eMedicine Specialties > Dermatology > Internal Medicine

Addison Disease: Differential Diagnoses & Workup

Author: Elizabeth A Liotta, MD, Assistant Professor, Department of Dermatology, Uniformed Services University of the Health Sciences
Coauthor(s): Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center; Alexander Brough, MD, Consulting Surgeon, Department of Dermatology, Sewell's Point Clinic
Contributor Information and Disclosures

Updated: Jan 21, 2009

Differential Diagnoses

Acanthosis Nigricans
Oral Manifestations of Systemic Diseases
Disorders of Oral Pigmentation
Vitiligo
Lentigo
Malignant Melanoma
Melasma

Other Problems to Be Considered

Anorexia nervosa6
Hypothyroidism
Depression
Acute abdomen
Pregnancy7
Polyglandular autoimmune disease
Primary adrenal lymphoma8

Workup

Laboratory Studies

  • The evaluation of patients with suspected Addison disease involves the diagnosis of adrenal insufficiency and then the identification of the site of the defect in the hypothalamic-pituitary axis.
    • Addison disease is a primary adrenal insufficiency with the defect in the adrenal gland.
    • Once the adrenal insufficiency is identified, the etiology of the adrenal insufficiency may be determined.
  • Initially, serum electrolytes should be checked because the results will most likely be abnormal.
    • Because aldosterone is absent, hyponatremia, with low chloride and hyperkalemia are often present.
    • Hyponatremia is the most common finding and occurs in 90% of patients.
    • Hyperkalemia is found in 60-70% of patients.
    • Hypercalcemia is uncommon and found in approximately 5-10% of patients.
  • The preliminary test for adrenal insufficiency is the measurement of serum cortisol levels from a sample of blood obtained in the morning. This is an insensitive screening test. Because of variations in cortisol levels due to the circadian rhythm, blood should be drawn when the levels are highest, usually between 6:00 and 8:00 am.
    • Morning cortisol levels greater than 19 mcg/dL (reference range, 5-25 mcg/dL) are considered normal, and no further workup is required.
    • Values less than 3 mcg/dL are diagnostic of Addison disease.
    • Values in the range of 3-19 mcg/dL are indeterminate, and further workup is needed.
  • The hypothalamic-pituitary axis can be evaluated by using 3 tests: the corticotropin (Cortrosyn) stimulation test, the insulin tolerance test, and the metyrapone test. Synthetic adrenocorticotropin 1-24 at a dose of 250 mcg works as a dynamic test. The elevated levels of renin and adrenocorticotropin verify the presence of the disease.
    • Cortrosyn is a synthetic corticotropin, which is intravenously administered with a dose of 350 mg. Serum cortisol levels are measured from blood samples drawn after 30 and 60 minutes.
      • Peak serum cortisol levels greater than 18 mcg/dL exclude the diagnosis of adrenal insufficiency because the response to stimulation is considered adequate at this level.
      • Cortisol levels of 13-17 mcg/dL are indeterminate.
      • Cortisol levels of less than 13 mcg/dL are diagnostic of adrenal insufficiency.
    • The insulin tolerance test is sensitive for adrenal insufficiency. This test involves hypoglycemic stress to induce cortisol production. The test requires close monitoring of the patient and is contraindicated in patients with a history of seizures or cardiovascular disease. The peak serum cortisol response is measured after an insulin challenge of 0.1-0.15 U/kg. A cortisol level of less than 18 mcg/dL and a serum glucose level of less than 40 mg/dL suggest adrenal insufficiency.
    • The metyrapone test involves disruption of the cortisol production pathway by inhibiting 11 B-hydroxylase, the enzyme that converts 11-deoxycortisol (11-s) to cortisol. Metyrapone (30 mg/kg) is intravenously injected at midnight, and cortisol and 11-s levels are measured 8 hours afterward. A normal response is an increase in serum 11-s levels to more than 7 mg/dL. Levels of 11-s that are less than 7 mg/dL are diagnostic of adrenal insufficiency.
  • Once the diagnosis of adrenal insufficiency is confirmed, the site of the defect in the hypothalamic-pituitary axis should be determined by using corticotropin sampling, corticotropin provocative testing, or corticotrophin-releasing hormone (CRH) provocative testing.
    • A serum corticotropin level of greater than 100 pg/mL is diagnostic of primary adrenal insufficiency.
    • A corticotropin infusion can help in differentiating primary insufficiency from a hypothalamic-mediated or pituitary-mediated adrenal insufficiency. An 8-hour intravenous infusion of 250 mg/d for 3-5 days is administered, and daily urine samples are checked for 17-hydroxysteroid levels. By day 5, a 3- to 5-fold increase in the urine 17-hydroxysteroid level is diagnostic of a secondary or tertiary insufficiency; in primary adrenal insufficiency, the urine 17-hydroxysteroid level does not increase.
    • The CRH test involves stimulation of the pituitary gland and measurement of serum cortisol and corticotropin levels. The CRH test can be used to differentiate primary, secondary, and tertiary adrenal insufficiencies.
  • After adrenal insufficiency is diagnosed and the defect in the hypothalamic-pituitary-adrenal axis is identified, the cause of the adrenal insufficiency can be evaluated.
    • Because primary adrenal insufficiency has numerous causes, the workup must be directed at the clinical findings.
    • Autoimmune disease and infectious etiologies are the 2 predominant causes; therefore, a workup for adrenal antibodies and tuberculosis should be part of the initial diagnostic evaluation.

