Guideline sources The following summarized guidelines for the evaluation and management of primary adrenal insufficiency (PAI) are prepared by our editorial team based on guidelines from the Endocrine Society (ES 2016). 1 Guidelines 1. Screening and diagnosis Indications for testing: obtain 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). B 2. Diagnostic investigations https://web.pathway.md/diseases/recWRkYdyophV7mpt 1/5 6/29/23, 11:28 PM Primary adrenal insufficiency Pathway Corticotropin stimulation test: perform a corticotropin stimulation test in patients with clinical symptoms or signs suggesting PAI, when the patient's condition and circumstance allow. A Show 2 more Morning cortisol: consider using a morning cortisol < 140 nmol/L in combination with ACTH as a preliminary test suggestive of adrenal insufficiency, if a corticotropin stimulation test is not feasible. C Plasma ACTH: obtain measurement of plasma ACTH to establish PAI. In patients with confirmed cortisol deficiency, a plasma ACTH > 2 times the ULN is consistent with PAI. B Plasma renin and aldosterone: obtain simultaneous measurements of plasma renin and aldosterone in patients with adrenal insufficiency, in order to assess for the presence of mineralocorticoid deficiency. B Evaluation for underlying etiology: Consider determining the etiology of PAI in all patients with confirmed disease. C Obtain the following tests in adult patients with PAI: serum 17-hydroxyprogesterone level to test for congenital adrenal hyperplasia in infants and selected children and adults 21-hydroxylase antibodies to test for autoimmune adrenalitis plasma VLCFAs to test for adrenoleukodystrophy in males with negative 21-hydroxylase antibodies CT scan of the adrenals to eliminate an adrenal infiltrative processes or metastases in all patients with an unknown etiology of adrenal insufficiency after laboratory testing. B 3. Medical management Corticosteroid replacement: administer corticosteroid therapy to all patients with confirmed PAI. A Show 3 more Mineralocorticoid replacement: initiate mineralocorticoid replacement with fludrocortisone (50-100 g PO daily) in all patients with confirmed aldosterone deficiency. A DHEA replacement: consider a trial of DHEA replacement in women with PAI and low libido, depressive symptoms, and/or low energy levels despite otherwise optimized corticosteroid and mineralocorticoid replacement. C Management of adrenal crisis: initiate immediate therapy with stress-dose intravenous hydrocortisone in patients with symptoms of severe adrenal insufficiency or adrenal crisis, prior to results of diagnostic tests. B Show 2 more 4. Nonpharmacologic interventions Salt intake: advise all patients with confirmed aldosterone deficiency not to restrict their salt intake. A https://web.pathway.md/diseases/recWRkYdyophV7mpt 2/5 6/29/23, 11:28 PM Primary adrenal insufficiency Pathway 5. Specific circumstances Pregnant patients: consider using hydrocortisone over cortisone acetate, prednisolone, or prednisone, in pregnant women with PAI. C Show 4 more Pediatric patients: consider using hydrocortisone in three or four divided doses in pediatric patients with PAI, rather than other types of corticosteroid replacement therapies, with doses adjusted according to individual need. C Show 3 more 6. Patient education Genetic counseling: consider genetic counseling for patients with PAI due to monogenic disorders. C Stress dose corticosteroids: educate patients regarding appropriate adjustment of corticosteroid dosing during stressful events, and regarding adrenal crisis prevention strategies including parenteral self- or lay-administration of emergency corticosteroids. B Corticosteroid injection kits: equip every patient with a corticosteroid injection kit for emergency use, and provide teaching on the appropriate method of administration. 7. Preventative measures Prevention of adrenal crisis: consider adjusting corticosteroid dose according to severity of illness or magnitude of the stressor to prevent adrenal crisis. C 8. Follow-up and surveillance Serial clinical assessment: consider referring adults and children with PAI to 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. C Monitoring of corticosteroid replacement: consider monitoring corticosteroid replacement using clinical assessment including body weight, postural BP, energy levels, and signs of frank corticosteroid excess. C Monitoring of mineralocorticoid replacement: monitor mineralocorticoid replacement primarily on the basis of clinical assessment such as salt craving, postural hypotension, or edema, and blood electrolyte measurements. B Monitoring of DHEA replacement: consider monitoring DHEA replacement by measuring morning serum DHEAS levels before the intake of the daily DHEA replacement dose. C Periodic screening for autoimmune diseases: consider periodic screening, at least annually, for autoimmune diseases known to be more prevalent in PAI patients in whom autoimmune origin of PAI has not been excluded. C https://web.pathway.md/diseases/recWRkYdyophV7mpt 3/5 6/29/23, 11:28 PM Primary adrenal insufficiency Pathway 9. Quality improvement Medical alert bracelet: equip all patients with a steroid emergency card and medical alert identification to alert health personnel regarding the need for increased corticosteroid doses in order to avert or treat adrenal crisis, and regarding the need for immediate parenteral steroid treatment in the event of an emergency. Clinical findings Symptoms Past medical history Abdominal pain Autoimmune disorders Abnormal behavior Integument exam Asthenia Body hair loss Hyperpigmentation Confusion Hematological findings Depression Diarrhea blood eosinophils Diffuse abdominal pain Fainting Fatigue Irritability Joint pain Leg pain Loss of appetite Low back pain Muscle pains Muscle weakness Nausea or vomiting Salt craving Sexual dysfunction Weakness Vital signs Hypotension Orthostatic hypotension Weight loss systolic BP Lab findings Hyperkalemia ACTH serum creatinine blood glucose serum glucose serum morning cortisol https://web.pathway.md/diseases/recWRkYdyophV7mpt 4/5 6/29/23, 11:28 PM Primary adrenal insufficiency Pathway serum morning serum cortisol serum sodium Diagnostic procedures Abnormal high-dose ACTH stimulation test Likelihood Ratios Pertinent positives The following findings increase the probability of primary adrenal insufficiency in adults. 1 2 Finding LR+ Value Decreased serum morning serum cortisol (< 140 nmol/L or < 5 g/dL) 36 Abnormal high-dose ACTH stimulation test 19.4 Decreased serum morning cortisol (< 280 nmol/L or < 10 g/dL) 2.7 Pertinent negatives The following findings decrease the probability of primary adrenal insufficiency in adults. 1 2 Finding LR- Value Normal high-dose ACTH stimulation test 0.01 serum morning cortisol not decreased ( 280 nmol/L or 10 g/dL) 0.5 serum morning serum cortisol not decreased ( 140 nmol/L or 5 g/dL) 0.6 References 1. Bornstein SR, Allolio B, Arlt W et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 Feb;101 2 364 89. Open 2. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med. 2003 Aug 5;139 3 194 204. Open 3. Erturk E, Jaffe CA, Barkan AL. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab. 1998 Jul;83 7 2350 4. Open https://web.pathway.md/diseases/recWRkYdyophV7mpt 5/5