Addison Disease: Early Detection and Treatment Principles



FREE PREVIEW Log in or buy this issue to read the full article. AAFP members and paid subscribers get free access to all articles. Subscribe now.


FREE PREVIEW Subscribe or buy this issue. AAFP members and paid subscribers get free access to all articles.

Am Fam Physician. 2014 Apr 1;89(7):563-568.

This clinical content conforms to AAFP criteria for continuing medical education (CME). See CME Quiz Questions.

  Patient information: A handout on this topic is available at http://familydoctor.org/familydoctor/en/diseases-conditions/addisons-disease.html.

Author disclosure: No relevant financial affiliations.

Primary adrenal insufficiency, or Addison disease, has many causes, the most common of which is autoimmune adrenalitis. Autoimmune adrenalitis results from destruction of the adrenal cortex, which leads to deficiencies in glucocorticoids, mineralocorticoids, and adrenal androgens. In the United States and Western Europe, the estimated prevalence of Addison disease is one in 20,000 persons; therefore, a high clinical suspicion is needed to avoid misdiagnosing a life-threatening adrenal crisis (i.e., shock, hypotension, and volume depletion). The clinical manifestations before an adrenal crisis are subtle and can include hyperpigmentation, fatigue, anorexia, orthostasis, nausea, muscle and joint pain, and salt craving. Cortisol levels decrease and adrenocorticotropic hormone levels increase. When clinically suspected, patients should undergo a cosyntropin stimulation test to confirm the diagnosis. Treatment of primary adrenal insufficiency requires replacement of mineralocorticoids and glucocorticoids. During times of stress (e.g., illness, invasive surgical procedures), stress-dose glucocorticoids are required because destruction of the adrenal glands prevents an adequate physiologic response. Management of primary adrenal insufficiency or autoimmune adrenalitis requires vigilance for concomitant autoimmune diseases; up to 50% of patients develop another autoimmune disorder during their lifetime.

More than 150 years ago, Thomas Addison described a group of patients with anemia and diseased adrenal glands at autopsy, a condition now known as primary adrenal insufficiency. Autoimmune adrenalitis is the most common cause of primary adrenal insufficiency, or Addison disease, in the United States. Less common causes include infection, hemorrhage, metastatic cancer, medication use, and adrenoleukodystrophy.

Autoimmune adrenalitis is a disorder in which the adrenal cortex is destroyed, resulting in the loss of mineralocorticoid, glucocorticoid, and adrenal androgen hormone production. Addison disease can be part of the autoimmune polyglandular syndromes (type 1 and 2), or it may present as an isolated disorder.1 This article focuses on the diagnosis and treatment of Addison disease as an isolated disorder, with a focus on the pathophysiology and treatment considerations of autoimmune adrenalitis.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferences

Addison disease, or primary adrenal insufficiency, is diagnosed after confirming an elevated ACTH level and an inability to stimulate cortisol levels with a cosyntropin stimulation test.

C

12, 22

Addison disease should be treated with a glucocorticoid (i.e., daily prednisone, twice daily hydrocortisone, or daily dexamethasone). Treatment should be titrated to the lowest dose that relieves symptoms.

C

1620

Addison disease should be treated with a mineralocorticoid (i.e., daily fludrocortisone). Treatment should be titrated to keep the plasma renin activity in the upper normal range.

C

21, 22

Dehydroepiandrosterone (DHEA) therapy may improve depression symptoms and health-related quality of life in women.

B

23

Physicians should remain vigilant for the development of concomitant autoimmune disorders in patients with Addison disease.

C

8, 2834


ACTH = adrenocorticotropic hormone.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferences

Addison disease, or primary adrenal insufficiency, is diagnosed after confirming an elevated ACTH level and an inability to stimulate cortisol levels with a cosyntropin stimulation test.

C

12, 22

Addison disease should be treated with a glucocorticoid (i.e., daily prednisone, twice daily hydrocortisone, or daily dexamethasone). Treatment should be titrated to the lowest dose that relieves symptoms.

C

1620

Addison disease should be treated with a mineralocorticoid (i.e., daily fludrocortisone). Treatment should be titrated to keep the plasma renin activity in the upper normal range.

C

21, 22

Dehydroepiandrosterone (DHEA) therapy may improve depression symptoms and health-related quality of life in women.

B

23

Physicians should remain vigilant for the development of concomitant autoimmune disorders in patients with Addison disease.

C

8, 2834


ACTH = adrenocorticotropic hormone.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go

The Authors

AARON MICHELS, MD, is an assistant professor in the Department of Pediatrics and Medicine at the Barbara Davis Center for Childhood Diabetes at the University of Colorado–Denver in Aurora.

NICOLE MICHELS, PhD, is an assistant professor of physiology in the Department of Biomedical Sciences at Rocky Vista University in Parker, Colo.

Address correspondence to Aaron Michels, MD, University of Colorado–Denver, Barbara Davis Center for Childhood Diabetes, 1775 Aurora Ct., Aurora, CO 80045 (e-mail: aaron.michels@ucdenver.edu). Reprints are not available from the authors.

REFERENCES

1. Michels AW, Eisenbarth GS. Immunologic endocrine disorders. J Allergy Clin Immunol. 2010;125(2 suppl 2):S226–S237.

2. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction [published correction appears in Endocr Rev. 2002;23(4):579]. Endocr Rev. 2002;23(3):327–364.

3. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350(20):2068–2079.

4. Betterle C, Volpato M, Rees Smith B, et al. II. Adrenal cortex and steroid 21-hydroxylase autoantibodies in children with organ-specific autoimmune diseases: markers of high progression to clinical Addison's disease. J Clin Endocrinol Metab. 1997;82(3):939–942.

