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Roberta Giordano, Marcella Balbo, Andreea Picu, Lorenza Bonelli, Rita Berardelli, Alberto Falorni, Ezio Ghigo, and Emanuela Arvat

Objective: In autoimmune polyglandular syndrome types 1, 2, and 4 primary adrenal insufficiency is present, but its diagnosis is often late. We investigated the function of the hypothalamic–pituitary–adrenal axis in a group of patients with autoimmune diseases (AP) without any symptoms and signs of hypoadrenalism.

Design: In 10 AP and 12 normal subjects (NS), we studied cortisol (F), aldosterone (A), and DHEA responses to 0.06 μg adrenocorticotropin (ACTH) (1–24) followed by 250 μg, ACTH and F responses to human corticotropin-releasing hormone (hCRH; 100 μg) and insulin tolerance test (ITT) (0.1 UI/kg).

Results: Basal F, A, DHEA, as well as urinary free cortisol and plasma renin activity levels in AP and NS were similar, whereas ACTH levels in AP were higher (P<0.05) than in NS. NS showed F, A, and DHEA response to both consecutive ACTH doses. In AP, the F, A, and DHEA responses to 250 μg ACTH were similar to those in NS, whereas the 0.06 μg ACTH dose did not elicit any significant response. The ACTH responses to hCRH and ITT in AP were higher (P<0.05) than in NS. The F response to hCRH in AP was lower (P<0.05) than in NS, whereas the F response to ITT in AP did not significantly differ from NS.

Conclusions: Enhancement of both basal and stimulated corticotrope secretion coupled with reduced adrenal sensitivity to low ACTH dose is present in AP patients without symptoms and signs of hypoadrenalism. This functional picture suggests that normal adrenal secretion is maintained due to corticotrope hyperfunction, suggesting the existence of some subclinical primary hypoadrenalism.

Free access

Annalisa Brozzetti, Stefania Marzotti, Daria La Torre, Maria Luisa Bacosi, Silvia Morelli, Vittorio Bini, Bruno Ambrosi, Roberta Giordano, Roberto Perniola, Annamaria De Bellis, Corrado Betterle, and Alberto Falorni


Steroid-producing cell autoantibodies (SCAs) directed against 21-hydroxylase autoantibodies (21OHAbs), 17α-hydroxylase autoantibodies (17OHAb), and cholesterol side-chain cleavage enzyme (side-chain cleavage autoantibodies, P450sccAb) characterize autoimmune primary ovarian insufficiency (SCA-POI). The aim of the study was to analyze IgG subclass specificity of autoantibodies related to adrenal and ovarian autoimmunity.


We studied 29 women with SCA-POI, 30 women with autoimmune Addison's disease (AAD) without POI, and 14 patients with autoimmune polyendocrine syndrome type 1 (APS1). 21OHAb isotypes were also analyzed in 14 subjects with preclinical AAD. Samples from 30 healthy women served as control group to determine the upper level of normality in the isotype assays.


Immunoradiometric assays with IgG subclass-specific secondary antibodies.


In 21OHAb-positive sera, IgG1 isotype was detected in 90% SCA-POI and non-POI AAD sera and 67% APS1 patients. IgG1 isotype was found in 69% 17OHAb-positive SCA-POI and 100% 17OHAb-positive APS1 sera, and in 60% P450sccAb-positive SCA-POI and 80% P450sccAb-positive APS1 sera. For 21OHAb, IgG4 isotype was detected in 17% SCA-POI, 7% non-POI AAD, and 8% APS1 sera. None of the 17OHAb-positive sera was positive for IgG4. In P450sccAb-positive sera, 15% POI and 20% APS1 sera were positive for IgG4. Two 21OHAb-positive SCA-POI (7%), one 21OHAb-positive AAD (3%), three P450sccAb-positive SCA-POI (15%), and two P450sccAb-positive APS1 (20%) sera were positive for IgG4, in the absence of IgG1. All preclinical AAD sera resulted as positive for IgG1-21OHAb, but not for IgG4-21OHAb.


The autoantibody responses in POI and AAD are IgG1 dominated, which suggests a predominant Th1 response. Selective IgG4 isotype specificity identified a small subset of patients with Th2-oriented response.

Free access

Annalisa Brozzetti, Stefania Marzotti, Cristina Tortoioli, Vittorio Bini, Roberta Giordano, Francesco Dotta, Corrado Betterle, Annamaria De Bellis, Giorgio Arnaldi, Vincenzo Toscano, Emanuela Arvat, Antonio Bellastella, Franco Mantero, and Alberto Falorni


Cytotoxic T lymphocyte antigen-4 (CTLA4) gene polymorphism has been associated with human autoimmune diseases, but discordant data are available on its association with autoimmune Addison's disease (AAD). We tested the human leukocyte antigen (HLA)-independent association of CTLA4+49 (A/G) (Ala 17) and/or CTLA4 CT60 (A/G) polymorphism with AAD.


DNA samples from 180 AAD patients and 394 healthy control subjects from continental Italy were analyzed, and association statistical analyses and meta-analysis of published studies were performed.


