Adrenal insufficiency (AI) is the insufficient secretions of corticosteroids that may cause partial or complete destruction of the adrenal glands.
Primary AI or Addison’s disease is due to the inability of the adrenal gland to produce steroid hormones even when the stimulus by the pituitary gland via corticotrophin is adequate or increased.
Secondary AI is due to disorders of the pituitary gland that causes production of low levels of adrenocorticotropic hormone that will result to reduced cortisol levels.
Tertiary AI is the inability of the hypothalamus to produce sufficient amount of corticotropin releasing hormone.
Signs and symptoms are usually nonspecific with insidious onset.
Common signs and symptoms are fatigue, weakness, salt craving, orthostatic hypotension, nausea, vomiting, abdominal pain, diarrhea, anorexia and weight loss.


Adrenocorticotropic Hormone (ACTH) Stimulation Test

  •  Also known as Corticosyn/Synacthen test
  • Performed to rule out adrenal insufficiency (AI)
    • Assess adrenal reserve and responsiveness
  • Baseline cortisol values <5 mcg/dL and ACTH concentration >100 pg/mL are usually diagnostic of primary adrenal insufficiency
  • Measure cortisol response every 30-60 minutes and 6 hours after administration of 250 mcg of synthetic ACTH intramuscular/intravenous (IM/IV)
    • Gold standard diagnostic test for primary adrenal insufficiency
    • Peak cortisol levels <500 mg nmol/L indicates adrenal insufficiency
    • A serum cortisol with or without ACTH stimulation that exceeds 550 nmol/L (>20 mcg/dL) excludes adrenal insufficiency
    • A normal response to ACTH stimulation is doubling of cortisol levels
    • Adrenal insufficiency is indicated by a serum cortisol level that fails to rise after adrenocorticotrophic hormone  administration
    • A normal response to ACTH stimulation is doubling of cortisol levels
    • Adrenal insufficiency is indicated by serum cortisol level that fails to rise after ACTH administration
    • Mild secondary adrenal insufficiency may result in close to normal cortisol levels and further confirmatory work-up may be necessary

Low-Dose Short Corticotropin Test

  • Suitable for detecting mild secondary adrenal insufficiency or if corticotropin is at low supply
  • Measure cortisol response at 20-60 minutes after administration of 1 mcg of Cosyntropin IV
    • Adrenal function is normal if serum cortisol level is ≥500 nmol/L (18 mcg/L)

Laboratory Tests

Further Testing to Distinguish Between Primary and Secondary/Tertiary Adrenal Insufficiency (AI)

  • Primary Adrenal Insufficiency
    • Plasma adrenocorticotropic hormone (ACTH) and associated peptides (β-LPT) are raised
    • Aldosterone increment level will be subnormal (from the same blood sample as stated above)
  • Secondary/Tertiary Adrenal Insufficiency
    • Aldosterone increment level, from the same blood sample as stated above, will be normal ≥150 pmol/L (5 ng/dL)
    • Plasma ACTH values are low-normal
    • Insulin-induced hypoglycemia test may be performed to distinguish normal subjects and patients with secondary adrenal insufficiency
      • Done by administration of 0.15 unit/kg of regular insulin IV bolus followed by every 15-minute interval blood glucose and cortisol management throughout the subsequent 2 hours
      • Blood glucose must fall <45 mg/mL for adequate stimulation
      • Normal response: >20 µg/dL plasma cortisol at any time during the test


Other Laboratory Examination

  • Complete blood count (CBC), electrolytes, blood urea nitrogen (BUN), creatinine, thyroid function test, chest X-ray, 24-hour urinary cortisol
  • Electrocardiogram (ECG)
    • May show peaked T waves in hyperkalemia


  • Computed tomography (CT) scan of the abdomen
    • May show adrenal hemorrhage, or calcification as seen in tuberculosis (TB) of the adrenal, or metastasis
  • Head computed tomography (CT) scan
    • May show pituitary destruction or pituitary mass lesion

Basic Laboratory Examination for Acute Adrenal Insufficiency (AI)

  • Obtain basal diagnostic bloods to measure cortisol and adrenocorticotropic hormone (ACTH) levels
  • Adrenal insufficiency (AI) is usually ruled out if plasma cortisol level is >700 nmol/L (25 mcg/dL)
  • Obtain history of past steroid use
  • Diagnosis can be confirmed with more detailed tests once patient recovers from acute illness
  • When there is prior history and/or strong clinical suspicion of acute AI, treatment is mandatory
  • Therapy should not be delayed for diagnostic studies
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