Full Guideline: Diagnosis and Treatment of Primary Adrenal Insufficiency
JCEM | February 2016
Stefan R. Bornstein (chair), Bruno Allolio, Wiebke Arlt, Andreas Barthel, Andrew Don-Wauchope, Gary D. Hammer, Eystein S. Husebye, Deborah P. Merke, M. Hassan Murad, Constantine A. Stratakis, and David J. Torpy
The 2016 guideline addresses:
- Treating and diagnosing patients during and after an adrenal crisis
- Testing and diagnosing in optimal circumstances
- Setting a regimen for glucocorticoid and mineralocorticoid replacement
- Treatment and monitoring in pregnancy and childhood
- Managing adrenal crisis in diagnosed individuals
- Monitoring and additional screening
Diagnosis and Treatment of Adrenal Insufficiency | ENDO 2017
Essential Points
The Endocrine Society recommends that acutely ill patients who have unexplained symptoms undergo diagnostic testing to rule out primary adrenal insufficiency. Those who have severe symptoms of the condition or adrenal crisis should undergo immediate treatment with medication until diagnostic test results are available. Health care providers should conduct a corticotropin stimulation test to confirm the diagnosis when the patient’s condition allows.
- Patients should undergo a blood test to measure levels of adrenocorticotropic hormone (ACTH) – the hormone that signals the adrenal glands to produce cortisol – to establish a primary adrenal insufficiency diagnosis.
- As part of the diagnostic process, patients should have blood tests to measure the levels of the hormones renin and aldosterone. This test determines if a person has a deficiency of the hormones used to regulate the balance of salt and water in the body.
- Patients who have a confirmed diagnosis of primary adrenal insufficiency should undergo glucocorticoid replacement therapy—typically with hydrocortisone (cortisol), the glucocorticoid hormone naturally produced by the adrenal glands.
- People who have primary adrenal insufficiency and a confirmed aldosterone deficiency should undergo replacement therapy—typically with the synthetic hormone fludrocortisone—to maintain the body’s salt and water balance. 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.
Summary of Recommendations
+ 1.0 Who should be tested and how?
- 1.1 We recommend diagnostic testing to exclude primary adrenal insufficiency (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|⊕⊕⊕⚪)
- 1.2 We recommend 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|⊕⊕⊕⊕)
- 1.3 In patients with severe adrenal insufficiency symptoms or adrenal crisis, we recommend immediate therapy with iv hydrocortisone at an appropriate stress dose prior to the availability of the results of diagnostic tests. (1|⊕⊕⊕⚪)
+ 2.0 Optimal diagnostic tests
- 2.1 We suggest 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|⊕⊕⚪⚪)
- 2.2 We suggest the low-dose (1 μg) corticotropin test for diagnosis of PAI only when the substance itself is in short supply. (2|⊕⊕⚪⚪)
- 2.3 If a corticotropin stimulation test is not feasible, we suggest 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|⊕⚪⚪⚪)
- 2.4 We recommend 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 >2-fold the upper limit of the reference range is consistent with PAI. (1|⊕⊕⊕⚪)
- 2.5 We recommend the simultaneous measurement of plasma renin and aldosterone in PAI to determine the presence of mineralocorticoid deficiency. (1|⊕⊕⊕⚪)
- 2.6 We suggest that the etiology of PAI should be determined in all patients with confirmed disease. (For diagnostic workup, see Table 2 and Figure 1.) (Ungraded best practice recommendation)
+ 3.0 Treatment of primary adrenal insufficiency in adults
Glucocorticoid replacement regimen
- 3.1 We recommend glucocorticoid therapy in all patients with confirmed PAI. (1|⊕⊕⊕⊕)
- 3.2 We suggest 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|⊕⊕⚪⚪)
- 3.3 As an alternative to hydrocortisone, we suggest using prednisolone (3–5 mg/d), administered orally once or twice daily, especially in patients with reduced compliance. (2|⊕⚪⚪⚪)
- 3.4 We suggest against using dexamethasone for the treatment of PAI because of risk of Cushingoid side effects due to difficulties in dose titration. (2|⊕⊕⚪⚪)
- 3.5 We suggest monitoring glucocorticoid replacement using clinical assessment including body weight, postural blood pressure, energy levels, signs of frank glucocorticoid excess. (2|⊕⊕⊕⚪)
