help button home button Endocrine Society Endocrine Reviews
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An erratum has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Betterle, C.
Right arrow Articles by Zanchetta, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Betterle, C.
Right arrow Articles by Zanchetta, R.
Endocrine Reviews 23 (3): 327-364
Copyright © 2002 by The Endocrine Society

Autoimmune Adrenal Insufficiency and Autoimmune Polyendocrine Syndromes: Autoantibodies, Autoantigens, and Their Applicability in Diagnosis and Disease Prediction

Corrado Betterle, Chiara Dal Pra, Franco Mantero and Renato Zanchetta

Chair of Clinical Immunology and Allergy (C.B., C.D.P., R.Z.), Chair and Division of Endocrinology (F.M.), Department of Medical and Surgical Sciences, University of Padova, I-35128, Padova, Italy

Correspondence: Address all correspondence and requests for reprints to: Professor Corrado Betterle, M.D., Chair of Clinical Immunology and Allergy, Department of Medical and Surgical Sciences, University of Padova, Via Ospedale 105, 35128 Padova, Italy. E-mail: corrado.betterle{at}unipd.it

Recent progress in the understanding of autoimmune adrenal disease, including a detailed analysis of a group of patients with Addison’s disease (AD), has been reviewed. Criteria for defining an autoimmune disease and the main features of autoimmune AD (history, prevalence, etiology, histopathology, clinical and laboratory findings, cell-mediated andhumoral immunity, autoantigens and their autoepitopes, genetics, animal models, associated autoimmune diseases, pathogenesis, natural history, therapy) have been described. Furthermore, the autoimmune polyglandular syndromes (APS) associated with AD (revised classification, animal models, genetics, natural history) have been discussed.

Of Italian patients with primary AD (n = 317), 83% had autoimmune AD. At the onset, all patients with autoimmune AD (100%) had detectable adrenal cortex and/or steroid 21-hydroxylase autoantibodies. In the course of natural history of autoimmune AD, the presence of adrenal cortex and/or steroid 21-hydroxylase autoantibodies identified patients at risk to develop AD. Different risks of progression to clinical AD were found in children and adults, and three stages of subclinical hypoadrenalism have been defined. Normal or atrophic adrenal glands have been demonstrated by imaging in patients with clinical or subclinical AD.

Autoimmune AD presented in four forms: as APS type 1 (13% of the patients), APS type 2 (41%), APS type 4 (5%), and isolated AD (41%). There were differences in genetics, age at onset, prevalence of adrenal cortex/21-hydroxylase autoantibodies, and associated autoimmune diseases in these groups. "Incomplete" forms of APS have been identified demonstrating that APS are more prevalent than previously reported.

A varied prevalence of hypergonadotropic hypogonadism in patients with AD and value of steroid-producing cells autoantibodies reactive with steroid 17{alpha}-hydroxylase or P450 side-chain cleavage enzyme as markers of this disease has been discussed. In addition, the prevalence, characteristic autoantigens, and autoantibodies of minor autoimmune diseases associated with AD have been described.

Imaging of adrenal glands, genetic tests, and biochemical analysis have been shown to contribute to early and correct diagnosis of primary non-autoimmune AD in the cases of hypoadrenalism with undetectable adrenal autoantibodies. An original flow chart for the diagnosis of AD has been proposed.




This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
A. Brozzetti, S. Marzotti, C. Tortoioli, V. Bini, R. Giordano, F. Dotta, C. Betterle, A. De Bellis, G. Arnaldi, V. Toscano, et al.
Cytotoxic T lymphocyte antigen-4 Ala17 polymorphism is a genetic marker of autoimmune adrenal insufficiency: Italian association study and meta-analysis of European studies
Eur. J. Endocrinol., February 1, 2010; 162(2): 361 - 369.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
R P Dias, L F Chan, L A Metherell, S H S Pearce, and A J L Clark
Isolated Addison's disease is unlikely to be caused by mutations in MC2R, MRAP or STAR, three genes responsible for familial glucocorticoid deficiency
Eur. J. Endocrinol., February 1, 2010; 162(2): 357 - 359.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
N. Tomar, H. Bora, R. Singh, N. Gupta, P. Kaur, S. S. Chauhan, Y. D. Sharma, and R. Goswami
Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family members
Eur. J. Endocrinol., February 1, 2010; 162(2): 407 - 421.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
M. Scacchi, L. Danesi, A. Cattaneo, E. Valassi, F. Pecori Giraldi, P. Radaelli, A. Ambrogio, E. D'Angelo, N. Mirra, L. Zanaboni, et al.
The pituitary-adrenal axis in adult thalassaemic patients
Eur. J. Endocrinol., January 1, 2010; 162(1): 43 - 48.
[Abstract] [Full Text] [PDF]