Imaging Studies

  • Both computed tomography (CT) and magnetic resonance imaging (MRI) demonstrate a diminished adrenal gland in patients with autoimmune destruction and an enlarged adrenal gland in patients with infection.
  • CT adequately shows the calcification that occurs in adrenal failure caused by tuberculosis. The calcification may be apparent in the acute phase of infection, but it is usually recognized in the chronic phase of infection.
  • Both CT and MRI reveal adrenal hemorrhages.
  • MRI is superior to CT in differentiating adrenal masses, but MRI cannot distinguish a tumor from an inflammatory process.9

Other Tests

  • Tissue cultures in patients with tuberculosis reveal acid-fast bacilli.

Histologic Findings

Histopathologic findings vary with the mechanism of destruction. Autoimmune destruction is characterized by a lymphocytic infiltrate. Surviving cortical cells show increased cytoplasm and nuclear atypia, which is believed to result from prolonged stimulation by corticotropin. Noncaseating granulomas are found when adrenal destruction is the result of sarcoidosis or a malignancy. Caseating granulomas are seen in patients with tuberculosis.

More on Addison Disease

Overview: Addison Disease
Differential Diagnoses & Workup: Addison Disease
Treatment & Medication: Addison Disease
Follow-up: Addison Disease
Multimedia: Addison Disease
References
[ CLOSE WINDOW ]

References

  1. Bergthorsdottir R, Leonsson-Zachrisson M, Oden A, Johannsson G. Premature mortality in patients with Addison's disease: a population-based study. J Clin Endocrinol Metab. Dec 2006;91(12):4849-53. [Medline].

  2. Burk CJ, Ciocca G, Heath CR, Duarte A, Dohil M, Connelly EA. Addison's disease, diffuse skin, and mucosal hyperpigmenation with subtle "flu-like" symptoms--a report of two cases. Pediatr Dermatol. Mar-Apr 2008;25(2):215-8. [Medline].

  3. Lamey PJ, Carmichael F, Scully C. Oral pigmentation, Addison's disease and the results of screening for adrenocortical insufficiency. Br Dent J. Apr 20 1985;158(8):297-8. [Medline].

  4. Shah SS, Oh CH, Coffin SE, Yan AC. Addisonian pigmentation of the oral mucosa. Cutis. Aug 2005;76(2):97-9. [Medline].

  5. Prat C, Vinas M, Marcoval J, Jucgla A. Longitudinal melanonychia as the first sign of Addison's disease. J Am Acad Dermatol. Mar 2008;58(3):522-4. [Medline].

  6. Adams R, Hinkebein MK, McQuillen M, Sutherland S, El Asyouty S, Lippmann S. Prompt differentiation of Addison's disease from anorexia nervosa during weight loss and vomiting. South Med J. Feb 1998;91(2):208-11. [Medline].

  7. Albert E, Dalaker K, Jorde R, Berge LN. Addison's disease and pregnancy. Acta Obstet Gynecol Scand. 1989;68(2):185-7. [Medline].

  8. Kita M, Mandala E, Saratzis A, et al. Primary adrenal lymphoma presenting as Addison's disease. Case report and review of the literature. Exp Clin Endocrinol Diabetes. Jun 2008;116(6):363-5. [Medline].

  9. Baker DE, Glazer GM, Francis IR. Adrenal magnetic resonance imaging in Addison's disease. Urol Radiol. 1988;9(4):199-203. [Medline].

  10. Arlt W, Callies F, van Vlijmen JC, Koehler I, Reincke M, Bidlingmaier M, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med. Sep 30 1999;341(14):1013-20. [Medline].

  11. Oelkers W. Dehydroepiandrosterone for adrenal insufficiency. N Engl J Med. Sep 30 1999;341(14):1073-4. [Medline].

  12. Cohen N, Gilbert R, Wirth A, Casley D, Jerums G. Atrial natriuretic peptide and plasma renin levels in assessment of mineralocorticoid replacement in Addison's disease. J Clin Endocrinol Metab. Apr 1996;81(4):1411-5. [Medline].

