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

Abstract Adrenal cortex antibodies (ACA) were measured by immunofluorescence in 8840 adult patients with organ-specific autoimmune diseases without overt hypoadrenalism. Sixty-seven (0.8%) patients were ACA-positive, with the highest prevalence in those with premature ovarian failure (8.9%). Forty-eight ACA-positive and 20 ACA-negative individuals were enrolled into a prospective study. Antibodies to steroid 21-hydroxylase (21-OH), steroid 17α-hydroxylase (17α-OH) and cytochrome P450 side chain cleavage enzyme (P450scc) were measured by immunoprecipitation assay. Human leucocyte antigens D-related (HLA-DR) genotyping was also carried out and adrenal function assessed by ACTH test. On enrollment, 75% of ACA-positive patients had a normal adrenal function, while 25% revealed a subclinical hypoadrenalism. 21-OH antibodies were positive in 91% of ACA-positive sera. Eleven patients were positive for steroid-cell antibodies by immunofluorescence, and 9 revealed a positivity for antibodies to 17α-OH and/or P450scc. During the prospective study, overt Addison’s disease developed in 21% and subclinical hypoadrenalism in 29% of ACA-positive patients, while 50% maintained normal adrenal function. Progression to Addison’s disease was more frequent in patients with subclinical hypoadrenalism, high titers of ACA and higher levels of 21-OH antibodies, complement-fixing ACA and HLA-DR3 status. All 20 persistently ACA-negative patients were also negative for antibodies to 21-OH, 17α-OH, and P450scc, and all maintained normal adrenal function during follow-up. In conclusion, the detection of ACA/21-OH antibodies in adults is a marker of low progression toward clinical Addison’s disease. .

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II. Adrenal Cortex and Steroid 21-Hydroxylase Autoantibodies in Children with Organ-Specific Autoimmune Diseases: Markers of High Progression to Clinical Addison’s Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.82.3.3849 ◽

1997 ◽

Vol 82 (3) ◽

pp. 939-942

Author(s):

Corrado Betterle ◽

Marina Volpato ◽

Bernard Rees Smith ◽

Jadwiga Furmaniak ◽

Shu Chen ◽

...

Keyword(s):

Autoimmune Diseases ◽

Adrenal Cortex ◽

Addison’S Disease ◽

Adrenal Function ◽

Side Chain ◽

Addison's Disease ◽

Side Chain Cleavage ◽

Chain Cleavage ◽

Organ Specific ◽

Cleavage Enzyme

Abstract Adrenal cortex autoantibodies (ACA) were measured by immunofluorescence in 808 children with organ-specific autoimmune diseases without adrenal insufficiency. ACA were found in 14 children (1.7%), mostly in hypoparathyroidism (48%). Ten ACA-positive and 12 ACA-negative children were followed up for a maximum of 10 yr by evaluation of adrenocortical function (ACTH test) and autoantibody status. In all patients steroid-producing cell autoantibodies were assessed by immunofluorescence and autoantibodies to steroid 21-hydroxylase, 17α-hydroxylase, and cytochrome P450 side-chain cleavage enzyme by immunoprecipitation assay. All 10 ACA-positive patients were positive for 21-hydroxylase autoantibodies. Six were positive for steroid-producing cell autoantibodies and 5 also for autoantibodies to 17α-hydroxylase and/or P450 side-chain cleavage enzyme. Overt Addison’s disease developed in 9 (90%) ACA/21-OH-antibody-positive children after 3–121 months, and 1 remaining child had subclinical hypoadrenalism. By contrast, all ACA/21-OH antibody-negative children maintained normal adrenal function. Adrenal failure was not related to ACA titres, sex, adrenal function, type of preexisting autoimmune disorder, or human leucocyte antigens D-related status. In conclusion, in children with autoimmune endocrine diseases, ACA/21-hydroxylase autoantibodies are important predictive markers for the development of Addison’s disease.

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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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.82.3.932 ◽

1997 ◽

Vol 82 (3) ◽

pp. 932-938 ◽

Cited By ~ 41

Author(s):

C. Betterle

Keyword(s):

Autoimmune Diseases ◽

Adrenal Cortex ◽

Addison’S Disease ◽

Adult Patients ◽

Addison's Disease ◽

Organ Specific

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II. Adrenal Cortex and Steroid 21-Hydroxylase Autoantibodies in Children with Organ-Specific Autoimmune Diseases: Markers of High Progression to Clinical Addison's Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.82.3.939 ◽

1997 ◽

Vol 82 (3) ◽

pp. 939-942 ◽

Cited By ~ 35

Author(s):

C. Betterle

Keyword(s):

Autoimmune Diseases ◽

Adrenal Cortex ◽

Addison’S Disease ◽

Addison's Disease ◽

Organ Specific

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Estimated Risk for Developing Autoimmune Addison’s Disease in Patients with Adrenal Cortex Autoantibodies

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-0860 ◽

2006 ◽

Vol 91 (5) ◽

pp. 1637-1645 ◽

Cited By ~ 76

Author(s):

Graziella Coco ◽

Chiara Dal Pra ◽

Fabio Presotto ◽

Maria Paola Albergoni ◽

Cristina Canova ◽

...

