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The Endocrine Society has issued its first ever clinical practice guideline on the diagnosis and treatment of primary adrenal insufficiency — a life-threatening endocrine disorder characterized by the insufficient production of glucocorticoids and/or mineralocorticoids by the adrenal cortex.
Commonly known as Addison’s disease, primary adrenal insufficiency is rare, with a reported prevalence of 100 to 140 cases per million and an incidence of 4 cases per million annually in Western societies.
The guideline, published online and in the February 2016 print issue of the Journal of Clinical Endocrinology & Metabolism, was co-sponsored by the European Society of Endocrinology and the American Association for Clinical Chemistry.
The task force charged with creating the guideline based its recommendations on the best available evidence from existing studies and systematic reviews on primary adrenal insufficiency, as well as results from 2 systematic reviews. Both reviews were commissioned by the task force.
One review evaluated the accuracy of high-dose adrenocorticotropic hormone (ACTH) vs low-dose ACTH stimulation tests used in the initial diagnosis of primary adrenal insufficiency; the other assessed various glucocorticoid replacement regimens.
The guideline includes recommendations in 5 areas:
- Who should be treated and how;
- Optimal diagnostic tests;
- Treatment of primary adrenal insufficiency in adults;
- Management and prevention of adrenal crisis; and
- Monitoring requirements.
The treatment section is further broken out into sections covering glucocorticoid replacement; mineralocorticoid replacement; dehydroepiandrosterone (DHEA) replacement; treatment during pregnancy; and treatment and monitoring during childhood.
Diagnosis: Screening and Confirmation
Due to the rarity of Addison’s disease as well as its nonspecific symptoms, diagnostic delays are common, potentially leading to increased morbidity and mortality.
To prevent these delays, the guideline recommends that primary adrenal insufficiency be ruled out in all patients with indicative clinical symptoms or signs, especially acutely ill patients, patients with predisposing factors such as autoimmune disorders or relevant drugs, and pregnant women with unexplained persistent nausea, fatigue, and hypotension.
“[T]he current most pressing need for the treatment of primary adrenal insufficiency is the early diagnosis,” task force member Andreas Barthel, MD, of the Universitätsklinikum Dresden and Endokrinologikum Ruhr in Bochum, Germany, wrote in an email to Endocrinology Advisor. “In order to accomplish this, we need to increase our awareness for the disease and add primary adrenal insufficiency early to the list of differential diagnosis in severely ill patients with particular symptoms and signs like hypotension, hyponatremia, fever, abdominal pain, hyperpigmentation, or hypoglycemia.”
Christian Koch, MD, professor of medicine and director of endocrinology at the University of Mississippi Medical Center, noted that the diagnosis of primary adrenal insufficiency in the community is currently suboptimal.
“Many physicians, mostly non-endocrinologists, do not currently have a very high level of suspicion for primary adrenal insufficiency, as indicated by the lack of knowledge that secondary adrenal insufficiency can be caused by administering high-dose topical glucocorticoids, inhaled glucocorticoids, injecting dexamethasone for sinusitis, and other conditions that should not call for glucocorticoid treatment,” he explained. “Hypoglycemia often is overlooked as a possible presentation of primary adrenal insufficiency. Hyponatremia also is often not investigated further for existing primary adrenal insufficiency before making a diagnosis of SIADH (syndrome of inappropriate antidiuretic hormone).”
The diagnostic tests recommended in the guideline include determination of serum cortisol and plasma ACTH for screening and the corticotropin stimulation test as a confirmatory test.
The task force recommends the standard-dose (250 mcg for adults and children 2 years of age and older, 15 mcg/kg for infants, and 125 mcg for children younger than 2) IV corticotropin stimulation (30- or 60-minute) test over other existing diagnostic tests. Peak cortisol levels below 500 nmol/L (18 mcg/dL) at 30 or 60 minutes are indicative of adrenal insufficiency.
While an alternative test that uses low-dose (1 mcg) corticotropin stimulation is available, it does not provide superior diagnostic accuracy, according to information in the guideline.
Patients presenting with severe adrenal insufficiency symptoms or adrenal crisis should receive immediate therapy with IV hydrocortisone in advance of receiving results from diagnostic testing, the recommendations state.
The guideline advises that the etiology of the disease be determined in all patients with confirmed primary adrenal insufficiency. “Interpretation of diagnostic testing for primary adrenal insufficiency is important and emphasized by considering rare conditions — inflammation, low albumin, critically ill patients, administration of estrogen, mitotane, etc — that alter cortisol-binding globulin and therefore the measured serum cortisol level,” noted Dr Koch.
Therapy: Glucocorticoids for Confirmed Primary Adrenal Insufficiency
The guideline suggests that all patients with confirmed primary adrenal insufficiency be treated with glucocorticoid therapy. The specific recommendation is for hydrocortisone (15 mg to 25 mg) or cortisone acetate (20 mg to 35 mg) in 2 or 3 divided oral doses per day, with prednisolone (3 mg to 5 mg per day), administered orally once or twice daily as an alternative, particularly for those with reduced compliance.
Dr Koch emphasized that the optimization of glucocorticoid therapy is a key component to the effective treatment of primary adrenal insufficiency.
“That means reducing noncompliance — often financial — in order to facilitate the widespread use of hydrocortisone over using other glucocorticoids that carry the risk of causing glucocorticoid excess. Ideally, a glucocorticoid and primary adrenal insufficiency replacement therapy should simulate the endogenous adrenal hormone situation with secretion around a circadian rhythm individualized for each patient with primary adrenal insufficiency,” Dr Koch said.
Mineralocorticoid replacement to maintain the body’s salt and water balance is recommended in the guideline for all patients with aldosterone deficiency. Patients receiving mineralocorticoid replacement therapy should be monitored by testing blood electrolyte levels and checking for symptoms such as salt craving, light-headedness, blood pressure changes, and swelling of the legs and feet.
Addressing Adrenal Crisis
Adrenal crises in primary adrenal insufficiency are characterized by hypotension, marked acute abdominal symptoms, and marked laboratory abnormalities, and require immediate treatment.
For the prevention of adrenal crisis, the task force recommends adjustments in glucocorticoid dose according to the severity of illness or magnitude of the stressor. The guideline also emphasizes the need for patient education about medication adjustments in stressful events, and suggests that patients be equipped with a steroid emergency card or medical alert identification in order to improve management and prevention of adrenal crisis.
Both Drs Koch and Barthel emphasize the need for patients with primary adrenal insufficiency to be followed by an endocrinologist or pediatric endocrinologist.
“The most important takeaway in the guideline is that diagnosis and treatment of primary adrenal insufficiency requires extensive experience and involvement of a specialist,” stated Dr Barthel.
