New PAI Guidelines Stress Importance of Treating Adrenal Crisis

Miriam E Tucker

January 21, 2016

The first-ever guidelines from the Endocrine Society on diagnosis and management of primary adrenal insufficiency (PAI) call for the use of the high-dose corticotropin stimulatory test as the gold standard for diagnosis in adults, hydrocortisone as first-line therapy, and urgent treatment of adrenal crisis.

The "Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline" was published online January 13 in the Journal of Clinical Endocrinology and Metabolism by an international 11-member expert panel chaired by Dr Stefan R Bornstein, director of the Medical Clinic III
and the Center for Internal Medicine, University Hospital, Dresden, Germany.

The document — which was cosponsored by the European Society of Endocrinology and the American Association for Clinical Chemistry — focuses specifically on PAI, particularly Addison's disease, and includes advice on management in children and pregnant women. (A previous Endocrine Society clinical guideline addressed congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency.)

"All forms of primary adrenal insufficiency are rare. Typical of rare diseases, there's not a lot of literature or randomized clinical trials….We brought together a group of experts to provide guidelines and expert opinions to help the physician in practice," pediatric endocrinologist and coauthor Deborah P Merke, MD, senior investigator at the National Institutes of Health Clinical Center, Bethesda, Maryland, told Medscape Medical News.

The document is divided into five sections: Who should be tested and how, optimal diagnostic tests, treatment in adults (with subsections on glucocorticoid, mineralocorticoid, and dehydroepiandrosterone replacement, and treatment during pregnancy and in children), management and prevention of adrenal crisis, and additional monitoring.

Diagnosis Often Missed: Corticotropin Stimulation Test Is Gold Standard

The diagnosis of PAI is often missed, Dr Merke noted, because "the signs and symptoms, such as persistent nausea, vomiting, and fatigue, could be mistaken for other things."

Clues to look for include unusual pigmentation — resulting from high pituitary ACTH levels — and a history of other autoimmune disorders such as type 1 diabetes or autoimmune thyroid disease. Other predisposing factors include infectious diseases such as tuberculosis, HIV infection, histoplasmosis, and drugs such as etomidate.

The panel recommends testing to rule out other causes in acutely ill patients with otherwise-unexplained volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or, especially in children, hypoglycemia.

For confirmation of PAI, they recommend the high-dose (250 µg for adults and children 2 years of age and older, 15 µg/kg for infants, and 125 µg for children less than 2 years of age) intravenous corticotropin stimulation (30- or 60-minute) test over other existing diagnostic tests.

A peak cortisol level below 500 nmol/L (18 µg/dL) at 30 or 60 minutes is indicative of adrenal insufficiency.

"The gold standard is the high-dose corticotropin test, with 250-µg ACTH stimulation of the adrenals. Physicians sometimes wonder if they should use lower vs higher dose or a random measurement.…We tried to look at this in terms of systematic review and didn't find good evidence for a lower dose. Sensitivity of the high dose is high, so we recommend that it still be considered the gold standard," Dr Merke explained.

Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase.

In autoantibody-negative individuals, other causes should be sought.

Importantly, for patients with severe adrenal-insufficiency symptoms or adrenal crisis, the panel recommends immediate therapy with intravenous hydrocortisone at an appropriate stress dose prior to the availability of the results of diagnostic tests.

"Adrenal crises are life-threatening. If you're really suspicious based on [signs and symptoms], don't withhold treatment before doing the definitive diagnostic tests. Those can be done later," Dr Merke stressed.

Hydrocortisone Recommended as First-Line Treatment

Glucocorticoid therapy is recommended for all patients with confirmed PAI, with hydrocortisone in two or three daily divided doses suggested as first-line treatment or prednisolone once or twice daily as an alternative if hydrocortisone isn't available.

The panel advises against using dexamethasone, because of the risk of cushingoid side effects due to difficulties in dose titration.

Dr Merke said that the panel conducted two systematic reviews of the various glucocorticoid products and found only observational studies to support a treatment recommendation but still generally advise the shorter-acting hydrocortisone over the longer-acting dexamethasone.

"Too much glucocorticoid replacement can cause obesity, hyperlipidemia, and osteoporosis in the long term. Shorter-acting hydrocortisone may result in less exposure and is also easier to use in lower doses," she said.

Along those lines, the panel also advised adjustment of treatment based on clinical response rather than hormonal monitoring to avoid overtreating. "A lot of clinicians like to measure ACTH….but if they try to normalize, they tend to overtreat. So, we recommend against hormonal monitoring."

For patients with confirmed aldosterone deficiency, the panel recommends mineralocorticoid replacement with fludrocortisone, without salt restriction.

And a trial of dehydroepiandrosterone (DHEA) replacement is advised for women with PAI and low libido, depressive symptoms, and/or low energy levels despite otherwise optimized glucocorticoid and mineralocorticoid replacement.

Pregnant women with PAI should be monitored for clinical symptoms and signs of glucocorticoid over- and underreplacement — such as fatigue, postural hypotension, or hypertension and hyperglycemia — with at least one review per trimester. Higher hydrocortisone doses may be necessary, especially during the third trimester.

Suggested treatment for children with PAI is also hydrocortisone, in three or four divided doses, dosed by body-surface area and adjusted as needed. Synthetic long-acting glucocorticoids such as prednisolone and dexamethasone are not recommended for children.

Addressing Adrenal Crisis

Patients who are suspected of having adrenal crisis should be treated immediately with parenteral injection of 100-mg (50-mg/m2 for children) hydrocortisone, followed by appropriate fluid resuscitation and 200-mg (50–100 mg/m2 for children) of hydrocortisone every 24 hours, with age- and body-surface–appropriate dosing.

Prednisolone can be used as an alternative for adrenal crisis if hydrocortisone is unavailable, while dexamethasone should be used only if no other glucocorticoid is available.

Patients should be educated about self-administering high doses of glucocorticoid at the first signs of stress, such as viral illness or surgery. They should carry medical-alert identification to inform health personnel of the need for increased glucocorticoid doses to avert or treat adrenal crisis and the need for immediate parenteral steroid treatment in case of emergency.

"For patients with known primary adrenal insufficiency, it's very important that physicians and patients are educated about what to do about stress. There are situations where the patient needs higher-dose steroids and if they don't get them they can die," Dr Merke said, noting that studies show that adrenal crisis is a major cause of increased mortality among PAI patients.

"That's the main thing I focus on when I see these patients. They will often encounter physicians who aren't familiar with adrenal insufficiency. If they go to the emergency department, eventually they'll get their stress dose but it might take a while.…There's a lot of lack of knowledge among healthcare providers that can lead to huge delays in their receiving their stress dose. If they get food poisoning or viral gastroenteritis, they need an injection of hydrocortisone right away. It's really important," she said.

Follow-up and a Sad Tribute

The guidelines also advise that adults and children with PAI be seen by an endocrinologist or a healthcare provider with endocrine expertise at least annually and infants at least every 3 to 4 months.

The writing panel dedicated the guidelines to coauthor and noted adrenal gland expert Bruno Allolio, MD, professor of medicine and head of the department of endocrinology at the University of Wuerzburg Medical University Hospital, Germany, who died suddenly in August 2015.

"It was very sad," Dr Merke said, adding, "He made a major contribution."

Dr Merke declared a "financial or business/organizational interest" in Diurnal Ltd, but no "significant financial interest or leadership positions. Disclosures for the coauthors are listed in the article.

J Clin Endocrinol Metab.Published online January 13, 2016. Article

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