Keyword(s):

Adrenal Cortex ◽

Cox Model ◽

Cumulative Risk ◽

Human Leukocyte ◽

Addison’S Disease ◽

Adrenal Function ◽

Addison's Disease ◽

Risk Algorithm ◽

Functional Factors ◽

Estimated Risk

Context: Patients with adrenal cortex autoantibodies (ACA) without overt autoimmune Addison’s disease (AAD) are at risk of adrenal failure. Design: To assess the contribution of different clinical, immunological, genetic, and functional factors in the progression to AAD, we followed up 100 ACA-positive and 63 ACA-negative patients without AAD for a maximum of 21 yr (mean 6.0 yr, median 4.8). ACA were measured by immunofluorescence and 21-OH autoantibodies (Abs) by RIA. Adrenal function was assessed by measuring basal levels of cortisol, aldosterone, ACTH, renin activity, and cortisol response to ACTH. The risk of developing AAD was calculated using survival and multivariate analyses. Results: AAD developed in 31 ACA-positive patients and one ACA-negative patient. The cumulative risk of disease in ACA-positive patients was 48.5% [95% confidence interval (CI) 40.8–56.1]. The cumulative risk was higher in children than adults (100 vs. 31.9%; P < 0.0001), males than females (68.6 vs. 42.7%; P = 0.006), patients with subclinical rather than normal adrenal function at entry (87.4 vs. 30.1%; P < 0.0001), patients with hypoparathyroidism and/or candidiasis than patients with other autoimmune or nonautoimmune diseases (100 vs. 29.7%; P < 0.0001), and patients with high rather than low-medium ACA titers (62.8 vs. 41.2%; P = 0.12). The presence of human leukocyte antigen (HLA)-DRB1 did not appear to contribute to the prediction of AAD. Adjusted hazard ratios by Cox model for the development of AAD were 3.37 for males (CI 1.38–8.24), 5.23 for hypoparathyroidism and/or candidiasis (CI 1.53–17.92), 3.33 for high antibody titers (CI 1.43–7.78), and 6.15 for impaired adrenal function at entry (CI 2.79–13.57). Conclusions: These results were used to construct a risk algorithm for estimating the probability of developing AAD from the combination of gender, age, adrenal function, antibody titer, and associated autoimmune disorders at entry. The values of estimated risk could be used to decide appropriate follow-up intervals and future immunointervention strategies.

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Autoantibodies to steroidogenic enzymes in patients with premature ovarian failure with and without Addison's disease

Acta Endocrinologica ◽

10.1530/eje.0.1480565 ◽

2003 ◽

pp. 565-570 ◽

Cited By ~ 43

Author(s):

C Dal Pra ◽

S Chen ◽

J Furmaniak ◽

BR Smith ◽

B Pedini ◽

...

Keyword(s):

Autoimmune Diseases ◽

Premature Ovarian Failure ◽

Addison’S Disease ◽

Ovarian Failure ◽

Lower Proportion ◽

Side Chain ◽

Addison's Disease ◽

Steroidogenic Enzymes ◽

Chain Cleavage ◽

Patients At Risk

DESIGN: Adrenal cortex autoantibodies (ACA), steroid-producing cell autoantibodies (StCA) and autoantibodies (Abs) to steroidogenic enzymes in three groups of patients with premature ovarian failure (POF), 15 with autoimmune Addison's disease (AD), 26 with non-adrenal autoimmune diseases and 31 with isolated POF, have been assessed. METHODS: ACA and StCA were measured using an immunofluorescence technique. Abs to 21-hydroxylase (21-OH), to 17alpha-hydroxylase (17alpha-OH) and to cytochrome P450 side-chain cleavage (P450scc) were measured using an immunoprecipitation assay. RESULTS: Seventy-three percent of patients with POF and AD were positive for StCA, 93% for 17alpha-OH and/or P450scc Abs, 93% for ACA and 100% for 21-OH Abs. Among patients with POF and non-adrenal autoimmune diseases, 8% were positive for StCA, 12% for 17alpha-OH and/or P450scc Abs, and 8% and 12% for ACA and 21-OH Abs respectively. StCA, 17alpha-OH and/or P450scc Abs were all found in 10% of patients with isolated POF, and 13% had ACA and 21-OH Abs. All StCA-, 17alpha-OH- and/or P450scc Abs-positive patients were also positive for ACA and 21-OH Abs. Two patients with isolated POF who were ACA and 21-OH Ab positive developed AD 3 and 5 Years after the onset of POF. CONCLUSION: This study has shown that, when POF is associated with AD, StCA, 17alpha-OH and/or P450scc Abs are present in the majority of patients, while in the other two groups these Abs are detectable in a much lower proportion of patients. Measurement of ACA/21-OH Abs in some patients with POF may be important in identifying patients at risk of developing overt AD.

