TOC |  STAT Endo

Acute Adrenal Insufficiency or Adrenal Crisis  (Addison's Disease)   

Weakness (99%), Pigmentation of skin (98%), Weight loss (97%), Abdominal pain (34%),  Nausea & Vomiting, diarrhea, Salt craving (22%), Diarrhea (20%), Constipation (19%), Syncope (16%), Vitiligo (9%), fever, lethargy.
Hypovolemia, orthostatic hypotension, tachycardia, hyponatremia, hyperkalemia

Low serum cortisol level, & inadequate serum cortisol response 30 or 60 min after IV or IM Cortrosyn (syntheticACTH) 0.25 mg (normal is >18-20 ug/dl with increment of 7 ug/dl or greater)

Obtain baseline serum cortisol and ACTH levels.  Normal response is indicated when the cortisol level at least doubles in response to ACTH stimulation.  

Plasma ACTH levels are typically elevated in patients with primary adrenal failure and are normal or unmeasurable in patients with primary ACTH deficiency.

CRH may help distinguish between hypothalamic and pituitary etiologies of secondary adrenal insufficiency.  If an insulin tolerance test shows no cortisol response to hypoglycemia, secondary hypoadrenalism is present. If in such a patient a CRH test elicits a prompt ACTH release, then, by inference, hypothalamic disease is likely; if CRH does not elicit release of ACTH, then presumably the lesion is in the pituitary.

Laboratory findings in Adrenal Insufficiency 
Primary Adrenal Insufficiency:
  1. Decreased cortisol
  2. Increased CRH
  3. Increased ACTH
Secondary Adrenal Insufficiency from Pituitary Etiology:
  1. Decreased or Inappropirately Normal ACTH
  2. Decreased Cortisol
  3. Increased CRH


Secondary Adrenal Insufficiency from Hypothalamic Etiology:
  1. Decreased CRH
  2. Decreased or Inappropriately Normal ACTH
  3. Decreased Cortisol 


  1. Volume Replacement: IV D5NS >2 -3 liters
  2. Glucocorticoid Replacement: IV hydrocortisone 100 mg q8h.
    During ACTH stimulation testing, dexamethasone (4 mg IV) can be used instead of hydrocortisone, to avoid interference with testing of cortisol levels.
  3. Fluorocortisol (mineralocorticoid) 0.1 mg qd
  4. Supportive Rx for glucose, electrolytes, calcium imbalance, temp. abnormalities, etc.
  5. Correct precipitating causes.


Acute Adrenocortical Insufficiency  
Steroid withdrawal is the most common cause of adrenocortical insufficiency, 
and it almost exclusively causes a glucocorticoid deficiency.

Adrenal crisis may result from an acute exacerbation of chronic insufficiency, usually caused by sepsis or surgical stress. Acute adrenal insufficiency can also be caused by adrenal hemorrhage (eg, Waterhouse-Friderichsen syndrome [fulminant meningococcemia]) and anticoagulation complications.

Causes of Primary Adrenal Insufficiency 

  • Acute Onset:  Adrenal Hemorrhage or Infarction
  • Slow Onset: 
    the most frequent cause is idiopathic atrophy, which is probably autoimmune in origin.
    - the adrenal gland destruction by TB or fungal infection, or AIDS-Related infections, 
    - hemorrhage, 
    - infiltrating diseases the adrenal glands, as lymphoma or metastases.
    - drugs: ketoconazole, etomidate, enzyme inhibitors (eg, metyrapone), or cytotoxic agents (eg, mitotane).
    - insufficient adrenal hormone production as a result of congenital adrenal hyperplasia, adrenoleukodystrophy (Males)/

Causes of Secondary Adrenal Insufficiency (relatively common) 
- may be caused by hypopituitary or hypothalamic etiology, or may result from suppression of the hypothalamic-pituitary axis (exogenous steroids use, endogenous steroids [ie, tumor]).  

  • Acute Onset: 
    - Pituitary Apoplexy
    - Pituitary or Hypothalamic surgery
    - Traumatic brain injury 
  • Slow Onset: 
    - Autoimmune disease: as: lymphocytic hypophysitis
    - Infectious disease: as Tuberculosis
    - Cancer: as Pituitary or Hypothalamic tumors, lymphoma
    - Trauma or Other injury: traumatic brain injury, subarachnoid hemorrhage, radiation
    - Drugs: megestrol acetate
    -Others: as Discontinuation of exogenous glucocorticoids, sarcoidosis, empty sella syndrome. 



