Are You Sure the Patient Has Adrenal Insufficiency?


Adrenal insufficiency can present either as an acute crisis with vascular collapse or as a chronic insufficiency, which has much more obscure symptomology. Adrenal insufficiency is either due to primary adrenal failure or secondary to hypothalamic/ pituitary diseases. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency causes 80% of adrenal insufficiency in infants. Diagnosis of the underlying cause (e.g. associated autoimmune disorders, neurological features of adrenoleukodystrophy, or disorders that may lead to adrenal infiltration) should include a validated assay of autoantibodies against 21-hydroxylase. CYP21A2 autoantibodies can develop several years before patients exhibit biochemical and clinical evidence of primary adrenal insufficiency, and 30% of patients who test positive progress to primary adrenal insufficiency within 2 years. If patients are CYP21A2 autoantibody-negative, the guideline recommends a computed tomography (CT) scan of the adrenals. This test may reveal infectious diseases like tuberculosis, or tumors.

If the patient has acute adrenal insufficiency, vascular collapse is often the first sign and the presentation can be post-surgical, in the emergency department or after multiple trauma. This complex is associated with lightheadedness, dizziness and weakness, or coma and obtundation. Headaches are rare but may be the first sign of pituitary apoplexy and secondary adrenal insufficiency.

If chronic adrenal insufficiency is suspected as an outpatient the symptoms are often vague and frequently consist of weight loss, fatigue, gastrointestinal pain that can be diffuse or epigastric, weight loss, salt craving and lassitude.

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  • Low blood pressure (acute and chronic), particularly orthostatic in nature, sometimes severe (acute).
  • Hyperpigmentation (primary adrenal insufficiency) is common but not diagnostic, epigastric tenderness is common.
  • In the setting of previous exogenous glucocorticoid use with rapid withdrawal there may be signs of excess glucocorticoids or Cushing’s syndrome with acute withdrawal.
Key Laboratory Findings
  • Inappropriately low serum cortisol particularly AM (0600-0800hr), cortisol less than 5 mcg/dl supportive of diagnosis, particularly in ICU/CCU setting.
  • ACTH level high (values greater than 200 pg/ml) supports primary adrenal insufficiency; low or normal ACTH (normal range: 20-50 pg/ml) with low AM Cortisol – secondary adrenal insufficiency.
  • The short corticotropin test (250 mcg) remains the gold standard for establishing a diagnosis. If a short corticotropin test is not possible, clinicians should screen initially by measuring morning plasma ACTH and cortisol levels. A plasma ACTH greater than twice the upper limit of the reference range is consistent with primary adrenal insufficiency

Additional tests are often required to establish the diagnosis including:

  • ACTH stimulation test (mandatory at some point): 250ug synthetic ACTH (cosyntropin) either IV or sc; cortisol at baseline (AM preferable), 30 and 60 minutes after injection: a value greater than 18-20 mcg/dl at either latter time points, excludes primary adrenal insufficiency, and most cases of secondary adrenal insufficiency.
  • Low serum sodium (primary and secondary), high potassium (primary), elevated BUN and Creatinine (primary and secondary), increased eosinophilia (primary), low serum osmolality (secondary), increased serum renin (primary), low serum aldosterone, inability to concentrate urine, high ADH level.

What Else Could the Patient Have?

In respect to acute adrenal insufficiency, vascular collapse can be due to acute hemorrhage, CNS disease, abdominal catastrophes, multiple trauma, sepsis or other conditions. Acute adrenal insufficiency can be superimposed on any of these other vascular events, as well as myocardial infarction, stroke or sepsis.

Chronic adrenal insufficiency can masquerade as a number of conditions related to weight loss including malignancy, anorexia nervosa, gastric ulcer, tuberculosis or other granulomatous diseases, HIV and hematologic disorders other than malignancy. As noted above, congenital adrenal hyperplasia is another potential chronic etiology.

Key Laboratory and Imaging Tests

The key test is the ACTH stimulation test which would detect virtually all cases of acute and chronic insufficiency. Occasionally, secondary insufficiency due to pituitary disease, such as postsurgical or postpartum hemorrhage, can be difficult to diagnose with single ACTH stimulation test. In that situation, oral metapyrone can be given in the evening prior to the AM cortisol. Metapyrone blocks the final step in cortisol synthesis and should lead to an increase in ACTH the following morning.

