Diagnosis and Treatment of Primary Adrenal Insufficiency

Publication Date: February 1, 2016

Diagnosis

Who Should Be Tested and How

The Endocrine Society (ES) recommends diagnostic testing to exclude PAI in acutely ill patients with otherwise unexplained symptoms or signs suggestive of PAI (volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation or, especially in children, hypoglycemia). ( 1-M )
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ES recommends confirmatory testing with the corticotropin stimulation test in patients with clinical symptoms or signs suggesting PAI when the patient’s condition and circumstance allow. ( 1-H )
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Optimal Diagnostic Tests

ES suggests the standard dose (250 μg for adults and children ≥2 y of age, 15 μg/kg for infants, and 125 μg for children <2 y of age) IV corticotropin stimulation (30 or 60 min) test over other existing diagnostics tests to establish the diagnosis of adrenal insufficiency. Peak cortisol levels below 500 nmol/L (18 μg/dL) (assay dependent) at 30 or 60 minutes indicate adrenal insufficiency. ( 2-L )
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ES suggests the low-dose (1 μg) corticotropin test for diagnosis of PAI only when the substance itself is in short supply. ( 2-L )
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If a corticotropin stimulation test is not feasible, ES suggests using a morning cortisol <140 nmol/L (5 μg/dL) in combination with ACTH as a preliminary test suggestive of adrenal insufficiency (until confirmatory testing with corticotropin stimulation is available). ( 2-VL )
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ES recommends measurement of plasma ACTH to establish PAI. The sample can be obtained at the same time as the baseline sample in the corticotropin test or paired with the morning cortisol sample. In patients with confirmed cortisol deficiency, a plasma ACTH >2x the upper limit of the reference range is consistent with PAI. ( 1-M )
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ES recommends the simultaneous measurement of plasma renin and aldosterone in PAI to determine the presence of mineralocorticoid deficiency. ( 1-M )
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ES suggests that the etiology of PAI should be determined in all patients with confirmed disease. (For diagnostic workup, see Table 2 and Figure 1.) ( UGPS )
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Treatment

Treatment of Primary Adrenal Insufficiency in Adults

In patients with severe adrenal insufficiency symptoms or adrenal crisis, ES recommends IMMEDIATE therapy with IV hydrocortisone at an appropriate stress dose prior to the availability of the results of diagnostic tests ( 1-M )
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Glucocorticoid Replacement Regimen

ES recommends glucocorticoid therapy in all patients with confirmed PAI. ( 1-H )
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ES suggests using hydrocortisone (15–25 mg) or cortisone acetate (20–35 mg) in two or three divided oral doses per day. The highest dose should be given in the morning at awakening, the next either in the early afternoon (2 h after lunch—two-dose regimen) or at lunch and afternoon (three dose regimen). Higher frequency regimens and size-based dosing may be beneficial in individual cases. ( 2-L )
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As an alternative to hydrocortisone, ES suggests using prednisolone (3–5 mg/d), administered orally once or twice daily, especially in patients with reduced compliance. ( 2-VL )
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ES suggests against using dexamethasone for the treatment of PAI because of risk of Cushingoid side effects due to difficulties in dose titration. ( 2-L )
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ES suggests monitoring glucocorticoid replacement using clinical assessment including body weight, postural blood pressure, energy levels, signs of frank glucocorticoid excess. ( 2-M )
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ES suggests against hormonal monitoring of glucocorticoid replacement and to adjust treatment only based on clinical response. ( 2-M )
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Mineralocorticoid Replacement in PAI

ES recommends that all patients with confirmed aldosterone deficiency receive mineralocorticoid replacement with fludrocortisone (starting dose, 50–100 μg in adults) and not restrict their salt intake. ( 1-H )
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ES recommends monitoring mineralocorticoid replacement primarily based on clinical assessment (salt craving, postural hypotension, or edema), and blood electrolyte measurements. ( 1-M )
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In patients who develop hypertension while receiving fludrocortisone, ES suggests reducing the dose of fludrocortisone. ( 2-VL )
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If blood pressure remains uncontrolled, ES suggests initiating antihypertensive treatment and continuing fludrocortisone. ( 2-VL )
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Dehydroepiandrosterone Replacement

ES suggests a trial of dehydroepiandrosterone (DHEA) replacement in women with PAI and low libido, depressive symptoms, and/or low energy levels despite otherwise optimized glucocorticoid and mineralocorticoid replacement. ( 2-L )
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ES suggests an initial period of 6 months of DHEA replacement. If the patient does not report a sustained, beneficial effect of replacement after 6 months, the DHEA should be discontinued. ( 2-L )
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ES suggests monitoring DHEA replacement by measuring morning serum DHEA sulfate (DHEAS) levels (aiming at the mid-normal range) before the intake of the daily DHEA replacement dose. ( 2-L )
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Treatment During Pregnancy