Testing Adrenal Function

The principal tests used to evaluate adrenal function include measurements of plasma ACTH and cortisol and of urinary 17-OHS and 24-hour urinary free cortisol.

Measurement of plasma cortisol and ACTH
Resting values of plasma cortisol are between 10 and 25 mg/dl in the morning and between 2 and 10 mg/dl at night. The plasma cortisol level is altered by changes in the amount of cortisol-binding globulin, which generally parallel changes in the level of thyroxine-binding globulin. For example, both proteins are raised by increased estrogen levels and lowered by hepatic disease. Resting levels of cortisol are often less significant than the responses of the hormone to physiologic stimuli. Thus, plasma cortisol levels are usually measured after administration of exogenous steroid to determine whether the pituitary-adrenal axis is susceptible to feedback inhibition (i.e., whether it is suppressible) and after ACTH administration to see whether the adrenal responds to stimulation.

The following are some well-standardized tests for the evaluation of adrenal function:

To determine pituitary-adrenal suppression, 1 mg of dexamethasone (a cortisol analogue) is given orally at 11:00 P.M., and the plasma cortisol level is measured at 8:00 A.M. the next day. A value of less than 5 mg/dl is normal.

To measure adrenal response, 0.25 mg of  Cortrosyn /cosyntropin (synthetic ACTH) is given intravenously. The plasma cortisol is measured at 0 and 30 or 60 minutes; a value of 20 mg/dl at any time during the test denotes normal adrenal responsiveness.

To assess pituitary-adrenal reserve, 3 g of metyrapone is administered orally at midnight, and plasma cortisol and 11-deoxycortisol (compound S) levels are obtained at 8:00 A.M. the next day. Metyrapone inhibits 11-hydroxylation, which leads to a fall in cortisol and a rise in ACTH. If the pituitary-adrenal reserve is intact, the plasma cortisol level should be less than 5 mg/dl and the 11-deoxycortisol level greater than 10 mg/dl.

An alternative method of measuring pituitary-adrenal reserve involves the intravenous administration of insulin, 0.15 U/kg. The ensuing hypoglycemia should elicit both cortisol (normal, 20 mg/dl) and growth hormone (> 8 ng/ml) responses. This test should be carried out in the presence of a physician prepared to administer 25 ml of 50 percent glucose intravenously in case of a hypoglycemic reaction.

To measure pituitary reserve of ACTH, ovine CRH can be administered in a dose of 1 mg/kg body weight. Both ACTH and plasma cortisol levels rise in normal individuals. This test can be performed at any time of day, but the sensitivity is greatest in the afternoon.

Plasma ACTH can be determined by immunoradiometric assay (IRMA), employing antibodies to both the N- and C-terminal domains of the hormone. Unlike radioimmunoassay, IRMA can reliably distinguish low, normal, and elevated ACTH levels.9

Urinary 17-OHS level
The urinary 17-OHS measurement has the advantage of integrating the secretion of cortisol during a 24-hour period, but its usefulness is limited because the level is elevated by obesity and depressed by hepatic and renal disease. Moreover, the collection of an accurately timed urine specimen is difficult for many patients.

24-Hour urinary free cortisol
The 24-hour urinary free cortisol test also requires accurately timed urine collections. Values in obese people rarely overlap with those in Cushing's syndrome patients, and hepatic disease does not distort the result. The urinary free cortisol excretion rate has become a valuable index of adrenal hyperfunction. It is less reliable for the detection of hypoadrenalism.

Scientific American Medicine 2000

See also  adrenal_insufficiency2005 (JAMA Vo. 294, Nov.16,2005) 



Diagnosis of Adrenal Insufficiency
Richard I. Dorin, MD; Clifford R. Qualls, PhD; and Lawrence M. Crapo, MD, PhD
Annals of Internal Medicine 5 August 2003 | Volume 139 Issue 3 | Pages 194-204
Conclusions: Cortisol response to cosyntropin varies considerably among healthy persons. The cosyntropin test performs well in patients with primary adrenal insufficiency, but the lower sensitivity in patients with secondary adrenal insufficiency necessitates use of tests involving stimulation of the hypothalamus if the pretest probability is sufficiently high. The operating characteristics of the 250-µg and 1-µg cosyntropin tests are similar.

Predisposing Factors to Adrenal Insufficiency 2009