Chapter 534. Adrenal Insufficiency

Signs and symptoms of adrenal insufficiency are listed in Table 534-1. Most patients with chronic adrenal insufficiency have weakness, fatigue, anorexia, weight loss, hypotension, and hyperpigmentation. Patients with acute adrenal insufficiency may have hypotension, shock, weakness, apathy, confusion, anorexia, nausea, vomiting, dehydration, abdominal or flank pain, hyperthermia, and hypoglycemia. Deficient adrenal androgen secretion will compromise the acquisition of virilizing secondary sexual characteristics (pubic and axillary hair, acne, axillary odor) in female adolescents.

Many conditions will cause adrenal insufficiency, including congenital adrenal hyperplasia (CAD), hypopituitarism with corticotropin (ACTH) deficiency, and primary adrenal disorders. Primary adrenal insufficiency is commonly termed Addison disease; in adults, over 80% of Addison disease is due to autoimmune adrenalitis. The adrenal disorders of infants, children, and adolescents differ from those of adults and are shown in Table 534-2. Adrenal disorders are typically divided into chronic and acute causes, but many acute presentations reflect emergence of an undiagnosed underlying chronic or developmental process. Acute presentations may be triggered by intercurrent illness, trauma, or surgery, with poor fluid and sodium intake. A correct diagnosis facilitates long-term management and genetic counseling and assessing associated features.1-3

Acute adrenal crisis commonly occurs in the child with undiagnosed chronic adrenal insufficiency at the time of additional stress (major illness, trauma, or surgery). The presenting symptoms and signs include abdominal pain, fever, hypoglycemia with seizures, weakness, apathy, nausea, vomiting, anorexia, hyponatremia, hypochloremia, acidemia, hyperkalemia, hypotension, shock, cardiovascular collapse, and death. Treatment requires fluid and electrolyte resuscitation, ample doses of glucocorticoids, chronic glucocorticoid and mineralocorticoid replacement, and treatment of the precipitating illness.

Massive adrenal hemorrhage with shock from blood loss can occur in large infants following traumatic delivery.4 A palpable flank mass can be distinguished from renal vein thrombosis by microscopic rather than gross hematuria; the diagnosis is confirmed by computerized tomography or ultrasonography.5 Massive adrenal hemorrhage may also be associated with meningococcemia (Waterhouse Friderichsen syndrome). A similar adrenal crisis may also occur rarely with septicemia from Streptococcus, Pneumococcus,Pseudomonas, diphtheria, and methicillin-sensitive or resistant Staphylococcus.6

Symptoms and signs of chronic adrenal insufficiency are shown in Table 534-1. In primary chronic adrenal insufficiency, the low concentrations of plasma cortisol stimulate the hypersecretion of ACTH, leading to hyperpigmentation, especially in skin exposed to sun and in flexor surfaces such as knees, elbows, and knuckles.

Diagnosis of adrenal insufficiency requires measurement of a low morning cortisol level with a high ACTH, confirmed by a minimal response of cortisol to a 60 minute intravenous ACTH test. Hyponatremia, hyperkalemia, low aldosterone, and elevated plasma renin activity (PRA) suggest a disturbance in mineralocorticoid production. Associated findings may include the appearance of a small heart on chest x ray, anemia, azotemia, eosinophilia, lymphocytosis, and hypoglycemia. Treatment requires physiologic glucocorticoid and mineralocorticoid replacement therapy.

Causes of primary chronic adrenal insufficiency are discussed below.

Autoimmune Adrenalitis

Autoimmune adrenalitis is rare in children. It occurs most frequently in 25- to 45-year-old adults. It is more common in women (60% to 70%) with an overall prevalence of about 1 in 25,000.7 Early in the course of autoimmune adrenalitis, one may see signs of glucocorticoid deficiency (weakness, fatigue, weight loss, hypoglycemia, anorexia) without signs of mineralocorticoid deficiency (hyponatremia, hyperkalemia, acidosis, tachycardia, hypotension, low voltage on EKG, small heart on chest x ray) or evidence of mineralocorticoid deficiency without glucocorticoid deficiency.