Home page
 Pediatr. Rev.Home page
Addison Disease
Pediatr. Rev., December 1, 2009; 30(12): 491 - 493.
[Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. La Marca, S. Marzotti, A. Brozzetti, G. Stabile, A. C. Artenisio, V. Bini, R. Giordano, A. De Bellis, A. Volpe, A. Falorni, et al.
Primary Ovarian Insufficiency due to Steroidogenic Cell Autoimmunity Is Associated with a Preserved Pool of Functioning Follicles
J. Clin. Endocrinol. Metab., October 1, 2009; 94(10): 3816 - 3823.
[Abstract] [Full Text] [PDF]

Home page
 Ann Clin BiochemHome page
I. Wallace, S. Cunningham, and J. Lindsay
The diagnosis and investigation of adrenal insufficiency in adults
Ann Clin Biochem, September 1, 2009; 46(5): 351 - 367.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
G. J Kahaly
Polyglandular autoimmune syndromes
Eur. J. Endocrinol., July 1, 2009; 161(1): 11 - 20.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
U. Elbelt, S. Hahner, and B. Allolio
Altered insulin requirement in patients with type 1 diabetes and primary adrenal insufficiency receiving standard glucocorticoid replacement therapy
Eur. J. Endocrinol., June 1, 2009; 160(6): 919 - 924.
[Abstract] [Full Text] [PDF]

Home page
 BMJ Case ReportsHome page
G. P. S. Shantha, A. A Kumar, V. Jeyachandran, D. Rajamanickam, E. Bhaskar, V. K Paniker, and G. Abraham
Paraneoplastic (non-metastatic) adrenal insufficiency preceded the onset of primary lung cancer by 12 weeks
BMJ Case Reports, May 25, 2009; 2009(may25_1): bcr0820080690 - bcr0820080690.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
W. Arlt
The Approach to the Adult with Newly Diagnosed Adrenal Insufficiency
J. Clin. Endocrinol. Metab., April 1, 2009; 94(4): 1059 - 1067.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Alimohammadi, N. Dubois, F. Skoldberg, A. Hallgren, I. Tardivel, H. Hedstrand, J. Haavik, E. S. Husebye, J. Gustafsson, F. Rorsman, et al.
Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen
PNAS, March 17, 2009; 106(11): 4396 - 4401.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
M. M Erichsen, K. Lovas, K. J Fougner, J. Svartberg, E. R Hauge, J. Bollerslev, J. P Berg, B. Mella, and E. S Husebye
Normal overall mortality rate in Addison's disease, but young patients are at risk of premature death
Eur. J. Endocrinol., February 1, 2009; 160(2): 233 - 237.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
L. Manetti, A. B Parkes, I. Lupi, G. Di Cianni, F. Bogazzi, S. Albertini, L. L. Morselli, V. Raffaelli, D. Russo, G. Rossi, et al.
Serum pituitary antibodies in normal pregnancy and in patients with postpartum thyroiditis: a nested case-control study
Eur. J. Endocrinol., December 1, 2008; 159(6): 805 - 809.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
I. Gavanescu, C. Benoist, and D. Mathis
B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients
PNAS, September 2, 2008; 105(35): 13009 - 13014.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
M. Alimohammadi, P. Bjorklund, A. Hallgren, N. Pontynen, G. Szinnai, N. Shikama, M. P. Keller, O. Ekwall, S. A. Kinkel, E. S. Husebye, et al.
Autoimmune Polyendocrine Syndrome Type 1 and NALP5, a Parathyroid Autoantigen
N. Engl. J. Med., March 6, 2008; 358(10): 1018 - 1028.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
B. Biondi and D. S. Cooper
The Clinical Significance of Subclinical Thyroid Dysfunction
Endocr. Rev., February 1, 2008; 29(1): 76 - 131.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. E. M. De Block, I. H. De Leeuw, and L. F. Van Gaal
Autoimmune Gastritis in Type 1 Diabetes: A Clinically Oriented Review
J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 363 - 371.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
K. Reimand, J. Perheentupa, M. Link, K. Krohn, P. Peterson, and R. Uibo
Testis-expressed protein TSGA10 an auto-antigen in autoimmune polyendocrine syndrome type I
Int. Immunol., January 1, 2008; 20(1): 39 - 44.
[Abstract] [Full Text] [PDF]