In the case of acute vascular collapse where you suspect adrenal insufficiency, blood should be drawn immediately for cortisol, renin, aldosterone and ACTH, and then the patient should be treated with intravenous dexamethasone and saline infusions. Further diagnostics can then be performed once the patient is stable, including adrenal CT scan (see below).

Other Tests That May Prove Helpful Diagnostically

For the etiology of adrenal insufficiency acute or chronic several other tests are helpful. CT of the adrenals will establish whether there are calcifications due to granulomatous diseases (e.g. tuberculosis, histoplasmosis, coccidioidomycosis), or adrenal hemorrhage (due to Coumadin or heparin), or metastatic adrenal disease (lung, pancreas, breast, colon). Most cases of adrenal insufficiency are related to auto immune causes; in general antibodies to adrenals are not helpful unless in the setting of multiple endocrine deficiencies, such as hypoparathyroidism (low calcium) hypothyroidism (high TSH), or gonadal failure (high LH/FSH).

Management and Treatment of the Disease

Acute adrenal insufficiency requires rapid replacement of fluids and glucocorticoids. 1-3 liters of 0.9% saline solution or 5% dextrose in 0.9% saline (to correct possible hypoglycemia) should be infused intravenously within the first 12-24 hours based on assessment of volume status and urine output. In a patient without a previous diagnosis of adrenal insufficiency, dexamethasone (4 mg intravenous bolus) is preferred because, in contrast to hydrocortisone, it is not measured in serum cortisol assays.

Hydrocortisone 100 mg IV given every 4-6 hours can be used instead of dexamethasone in cases in which the diagnosis is known. Glucocorticoids can be tapered over 3 days to maintenance doses of 20 mg hydrocortisone in the a.m. and 10 mg in the p.m. or 7.5 mg prednisone per day. Hydrocortisone is preferred because of its mineralocorticoid activity if the patient is suspected of having primary adrenal insufficiency.

If the patient has primary adrenal insufficiency addition of a mineralocorticoid is preferred to keep doses of glucocorticoid to a minimum. Fludrocortisone (flurinef, 0.1 mg per day is recommended). For secondary adrenal insufficiency, no mineralocorticoid is indicated but attention should be paid to other endocrine disorders that might require replacement, such as hypothyroidism or hypoparathyroidism. Adrenal sex steroids such as DHEA and DHEA-S don’t usually require replacement although some studies suggest that women have improved quality of life when given 50 mg of DHEA daily along with hydrocortisone and flurinef.

Chronic Adrenal insufficiency. As noted above, depending on the etiology and if it is primary or secondary, short acting glucocorticoid with or without mineralocorticoid indicated. Long acting glucocorticoids such as dexamethasone are not indicated for chronic treatment due to long term side effects. The Endocrine Society guideline recommends once-daily fludrocortisone (with median dose of 0.1 mg) and hydrocortisone (15-25 mg/day) or cortisone acetate replacement (20-35 mg/day) given in 2 to 3 daily doses as the preferred regimens. – See more at:

Monitoring replacement. The usual replacement regimen means the lowest possible glucocorticoid dose that maintains a good quality of life. Monitoring for mineralocorticoid deficiency in primary adrenal insufficiency requires a yearly check of plasma renin. High renin levels (above 4ng/ml) usually indicate a need for an increase in flurinef up to 0.2 mg per day.

Replacement pre-operatively or for acute illnesses. The rule of 3×3 (i.e. three times the replacement dose for 3 days) is usually followed by the patient for febrile illnesses or minor surgical procedures. For surgical procedures the severity of the surgery is considered. For minor procedures such as herniorrhaphy, a dose equivalent to hydrocortisone 25 mg is suggested for the day of operation only, with a return to the usual replacement dose on the second day.

For moderate surgery (e.g. cholecystectomy, joint replacement), divided intravenous doses equivalent to hydrocortisone 75 mg are suggested on the day of surgery and the first post-operative day, with a return to the usual dose on the second post-operative day . A total daily dose equivalent to 100-150 mg hydrocortisone for major surgical procedures (e.g. cardiac bypass) should be given in divided doses for 2-3 days, after which the usual dose should be given.

What’s the Evidence?/References