Autoimmune adrenalitis is associated with specific human leucocyte antigen (HLA) haplotypes and with polymorphisms in the gene for cytotoxic T-lymphocyte-associated antigen 4 (CLTA 4), which may be broadly involved in susceptibility to autoimmune disease.8-10 The diagnosis of autoimmune adrenalitis is based on finding antiadrenal antibodies; in many cases, the adrenal antigens are the steroidogenic enzymes P450scc, P450c17, and P450c21.7,11,12 It is likely that cell-mediated immunity is responsible for destruction of adrenocortical cells, resulting in a secondary discharge of cellular contents into the circulation, with subsequent development of secondary “marker” antibodies against these P450s. About half of adult patients with autoimmune adrenalitis also have autoimmune disease of another endocrine tissue. Some of these autoimmune polyendocrine syndromes (APSs) are more prevalent in childhood.

Type 1 Autoimmune Polyendocrine Syndrome

APS1, or autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia (APECED), is characterized by chronic mucocutaneous candidiasis, autoimmune Addison disease, and hypoparathyroidism7,13; at least 2 of these features must be present to make the diagnosis. The age of onset is highly variable. Chronic mucocutaneous candidiasis usually appears in early childhood and affects the mouth and nails. The hypoparathyroidism typically presents with clinical hypocalcemia during mid- or late childhood, but hypocalcemia may be masked by untreated adrenal insufficiency. The adrenal disorder usually presents in childhood or adolescence; autoimmune adrenal disease may be a presenting feature in about 5% of cases.13 Additional autoimmune features include alopecia and vitiligo; gastritis, chronic diarrhea, and malabsorption with or without pernicious anemia; hypergonadotropic hypogonadism (especially in women); and, less commonly, hepatitis, thyroiditis, interstitial nephritis, myositis, dental enamel hypoplasia, acquired asplenia, and type 1 diabetes mellitus. Keratoconjunctivitis is an associated feature that requires careful monitoring and treatment to prevent blindness. Oral or esophageal squamous cell carcinoma occurs in 10% of affected adults.13 APS1 is common among people of Finnish (1:15,000), Sardinian, and Iranian Jewish (1:9000) ancestry.1 APS1 is caused by recessively inherited mutations in the AIRE (for autoimmune regulator) gene.14,15

Type 2 Autoimmune Polyendocrine Syndrome

APS2, Schmidt’s syndrome, refers to the relatively common association of autoimmune adrenalitis with thyroiditis or type 1 diabetes.16,17 APS2 is more common in females (3:1 ratio), is HLA-linked and is generally seen in young or middle-aged adults, but can present at almost any age. Primary (hypergonadotropic) ovarian failure is seen in up to one quarter of post-pubertal females with APS2, but primary testicular failure is rare.1 Pernicious anemia, hepatitis, vitiligo and alopecia may also be seen, but the hypoparathyroidism and mucocutaneous candidiasis typical of APS1 are not seen in APS2. APS2 is associated with the same HLA markers as idiopathic autoimmune adrenalitis, which may simply be a form of APS2.

Adrenal Hypoplasia Congenita

Adrenal hypoplasia congenita (AHC) (congenital adrenal hypoplasia) is a disorder of adrenal development that can occur with several different inheritance patterns and with a variety of associated or syndromic features. X-linked adrenal hypoplasia congenita (AHC), caused by mutations of DAX1 is the most common form of AHC. The definitive zone of the fetal adrenal does not develop, and the fetal zone is vacuolated and cytomegalic. About half of boys with AHC present with salt loss and glucocorticoid insufficiency in early infancy; the rest present more insidiously with chronic adrenal insufficiency throughout childhood.2 Hypogonadotropic hypogonadism or arrested puberty is an associated feature, although early puberty with subsequent pubertal arrest has been reported.

DAX1 encodes a nuclear transcription factor that is involved in adrenal and testicular development, as well as is expressed in the pituitary gonadotropes. About two thirds of boys with AHC have DAX1 point mutations.2,16 The other one third have DAX1 gene deletions either in isolation or as part of a contiguous gene deletion syndrome involving a telomeric X-linked mental retardation locus or centromeric loci for glycerol kinase deficiency and sometimes ornithine transcarbamylase and Duchenne muscular dystrophy.