  13. Bauerschmitz J, Bork K. Multifocal disseminated lipoatrophy secondary to intravenous corticosteroid administration in a patient with adrenal insufficiency. J Am Acad Dermatol. May 2002;46(5 Suppl):S130-2. [Medline].

  14. Ai J, Leonhardt JM, Heymann WR. Autoimmune thyroid diseases: etiology, pathogenesis, and dermatologic manifestations. J Am Acad Dermatol. May 2003;48(5):641-59; quiz 660-2. [Medline].

  15. Betterle C, Volpato M. Adrenal and ovarian autoimmunity. Eur J Endocrinol. Jan 1998;138(1):16-25. [Medline].

  16. Burke MP, Opeskin K. Adrenocortical insufficiency. Am J Forensic Med Pathol. Mar 1999;20(1):60-5. [Medline].

  17. Dunlop D. Eighty-six cases of Addison's Disease. Br Med J. Oct 12 1963;5362:887-91. [Medline].

  18. Grant DB, Barnes ND, Moncrieff MW, Savage MO. Clinical presentation, growth, and pubertal development in Addison's disease. Arch Dis Child. Oct 1985;60(10):925-8. [Medline].

  19. Grinspoon SK, Biller BM. Clinical review 62: Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab. Oct 1994;79(4):923-31. [Medline].

  20. Hunt G, Todd C, Kyne S, Thody AJ. ACTH stimulates melanogenesis in cultured human melanocytes. J Endocrinol. Jan 1994;140(1):R1-3. [Medline].

  21. Jabbour SA. Cutaneous manifestations of endocrine disorders: a guide for dermatologists. Am J Clin Dermatol. 2003;4(5):315-31. [Medline].

  22. Jeffcoate W. Assessment of corticosteroid replacement therapy in adults with adrenal insufficiency. Ann Clin Biochem. Mar 1999;36 ( Pt 2):151-7. [Medline].

  23. Kong MF, Jeffcoate W. Eighty-six cases of Addison's disease. Clin Endocrinol (Oxf). Dec 1994;41(6):757-61. [Medline].

  24. Laureti S, Vecchi L, Santeusanio F, Falorni A. Is the prevalence of Addison's disease underestimated?. J Clin Endocrinol Metab. May 1999;84(5):1762. [Medline].

  25. Luken KK. Clinical manifestations and management of Addison's disease. J Am Acad Nurse Pract. Apr 1999;11(4):151-4. [Medline].

  26. Mason AS, Meade TW, Lee JA, Morris JN. Epidemiological and clinical picture of Addison's disease. Lancet. Oct 5 1968;2(7571):744-7. [Medline].

  27. Nerup J. Addison's disease--clinical studies. A report fo 108 cases. Acta Endocrinol (Copenh). May 1974;76(1):127-41. [Medline].

  28. Nieman LK, Chanco Turner ML. Addison's disease. Clin Dermatol. Jul-Aug 2006;24(4):276-80. [Medline].

  29. Orth DN, Kovacs WJ. The adrenal cortex. In: DeGroot LJ, Jameson JL, eds. William's Textbook of Endocrinology. 9th ed. Philadelphia, Pa: WB Saunders; 1998.

  30. Tobin MV, Aldridge SA, Morris AI, Belchetz PE, Gilmore IT. Gastrointestinal manifestations of Addison's disease. Am J Gastroenterol. Oct 1989;84(10):1302-5. [Medline].

  31. Villabona CM, Sahun M, Ricart W, Serres X, Maroto A, Fernandez-Real JM, et al. Tuberculous Addison's disease. Utility of CT in diagnosis and follow-up. Eur J Radiol. Nov 1993;17(3):210-3. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

Addison disease, Addison's disease, primary adrenal insufficiency, chronic adrenal insufficiency, hypoadrenalism, polyglandular autoimmune diseases, polyglandular autoimmune disease I, PGAD I, polyglandular autoimmune disease II, PGAD II, Schmidt syndrome, addisonian crisis, adrenocorticotropic hormone, ACTH, corticotropin, melanocyte-stimulating hormone, MSH

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Elizabeth A Liotta, MD, Assistant Professor, Department of Dermatology, Uniformed Services University of the Health Sciences
Elizabeth A Liotta, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Alexander Brough, MD, Consulting Surgeon, Department of Dermatology, Sewell's Point Clinic
Alexander Brough, MD is a member of the following medical societies: American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Robin Travers, MD, Assistant Professor of Medicine (Dermatology), Dartmouth University School of Medicine; Staff Dermatologist, New England Baptist Hospital; Private Practice, SkinCare Physicians
Robin Travers, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Informatics Association, Massachusetts Medical Society, Medical Dermatology Society, and Women's Dermatologic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine
Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology
Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Honoraria Consulting; Centocor Honoraria Consulting; Genetech Honoraria Consulting; Celgene Honoraria Consulting

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

RELATED MEDSCAPE ARTICLES
Articles
 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.