Adrenal Insufficiency

Diagnosis

Indications for Testing

  • Symptoms consistent with adrenal insufficiency (eg, hypotension, weakness)
  • Presence of disease process associated with adrenal insufficiency

Laboratory Testing

  • Initial testing
    • Measure early morning serum cortisol
      • Cortisol ≥5 µg/dL makes primary adrenal insufficiency less likely
        • If serious consideration is given to this diagnosis, perform stimulation testing
    • Follow abnormal cortisol results 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
  • Testing based on ACTH result
    • ACTH stimulation test (cosyntropin)
      • Measures cortisol response to cosyntropin (250 µg using serial cortisol measures at 0, 30, and 60 minutes)
        • Cortisol <5 µg/dL – primary severe adrenal failure
        • Cortisol >20 µg/dL – normal; adrenal insufficiency unlikely
        • Cortisol ≤20 µg/dL but ≥5 µg/dL – evaluate for pituitary failure; secondary 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
          • If 11 deoxycortisol ≤7 µg/dL – pituitary failure likely; order MRI/CT
            • If still not clear – corticotropin releasing hormone (CRH) stimulus testing
              • If ACTH <10 pg/mL – pituitary failure likely
  • Autoimmune etiology confirmation – presence of 21-hydroxylase antibodies confirm autoimmune etiology

Imaging Studies

  • MRI/CT based on stimulation testing results
    • 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 is defined as hypofunction of the adrenal gland with decreased or absent cortisol secretion.

Epidemiology

  • Incidence – estimated at 5-10/100,000 (Charmandari, 2014)
  • Sex – M:F, equal

Classification

  • Primary or secondary insufficiency

Etiology

  • Primary adrenal insufficiency
    • Autoimmune
      • Addison disease
        • Frequent association with other endocrine diseases
        • Autoantibodies to 21-hydroxylase – frequently present
      • Autoimmune polyendocrine syndromes
        • Epidemiology
          • Incidence – 1-2/100,000
          • Age – 30s
          • Sex – M<F, 1:3
        • Classification
          • Type 1 associated characteristics
          • Type 2 associated characteristics
          • Type 4 associated characteristics
            • Other  autoimmune disorders excluding thyroid disease and type 1 DM
          • Types 1 and 2 may also include other autoimmune disorders – vitiligo, chronic atrophic gastritis, alopecia
    • Infection
    • Anatomic destruction of the gland
      • Surgical removal
      • Bilateral hemorrhage into the gland – may be associated with anticoagulant therapy
      • Invasion of the gland
        • Metastases – lung, stomach, breast, and colon most common
        • Infiltrative disorders – lymphoma, amyloid iron overload
    • Genetic disorders (eg, adrenoleukodystrophy, congenital adrenal hyperplasia [CAH])
    • Medications – etomidate, ketoconazole, metyrapone
  • Secondary adrenal insufficiency (central insufficiency)
    • Drug induced (eg, corticosteroids)
    • Hypopituitarism
      • Postpartum hemorrhage – Sheehan syndrome
      • Pituitary radiation
      • Pituitary surgery
      • Acute interruption of prolonged corticosteroids
      • Pituitary infiltrative disease – sarcoidosis, granulomatosis with polyangiitis
      • Traumatic brain injury
    • Lymphocytic hypophysitis – may be part of autoimmune polyendocrine syndrome

Pathophysiology

  • Primary – combined glucocorticoid and mineralocorticoid deficiency
  • Secondary – 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)
    • Hypotension which is unresponsive to fluids
    • Mainly attributable to mineralocorticoid deficiency

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
Use for evaluation of adrenal axis disorders    
Adrenocorticotropic Hormone 0070010
Method: Quantitative Chemiluminescent Immunoassay

Aids in the diagnosis of adrenal insufficiency and determining the presence of anterior pituitary tumors

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 autoimmune 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, diagnose, and monitor diseases associated with excess or deficient cortisol production

Adrenocorticotropic Hormone Stimulation, 60 Minutes 0070033
Method: Quantitative Chemiluminescent Immunoassay

Screen, diagnose, and monitor diseases associated with excess or deficient cortisol production

Adrenocorticotropic Hormone Stimulation, 30 Minutes 0070032
Method: Quantitative Chemiluminescent Immunoassay

Screen, diagnose, and monitor diseases associated with excess or deficient cortisol production

Aldosterone 30 Minute 0070016
Method: Quantitative Chemiluminescent Immunoassay

Use in aldosterone suppression or loading testing

Aldosterone 60 Minute 0070017
Method: Quantitative Chemiluminescent Immunoassay

Use in aldosterone suppression or stimulation testing

Aldosterone, Serum 0070015
Method: Quantitative Chemiluminescent Immunoassay

The combined aldosterone/renin tests are preferred or aldosterone and renin, direct with ratio for diagnosing hyperaldosteronism

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

Screen, diagnose, and monitor diseases associated with excess or deficient cortisol production

Cortisol, Serum or Plasma 0070030
Method: Quantitative Chemiluminescent Immunoassay

Differential diagnosis of Cushing syndrome

Screen and diagnose primary and secondary adrenal insufficiency

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

Screen for adrenal insufficiency