61: Adrenal Insufficiency

Key Points

• Disease summary:

  • Adrenal insufficiency is caused by a defective production of adrenal hormones due to a primary disorder of the adrenal gland or dysregulation of the hypothalamic-pituitary-adrenal axis.

  • Hereditary factors have been known to play a role in developing this condition.

  • Adrenal insufficiency is categorized as primary (failure of the adrenals to produce cortisol and/or aldosterone and/or androgens), secondary (deficient production of pituitary adrenocorticotropic hormone [ACTH]), or tertiary (impaired production of corticotropin-releasing hormone [CRH] by hypothalamus)

  • Primary adrenal insufficiency is classified as

    • Autoimmune—polyglandular syndromes type 1, 2, or other autoimmune conditions

    • Infectious—Waterhouse-Friderichsen syndrome (Neisseria meningitidis, Mycobacterium tuberculosis, Streptococcus pneumoniae, cytomegalovirus, histoplasmosis, etc)

    • Bilaterally metastatic disease: lung, breast, gastrointestinal carcinomas

    • Vascular-bilateral adrenal hemorrhage (hemorrhagic diathesis, trauma)

    • Genetic syndromes related to deficiency of enzymes in steroidogenesis and cholesterol metabolism, transcription factors, storage diseases, corticotropin receptor and signaling, sterol secretion, etc

    • Medications: mitotane, aminoglutethimide, ketoconazole, metyrapone, mifepristone RU486, megestrol, rifampicin, anticonvulsants (phenytoin), and others

  • Secondary adrenal insufficiency causes

    • Hypopituitarism (congenital, acquired, primary or metastatic tumor, radiation)

    • Iatrogenic (high-dose glucocorticoid therapy)

  Clinical presentation of adrenal insufficiency is variable. Based on the causative factors various clinical expressions of the disease have been observed. The condition may have an abrupt or gradual onset or may appear in childhood or late in life.

• Hereditary basis:

  • Conditions inherited in an autosomal recessive pattern

    • 21-hydroxylase deficiency (the most common form of congenital adrenal hyperplasia (CAH)

    • 17-alpha-hydroxylase deficiency(<1% of all cases of CAH)

    • 11-beta-hydroxylase deficiency (represents 5%-8% of all cases)

    • 3-beta-hydroxysteroid dehydrogenase (HSD) type II deficiency

    • Lipoid congenital adrenal hyperplasia (the most severe form of CAH)

    • Smith-Lemli-Opitz (SLO) syndrome

    • Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis

    • Wolman disease

    • Familial glucocorticoid deficiency 1 (>50% of patients do not have mutations in the MC2R gene)

    • Triple A syndrome

    • Polyglandular autoimmune syndrome type 1

    • Sitosterolemia

    • Zellweger syndrome

    • Panhypopituitarism: HESX1, OTX2, LHX4, PROP1, TBX19

  Condition inherited in an autosomal dominant inheritance

  • Glucocorticoid receptor deficiency

  Condition inherited in an X-linked recessive pattern

  • Congenital adrenal hypoplasia (X-linked)

  • Congenital adrenal hypoplasia (SF1 linked)

  • Adrenoleukodystrophy

  • Hyperglycerolemia

  • Panhypopituitarism: SOX3

Diagnostic Criteria and Clinical Characteristics

As there are so many genetic etiologies without a uniform picture (ie, ambiguous genitalia for some, alacrima for others, mucocutaneous candidiasis in AIRE patients, etc), the biochemical screening and diagnosis prevails:

• Plasma cortisol at 8 am less than 3 μg/dL

• Plasma cortisol less than 18 μg/dL (495 nmol/L) 30 to 60 minutes after 250 μg cosyntropin IV or IM

• Plasma aldosterone increment less than 5 ng/dL (150 pmol/L) after cosyntropin

Clinical Characteristics

The clinical presentation of adrenal insufficiency is directly correlated with the degree of loss of adrenal function. Individuals with chronic primary adrenal insufficiency may present with a variety of symptoms and clinical signs related to the extent of glucocorticoid, mineralocorticoid, and androgen deficiency. Patients with secondary adrenal insufficiency usually preserve their mineralocorticoid function for a ...