of age.

Laboratory Findings

Because the adrenal glands themselves are not directly affected, the diagnosis of secondary adrenal insufficiency is sometimes challenging. Historical gold standard dynamic tests include insulin-induced hypoglycemia, which provides a potent stress to the entire hypothalamic-pituitary-adrenal (HPA) axis. This test requires constant attendance by a physician and is considered by many endocrinologists to be too dangerous for routine use. A second gold standard test uses metyrapone, a specific inhibitor of steroid 11β-hydroxylase (CYP 11B1) to block cortisol synthesis, thus removing the normal negative feedback of cortisol on ACTH secretion. Although there a several protocols for this test, one version administers 30 mg/kg of metyrapone orally at midnight, with a blood sample obtained for cortisol and 11-deoxycortisol (the substrate for 11β-hydroxylase) at 8 AM. A low cortisol level (<5 µg/dL) demonstrates adequate suppression of cortisol synthesis, and an 11-deoxycortisol level >7 µg/dL indicates that ACTH has responded normally to the cortisol deficiency by stimulating the adrenal cortex. This test should be used with caution outside the research setting because it can precipitate adrenal crises in patients with marginal adrenal function; the drug is not available in all locales.

At present, the most commonly used test to diagnose secondary adrenal insufficiency is low-dose ACTH stimulation testing (1 µg/1.73 m² of cosyntropin given intravenously), the rationale being that there will be some degree of atrophy of the adrenal cortex if normal physiologic ACTH stimulation is lacking. Thus, this test may be falsely negative in cases of acute compromise of the pituitary (e.g., injury or surgery). Such circumstances rarely pose a diagnostic dilemma; in general, this test provides excellent sensitivity and specificity. Although assays vary somewhat, a threshold cortisol level of 18-20 µg/dL 30 minutes after cosyntropin administration may be used to dichotomize normal and abnormal responses.

At present, there seems to be little reason to use stimulation with corticotrophin-releasing hormone (CRH) instead of ACTH; although the CRH test has the theoretical advantage of testing the ability of the anterior pituitary to respond to this stimulus by secreting ACTH, in practice it doesn’t provide improved sensitivity and specificity, and the agent is not as widely available.

Treatment

Iatrogenic secondary adrenal insufficiency (caused by chronic glucocorticoid administration) is best avoided by use of the smallest effective doses of systemic glucocorticoids for the shortest period of time. When a patient is thought to be at risk, tapering the dose rapidly to a level equivalent to or slightly less than physiologic replacement (∼10 mg/m²/24 hr of hydrocortisone) and further tapering over several wk can allow the adrenal cortex to recover without development of signs of adrenal insufficiency. Patients with anatomic lesions of the pituitary should be treated indefinitely with glucocorticoids. Mineralocorticoid replacement is not required. In patients with panhypopituitarism, treating cortisol deficiency can increase free water excretion, thus unmasking central diabetes insipidus. Electrolytes must be monitored carefully when initiating cortisol therapy in panhypopituitary patients.

Bibliography

Ahmad T, Borchert M, Geffner M. Optic nerve hypoplasia and hypopituitarism. Pediatr Endocrinol Rev. 2008;5:772-777.

de Lind van Wijngaarden RF, Joosten KF, van den BS, et al. The relationship between central adrenal insufficiency and sleep-related breathing disorders in children with Prader-Willi syndrome. J Clin Endocrinol Metab. 2009;94:2387-2393.

Gonc EN, Kandemir N, Kinik ST. Significance of low-dose and standard-dose ACTH tests compared to overnight metyrapone test in the diagnosis of adrenal insufficiency in childhood. Horm Res. 2003;60:191-197.

Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab. 2008;93:4245-4253.

Kelberman D, Dattani MT. Role of transcription factors in midline central nervous system and pituitary defects. Endocr Dev. 2009;14:67-82.

Rose SR, Danish RK, Kearney NS, et al. ACTH deficiency in childhood cancer survivors. Pediatr Blood Cancer. 2005;45:808-813.

Zollner EW. Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids (Part 2)—the risk as determined by gold standard adrenal function tests: a systematic review. Pediatr Allergy Immunol. 2007;18:469-474.

569.3 Adrenal Insufficiency in the Critical Care Setting

Perrin C. White

Etiology

Adrenal insufficiency in the context of critical illness is encountered in up to 20-50% of pediatric patients, often as a transient condition. In many cases, it is considered to be “functional” or “relative” in nature, meaning that cortisol levels are within normal limits but cannot increase sufficiently to meet the demands of critical illness. The causes are heterogeneous, and some were discussed in Chapter 569.1. They include adrenal hypoperfusion from shock, particularly septic shock, as is often seen in meningococcemia. Inflammatory mediators during septic shock, particularly interleukin-6, can suppress ACTH secretion, directly suppress cortisol secretion, or both. Etomidate, used as sedation for intubation, inhibits steroid 11β-hydroxylase and thus blocks cortisol biosynthesis. Neurosurgical patients with closed head trauma, or with tumors that involve the hypothalamus or pituitary, might have ACTH deficiency in the context of panhypopituitarism. Some children have been previously treated with systemic corticosteroids (e.g., children with leukemia) and have suppression of the hypothalamic-pituitary-adrenal axis for that reason. In the intensive care nursery, premature infants have not yet developed normal cortisol biosynthetic capacity (Chapter 568.2) and thus may not be able to secrete adequate amounts of this hormone when ill.

Clinical Manifestations

Cortisol is required for catecholamines to have their normal pressor effects on the cardiovascular system (Chapter 568.4). Accordingly, adrenal insufficiency is often suspected in hypotensive patients who do not respond to intravenous pressor agents. Patients may be at increased risk for hypoglycemia or a presentation resembling the syndrome of inappropriate antidiuretic hormone secretion (SIADH), but these conditions commonly occur in the context of sepsis, and the contribution of adrenal insufficiency may be difficult to distinguish.

Laboratory Findings

Although low random cortisol levels in severely stressed patients are certainly abnormal, very high levels are also associated with poor outcome such patients; the latter situation presumably reflects a maximally stimulated adrenal cortex with diminished reserve. ACTH (cosyntropin) stimulation testing is generally considered the best way to diagnose adrenal insufficiency in this setting (Chapter 569.1); evidence suggests that the low-dose (1 µg/1.73 m²) test may be superior to the 250 µg standard dose test, although this remains controversial. Generally, a peak cortisol level <18 µg/dL or an increment of <9 µg/dL from baseline is considered suggestive for adrenal insufficiency in this context. In evaluating cortisol levels, it should be remembered that cortisol in the circulation is normally mostly bound to cortisol binding globulin; in hypoproteinemic states total cortisol levels may be decreased, whereas free cortisol levels might be normal. It may be prudent to measure free cortisol before initiating treatment when total cortisol is low and albumin is <2.5 g/dL, but such measurements are not readily available in all institutions.