Differential Diagnosis

Because of its protean manifestations that include tiredness, weakness, dehydration, nausea, vomiting, and diarrhea. Addison disease can be confused with many other conditions such as primary anemias, gastrointestinal disorders, cancer, psychiatric disease, and even malingering. However, the laboratory findings of hyponatremia, hyper-kalemia, acidosis, and/or hypoglycemia should raise the specter of adrenal insufficiency in the clinician's differential diagnosis of the patient's problems.

While the 1-hour cosyntropin test was used in this patient to diagnose glucocorticoid insufficiency, other tests are available such as the cortisol response to insulin-induced hypoglycemia, prolonged cosyntropin stimulation test, and the metyrapone test. Because of its diurnal variation, measurements of ACTH are of limited value in differentiating primary from central adrenal insufficiency. If the physician wants to directly measure aldosterone, it can be measured in blood or in a timed urine collection. In timed urine collections, sodium excretion should also be measured with creatinine measured as an index of the completeness of the collection. If measured in blood, a renin measurement should be paired with the aldosterone measurement. Isolated mineralocorticoid insufficiency is a rare inborn error. Renin deficiency can occur in cases of longstanding diabetes but is otherwise uncommon.

The major causes of primary adrenal insufficiency include autoimmune destruction of the adrenal cortex (^70% of cases) and infection (^20% of cases). A minority of cases (~10%) result from: coagulopathy, trauma (with or without hemorrhage), adrenalectomy (e.g., postsurgical), cancer (e.g., infiltrative or metastatic disease), inborn errors, drugs (e.g., mitotane, aminoglutethimide, trilostane, ketoconazole, metyrapone, and RU-486), amyloidosis, and congenital adrenal aplasia.

Autoimmune destruction of the adrenal cortex is histologically recognized by a lym-phocytic infiltration of the cortex (e.g., "adrenalitis") with consequent endocrine cell death and gland atrophy. Autoimmune Addison disease can exist as an isolated condition or can exist as part of an autoimmune polyglandular (e.g., "polyendocrine") syndrome (APS). Two types of APS have been recognized: APS type 1 and APS type 2.

The diagnosis of APS type 1 is established when at least two of the following three findings are identified in a patient: mucocutaneous candidiasis, hypoparathyroidism, and Addison disease/adrenal autoantibodies. APS type 1 has also been termed the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome because associated disorders include dental enamel hypoplasia and nail dystrophy. Other associated diseases in APS type 1 patients include gonaditis (producing primary gonadal failure in women) and autoimmune hepatitis. Less commonly associated conditions are type 1 diabetes mellitus, autoimmune thyroid disease, vitiligo, alopecia, fat malabsorption, IgA deficiency, pernicious anemia, red cell aplasia, and progressive myopathy.

The diagnosis of APS type 2 is confirmed when Addison disease (or adrenal autoanti-bodies) is associated with type 1 diabetes mellitus and/or autoimmune thyroid disease. Less often associated disorders include gonaditis, hypophysitis, autoimmune hepatitis, vitiligo, alopecia, dermatitis herpetiformis, IgA deficiency, celiac disease, pernicious anemia, immune thrombocytopenia, myasthenia gravis, stiffman syndrome, and Parkinson disease. Because this patient had Addison disease and TPOA, he likely has APS type 2.

APS type 1 is an autosomal recessive disease resulting from mutations in a transcription factor named the autoimmune regulator (AIRE). By its nature, APS type 1 is equally common in males and females. Also as an inborn error, it presents in childhood. APS type 2 is more typical of traditional autoimmune diseases being more common in women than in men that presents in later childhood or early adulthood. APS type 2 is polygenic with an HLA influence on its development.

The differential diagnosis of central adrenal insufficiency includes suppression of the hypothalamic-pituitary-adrenal axis by exogenous glucocorticoids, destructive pituitary tumors and their treatment, destructive hypothalamic tumors and their treatment, cerebral trauma, irradiation, infection, bleeding, congenital malformations of the pituitary gland or hypothalamus, and idiopathic hypopituitarism.

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