FROM THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
New guidelines on the diagnosis and management of primary adrenal insufficiency stress the importance of early recognition and the need to prevent life-threatening adrenal crises in these patients.
These are the first clinical practice guidelines on primary adrenal insufficiency (PAI), also known as Addison’s disease, issued by Endocrine Society ( J Clin Endocrinol Metab. 2016 Jan 13:jc20151710 [Epub ahead of print] ).
“Because it’s a rare disease and symptoms can mimic common conditions, adrenal insufficiency is often, at least initially, overlooked,” guideline co-author Dr. Deborah Merke , a senior investigator with the National Institutes of Health Clinical Center in Bethesda, Md., said. “So the main goal of these clinical practice guidelines is to improve patient care.”
The guidelines suggest clinicians should have a low diagnostic threshold in acutely ill patients with unexplained symptoms or signs suggestive of PAI such as volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or, especially in children, hypoglycemia.
This low diagnostic threshold for PAI should also be extended to pregnant women with unexplained persistent nausea, fatigue, and hypotension.
For adult patients with a suspected adrenal crisis, an immediate parenteral injection of hydrocortisone 100 mg should be given, followed by appropriate fluid resuscitation and 200 mg of hydrocortisone for 24 hours, according to the guidelines, which were co-sponsored by the European Society of Endocrinology and American Association for Clinical Chemistry .
Despite a known association between adrenal crisis and mortality, there is a knowledge gap regarding how to prevent, recognize, and reduce the risk of these life-threatening events, Dr. Merke said.
To that end, the task force has taken a page from the diabetes community in recommending all PAI patients carry steroid emergency identification cards and be equipped with a glucocorticoid injection kit for emergency use and be educated on how to use it.
The guidelines also advocate education about stress dosing to counter the increased demand for corticosteroids during periods of stress, which can encompass something as common as the flu.
“Just like diabetics carry around emergency medicines, it’s important for patients with adrenal insufficiency to carry around an emergency kit and to realize that should they start to get sick, they need to increase their doses,” she said. “There often seems to be a lack of awareness among physicians as well that these patients have a potentially life-threatening condition, should they get a common illness.”
One of the key unanswered clinical questions the task force sought to address was whether the widely used high-dose (250 mcg) corticotropin stimulation test, also known as the adrenocorticotropin (ACTH) or short Synacthen test, should be replaced by the low-dose test (1 mcg) to diagnosis PAI.
Despite a review of published data and a systematic review commissioned by the task force, “We didn’t come up with much scientific evidence to say we should be changing the historic standard,” Dr. Merke said.
The systematic review identified only five studies of high-dose corticotropin testing specifically in PAI and none of low-dose testing. The low-dose test has shown higher sensitivity in the detection of adrenal insufficiency in critically ill patients and secondary adrenal insufficiency, but the limited available data suggest it does not provide better diagnostic accuracy for PAI than the high-dose test.
As a result, the guidelines recommend the standard, short corticotropin test (250 mcg for adults and children aged at least 2 years) as the “gold standard” diagnostic test to establish a PAI diagnosis.
The low-dose (1 mcg) test is recommended only when corticotropin is in short supply, which is not typically a problem in the United States, she said.
If corticotropin testing isn’t feasible, a combination of a morning plasma ACTH and cortisol levels (less than 5 mcg/dL) can be used as an initial screening, though confirmatory testing with corticotropin stimulation is strongly recommended.
Glucocorticoid therapy is recommended in all patients with confirmed PAI based on the highest quality of evidence, with a clear preference given for the short-acting steroids, Dr. Merke observed.
Hydrocortisone 15 mg-25 mg or cortisone acetate 20 mg-35 mg given in two to three divided doses per day is suggested for adults, with the highest dose to be given in the morning. Once- or twice-daily prednisolone 3 mg-5 mg is suggested as an alternative.
Hydrocortisone is also suggested over cortisone acetate, prednisolone, or prednisone for pregnant women and recommended for children (about 8 mg/m2 per day), but the evidence supporting these items was of low quality.
The guidelines suggest against using dexamethasone, the longest-acting glucocorticoid, because of the potential long-term side effects of overt-treatment and the frequent appearance of cushingoid side effects. They also recommend against dexamethasone in pregnant women because it is not inactivated in the placenta.
The guidelines are also quite clear in their suggestion against hormonal monitoring of glucocorticoid replacement and instead favor adjusting treatment based only on clinical response.
“This is a very important suggestion that we made because often clinicians use ACTH to adjust doses and this commonly results in overreplacement and there are side effects to overreplacement,” including weight gain, insomnia, and peripheral edema, Dr. Merke said.
A second systematic review commissioned by the task force involving 15 observational studies of glucocorticoid replacement regimens uncovered very sparse data on mortality, bone density, and incidence of adrenal crisis.
It has been suggested that newer extended-release and dual-release glucocorticoid formulations may result in higher health-reality quality of life than once-, twice-, or thrice-daily regimens, but once again, the evidence was insufficient to support a specific recommendation.
Dr. Merke acknowledged that many of the guidelines recommendations were ungraded or best practices, reflecting the lack of randomized clinical trials in PAI.
“I think that’s why it was so important for us to do this,” she said. “We had a group of experts that were very familiar with this disease providing guidance, but I think it’s also one reason why physicians out there in practice get confused about exactly what to do because of the lack of hard evidence. … It does certainly cry for the need for more studies in these rare diseases.”
The guidelines were funded by the Endocrine Society, and the authors reported receiving no external funding or remuneration.
