4. Testing and Diagnosis

Due to the combination of nonspecific symptoms, a slow onset of those symptoms and the fact that adrenal insufficiency is considered a rare condition, diagnosis is often delayed, on average up to 5 years. 

There are no routinely checked lab parameters that would easily point towards the diagnosis. Although a high percentage of patients show low blood levels of sodium and glucose as well as high blood levels of potassium at the time they are diagnosed with primary adrenal insufficiency, the findings are often borderline and do not necessarily raise a “red flag”.

Proof or diagnosis of adrenal insufficiency depends entirely on demonstrating that the adrenal glands produce no or only minimal cortisol. The initial testing is simple and labs can be ordered by any physician.

The confirmation of the clinical diagnosis of adrenal insufficiency includes three steps:

1. Demonstrating an inappropriately low cortisol secretion.
2. Evaluating of the HPA axis
3. Confirming / excluding a cause of the primary disorder

4.1. Lab Tests

The morning serum cortisol checks baseline adrenal cortisol production. It should be drawn between 8 and 9am.

The HPA axis is evaluated by determining whether the cortisol deficiency is a) dependent on or independent of corticotropin (ACTH) production and b) the mineralocorticoid secretion in patients without ACTH deficiency.

The baseline ACTH test evaluates pituitary corticotropin (ACTH) production. It should be drawn simultaneously with the morning cortisol sample.

The morning cortisol and the baseline ACTH are sampled and interpreted together and should indicate the direction for further testing and/or referral to a specialist.

The ACTH stimulation test (also called corticotropin or Synacthen test) evaluates the stimulated adrenal cortisol response. ACTH is given as an intramuscular (IM) or intravenous (IV) injection to test the stress response of the adrenal glands. The blood cortisol concentrations are measured at the time of the injection (=baseline) as well as 30 min and 60 min later.
Healthy adrenal glands are expected to respond to the ACTH injection with a drastic increase of blood cortisol levels. People with non-functioning adrenal glands do not show this response and the increase of blood cortisol is minimal (if some adrenal function remains) or missing.

The ACTH stimulation test
Wrongly, the ACTH stimulation test is often ordered first. It is important to request that the baseline ACTH is sampled BEFORE the injection for the ACTH stimulation test. If the problem originates in the pituitary or hypothalamus, it can go undetected by the ACTH stimulation test alone, leading to misdiagnosis:
A lack of an appropriate response may indicate adrenal atrophy in patients with chronic secondary adrenal insufficiency.
An adequate response to the ACTH stimulation test does not eliminate the possibility of secondary or tertiary adrenal insufficiency.

The Metyrapone and the Insulin Tolerance Test (ITT), are used to measure stimulated pituitary ACTH production if secondary or tertiary adrneal insufficiency is suspected. Choice of which test to use is based on patient profile. Current recommendations favour the Metyrapone test. It is more accurate, less expensive, and easier to administer than the ITT.

Pre-testing considerations
The following hormones or drugs may interfere with accurate test results.
– Glucocorticoids or corticosteroids in any form, including topical, inhaled, injected, and oral tablets/capsules.
– Birth control or other estrogens, including soybean food products and menopause formulas.
– Drugs that inhibit cortisol biosynthesis, such as etomidate, ketoconazole, fluconazole, metyrapone, and suramin.
– Drugs that accelerate the metabolism of cortisol and most synthetic glucocorticoids by inducing hepatic mixed-function oxygenase enzymes, such as phenytoin, barbiturates, mitotane, and rifampin.
– High dose progestins or chronic administration of opiates.

4.2. Imaging Tests

Imaging tests such as a CT Scan or MRI are used to confirm or exclude any infiltrative process of the adrenals or hypothalamic and pituitary regions of the brain that would compromise normal hormone production.

Patients with no associated autoimmune disease should undergo a CT (computer tomography) scan of the adrenal glands to find the underlying cause. In developing countries and immigrant populations tuberculosis should be ruled out as a cause. A CT scan can also be helpful to detect rare causes such as bilateral adrenal lymphoma, adrenal metastases, sarcoidosis or amyloidosis.

If secondary or tertiary adrenal insufficiency is suspected an MRI of the hypothalamic and pituitary regions should be done. It can reveal pituitary tumours such as adenomas, meningiomas, metastases, sarcoidosis or other disease.

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> CHAPTER OVERVIEW
Anatomy/Physiology | Types of Adrenal Insufficiency | Symptoms | Testing/Diagnosis | Treatment | Stress dosing/Sick day Management | Adrenal Crisis | Quality of Life and Risks | Other Conditions and Drugs | Long-term Management | Suggested Reading | Literature/References

Author: Gisela Spallek, MD PhD
Edited by Maria Stewart, Director of AIC and deputy editor Des Rolph, Associate Director of AIC