Boys with AHC respond well to glucocorticoid and mineralocorticoid replacement therapy. Testosterone replacement therapy is needed at adolescence. Female carriers of DAX1 mutations are unaffected. Close monitoring and genetic counseling can help to prevent life-threatening adrenal crises in other family members.17 Thus, a family history of adrenal failure, unexplained death, or pubertal abnormalities in the male relatives of a boy with adrenal insufficiency suggest AHC.

Autosomal Forms of Adrenal Hypoplasia

Autosomal forms of adrenal hypoplasia can be seen in 46,XY females with mutations in SF1. Primary adrenal failure can be associated with Pena-Shoekir syndrome type I, pseudotrisomy 13, Meckel syndrome, and Pallister-Hall syndrome, and with defects in WNT3.18 Primary adrenal hypoplasia also appears to be part of the IMAGe syndrome (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, genitourinary anomalies).19

ACTH Resistance Syndromes

Hereditary unresponsiveness to ACTH (familial glucocorticoid deficiency, FGD) can present as an acute adrenal crisis precipitated by an intercurrent illness in an infant or with the signs and symptoms of chronic adrenal insufficiency in childhood. Several autosomal recessive causes of FGD have been identified.20 Patients with FGD usually produce mineralocorticoids, because production of aldosterone by the adrenal zona glomerulosa is regulated principally by the renin angiotensin system. Thus, the presenting picture consists of failure to thrive, lethargy, pallor, hyperpigmentation, and hypoglycemia, often associated with seizures. Familial glucocorticoid deficiency type 1 (FGD1) results from recessive mutations in the ACTH receptor,20-22 accounting for ~25% of cases of FGD. Patients with FGD1 have the typical findings of glucocorticoid deficiency; hypoglycemia is common, and ACTH can be markedly elevated. Tall stature and increased head circumference have been reported.22,23 Replacement doses of glucocorticoids usually prevent adrenal crises but may not suppress elevated ACTH levels completely.20Familial glucocorticoid deficiency type2 (FGD2), which is clinically indistinguishable from FGD1, is caused by mutations in the melanocortin 2 receptor accessory protein, MRAP,20,24 accounting for about 20% of cases of FGD. MRAP appears to play a role in trafficking the ACTH receptor from the endoplasmic reticulum to the cell membrane. Triple A (Allgrove) Syndrome consists of ACTH-resistant adrenal insufficiency (80% of individuals), achalasia of the cardia (85%), and alacrima (90%).25 Mineralocorticoid insufficiency is reported in only about 15% of cases, but many patients also have progressive neurological symptoms (intellectual impairment, sensorineural deafness, peripheral and cranial neuropathies, optic atrophy, Parkinsonism, and autonomic dysfunction).21,26,27 Triple A syndrome is caused by mutations in the gene for a WD-repeat protein termed ALADIN.28,29 Clinical findings can vary even within the same family. Adrenal insufficiency is rarely the presenting feature. Thus, a detailed family history of achalasia, alacrima, or neurological disorders is important when evaluating a patient with primary adrenal failure.

Metabolic Disorders

Adrenoleukodystrophy (Schilder disease), peroxisome biosynthesis disorders (eg, Zellweger syndrome spectrum), disorders of cholesterol synthesis and metabolism (eg, Wolman disease, cholesterol ester storage disease, Smith-Lemli-Opitz syndrome), and mitochondrial disorders (eg, Kearns-Sayre syndrome) can also cause chronic primary adrenal insufficiency. These are discussed in more detail in Sections 11 and 29.

Other Causes

Chronic adrenal insufficiency may result from other causes. Hemorrhage and infections, discussed above as causes of acute primary adrenal insufficiency, may spare some adrenal tissue, leaving severely compromised, rather than totally absent, adrenal function. The result, as with autoimmune adrenalitis, is a chronic disorder with insidious onset of the broad range of nonspecific findings described above. Tuberculosis, fungal infections (eg, histoplasmosis, coccidiomycosis), viral infections (eg, HIV, CMV), metastases, amyloidosis, and sarcoidosis may cause a similar clinical picture. Cortisol biosynthesis can also be inhibited by aminoglutethimide, etomidate, suramin, and ketoconazole.

