Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline

Abstract

Objective: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency.

Participants: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review.

Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence.

Consensus process: The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members responding to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments.

Conclusions: We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 μg) as the "gold standard" diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (∼8 mg/m(2)/d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease.

Figure 1.

Algorithm for the diagnostic approach to the patient with PAI. The most common causes of PAI are autoimmune destruction of the adrenal cortex in adults and CAH in children. These etiologies can be screened for using 21-hydroxylase antibodies and a baseline serum 17-hydroxyprogesterone level. Males with negative 21-hydroxylase antibodies should be tested for adrenoleukodystrophy with plasma VLCFAs. If these diagnoses are excluded, a CT scan of the adrenals may reveal evidence of adrenal infiltrative processes or metastases. The individual's clinical picture and family history may render some steps in the algorithm redundant or suggest specific genetic syndromes. The latter includes subtypes of autoimmune polyglandular syndromes or specific rare genetic disorders where adrenal failure is part of a broader phenotype. A list of differential diagnoses is provided in Table 2. AHC, adrenal hypoplasia congenita; AI, adrenal insufficiency; VLCFA, very long chain fatty acid. ^a 17-OH-progesterone >1000 ng/dL is diagnostic for 21-OH deficiency (14). ^b VLCFA should be measured in the initial evaluation of preadolescent boys. [Adapted from E. S. Husebye, et al: Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med. 2014;275:104–115 (181), with permission. © John Wiley & Sons, Inc.]