TaqMan minor groove binder chemistry assays and PCR fragment length polymorphism assays were used.


Frequency of allele G of CTLA4+49 was significantly increased among AAD patients (40% alleles) than among healthy controls (27% alleles; P<0.0001). CTLA4 CT60 polymorphism was associated with AAD only in the heterozygous A/G individuals. The frequency of +49 AG+GG genotypes was significantly higher among AAD patients than among healthy control subjects, in both a co-dominant (P<0.0001) and G dominant model (P<0.0001). CTLA4+49 allele G was significantly associated with disease risk in both patients with isolated AAD and in patients with autoimmune polyendocrine syndrome. Multivariate logistic regression analysis showed that CTLA4+49 allele G was positively associated with AAD (P<0.0001, odds ratio (OR)=2.43, 95% confidence interval=1.54–3.86) also after correction for DRB1*03-DQA1*0501-DQB1*0201, DRB1*04-DQA1*0301-DQB1*0302, and sex. Meta-analysis of five studies revealed a significant association of CTLA4+49 allele G with AAD (P<0.0001) with an overall OR of 1.48 (1.28–1.71).


The CTLA4+49 polymorphism is strongly associated with genetic risk for AAD, independently from the well-known association with HLA class II genes.

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Marissa Penna-Martinez, Gesine Meyer, Anette Bøe Wolff, Beate Skinningsrud, Corrado Betterle, Alberto Falorni, William Er Ollier, Dag Undlien, Eystein Sverre Husebye, Simon H S Pearce, Anna L Mitchell, and Klaus Badenhoop


While vitamin D regulates immune cells, little is known about it in autoimmune Addison´s disease (AAD). We investigated the vitamin D status in AAD patients from five European populations to assess its deficiency. In addition, we studied two case-control cohorts for vitamin D metabolism and pathway genes.


Cross-sectional study


A total of 1028 patients with AAD from Germany (n=239), Italy (n=328), Norway (n=378), UK (n=44) and Poland (n=39) and 679 controls from Germany (n=301) and Norway (n=378) were studied for 25(OH)D3 (primary objective). Secondary objectives (1,25(OH)2D3 and pathway genes) were examined in case-controls from Germany and Norway correlating 25(OH)D3 and single nucleotide polymorphisms within genes encoding the vitamin D receptor (VDR), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1); 24-hydroxylase (CYP24A1) and vitamin D binding protein (GC/DBP).


Vitamin D deficiency (25(OH)D3 10-20 ng/ml) was highly prevalent in AAD patients (34-57%), 5-22% were severely deficient (<10 ng/ml), 28-38% insufficient (20-30 ng/ml) and only 7-14% sufficient (>30 ng/ml). Lower 25(OH)D3 and 1,25(OH)2D3 levels were observed both in Norwegian and German AAD (p = 0.03/0.003 and p = 1 x 10-5/< 1 x 10-7, respectively) the former was associated with CYP2R1 (rs1553006) genotype G. Whereas controls achieved sufficient median 25(OH)D3 in summers (21.4 to 21.9 ng/ml), AAD patients remained largely deficient (18.0 to 21.2 ng/ml) and synthesize less 1,25(OH)2D3.


Vitamin D deficiency and insufficiency are highly prevalent in AAD patients. The vitamin D status of AAD may be influenced by genetic factors and suggests individual vitamin D requirements throughout the year.

Free access

Annamaria De Bellis, Giuseppe Bellastella, Alberto Falorni, Ernesto Aitella, Mariluce Barrasso, Maria Ida Maiorino, Elio Bizzarro, Antonio Bellastella, Dario Giugliano, Katherine Esposito, and On the behalf of the Italian Addison Network


Women with autoimmune Addison’s disease with normal ovulatory cycles but positive for steroid cell antibodies (StCA) have been considered at risk of premature ovarian insufficiency (POI).


Thirty-three women younger than 40 years, with subclinical-clinical autoimmune Addison’s disease but with normally ovulatory menses, were followed up for 10 years to evaluate the long-term time-related variations of StCA, ovarian function and follicular reserve. All patients and 27 control women were investigated at the start and every year for the presence and titre of StCA (by indirect immunofluorescence), serum concentrations of anti-Mullerian hormone (AMH) and ovarian function at four consecutive menses every year.


At the start of the study StCA were present in 16 women (group 1), at low/middle titres (≤1:32) in seven of them (43.8%, group 1A), at high titres (>1:32) in the remaining nine patients (group 1B, 56.2%), while they were absent from 17 patients (group 2). During the follow-up period, all women in group 1A remained StCA-positive at low/middle titres with normal ovulatory menses and normal gonadotrophin and AMH levels, while all patients in group 1B showed a further increase of StCA titres (1:128–1:256) and progressed through three stages of ovarian function. None of the patients in group 2 and controls showed the appearance of StCA or ovarian dysfunction during the follow-up.


The presence of StCA at high titres can be considered a good predictive marker of subsequent development of autoimmune POI. To single out the stages of autoimmune POI may allow a timely therapeutic choice in the subclinical and early clinical stages.