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Italian Addison Network Study: Update of Diagnostic Criteria for the Etiological Classification of Primary Adrenal Insufficiency

Departments of Internal Medicine (A.F., S.L., F.S.) and Gynecologic, Obstetric, and Paediatric Sciences (V.B.), University of Perugia, 06126 Perugia, Italy; Department of Clinical and Experimental Medicine and Surgery (A.D.B., A.Bi., A.Be.), "F. Magrassi–A. Lanzara," Second University of Naples, 80131 Naples, Italy; Department of Medical and Surgical Sciences (R.Z., F.M., C.B.), University of Padova, 35131 Padova, Italy; Department of Clinical Sciences (C.T., F.D.), University of Rome "La Sapienza," 00161 Rome, Italy; Department of Internal Medicine (G.A.), University of Ancona, 60131 Ancona, Italy; and Institute of Endocrine Sciences (P.B.-P.), University of Milan, 20122 Milan, Italy

Address all correspondence and requests for reprints to: Fausto Santeusanio, M.D., Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, Via E. Dal Pozzo, I-06126 Perugia, Italy. E-mail: fsant{at}unipg.it.

Primary adrenal insufficiency (PAI) is clinically evident in one in 8000 individuals. A correct etiological classification is critical for correct disease management. To update the diagnostic criteria for the etiological classification of PAI, a multicentric network was established in Italy, and 222 patients with PAI were studied. Both 21-hydroxylase and adrenal cortex autoantibodies (21OHAb and ACA, respectively) were tested in two independent laboratories on coded samples and found in 65–66% and 58–61% of cases, respectively. Autoimmune polyendocrine syndrome I was diagnosed in 11 of the 222 patients. Of the remaining 211 patients, 38 (18%) had a nonautoimmune form of PAI. In 145 subjects (65%), the presence of adrenal autoantibodies, without signs of other forms of PAI, led to a diagnosis of autoimmune Addison’s disease. In six cases (3%), PAI remained idiopathic. Logistic regression analysis showed a 92.2–92.7% probability of correct reclassification for the two 21OHAb assays and 84.5–85.9% for the ACA assays. We conclude that the simultaneous presence of both 21OHAb and ACA permits unambiguous diagnosis of autoimmune Addison’s, whereas subjects with low antibody titers should undergo both instrumental and biochemical tests to exclude other causes of PAI. Lastly, we developed a comprehensive flowchart for the classification of PAI for use in routine clinical practice.

This work was supported by a grant from the Ministry of University and Scientific Research, Project "Morbo di Addison: forme cliniche, eziopatogenesi e storia naturale," PRIN 2001063439.

A.F. and S.L. contributed equally to this work.

In addition to the authors, the following members of the SIE Addison Study Group contributed to the collection of data and blood samples from patients with primary adrenal insufficiency: B. Ambrosi (Milan), A. Angeli (Turin), E. Arvat (Turin), A. Baccarelli (Milan), L. Barbetta (Milan), M. Boscaro (Ancona), F. Cavagnini (Milan), C. Dal Pra (Padova), E. Ghigo (Turin), R. Giordano (Turin), F. Loré (Siena), M. Mannelli (Florence), G. Mantovani (Milan), P. Paccotti (Turin), F. Pecori-Gilardi (Milan), R. Perniola (Lecce), M. Terzolo (Turin), P. Toja (Milan), M. Torlontano (S. Giovanni Rotondo), V. Toscano (Rome), and V. Trischitta (S. Giovanni Rotondo).

Abbreviations: AAD, Autoimmune Addison’s disease; ACA, adrenal cortex autoantibody; AHC, adrenal hypoplasia congenita; ALD, adrenoleukodystrophy; CI, confidence interval; CT, computed tomography; MRI, magnetic resonance imaging; 21OH, steroid-21-hydroxylase; 21OHAb, 21OH autoantibody; PAI, primary adrenal insufficiency; TBC, tuberculosis; TBC-AD, TBC Addison’s disease; VLCFA, very long chain fatty acid.

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