Home page
 J. Histochem. Cytochem.Home page
E. S. Pires, P. K. Meherji, R. R. Vaidya, F. R. Parikh, M. N. Ghosalkar, and V. V. Khole
Specific and Sensitive Immunoassays Detect Multiple Anti-ovarian Antibodies in Women With Infertility
J. Histochem. Cytochem., December 1, 2007; 55(12): 1181 - 1190.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
M. Rotondi, L. Chiovato, S. Romagnani, M. Serio, and P. Romagnani
Role of Chemokines in Endocrine Autoimmune Diseases
Endocr. Rev., August 1, 2007; 28(5): 492 - 520.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
L. Manetti, I. Lupi, L. L. Morselli, S. Albertini, M. Cosottini, L. Grasso, M. Genovesi, G. Pinna, S. Mariotti, F. Bogazzi, et al.
Prevalence and Functional Significance of Antipituitary Antibodies in Patients with Autoimmune and Non-Autoimmune Thyroid Diseases
J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2176 - 2181.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
I. Gavanescu, B. Kessler, H. Ploegh, C. Benoist, and D. Mathis
Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity
PNAS, March 13, 2007; 104(11): 4583 - 4587.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
P. Candeloro, C. B. Voltattorni, R. Perniola, M. Bertoldi, C. Betterle, M. Mannelli, R. Giordano, A. De Bellis, C. Tiberti, S. Laureti, et al.
Mapping of Human Autoantibody Epitopes on Aromatic L-Amino Acid Decarboxylase
J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 1096 - 1105.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
R. Bergthorsdottir, M. Leonsson-Zachrisson, A. Oden, and G. Johannsson
Premature Mortality in Patients with Addison's Disease: A Population-Based Study
J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 4849 - 4853.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
R. Giordano, M. Balbo, A. Picu, L. Bonelli, R. Berardelli, A. Falorni, E. Ghigo, and E. Arvat
Corticotrope hypersecretion coupled with cortisol hypo-responsiveness to stimuli is present in patients with autoimmune endocrine diseases: evidence for subclinical primary hypoadrenalism?
Eur. J. Endocrinol., September 1, 2006; 155(3): 421 - 428.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. De Bellis, M. Salerno, M. Conte, C. Coronella, G. Tirelli, M. Battaglia, V. Esposito, G. Ruocco, G. Bellastella, A. Bizzarro, et al.
Antipituitary Antibodies Recognizing Growth Hormone (GH)-Producing Cells in Children with Idiopathic GH Deficiency and in Children with Idiopathic Short Stature
J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2484 - 2489.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
G. Coco, C. Dal Pra, F. Presotto, M. P. Albergoni, C. Canova, B. Pedini, R. Zanchetta, S. Chen, J. Furmaniak, B. Rees Smith, et al.
Estimated Risk for Developing Autoimmune Addison's Disease in Patients with Adrenal Cortex Autoantibodies
J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1637 - 1645.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
H. A. Tran
Incidental Adrenal Insufficiency
JAMA, March 8, 2006; 295(10): 1124 - 1124.
[Full Text] [PDF]

Home page
 LupusHome page
D Shepshelovich and Y Shoenfeld
Prediction and prevention of autoimmune diseases: additional aspects of the mosaic of autoimmunity
Lupus, March 1, 2006; 15(3): 183 - 190.
[Abstract] [PDF]

