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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1272
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 176-179
Copyright © 2006 by The Endocrine Society

Helicobacter pylori Infection and Autoimmune Thyroid Disease in Young Patients: The Disadvantage of Carrying the Human Leukocyte Antigen-DRB1*0301 Allele

Daniela Larizza, Valeria Calcaterra, Miryam Martinetti, Riccardo Negrini, Annalisa De Silvestri, Mariangela Cisternino, A. M. Iannone and Enrico Solcia

Departments of Pediatric Sciences (D.L., V.C., M.C.) and Pathology (E.S.), University of Pavia and Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy; Immunohematology and Transfusion Center (M.M., A.M.I.) and Clinical Epidemiology and Biometry Unit (A.D.S.), Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy; and Institute of Internal Medicine (R.N.), Spedali Civili, 25125 Brescia, Italy

Address all correspondence and requests for reprints to: Professor Larizza Daniela, Department of Pediatric Sciences, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, P.le Golgi n. 2, 27100 Pavia, Italy. E-mail: d.larizza{at}smatteo.pv.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context and Objective: Pathogenesis of autoimmune thyroid disease (ATD) is multifactorial. Helicobacter pylori (Hp) infection has been proposed to be involved in nongastrointestinal conditions and reported more frequently in ATD adult patients. We evaluated the prevalence of Hp antibodies in young ATD patients and investigated the possibility that a susceptible immunogenetic profile could influence the development of ATD in subjects with Hp infection.

Subjects and Methods: We retrospectively studied 90 children with ATD (median age 11.2 yr), 70 age- and sex-matched healthy subjects as controls, and 65 patients with Turner syndrome (median age 18.8 yr). Antibodies to Hp were determined at diagnosis in ATD patients and, in Turner patients, at the last control in cases without ATD and before the appearance of thyroid autoantibodies in the others. Serological and molecular human leukocyte antigen (HLA) typing for classes I and II polymorphisms was performed.

Results: Prevalence of positive Hp serology resulted significantly higher in ATD patients than controls (P = 0.032). No association was found between individual HLA alleles and Hp serology. HLA-A1, B8, and DRB1*0301 were found significantly associated with ATD. A significant interaction between HLA-DRB1*0301 and Hp infection was present in ATD patients and not controls (P = 0.007), suggesting that the copresence of these two factors might favor ATD development. A similar phenomenon was observed in Turner syndrome patients (P = 0.02; cumulative Mantel test, P = 0.0001).

Conclusions: Another target of Hp-elicited immune inflammatory response might be the thyroid gland in subjects with a peculiar immunogenetic profile so that ATD may be a consequence. Our findings suggest the opportunity of eradicating Hp infection in children with ATD and/or susceptible HLA alleles.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE PATHOGENESIS OF autoimmune thyroid disease (ATD) is multifactorial, including both genetic and environmental factors; among these, bacterial and viral agents also have been suspected to play a role. For instance, Yersinia enterocolitica seems involved in the pathogenesis of Graves’ disease (GD), probably through a mechanism of molecular mimicry between bacterial antigens and thyroid constituents (1, 2, 3).

Helicobacter pylori (Hp) is a Gram-negative gastric pathogen that is responsible for gastritis, gastric and duodenal ulcers (4), gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer (5). Furthermore, there is evidence that Hp infection can induce autoimmune processes against mucosa (6), with consequent autoimmune gastritis. Hp infection has been also proposed to be involved in the pathogenesis of nongastrointestinal conditions such as rosacea, ischemic heart disease (7, 8), and type 1 diabetes (9, 10). Finally, Hp infection has been reported to be more frequent in adult patients affected by ATD (11, 12, 13).

The aim of the present study was to evaluate the prevalence of Hp infection in young patients affected by ATD at the time of their first diagnosis. Furthermore, we investigated the possibility that a susceptible immunogenetic profile could influence the development of autoimmune thyroiditis in subjects with Hp infection.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Study design

Patients newly diagnosed with ATD in our Pediatric Department during the years 1982–1999 were submitted for determination of Hp antibodies and human leukocyte antigen (HLA) typing; all of them were from northern Italy. We searched for a possible association between ATD, HLA alleles, and Hp infection through a case-control study. In addition, because thyroid autoimmune disorders are very frequent in Turner syndrome, we also tested this association in cross-sectional studies in a group of Turner patients.

Patients

We retrospectively studied the following groups of patients. The first group consisted of 90 children with ATD (75 females and 15 males, median age at diagnosis 11.2 yr, range 1.1–21.8 yr). Sixty-five patients (52 females and 13 males, median age at diagnosis 11.1 yr, range 1.1–17.3 yr) had autoimmune thyroiditis (AT); 49 were treated with substitutive L-thyroxine, and 16 were euthyroid. Twenty-five patients (23 females and two males, median age at diagnosis 11.7 yr, range 3.1–21.8 yr) were affected by GD; 24 of them were treated with methimazole. Diagnosis of AT and GD had been determined on the basis of the presence of antithyroid antibodies (antibodies to thyroid peroxidase, thyroglobulin, and antibodies directed against TSH receptor); typical ultrasound aspects of the thyroid gland; and in some patients, before ultrasonography was available, fine-needle aspiration biopsy and cytology.