5. Betterle C, Volpato M, Rees Smith B, et al. I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison's disease. J Clin Endocrinol Metab. 1997;82(3):932–938.

6. Coco G, Dal Pra C, Presotto F, et al. Estimated risk for developing auto-immune Addison's disease in patients with adrenal cortex autoantibodies. J Clin Endocrinol Metab. 2006;91(5):1637–1645.

7. Baker PR, Nanduri P, Gottlieb PA, et al. Predicting the onset of Addison's disease: ACTH, renin, cortisol, and 21-hydroxylase autoantibodies. Clin Endocrinol (Oxf). 2012;76(5):617–624.

8. Erichsen MM, Løvås K, Skinningsrud B, et al. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J Clin Endocrinol Metab. 2009;94(12):4882–4890.

9. Burke CW. Adrenocortical insufficiency. Clin Endocrinol Metab. 1985;14(4):947–976.

10. Bleicken B, Hahner S, Ventz M, Quinkler M. Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients. Am J Med Sci. 2010;339(6):525–531.

11. Bouachour G, Tirot P, Varache N, Gouello JP, Harry P, Alquier P. Hemodynamic changes in acute adrenal insufficiency. Intensive Care Med. 1994; 20(2):138–141.

12. Schmidt IL, Lahner H, Mann K, Petersenn S. Diagnosis of adrenal insufficiency: evaluation of the corticotropin-releasing hormone test and basal serum cortisol in comparison to the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease. J Clin Endocrinol Metab. 2003;88(9):4193–4198.

13. Betterle C, Scalici C, Presotto F, et al. The natural history of adrenal function in autoimmune patients with adrenal autoantibodies. J Endocrinol. 1988;117(3):467–475.

14. Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab. 1991;72(4):773–778.

15. May ME, Carey RM. Rapid adrenocorticotropic hormone test in practice. Retrospective review. Am J Med. 1985;79(6):679–684.

16. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361(9372):1881–1893.

17. Crown A, Lightman S. Why is the management of glucocorticoid deficiency still controversial: a review of the literature. Clin Endocrinol (Oxf). 2005;63(5):483–492.

18. Bleicken B, Hahner S, Loeffler M, et al. Influence of hydrocortisone dosage scheme on health-related quality of life in patients with adrenal insufficiency. Clin Endocrinol (Oxf). 2010;72(3):297–304.

19. Debono M, Ross RJ, Newell-Price J. Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy. Eur J Endocrinol. 2009;160(5):719–729.

20. Quinkler M, Hahner S. What is the best long-term management strategy for patients with primary adrenal insufficiency? Clin Endocrinol (Oxf). 2012;76(1):21–25.

21. Smith SJ, MacGregor GA, Markandu ND, et al. Evidence that patients with Addison's disease are undertreated with fludrocortisone. Lancet. 1984;1(8367):11–14.

22. Oelkers W, Diederich S, Bähr V. Diagnosis and therapy surveillance in Addison's disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone. J Clin Endocrinol Metab. 1992;75(1):259–264.

23. Alkatib AA, Cosma M, Elamin MB, et al. A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency. J Clin Endocrinol Metab. 2009;94(10):3676–3681.

24. Oelkers W, Diederich S, Bähr V. Therapeutic strategies in adrenal insufficiency. Ann Endocrinol (Paris). 2001;62(2):212–216.

25. Kannan CR. Diseases of the adrenal cortex. Dis Mon. 1988;34(10):601–674.

26. Samuels MH. Effects of variations in physiological cortisol levels on thyrotropin secretion in subjects with adrenal insufficiency: a clinical research center study. J Clin Endocrinol Metab. 2000;85(4):1388–1393.

27. Armstrong L, Bell PM. Addison's disease presenting as reduced insulin requirement in insulin dependent diabetes. BMJ. 1996;312(7046):1601–1602.

28. Zelissen PM, Bast EJ, Croughs RJ. Associated autoimmunity in Addison's disease. J Autoimmun. 1995;8(1):121–130.

29. Kasperlik-Zaluska AA, Migdalska B, Czarnocka B, Drac-Kaniewska J, Niegowska E, Czech W. Association of Addison's disease with autoimmune disorders—a long-term observation of 180 patients. Postgrad Med J. 1991;67(793):984–987.

30. Blizzard RM, Chee D, Davis W. The incidence of adrenal and other antibodies in the sera of patients with idiopathic adrenal insufficiency (Addison's disease). Clin Exp Immunol. 1967;2(1):19–30.

31. McHardy-Young S, Lessof MH, Maisey MN. Serum TSH and thyroid antibody studies in Addison's disease. Clin Endocrinol (Oxf). 1972;1(1):45–56.

32. Nerup J. Addison's disease—clinical studies. A report of 108 cases. Acta Endocrinol (Copenh). 1974;76(1):127–141.

33. O'Leary C, Walsh CH, Wieneke P, et al. Coeliac disease and autoimmune Addison's disease: a clinical pitfall. QJM. 2002;95(2):79–82.

34. Husebye ES, Løvås K. Immunology of Addison's disease and premature ovarian failure. Endocrinol Metab Clin North Am. 2009;38(2):389–405.

35. Baker V. Life plans and family-building options for women with primary ovarian insufficiency. Semin Reprod Med. 2011;29(4):362–372.



Copyright © 2014 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.

Want to use this article elsewhere? Get Permissions

Article Tools

  • Download PDF
  • Print page
  • Share this page
  • AFP CME Quiz

More in Pubmed

Navigate this Article