Adrenal insufficiency is defined as hypofunction of the adrenal gland with decreased or absent cortisol secretion.

Epidemiology

• Incidence – estimated at 5/100,000
• Sex – M:F, equal

Classification

• Primary or secondary insufficiency

Etiology

• Causes of primary adrenal insufficiency
  • Autoimmune  (Addison disease)
    • Frequent association with other endocrine diseases
      • Autoimmune polyendocrine syndromes
        • Epidemiology
          • Incidence – 1-2/100,000
          • Age – usually in 30s
          • Sex – M<F, 1:3
        • Most frequent endocrine abnormality is adrenal insufficiency
        • Type 1
          • Addison disease
          • Chronic mucocutaneous candidiasis
          • Hypoparathyroidism
        • Type 2
          • Diabetes mellitus type 1 (DM1)
          • Addison disease with hypothyroidism – Schmidt syndrome
      • Both types 1 and 2 may also include:
        • DM1
        • Other autoimmune disorders – vitiligo, chronic atrophic gastritis, alopecia
    • Autoantibodies to 21-hydroxylase are frequently present
  • Anatomic destruction of the gland
    • Surgical removal
    • Bilateral hemorrhage into the gland
      • Associated with anticoagulant therapy
    • Invasion of the gland
      • Metastatic cancer is extremely rare
  • Infection
    • Bacterial
      • Tuberculosis
      • Meningococcus (Waterhouse-Friderichsen) – rare
      • Pseudomonas – rare
    • Fungal – histoplasmosis, coccidioidomycosis
    • Viral – cytomegalovirus (CMV), AIDS
  • Congenital adrenal hyperplasia (CAH)
• Causes of secondary adrenal insufficiency
  • Hypopituitarism
    • Postpartum hemorrhage – Sheehan syndrome
    • Pituitary radiation
    • Pituitary surgery
    • Acute interruption of prolonged corticosteroids
    • Pituitary infiltrative disease – tuberculosis, sarcoidosis, Wegener granulomatosis
  • Exogenous glucocorticoid administration
  • Lymphocytic hypophysitis – may be part of autoimmune polyendocrine syndrome

Pathophysiology

• Primary – glucocorticoid and mineralocorticoid deficiency
• Secondary – only glucocorticoid deficiency

Clinical Presentation

• Insidious onset of fatigue, weakness, anorexia, nausea and emesis
• Cutaneous hyperpigmentation – diffuse tan, brown or bronzing
  • Does not occur in secondary insufficiency
• Orthostatic hypotension
• Diarrhea, abdominal pain
• Acute presentation may occur in patients with mild adrenal insufficiency who are stressed (eg, critical illness, surgery)
  • Mainly attributable to mineralocorticoid deficiency
  • Hypotension which is unresponsive to fluids

Treatment

• Primary – glucocorticoids and mineralocorticoids in primary
• Secondary – glucocorticoids only
• Increase glucocorticoid dosing during acute illness

Indications for Testing

• Presence of disease process associated with adrenal insufficiency and other symptoms consistent with adrenal insufficiency

Laboratory Testing

• Initial testing
  • Measure early morning serum cortisol
    • Cortisol ≥5 µg/dL makes primary adrenal insufficiency less likely; however, if serious consideration is given to this diagnosis, perform stimulation testing
  • Follow with adrenocorticotropic hormone (ACTH) testing
    • If ACTH >300 pg/dL – adrenal failure likely
    • If ACTH <10 pg/dL – pituitary failure likely
    • If ACTH between 10 pg/dL and 300 pg/dL – administer ACTH (cosyntropin) stimulation test
• Stimulation
  • ACTH (cosyntropin) stimulation test – cortisol response to cosyntropin (250 µg followed by serial cortisol measures at 30 and 60 minutes)
    • Cortisol <5 µg/dL – adrenal failure
    • Cortisol >20 µg/dL – normal
    • Cortisol ≤20 µg/dL but ≥5 µg/dL – evaluate for pituitary failure; adrenal insufficiency likely
  • Evaluation for pituitary failure
    • Insulin tolerance testing (ITT)
    • Metyrapone overnight testing
      • If 11 deoxycortisol >7 µg/dL – adrenal failure unlikely; MRI/CT of adrenal glands
    • CT/MRI anatomic location based on cortisol ratios (see Adrenal Insufficiency Testing Algorithm)
      • If 11 deoxycortisol ≤7 µg/dL – pituitary failure likely; order MRI/CT
        • If still unsure – corticotropin releasing hormone (CRH) stimulus testing
          • If ACTH <10 pg/mL – pituitary failure likely

Imaging Studies

• MRI/CT based on stimulation testing
• If stimulation testing or absolute cortisol suggests adrenal failure – MRI/CT of adrenal glands
• If stimulation testing suggests pituitary failure – MRI/CT of pituitary

Differential Diagnosis

• Bronchogenic carcinoma
• Hemochromatosis
• M. tuberculosis
• Congenital adrenal hyperplasia
• Malnutrition

Tests generally appear in the order most useful for common clinical situations

General

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ARUP Institute for Clinical and Experimental Pathology®

• La'ulu SL, Roberts WL. Performance characteristics of the Architect cortisol immunoassay. Clin Chim Acta. 2008; 388 (1-2) :219-221.PubMed

Congenital Adrenal Hyperplasia
Electrolyte Abnormalities, Life Threatening
Hemochromatosis
Hypopituitarism
Mycobacterium tuberculosis
Sepsis