Polyglandular Autoimmune Syndromes: Immunogenetics and Long-Term Follow-Up
Abstract
Polyglandular autoimmune syndromes (PAS) are rare polyendocrinopathies characterized by the failure of several endocrine glands as well as nonendocrine organs, caused by an immune-mediated destruction of endocrine tissues. This article summarizes extensive clinical, epidemiological, serological, and genetic data of a large collective of patients with PAS (n = 360). Since 1988, more than 15,000 adult patients with endocrine diseases have been screened at the endocrine center of the Mainz University, and 151 of 360 patients with PAS have regularly been followed. Type 1 diabetes, Graves' disease, Hashimoto thyroiditis, Addison's disease, vitiligo, alopecia, hypogonadism, and pernicious anemia were observed in 61%, 33%, 33%, 19%, 20%, 6%, 5%, and 5%, respectively. The most common disease combination was type 1 diabetes and autoimmune thyroid disease. In most patients, type 1 diabetes was the first manifestation of PAS (48%). The longest time intervals between manifestations of the first and second immune endocrinopathies occurred between type 1 diabetes and thyroid disease (13.3 +/- 11.8 yr) and between vitiligo and thyroid disease (16.3 +/- 13.3 yr), but a shorter time interval was observed between Addison's and thyroid diseases. Of the 471 patients with type 1 diabetes screened, 83 (17.6%) were positive for PAS. Subsequently, sera of 126 patients with PAS, 287 with type 1 diabetes, and 303 matched controls were compared for human leukocyte antigens. Patients with PAS had significantly higher frequencies of the human leukocyte antigens A24, A31, B8, B51, B62, DR3, and DR4 (relative risk, 2.35, 2.74, 2.47, 7.17, 2.22, 1.94, and 2.46) vs. controls, and for A31, B15, B52, B55, DR2, DR11, and DR13 (relative risk, 2.51, 7.96, 3.99, 5.36, 4.46, 2.89, and 3.26) vs. type 1 diabetes patients without PAS. In conclusion, patients with autoimmune endocrine disease should be followed on a regular basis. In subjects at risk for PAS, functional screening every 3 yr is warranted. If clinical disease is present, serological measurement of organ-specific antibodies should follow.
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The risk of developing Addison disease is 10 times higher in patients with type 1 diabetes mellitus than in the general population.
“Since the risk of developing AD is 10 times higher in patients with T1DM than in the general population, and the combination of concomitant T1DM and AD is associated with a more than 4-fold increase in the risk of premature death compared with patients with T1DM alone, awareness of this risk is of paramount importance to physicians managing patients with T1DM [6, 7].”
From Onset of Addison Disease in a Patient Using the Advanced Hybrid Closed-Loop MiniMed 780G: Diagnostic Challenges (2025) · cites this paper as [6]
The “Comparison of type 1 diabetes patients vs. patients with PAS II” section reports adrenal failure in 4.2% of 471 patients with type 1 diabetes. It gives no general-population comparison or tenfold estimate for developing Addison disease. The paper’s separate “10 times” figure concerns islet autoantibodies in offspring with particular genotypes, not Addison disease. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe combination of concomitant type 1 diabetes mellitus and Addison disease is associated with a more than 4-fold increase in the risk of premature death compared with patients with type 1 diabetes mellitus alone.
“Since the risk of developing AD is 10 times higher in patients with T1DM than in the general population, and the combination of concomitant T1DM and AD is associated with a more than 4-fold increase in the risk of premature death compared with patients with T1DM alone, awareness of this risk is of paramount importance to physicians managing patients with T1DM [6, 7].”
From Onset of Addison Disease in a Patient Using the Advanced Hybrid Closed-Loop MiniMed 780G: Diagnostic Challenges (2025) · cites this paper as [6]
The section 'Comparison of type 1 diabetes patients vs. patients with PAS II' reports adrenal failure among patients with type 1 diabetes, but not mortality. Searches for premature death, mortality, and a fourfold risk found no passage comparing deaths in patients with both conditions against those with type 1 diabetes alone. Page numbers were not available in our copy. (LLM, conf=0.72)
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Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber for the American Association, K. A. (2012) · Thyroid · doi:10.1089/thy.2012.0205 · Cited by 1,053 · see citing works
Hashimotos' thyroiditis: epidemiology, pathogenesis, clinic and therapy
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“…than in the general population, and the combination of concomitant T1DM and AD is associated with a more than 4-fold increase in the risk of premature death compared with patients with T1DM alone, awareness of this risk is of paramount importance to physicians managing patients with T1DM [6, 7].”
- Authors
- Dittmar, M., & Kahaly, G. J.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Kahaly, George J.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2003-07
- Volume
- 88
- Issue
- 7
- Pages
- 2983-2992
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2011407843
- Cited by
- 367
- References
- 2
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 16 · 2023: 26 · 2022: 16 · 2021: 15 · 2020: 14 · 2019: 23 · 2018: 9 · 2017: 10 · 2016: 15 · 2015: 23 · 2014: 17 · 2013: 24 · 2012: 18
- FWCI
- 7.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- autoimmune polyglandular syndrome, polyendocrinopathy, type 1 diabetes, autoimmune thyroid disease, Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, hypogonadism, pernicious anemia, human leukocyte antigen, HLA-DR3, HLA-DR4, HLA-B51, HLA-B8, HLA-A31, HLA-A24, HLA-B52, HLA-B15, HLA-B62, HLA-B*57, HLA-B*58, HLA-B60, HLA-B61, HLA-B
- MeSH terms
- Adult, Autoantibodies, Diabetes Mellitus, Type 1, Female, Follow-Up Studies, Genes, Dominant, Histocompatibility Testing, Humans, Male, Middle Aged, Organ Specificity, Risk Factors, Incidence, Prevalence, Polyendocrinopathies, Autoimmune, Sex Distribution
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