A 14-year-old girl with a history of type I diabetes mellitus is brought to her pediatrician because of a 2-month history of fatigue, dizziness, and nausea. On physical exam, she is found to have orthostatic hypotension and the pediatrician notes that she has hyperpigmentation of dorsum of her hands and over her knees (Figures 196-1 and 196-2). The pediatrician is concerned about adrenal insufficiency and promptly refers the girl to an endocrinologist. The girl is found to have a low early morning serum cortisol, high serum adrenocorticotropin hormone level, and anti-adrenal antibodies, confirming the diagnosis of primary adrenal insufficiency.

Addison’s disease refers to dysfunction or hypofunction of the adrenal cortex which leads to primary adrenal insufficiency. The adrenal cortex is unable to produce and secrete glucocorticoids (cortisol) and mineralocorticoids (aldosterone), leading to an increase in adrenocorticotropin hormone (ACTH) and systemic effects in children, such as fatigue and gastrointestinal symptoms. Hyperpigmentation of the skin is a distinguishing feature. In children, congenital adrenal hyperplasia is the most common cause of Addison’s disease (see Chapter 197, Congenital Adrenal Hyperplasia). The second most common cause of Addison’s disease worldwide is tuberculosis and other granulomatous disorders. In developed countries, the second most common cause is autoimmune disease, which is the focus of this chapter.¹

Primary adrenal insufficiency, adrenocortical hypofunction.

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  Addison’s disease is rare, with a prevalence of 140 per million.¹

  
  
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  Autoimmune Addison’s disease constitutes 15 percent of all cases of primary adrenal insufficiency and usually presents during childhood.

  
  
  
  
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    Other causes include infection, adrenal hypoplasia congenital (congenital adrenal hypoplasia caused by a mutation in the DAX1 gene), and adrenoleukodystrophy.²

  
  
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  Approximately 1/2 of patients with this disorder also have autoimmune disorders of other endocrine glands. This condition is known as autoimmune polyglandular syndrome (APS) and occurs more often in females (70%).

  
  
  
  
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    Isolated autoimmune disease is more prevalent in males (71%).²

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  Addison’s disease is thought to result from autoimmune attack of the adrenal gland, leading to destruction of the cortical parenchyma.

  
  
  
  
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    There is evidence that both humoral and cell-mediated immunity are involved.²

  
  
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  Autoimmune Addison’s disease is often associated with other autoimmune phenomena, especially polyglandular syndromes.

  
  
  
  
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    APS1 (also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, or APECED)—This syndrome includes adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous candidiasis. Autosomal recessive mutations in the autoimmune regulator (AIRE) gene are responsible.

    
    
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    APS2 (also known as Schmidt syndrome)—This entity consists of adrenal insufficiency, thyroiditis, and diabetes mellitus type 1. It is more prevalent than APS1.³

  
  
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  Destruction of the adrenal cortex leads to low cortisol and low aldosterone, producing the symptoms of Addison’s disease. Low cortisol also leads to increased synthesis of the prohormone pro-opiomelanocortin, which is cleaved to form ACTH and melanocyte stimulating hormone (MSH). Increased MSH levels in turn lead to increased melanin synthesis in melanocytes causing hyperpigmentation.²