Adrenal Insufficiency


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 – primary severe 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) – not recommended in children <6 years
      • 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
  • 21-hydroxylase antibodies confirm autoimmune etiology

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

Clinical Background

Adrenal insufficiency (sometimes referred to as Addison disease) is defined as hypofunction of the adrenal gland with decreased or absent cortisol secretion.


  • Incidence – estimated at 5-10/100,000
  • Sex – M:F, equal


  • Primary or secondary insufficiency


  • Causes of primary adrenal insufficiency
    • Autoimmune  (Addison disease) – frequent association with other endocrine diseases
    • Autoimmune polyendocrine syndromes
      • Epidemiology
      • Most frequent endocrine abnormality is adrenal insufficiency 
        • Incidence – 1-2/100,000
        • Age – usually in 30s
        • Sex – M<F, 1:3
      • Classification
        • Type 1 associated characteristics
        • Type 2 associated characteristics
        • Types 1 and 2 may also include other autoimmune disorders – vitiligo, chronic atrophic gastritis, alopecia
      • Autoantibodies to 21-hydroxylase – frequently present
    • Anatomic destruction of the gland
      • Surgical removal
      • Bilateral hemorrhage into the gland – associated with anticoagulant therapy
      • Invasion of the gland
        • Metastases – lung, stomach, breast, and colon most common
        • Infiltrative disorders – lymphoma, amyloid iron overload
    • Infection
    • Genetic disorders (eg, adrenoleukodystrophy, congenital adrenal hyperplasia [CAH])
    • Medications – etomidate, ketoconazole, metyrapon
  • Causes of secondary adrenal insufficiency (central insufficiency)
    • Hypopituitarism
      • Postpartum hemorrhage – Sheehan syndrome
      • Pituitary radiation
      • Pituitary surgery
      • Acute interruption of prolonged corticosteroids
      • Pituitary infiltrative disease – sarcoidosis, granulomatosis with polyangiitis
      • Traumatic brain injury
    • Drug induced (eg, corticosteroids)
    • Lymphocytic hypophysitis – may be part of autoimmune polyendocrine syndrome


  • 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

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Cortisol by LC-MS/MS, Serum or Plasma 2003250
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Initial screen for adrenal insufficiency    
Adrenocorticotropic Hormone 0070010
Method: Quantitative Chemiluminescent Immunoassay
Help differentiate adrenal versus pituitary etiology of adrenal failure Some types of synthetic ACTH are not detected by this assay  
11-Deoxycortisol Quantitative by HPLC-MS/MS, Serum or Plasma 0092331
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Measured after metyrapone testing    
21-Hydroxylase Antibody 0070265
Method: Quantitative Radioimmunoassay
Secondary testing after adrenal insufficiency established to diagnose Addison disease    
Additional Tests Available
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Adrenocorticotropic Hormone Stimulation, 0 Minutes 0070031
Method: Quantitative Chemiluminescent Immunoassay

Screen for adrenal insufficiency

Adrenocorticotropic Hormone Stimulation, 60 Minutes 0070033
Method: Quantitative Chemiluminescent Immunoassay
Screen for adrenal insufficiency
Adrenocorticotropic Hormone Stimulation, 30 Minutes 0070032
Method: Quantitative Chemiluminescent Immunoassay
Aldosterone 30 Minute 0070016
Method: Quantitative Chemiluminescent Immunoassay
Aldosterone 60 Minute 0070017
Method: Quantitative Chemiluminescent Immunoassay
Aldosterone, Serum 0070015
Method: Quantitative Chemiluminescent Immunoassay

Differentiate primary adrenal insufficiency from secondary adrenal insufficiency

Cortisol, Free 0098391
Method: Equilibrium Dialysis/Quantitative Electrochemiluminescent Immunoassay

Screen for adrenal insufficiency

Cortisol, Serum or Plasma 0070030
Method: Quantitative Chemiluminescent Immunoassay

Screen for adrenal insufficiency

Potassium, Plasma or Serum 0020002
Method: Quantitative Ion-Selective Electrode

Screen for adrenal insufficiency