Home page
 Eur J EndocrinolHome page
C. Betterle, F. Lazzarotto, A. C. Spadaccino, D. Basso, M. Plebani, B. Pedini, S. Chiarelli, and M. Albergoni
Celiac disease in North Italian patients with autoimmune Addison's disease
Eur. J. Endocrinol., February 1, 2006; 154(2): 275 - 279.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
R. N. Miguel, S. Chen, L. Nikfarjam, S. Kominami, B. Carpenter, C. Dal Pra, C. Betterle, R. Zanchetta, T. Nakamatsu, M. Powell, et al.
Analysis of the interaction between human steroid 21-hydroxylase and various monoclonal antibodies using comparative structural modelling
Eur. J. Endocrinol., December 1, 2005; 153(6): 949 - 961.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
F. Presotto, F. Fornasini, C. Betterle, G. Federspil, and M. Rossato
Acute adrenal failure as the heralding symptom of primary antiphospholipid syndrome: report of a case and review of the literature
Eur. J. Endocrinol., October 1, 2005; 153(4): 507 - 514.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
J. R. Lindsay and L. K. Nieman
The Hypothalamic-Pituitary-Adrenal Axis in Pregnancy: Challenges in Disease Detection and Treatment
Endocr. Rev., October 1, 2005; 26(6): 775 - 799.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
D. Goswami and G. S. Conway
Premature ovarian failure
Hum. Reprod. Update, July 1, 2005; 11(4): 391 - 410.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
J. M. Barker, J. Yu, L. Yu, J. Wang, D. Miao, F. Bao, E. Hoffenberg, J. C. Nelson, P. A. Gottlieb, M. Rewers, et al.
Autoantibody "Subspecificity" in Type 1 Diabetes: Risk for organ-specific autoimmunity clusters in distinct groups
Diabetes Care, April 1, 2005; 28(4): 850 - 855.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Rotondi, A. Falorni, A. De Bellis, S. Laureti, P. Ferruzzi, P. Romagnani, A. Buonamano, E. Lazzeri, C. Crescioli, M. Mannelli, et al.
Elevated Serum Interferon-{gamma}-Inducible Chemokine-10/CXC Chemokine Ligand-10 in Autoimmune Primary Adrenal Insufficiency and in Vitro Expression in Human Adrenal Cells Primary Cultures after Stimulation with Proinflammatory Cytokines
J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2357 - 2363.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
L Nikfarjam, S Kominami, T Yamazaki, S Chen, R Hewer, C Dal Pra, T Nakamatsu, C Betterle, R Zanchetta, B Rees Smith, et al.
Mechanism of inhibition of cytochrome P450 C21 enzyme activity by autoantibodies from patients with Addison's disease
Eur. J. Endocrinol., January 1, 2005; 152(1): 95 - 101.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
G. B. Piccoli, E. Mezza, M. Burdese, M. Terzolo, G. Grassi, F. Bermond, G. Soragna, M. Gai, F. Dani, A. Jeantet, et al.
Progression of renal failure without proteinuria in a patient with type 1 diabetes
Nephrol. Dial. Transplant., December 1, 2004; 19(12): 3197 - 3199.
[Full Text] [PDF]

Home page
 CMAJHome page
C. Barnard, R. Kanani, and J. N. Friedman
Her tongue tipped us off...
Can. Med. Assoc. J., August 31, 2004; 171(5): 451 - 451.
[Full Text] [PDF]

Home page
 NEJMHome page
G. S. Eisenbarth and P. A. Gottlieb
Autoimmune Polyendocrine Syndromes
N. Engl. J. Med., May 13, 2004; 350(20): 2068 - 2079.
[Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Falorni, S. Laureti, A. De Bellis, R. Zanchetta, C. Tiberti, G. Arnaldi, V. Bini, P. Beck-Peccoz, A. Bizzarro, F. Dotta, et al.
Italian Addison Network Study: Update of Diagnostic Criteria for the Etiological Classification of Primary Adrenal Insufficiency
J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1598 - 1604.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
R. Giordano, M. Pellegrino, S. Oleandri, M. Baldi, M. Balbo, S. Laureti, A. Falorni, E. Ghigo, and E. Arvat
Adrenal Sensitivity to Adrenocorticotropin 1-24 Is Reduced in Patients with Autoimmune Polyglandular Syndrome
J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 675 - 680.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Dittmar and G. J. Kahaly
Polyglandular Autoimmune Syndromes: Immunogenetics and Long-Term Follow-Up
J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 2983 - 2992.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
R. Gianani and G. S. Eisenbarth
Autoimmunity to Gastrointestinal Endocrine Cells in Autoimmune Polyendocrine Syndrome Type I
J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1442 - 1444.
[Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
R. Silverstein and D. C. Johnson
Endogenous versus exogenous glucocorticoid responses to experimental bacterial sepsis
J. Leukoc. Biol., April 1, 2003; 73(4): 417 - 427.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2002 by The Endocrine Society