Solucortef I.V. was started and fluid support was continued. Endocrinology assisted in managing the patient during her admission. Her aldosterone level was <1.6 (normal 4 to 30), and her adrenal auto-antibodies (21-OH antibodies) were 96 (normal <1), all consistent with the diagnosis of Addison’s disease. Thyroid studies and Hemaglobin A1C were normal. ACTH levels were elevated, ruling out a centrally mediated etiology. Adrenal antibodies were extremely high, confirming the diagnosis of Addison’s disease. Solucortef was converted to oral hydrocortisone with instruction to double or triple the dose during stress, and fludrocortisone was started. Interestingly, the week this patient was admitted, there were two additional patients admitted to the Intensive Care Unit with Addison’s disease with variable presentations.

Addison’s disease has a prevalence rate of 35 to 144 per million. Although it is rare, it remains an important consideration in patients presenting with syncope, hypotension, weakness, emesis or lethargy, and it must be diagnosed before adrenal crisis occurs. Its presentation can be subtle (Table 1). Signs and symptoms of this entity result from depletion of glucocorticoids, mineralocorticoids, and adrenal androgens. Deficiency in glucocorticoids leads to nausea, vomiting, fatigue, fasting hypoglycemia, water retention with subsequent hyponatremia and morning headaches. Deficiency in mineralocorticoids (aldosterone) can lead to hyponatremia, hyperkalemia, hypotension, salt craving, weakness, weight loss and increased renin levels. Patients can present in adrenal crisis with advanced illness, shock, hypoglycemia and severe electrolyte disturbances. They often have hyperpigmentation of their skin, most pronounced on elbows, knees, palmar creases, axilla and gingiva. The pituitary detects the low cortisol levels and responds by secreting high levels of ACTH. The precursor of ACTH is cleaved to become melanocortin, ACTH and beta-lipotopin. Melanocortin then stimulates high levels of melanin and darkening of the skin.

The list of etiologies of primary adrenal insufficiency is long and varied (Table 2). In the past, TB and adrenal hemorrhage were major causes, though now 80 percent of cases are of autoimmune origin. Fifty percent of patients with Addison’s disease have polyglandular autoimmune syndrome (PAS 1, PAS2), with the rate rising to 70 percent in female patients. A careful search for Type 1 diabetes mellitus, autoimmune thyroid disease or hypoparathyroidism should be carried out in all these patients. There is also a close association with celiac disease. Once diagnosed, these patients require close ongoing follow-up with their pediatrician and endocrinologist to ensure appropriate medication dosing, education on stress dosing during times of illness or procedures, management of side effects from long-term steroid use, monitoring for signs and symptoms of other related autoimmune conditions and compliance with lifelong therapy.

Deborah J. Andresen, M.D., F.A.A.P., is a pediatric hospitalist at Children’s Healthcare of Atlanta.

Julius Sherwinter, M.D., F.A.A.P, is Section Chief of Pediatric Nephrology at Children’s Healthcare of Atlanta and Chairman of Physician Continuing Medical Education at Children’s. He is also Clinical Associate Professor at Emory University School of Medicine.

TABLE 1: SUGGESTIVE HISTORICAL, PHYSICAL and LAB FINDINGS

TABLE 2: ETIOLOGY OF PRIMARY ADRENAL INSUFFICIENCY

Autoimmune disease
Autoimmune adrenalitis, Autoimmune Polyendocrine Syndrome (APS, Types 1 or 2)

Infections
TB, histoplasmosis, coccidiomycosis, syphilis, HIV

Cancer, Infiltrative
Metastatic cancer (lung, colon), lymphoma, amyloidosis    

Drugs
Aminoglutethimide, Ketoconazole, Phenytoin, Etomidate, Barbiturates, Rifampin, Megestrol

Hemorrhage or infarcts
Bilateral adrenal hemorrhage in the newborn, Waterhouse-Friderichsen syndrome, antiphospholipid syndrome

Peroxisomal defects
Adrenoleukodystrophy (ALD), Refsum disease, Zellweger syndrome

Abnormal Development
Congenital Adrenal Hypoplasia (AHC)-Mutations to SF1 Transcription Factor, DAX-1 gene mutations, ACTH receptor gene mutations

IMAGe syndrome

Disorders of Steroidogenesis
Congenital Adrenal Hyperplasia, Defects in Aldosterone production, Smith–Lemli-Opitz Syndrome

Wolman Disease