ES suggests that pregnant patients with PAI be monitored for clinical symptoms and signs of glucocorticoid over- and under-replacement (eg, normal weight gain, fatigue, postural hypotension or hypertension, hyperglycemia), with at least one review per trimester. ( UGPS )
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ES suggests that, based on the individual clinical course, an increase in hydrocortisone dose should be implemented, in particular during the third trimester. (UGPS)
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In pregnant women with PAI, ES suggests using hydrocortisone over cortisone acetate, prednisolone, or prednisone (2-L)
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and recommends against using dexamethasone because it is not inactivated in the placenta. (1-L)
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ES recommends hydrocortisone stress dosing during the active phase of labor, similar to that used in major surgical stress. (UGPS)
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Treatment and Monitoring During Childhood

In children with PAI, ES suggests treatment with hydrocortisone in three or four divided doses (total starting daily dose of 8 mg/m2 body surface area) over other types of glucocorticoid replacement therapies, with doses adjusted according to individual need. ()
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In children with PAI, ES suggests avoiding synthetic, long-acting glucocorticoids (eg, prednisolone, dexamethasone)
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ES suggests monitoring glucocorticoid replacement by clinical assessment, including growth velocity, body weight, blood pressure, and energy levels. ()
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In children with PAI and confirmed aldosterone deficiency, ES recommends treatment with fludrocortisone (starting dosage, 100 μg/d). For infants, ES recommends sodium chloride supplements in the newborn period and up to the age of 12 months.
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Management and Prevention of Adrenal Crisis in Patients with PAI

ES recommends that patients with suspected adrenal crisis should be treated with an immediate 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/24 hours (via continuous IV therapy or 6 hourly injection); age- and body surface-appropriate dosing is required in children (see Table 3). ( 1-M )
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If hydrocortisone is unavailable, ES suggests prednisolone as an alternative. Dexamethasone is the least preferred alternative and should be given only if no other glucocorticoid is available. ( 2-L )
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For the prevention of adrenal crisis, ES suggests adjusting glucocorticoid dose according to severity of illness or magnitude of the stressor. ( 2-L )
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ES suggests patient education concerning glucocorticoid adjustments in stressful events and adrenal crisis prevention strategies including parenteral self- or lay-administration of emergency glucocorticoids. ( UGPS )
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ES recommends that all patients should be equipped with a steroid emergency card and medical alert identification to inform health personnel of the need for increased glucocorticoid doses to avert or treat adrenal crisis and the need of immediate parenteral steroid treatment in the event of an emergency. ( UGPS )
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ES recommends that every patient should be equipped with a glucocorticoid injection kit for emergency use and be educated on how to use it. ( UGPS )
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Additional Monitoring Requirement

ES suggests that adults and children with PAI be seen by an endocrinologist or a healthcare provider with endocrine expertise at least annually. Infants should be seen at least every 3–4 months. ( UGPS )
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ES suggests that PAI patients be evaluated annually for symptoms and signs of over- and under-replacement. ( UGPS )
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ES suggests periodic screening for autoimmune diseases known to be more prevalent in PAI patients in whom autoimmune origin of PAI has not been excluded. The optimal frequency of screening is unknown but can be done annually. These conditions include thyroid disease, diabetes mellitus, premature ovarian failure, celiac disease, and autoimmune gastritis with vitamin B12 deficiency. ( 2-L )
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ES suggests patient education about increasing the dosage of glucocorticoids during intercurrent illness, fever, and stress. This education includes identification of precipitating symptoms and signs and how to act in impending adrenal crisis. ( UGPS )
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ES suggests genetic counseling for patients with PAI due to monogenic disorders. ( UGPS )
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Recommendation Grading

Disclaimer

Overview

Title

Diagnosis and Treatment of Primary Adrenal Insufficiency

Authoring Organization

Endorsing Organization

Publication Month/Year

February 1, 2016

Supplemental Implementation Tools

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Female, Male, Adolescent, Adult, Child, Infant, Older adult

Health Care Settings

Ambulatory

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Assessment and screening, Diagnosis, Management, Treatment

Diseases/Conditions (MeSH)

D000309 - Adrenal Insufficiency

Keywords

primary adrenal insufficiency, PAI, hypocortisolism, Addison's disease

Source Citation

Stefan R. Bornstein, Bruno Allolio, Wiebke Arlt, Andreas Barthel, Andrew Don-Wauchope, Gary D. Hammer, Eystein S. Husebye, Deborah P. Merke, M. Hassan Murad, Constantine A. Stratakis, David J. Torpy, Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 2, 1 February 2016, Pages 364–389, https://doi.org/10.1210/jc.2015-1710