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Addison's disease: a survey on 633 patients in Padova

Acta Endocrinologica ◽

10.1530/eje-13-0528 ◽

2013 ◽

Vol 169 (6) ◽

pp. 773-784 ◽

Cited By ~ 37

Author(s):

Corrado Betterle ◽

Riccardo Scarpa ◽

Silvia Garelli ◽

Luca Morlin ◽

Francesca Lazzarotto ◽

...

Keyword(s):

Autoimmune Diseases ◽

Adrenal Cortex ◽

Gene Mutations ◽

Addison’S Disease ◽

Addison's Disease ◽

Genetic Profile ◽

Recent Onset ◽

Autoimmune Polyendocrine Syndrome ◽

Adrenal Imaging ◽

Genetic Features

ObjectiveAddison's disease (AD) is a rare endocrine condition.DesignWe aimed to evaluate clinical, immunologic, adrenal imaging, and genetic features in 633 Italian patients with AD followed up since 1967.MethodsAdrenal cortex autoantibodies, presence of other autoimmune and nonautoimmune diseases, nonadrenal autoantibodies, adrenal imaging, and genetic profile for HLA-DRB1 and AIRE were analyzed.ResultsA total of 492 (77.7%) patients were found to be affected by autoimmune AD (A-AD), 57 (9%) tuberculous AD, 29 (4.6%) genetic-associated AD, 10 (1.6%) adrenal cancer, six (0.94%) post-surgical AD, four (0.6%) vascular disorder-related AD, three (0.5%) post-infectious AD, and 32 (5.1%) were defined as idiopathic. Adrenal cortex antibodies were detected in the vast majority (88–100%) of patients with recent onset A-AD, but in none of those with nonautoimmune AD. Adrenal imaging revealed normal/atrophic glands in all A-AD patients: 88% of patients with A-AD had other clinical or subclinical autoimmune diseases or were positive for nonadrenal autoantibodies.Based on the coexistence of other autoimmune disorders, 65.6% of patients with A-AD were found to have type 2 autoimmune polyendocrine syndrome (APS2), 14.4% have APS1, and 8.5% have APS4. Class II HLA alleles DRB1*03 and DRB1*04 were increased, and DRB1*01, DRB1*07, DRB1*013 were reduced in APS2 patients when compared with controls. Of the patients with APS1, 96% were revealed to have AIRE gene mutations.ConclusionsA-AD is the most prevalent form of adrenal insufficiency in Italy, and ∼90% of the patients are adrenal autoantibody-positive at the onset. Assessment of patients with A-AD for the presence of other autoimmune diseases should be helpful in monitoring and diagnosing APS types 1, 2, or 4 and improving patients' care.

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21-hydroxylase autoantibodies in adult patients with endocrine autoimmune diseases are highly specific for Addison's disease

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.1997.262-ce1153.x ◽

1997 ◽

Vol 107 (2) ◽

pp. 341-346 ◽

Cited By ~ 68

Author(s):

A. FALORNI ◽

S. LAURETI ◽

A. NIKOSHKOV ◽

M. L. PICCHIO ◽

B. HALLENGREN ◽

...

Keyword(s):

Autoimmune Diseases ◽

Addison’S Disease ◽

Adult Patients ◽

Addison's Disease

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Co-aggregation and heritability of organ-specific autoimmunity: a population-based twin study

Acta Endocrinologica ◽

10.1530/eje-20-0049 ◽

2020 ◽

Vol 182 (5) ◽

pp. 473-480 ◽

Cited By ~ 5

Author(s):

Jakob Skov ◽

Daniel Eriksson ◽

Ralf Kuja-Halkola ◽

Jonas Höijer ◽

Soffia Gudbjörnsdottir ◽

...

Keyword(s):

Autoimmune Diseases ◽

Atrophic Gastritis ◽

Genetic Factors ◽

Monozygotic Twins ◽

Twin Studies ◽

Addison’S Disease ◽

Addison's Disease ◽

Graves Disease ◽

Dizygotic Twins ◽

Organ Specific

Objective Co-aggregation of autoimmune diseases is common, suggesting partly shared etiologies. Genetic factors are believed to be important, but objective measures of environmental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at estimating heritability and genetic overlap in seven organ-specific autoimmune diseases. Design Prospective twin cohort study. Methods We used a cohort of 110 814 twins to examine co-aggregation and heritability of Hashimoto’s thyroiditis, atrophic gastritis, celiac disease, Graves’ disease, type 1 diabetes, vitiligo and Addison’s disease. Hazard ratios (HR) were calculated for twins developing the same or different disease as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estimate the genetic influence on co-aggregation. Heritability for individual disorders was calculated using structural equational modeling adjusting for censoring and truncation of data. Results Co-aggregation was more pronounced in monozygotic twins (median HR: 3.2, range: 2.2–9.2) than in dizygotic twins (median HR: 2.4, range: 1.1–10.0). Heritability was moderate for atrophic gastritis (0.38, 95% CI: 0.23–0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49–0.71) for Graves’ disease to 0.97 (95% CI: 0.91–1.00) for Addison’s disease. Conclusions Overall, co-aggregation was more pronounced in monozygotic than in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co-aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our results validate and refine previous heritability estimates based on smaller twin cohorts.

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