Addison Disease

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Description

  • Primary adrenal gland insufficiency, which results from partial or complete (>90%) destruction of the adrenal cells with inadequate secretion of glucocorticoids and mineralocorticoids
  • 80% of cases are caused by an autoimmune process, followed by tuberculosis (TB), AIDS, systemic fungal infections, and adrenoleukodystrophy.
  • Addison disease (primary adrenocortical insufficiency) can be differentiated from secondary (pituitary failure) and tertiary (hypothalamic failure) causes because mineralocorticoids are intact in secondary and tertiary.
  • Addisonian (adrenal) crisis: acute complication of adrenal insufficiency (circulatory collapse, dehydration, hypotension, nausea, vomiting, hypoglycemia); usually precipitated by an acute physiologic stressor(s) such as surgery, illness, exacerbation of comorbid process, and/or acute withdrawal of long-term corticosteroid therapy (defined as >3 months use of steroid)
  • System(s) affected: endocrine/metabolic
  • Synonym(s): adrenocortical insufficiency; corticoadrenal insufficiency; primary adrenocortical insufficiency

Epidemiology

  • Predominant age: all ages; typical age of presentation is 30 to 50 years.
  • Predominant sex: females and children > males (slight)
  • No racial predilection

Incidence
0.6/100,000
Prevalence
40 to 60 cases in 1 million population

Etiology and Pathophysiology

  • Autoimmune adrenal insufficiency (~80% in United States)
  • Infectious causes: TB (most common cause worldwide), HIV (most common infectious cause in United States, often with concomitant infections such as cytomegalovirus), Waterhouse-Friderichsen syndrome (most commonly meningococcus), fungal disease
  • Bilateral adrenal hemorrhage and infarction (for patients on anticoagulants)
  • Antiphospholipid antibody syndrome
  • Lymphoma, Kaposi sarcoma, metastasis (lung, breast, kidney, colon, melanoma); tumor must destroy 90% of gland to produce hypofunction.
  • Drugs (e.g., ketoconazole, fluconazole, etomidate, methadone, mitotane, megestrol, medroxyprogesterone acetate, chronic opiate use, metyrapone, aminoglutethimide)
  • Surgical adrenalectomy, radiation therapy
  • Sarcoidosis, hemochromatosis, amyloidosis
  • Congenital enzyme defects (deficiency of 21-hydroxylase enzyme is most common), neonatal adrenal hypoplasia, congenital adrenal hyperplasia, familial glucocorticoid insufficiency, autoimmune polyglandular autoimmune syndromes 1 and 2, adrenoleukodystrophy
  • Idiopathic
  • Abnormalities of β-oxidation of very long–chain fatty acids, most common cause of adrenal insufficiency in male child <7 years of age
  • Destruction of the adrenal cortex resulting in deficiencies in cortisol, aldosterone, and androgens

Genetics

  • Autoimmune polyglandular syndrome (APS) type 2 genetics are complex and are associated with adrenal insufficiency.
  • APS type 1 is caused by mutations of the autoimmune regulator gene. Nearly all have the following triad: adrenal insufficiency, hypoparathyroidism, and mucocutaneous candidiasis before adulthood.
  • Adrenoleukodystrophy is an X-linked recessive disorder resulting in toxic accumulation of unoxidized long-chain fatty acids.
  • Increased risk with cytotoxic T-lymphocyte antigen 4 (CTLA-4)

Risk Factors

  • 40% of patients have a first- or second-degree relative with associated disorders.
  • Chronic steroid use, then experiencing severe infection, trauma, or surgical procedures

General Prevention

  • Focus on prevention of complications. Anticipate adrenal crisis and treat before symptoms begin.
  • Elective surgical procedures require upward adjustment in steroid dose.

Commonly Associated Conditions

  • Diabetes mellitus
  • Graves disease
  • Hashimoto thyroiditis
  • Hypoparathyroidism
  • Hypercalcemia
  • Ovarian failure
  • Pernicious anemia
  • Myasthenia gravis
  • Vitiligo
  • Chronic moniliasis
  • Sarcoidosis
  • Sjögren syndrome
  • Chronic active hepatitis
  • Schmidt syndrome

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