- 3.6 We suggest against hormonal monitoring of glucocorticoid replacement and to adjust treatment only based on clinical response. (2|⊕⊕⊕⚪)
Mineralocorticoid replacement in PAI
- 3.7 We recommend 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|⊕⊕⊕⊕)
- 3.8 We recommend monitoring mineralocorticoid replacement primarily based on clinical assessment (salt craving, postural hypotension, or edema), and blood electrolyte measurements. (1|⊕⊕⊕⚪)
- 3.9 In patients who develop hypertension while receiving fludrocortisone, we suggest reducing the dose of fludrocortisone. (2|⊕⚪⚪⚪)
- 3.10 If blood pressure remains uncontrolled, we suggest initiating antihypertensive treatment and continuing fludrocortisone. (2|⊕⚪⚪⚪)
- Dehydroepiandrosterone replacement
- 3.11 We suggest 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|⊕⊕⚪⚪)
- 3.12 We suggest 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|⊕⊕⚪⚪)
- 3.13 We suggest monitoring DHEA replacement by measuring morning serum DHEA sulfate (DHEAS) levels (aiming at the midnormal range) before the intake of the daily DHEA replacement dose. (2|⊕⊕⚪⚪)
Treatment during pregnancy
- 3.14 We suggest 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. (Ungraded best practice statement)
- 3.15 We suggest that, based on the individual clinical course, an increase in hydrocortisone dose should be implemented, in particular during the third trimester. (Ungraded best practice statement)
- 3.16 In pregnant women with PAI, we suggest using hydrocortisone over cortisone acetate, prednisolone, or prednisone (2|⊕⊕⚪⚪) and recommend against using dexamethasone because it is not inactivated in the placenta. (1|⊕⊕⚪⚪)
- 3.17 We recommend hydrocortisone stress dosing during the active phase of labor, similar to that used in major surgical stress. (1|⊕⊕⚪⚪)
Treatment and monitoring during childhood
- 3.18 In children with PAI, we suggest treatment with hydrocortisone in three or four divided doses (total starting daily dose of 8 mg/m2body surface area) over other types of glucocorticoid replacement therapies, with doses adjusted according to individual need. (2|⊕⊕⚪⚪)
- 3.19 In children with PAI, we suggest avoiding synthetic, long-acting glucocorticoids (eg, prednisolone, dexamethasone). (2|⊕⊕⚪⚪)
- 3.20 We suggest monitoring glucocorticoid replacement by clinical assessment, including growth velocity, body weight, blood pressure, and energy levels. (Ungraded best practice statement)
- 3.21 In children with PAI and confirmed aldosterone deficiency, we recommend treatment with fludrocortisone (starting dosage, 100 μg/d). For infants, we recommend sodium chloride supplements in the newborn period and up to the age of 12 months. (1|⊕⊕⚪⚪)
+ 4.0 Management and prevention of adrenal crisis in patients with PAI
- 4.1 We recommend 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|⊕⊕⊕⚪)
- 4.2 If hydrocortisone is unavailable, we suggest prednisolone as an alternative. Dexamethasone is the least-preferred alternative and should only be given if no other glucocorticoid is available. (2|⊕⊕⚪⚪)
- 4.3 For the prevention of adrenal crisis, we suggest adjusting glucocorticoid dose according to severity of illness or magnitude of the stressor. (2|⊕⊕⚪⚪)
- 4.4 We suggest patient education concerning glucocorticoid adjustments in stressful events and adrenal crisis-prevention strategies including parenteral self- or lay-administration of emergency glucocorticoids. (Ungraded best practice statement)
- 4.5 We recommend 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. (Ungraded best practice statement)
- 4.6 We recommend that every patient should be equipped with a glucocorticoid injection kit for emergency use and be educated on how to use it. (Ungraded best practice statement)
+ 5.0 Additional monitoring requirement
- 5.1 We suggest 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 to 4 months. (Ungraded best practice statement)
- 5.2 We suggest that PAI patients be evaluated annually for symptoms and signs of over- and under-replacement. (Ungraded best practice statement)
- 5.3 We suggest 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|⊕⊕⚪⚪)
- 5.4 We suggest 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. (Ungraded best practice statement)
- 5.5 We suggest genetic counseling for patients with PAI due to monogenic disorders. (Ungraded best practice statement)