ACTH is required for adrenal growth and gene transcription, hence impaired ACTH synthesis or release (hypothalamic defects, hypopituitarism, disorders of POMC synthesis and processing, and steroid treatment) can cause secondary adrenal insufficiency. Secondary adrenal insufficiency typically spares mineralocorticoid synthesis, as angiotensin II is the primary drive to the zona glomerulosa. Glucocorticoids are needed for renal free water clearance; hence, in the patient with hypopituitarism and adrenal insufficiency, treatment of secondary adrenal insufficiency may unmask deficient antidiuretic hormone, precipitating diabetes insipidus. Conversely, the hypothyroidism from TSH deficiency will slow the metabolism of cortisol produced, protecting the patient from adrenal insufficiency. Treatment of hypothyroidism with thyroxine will accelerate metabolism of cortisol, unmasking adrenal insufficiency due to ACTH deficiency, potentially precipitating an acute adrenal crisis. Careful evaluation of the pituitary adrenal axis is required in hypopituitarism with secondary hypothyroidism. Many clinicians will choose to “cover” a patient with small doses of glucocorticoids (one fourth to one half of physiologic replacement) during initial treatment of such secondary hypothyroidism. Combined deficiency of growth hormone and ACTH will strongly predispose the patient to hypoglycemia, as both hormones act to raise plasma glucose, especially in infancy.

Hypothalamic and Pituitary Disorders

Tumors and radiotherapy can cause ACTH deficiency from hypothalamic damage. Craniopharyngioma30-45 is associated with ACTH deficiency in about 25% of patients46,47; the frequency may be higher in germinoma and astrocytoma.48 Adrenal insufficiency is rarely the presenting complaint but contributes to the clinical picture. Most patients with hypothalamic tumors will have ACTH deficiency following surgery or radiation therapy. These patients should receive glucocorticoid coverage during treatment, irrespective of the status of the hypothalamic-pituitary-adrenal axis when the tumor is identified. Close attention to water balance is essential. Whole brain radiation may cause both hypothalamic and pituitary damage, with secondary ACTH deficiency sometimes manifesting years later.49 ACTH deficiency may be a component of multiple pituitary hormone deficiency (MPHD, panhypopituitarism) as discussed in Chapter 523. Isolated ACTH insufficiency is rare, sometimes caused by recessive mutations in a factor regulating POMC transcription.50-52 These patients usually present with severe, early-onset ACTH insufficiency, hypoglycemia and prolonged jaundice, and, occasionally, neonatal death. Hypocortisolemia due to isolated ACTH insufficiency has also been described with hippocampal (memory) defects and hair abnormalities (alopecia) as part of the Triple H syndrome, a possible autoimmune association.53-56 Defects in POMC synthesis and processing can also disrupt ACTH production and action. Recessive mutations that affect multiple POMC peptides cause a syndrome characterized by red hair, pale skin, obesity, and secondary adrenal insufficiency. These clinical signs may be subtle in patients with naturally dark hair and pigmented skin, or red hair may darken in adulthood.57 Recessive mutations in pro-hormone convertase 1 can cause hypocortisolemia, hypoglycemia, obesity, hypogonadotropic hypogonadism, and persistent malabsorptive diarrhea.58,59

Long-Term Steroid Therapy

Long term glucocorticoid therapy will suppress the synthesis and storage of ACTH, decrease the synthesis and storage of CRF, and suppress CRF receptors in the pituitary. Recovery of the hypothalamic pituitary axis following suppression from long term glucocorticoid therapy often requires considerable time (see Chapter 536). Patients successfully withdrawn from glucocorticoid therapy or successfully treated for Cushing disease may normalize their plasma cortisol values fairly rapidly while continuing to have diminished adrenal reserve for over 6 months. Inhaled steroids, nasal sprays, and even steroid eye drops can cause suppression of the adrenal axis, so vigilance may be needed following their withdrawal or at time of additional stress (eg, surgery, intercurrent illness).60,62