Primary Adrenal Insufficiency

Descriptive text is not available for this imageBASICS

DESCRIPTION

Deficiency in adrenal gland cortisol and/or aldosterone secretion

EPIDEMIOLOGY

  • Etiology and incidence vary by age.
    • Newborn period: adrenal insufficiency associated with congenital adrenal hyperplasia (CAH) (1/10,000 to 15,000 live births).
    • Infancy or early childhood: adrenal hypoplasia congenita (1/12,500 live births)
    • Late infancy or toddler period: adrenocorticotropic hormone (ACTH) unresponsiveness (rare)
    • Late in 1st decade of life: Adrenoleukodystrophy presents with neurologic symptoms. Signs and symptoms of adrenal insufficiency in persons with adrenoleukodystrophy may first present at any age (prevalence 1/20,000 to 60,000).
    • Late childhood and adolescence: Addison disease (rare); usually presents between the ages of 20 and 50 years (prevalence 1/10,000 adults)
  • Sex
    • CAH and ACTH unresponsiveness affect both sexes equally.
    • Adrenal hypoplasia congenita and adrenoleukodystrophy are both X-linked disorders and predominantly affect males.
    • Addison disease is more common in females.

RISK FACTORS

Genetics

  • CAH: autosomal recessive inheritance associated with a gene defect in one of multiple adrenal steroidogenic enzymes, most commonly CYP21A2 for the 21-hydroxylase gene
  • Adrenal hypoplasia congenita: X-linked mutation in DAX1 gene
  • ACTH unresponsiveness: autosomal recessive ACTH receptor defect
  • Adrenoleukodystrophy
    • X-linked recessive disorder of very-long-chain fatty acid metabolism due to ABCD1 gene mutation
    • An autosomal recessive form of the disease exists which presents during infancy.
  • Autoimmune adrenal insufficiency
    • One cause of Addison disease
    • May be isolated or part of autoimmune polyglandular syndromes (APSs)
    • AIRE1 gene mutations cause APS type 1.
    • APS type 2 is associated with human leukocyte antigens (HLAs) DR3 and DR4.

PATHOPHYSIOLOGY

  • CAH: a group of enzymatic disorders of steroid metabolism, of which 21-hydroxylase deficiency is the most common (Appendix IV, Table 13)
  • Adrenal hypoplasia congenita: a defect in adrenal organogenesis
  • ACTH unresponsiveness
    • Inherited ACTH receptor defect, resulting in isolated glucocorticoid deficiency with hypoglycemia in infancy and hyperpigmentation
  • Adrenoleukodystrophies
    • Inherited disorders of impaired peroxisomal degradation of very-long-chain fatty acids, resulting in adrenal insufficiency and progressive neurologic deterioration
  • Addison disease
    • Primary hypoadrenalism due to bilateral destruction of the adrenal cortices
    • This can be due to autoimmune destruction (isolated or associated with APS), tuberculosis, hemorrhage, fungal infection, neoplastic infiltration, or AIDS.
  • Waterhouse-Friderichsen syndrome:
    • Bilateral adrenal gland hemorrhage classically associated with fulminant meningococcemia
    • Also reported with Staphylococcus aureus and Streptococcus pneumoniae

COMMONLY ASSOCIATED CONDITIONS

  • Adrenal hypoplasia congenita is associated with hypogonadotropic hypogonadism.
  • APSs are associated with other autoimmune disorders:
    • APS type 1: mucocutaneous candidiasis, hypoparathyroidism
    • APS type 2: autoimmune thyroid disease, type 1 diabetes
    • Both types can also present in conjunction with multiple other autoimmune disorders (e.g., primary ovarian or testicular insufficiency, celiac disease, pernicious anemia, vitiligo, autoimmune hepatitis).
  • Adrenoleukodystrophy is associated with progressive neurologic disease.

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