A clinical practice guideline on primary adrenal insufficiency (PAI) released by the Endocrine Society and co-sponsored by AACC calls for diagnostic testing to exclude PAI in acutely ill patients with otherwise unexplained symptoms or signs suggestive of PAI. The guideline also recommends corticotropin stimulation testing to confirm PAI diagnosis—provided that the patient is able to undergo such a test—and it details other optimal diagnostic tests.

“Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline” has been published by the Journal of Clinical Endocrinology & Metabolism (JCEM).

Andrew Don-Wauchope, MB.BCh, MD, FRCP Edin, FCPath, FRCPath, FRCPC, served as AACC’s representative on the guideline committee. He is an associate professor of pathology and molecular medicine at McMaster University in Hamilton, Ontario, Canada.

PAI, also referred to as Addison’s disease, arises when a patient doesn’t produce enough cortisol, a hormone necessary for maintaining functions such as the body’s immune system and its response to stress, cardiovascular function, blood pressure, and the ability to convert food into energy. Individuals who suffer from this condition can experience gastrointestinal problems, fatigue, muscle weakness, and weight loss.

“Diagnosing primary adrenal insufficiency remains challenging because many of the symptoms are associated with a variety of health conditions,” said Stefan R. Bornstein, MD, PhD, of the Universitätsklinikum in Dresden, Germany, and King’s College in London, U.K., and chair of the task force that authored the guideline, in a statement from AACC.

Bornstein emphasizes that immediate treatment of symptoms is key, as delaying this step can raise the chances of a patient dying from this condition. This is necessary even if someone is awaiting a test to confirm a diagnosis, he said.

The guideline recommends intravenous corticotropin stimulation testing with a 250 µg dose for adults and children older than age 2 over other tests to diagnose PAI. Peak cortisol levels <500 nmol/L (18 µg/dL) at 30 or 60 minutes indicate adrenal insufficiency. When corticotropin stimulation testing is not feasible, the authors suggest using a morning cortisol <140 nmol/L (5 µg/dL) in combination with adrenocorticotropic hormone (ACTH) testing as a preliminary diagnostic until confirmatory testing can be done.

“The guideline discusses the recommended cut-point for the 30- or 60-minute sample as being dependent on the cortisol method. For simplicity, it still states the traditional 500 nmol/L (18µ/dl) as this is how the systematic review analyzed the data,” Don-Wauchope told CLN Stat. “Even though cortisol has a good degree of standardization there are still significant bias between methods. The guideline provides references to the studies that demonstrate that there should be differences in cut-point based on the laboratory method being used. Each laboratory should consider the typical bias for its method against other methods as assessed by a proficiency testing scheme.”

Don-Wauchope added that laboratories “might also need to consider the typical performance of their instrument(s). This information should be available so that they can provide relevant information to the physicians interpreting the synacthen (ACTH) test results.

Blood tests to measure renin and aldosterone hormones should be part of the diagnostic process. Glucocorticoid replacement therapy is recommended for all patients with confirmed cases of PAI.

For patients with confirmed PAI and aldosterone deficiency, the guidelines suggested mineralocorticoid replacement therapy with fludrocortisone, at a starting dose of 50 –100 g for adults. “Anyone receiving this therapy should be monitored by testing blood electrolyte levels and checking for symptoms like salt craving, light-headedness, blood pressure changes and swelling of the legs and feet,” according to AACC’s statement, which summarized the guidelines’ main recommendations.

The guideline’s section on the perspectives and demand for future research also has implications for laboratories, Don-Wauchope told CLN Stat. “There is increasing interest in salivary testing for cortisol as an alternative test to serum cortisol.” This section of the guideline also mentions using more specific methodologies such as liquid chromatography-tandem mass spectrometry to analyze cortisol.

The laboratory community needs to continue to work at improving its assays, and the advice it provides around the interpretation, Don-Wauchope noted. “This is all part of our quality process. Specifically for cortisol we should be looking at reference method targets for our proficiency testing as this would better enable bias assessment.”