Adrenal Insufficiency

Adrenal insufficiency, a potentially fatal condition in the case of adrenal crisis, is defined as hypofunction of the adrenal gland with decreased or absent hormone secretion. It can be classified as primary, secondary, or tertiary. Primary adrenal insufficiency (PAI), also known as Addison disease, is due to damage to or loss of adrenal tissue, which results in deficiency of all adrenocortical hormones. These hormones include mineralocorticoids, glucocorticoids, and androgens. Addison disease is most common in high-income countries. PAI can also be caused by​ congenital adrenal hyperplasia (CAH) (a group of rare genetic conditions) or other diseases that affect the adrenal gland. Secondary and tertiary adrenal insufficiency (known collectively as adrenal insufficiency) result from dysfunction along the hypothalamic-pituitary axis, which leads to deficiency of the glucocorticoid hormones.  Both secondary and tertiary adrenal insufficiency can also result from use of glucocorticoid drugs, such as prednisolone.

The recommended initial laboratory workup in the evaluation of adrenal insufficiency is the adrenocorticotropic hormone (ACTH) stimulation test. Patients in acute adrenal crisis, however, require prompt treatment and stabilization before diagnostic evaluation.   Subsequent testing may help differentiate primary and secondary adrenal insufficiency and identify the etiology.

Quick Answers for Clinicians

Who should be tested for adrenal insufficiency?

Acutely ill patients with symptoms of primal adrenal insufficiency (PAI) that cannot be explained by another cause should be tested.  Other patient types who should be tested include individuals with certain autoimmune disorders or infections and pregnant women with fatigue, hypotension, and nausea unrelated to pregnancy alone. 

What are the recommended tests for evaluation of adrenal insufficiency?

The short corticotropin test (also called the adrenocorticotropic hormone [ACTH] stimulation test) administered with a 250 μg dose is considered the gold standard test to confirm a diagnosis of primary adrenal insufficiency (PAI).   If the stimulation test is not available, a combination of morning cortisol and plasma ACTH testing can be used preliminarily. 

Which testing algorithms are related to this topic?

Indications for Testing

The early symptoms of adrenal insufficiency are nonspecific, which may lead to delayed diagnosis. They include:

  • Weakness
  • Fatigue
  • Loss of appetite and weight loss
  • Nausea
  • Musculoskeletal pain
  • Dizziness

Symptoms suggestive of PAI include:

  • Extracellular fluid volume reduction
  • Abdominal pain
  • Hypotension
  • Hyponatremia
  • Hyperkalemia
  • Fever
  • Hyperpigmentation
  • Hypoglycemia, especially in pediatric patients

If untreated, patients may experience adrenal crisis and death. Clinicians should use a low threshold for diagnostic evaluation in :

  • Acutely ill patients
  • Patients with predisposing factors (eg, type 1 diabetes mellitus, autoimmune gastritis, HIV, tuberculosis)
  • Patients taking certain medications, such as adrenal enzyme inhibitors, phenytoin, and St. John’s wort
  • Pregnant women with unexplained fatigue, constant nausea, and hypotension

Laboratory Testing                            

Patients in acute adrenal crisis require prompt treatment and stabilization before diagnostic evaluation.  

Initial Diagnostic Testing

Adrenocorticotropic Hormone Stimulation Test

The recommended initial diagnostic tool to determine adrenal insufficiency (and the gold standard test for diagnosing PAI) is the short corticotropin test (also called the ACTH stimulation test) with cortisol response measurements at 0, 30, and/or 60 minutes.   The recommended standard dose of cosyntropin is 250 μg for adults and children 2 years and older, 125 μg for children younger than 2 years, and 15 μg/kg for infants.  A low-dose (1 μg) version of the test should be used only when the corticotropic agent is in short supply.  Intravenous administration is recommended over intramuscular administration. 

Serum Cortisol and Plasma Adrenocorticotropic Hormone ​Measurement

When a short corticotropin test is not possible or feasible, the combination of morning cortisol and ACTH measurement is a preliminary option until the stimulation test can be performed to confirm the diagnosis, unless the combined results of the two tests (morning cortisol and ACTH measurement) are unquestionable.  Test results for pregnant women and critically ill patients should be interpreted with caution because cortisol levels are naturally altered in these conditions.

Additional Testing

Once a diagnosis of adrenal insufficiency has been established, further testing should be performed to identify the underlying cause  of the insufficiency and determine other medical implications. Imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) may also be necessary when an adenoma, lesion, or infection is suspected as the cause. 

Aldosterone and Renin Testing

Simultaneous measurement of aldosterone and plasma renin is recommended in cases of adrenal insufficiency to determine whether the patient has mineralocorticoid deficiency.  Such testing also helps with diagnosis in the early phase of PAI development (when the deficiency may be the only indication) and in differentiating primary from secondary adrenal insufficiency.  A high plasma renin activity measurement with a low or inappropriately normal serum aldosterone concentration is suggestive of PAI.   Both aldosterone and renin levels are typically normal in secondary insufficiency.  Aldosterone deficiency also leads to low levels of sodium and high levels of potassium in the blood.

21-Hydroxylase Antibody Testing

A positive 21-hydroxylase antibody test result confirms an autoimmune etiology of PAI, in which the body’s own immune response attacks adrenal tissue. If the 21-hydroxylase test result is negative, other causes should be investigated. 

17-Hydroxyprogesterone Testing

For infants and also children and adults with PAI with suspected CAH, consider 17-hydroxyprogesterone testing to determine if CAH or a genetic syndrome is the etiology. 

Pituitary Function Evaluation

In cases of secondary adrenal insufficiency, assess the hypothalamic-pituitary axis with imaging.  See the Hypopituitarism ARUP Consult topic for further testing information.

Monitoring

Monitoring of glucocorticoid replacement should be based on clinical assessment; hormonal monitoring is generally not recommended.  For patients receiving mineralocorticoid replacement therapy, monitoring includes clinical assessment and blood electrolyte measurements.  Morning serum DHEA sulfate levels should be used to monitor women receiving dehydroepiandrosterone (DHEA) replacement therapy.​ 

ARUP Laboratory Tests

Initial Testing

Recommended Initial Testing for Diagnosis of Adrenal Insufficiency
Additional Testing for Diagnosis of Adrenal Insufficiency

Additional Testing

Testing for Mineralocorticoid Deficiency
Testing for Etiology of Adrenal Insufficiency
Monitoring Tests
Related Tests

Medical Experts

Contributor

Kroner

 
Grace M. Kroner, PhD
Clinical Chemistry Fellow at ARUP Laboratories and University of Utah
Contributor

References

Additional Resources