The second group consisted of 65 patients with Turner syndrome (median age at evaluation 18.8 yr, range 2.6–37.1 yr). Karyotype was 45,X in 42 cases, whereas mosaics and/or structural abnormalities of the X chromosome were found in the others. Thirty patients developed thyroid autoimmunity at the median age of 16.8 yr (range 4.6–31 yr), and six underwent substitutive treatment for hypothyroidism. Turner patients without thyroid antibodies were evaluated at a median age of 21.8 yr (range 2.6–37.1 yr). No statistically significant difference was present in the median age of the two groups of Turner patients.

Controls

As a control group, we chose 70 age- and sex matched subjects (15 males and 55 females; mean age 10 yr, range 2–20 yr; 28 were younger than 10 yr and 42 older) free of autoimmune disorders, coming from the same geographic area and evaluated during the same years as the patients. They had undergone clinical and laboratory evaluation as relatives of patients with congenital adrenal hyperplasia, with negative results. All the controls were subsequently evaluated for Hp serology, taking advantage of their harvested sera; 60 of them were HLA typed at the same resolution level as the patients. No statistically significant difference was present between ATD patients and controls for age and sex.

Hp-specific antibody determination

Antibodies to Hp were determined at the time of the first diagnosis in patients affected by ATD. In Turner patients serology for Hp was evaluated at the last control in cases without thyroid autoimmunity and before the appearance of thyroid autoantibodies in the others. As reported above, no significant difference was present in the median age of the two groups.

This retrospective study was possible, because sera had been taken from all patients, with either ATD or Turner syndrome, at the diagnosis as well as every 6 months during the follow-up.

Circulating antibodies against Hp were detected by a competitive ELISA test based on a monoclonal antibody against a 64-kDa specific Hp antigen. Briefly, 100 µl of undiluted serum sample and calibrators were added to microwells coated with a sonicate of Hp; 100 ml of peroxidase conjugated HpN45 were then added to all the wells. After 1 h of incubation, the plate was washed, color was developed with a tetramethylbenzidine solution, and absorbances read at 450. Anti-Hp titers were expressed in arbitrary units (units per milliliter) [95% confidence intervals (CIs)]. The intra- and interassay coefficients of variation of the assay were between 0.9 and 5.1% and between 3.2 and 9.7%, respectively; specificity of this method was 95% and sensitivity 100% (14).

HLA typing

Serological HLA typing for class I (HLA-A, B, C) and II (HLA-DR, DQ) antigens was obtained in all cases by means of standard microlymphocytotoxicity tests (15). Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 genes was performed using the PCR-sequence-specific primer technique (16).

The study protocol was approved by the ethical committee of our institution. All the patients and/or their parents gave their written consent after being informed about the nature of the study.

Statistical analysis

For the case-control study, association between ATD and HLA alleles or Hp antibodies was tested with {chi}2 or Fisher exact test as appropriate. P < 0.05 was considered significant. Then a multivariate logistic regression model was applied using ATD as dependent variable and HLA-DRB1*0301 allele, Hp antibodies, and their interaction as explicative variables.

In cross-sectional studies the relative risk of carrying both HLA-DRB1*0301 and Hp antibodies was assessed and tested with the {chi}2 test.

The difference in the median age of the two groups of patients with Turner syndrome was tested with the nonparametric Mann-Whitney U test.

Finally, we used the Mantel test to combine the odds ratios (ORs) in a stratified data set, where the strata were formed by the ATD/control sample and the Turner sample.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
ATD patients

In the ATD sample, 24 of 90 patients (26.7%), eight of 25 (32%) with GD, and 16 of 65 (24.6%) with AT were positive for Hp antibodies; there were 20 of 75 positive females (26.6%) and four of 15 males (26.6%); eight of 38 patients (21%) were younger than 10 yr and 16 of 52 (30.7%) older. In the control group, nine of 70 subjects (12.8%) tested positive for Hp antibodies; there were one of 15 positive male (6.6%) and eight of 55 (14.5%) females; three of 28 subjects younger than 10 yr (10.7%) and six of 42 older (14.3%) tested positive for Hp serology.

The overall prevalence of positive Hp serology was significantly higher in ATD patients than in controls (24 of 90, 26.7% vs. nine of 70, 12.8%; P = 0.032; OR 2.46; 95% CI 1.04–6.24), also taking in account sex and age (Mantel test P = 0.03 and P = 0.01, respectively). The difference between patients and controls also had statistically significant results when ATD patients were stratified into two subgroups, those with AT and those with GD (Table 1Go).


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  		TABLE 1. Prevalence of Hp antibody positivity in patients with AT, patients with GD, and controls

 
Seventy-one HLA serological typings (142 haplotypes) and 88 HLA genomic typings (176 haplotypes) were available for statistical analysis. No relationship was found between individual HLA alleles and Hp serology, either among patients (cumulatively considered and subdivided in AT and GD subgroups) or controls, thus ruling out the possibility that the HLA investigated alleles may favor or inhibit the infection. However, when association between alleles and thyroid disease was investigated, HLA-A1, -B8, and -DRB1*0301 alleles were significantly associated with ATD, AT, and GD (Table 2Go, A and B). Of the remaining HLA alleles, none was found to be associated with ATD.


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  		TABLE 2. Frequency of HLA-A1, HLA-B8, and HLA-DRB1*0301 alleles in patients with AT and controls (A) and in patients with GD and controls (B)

 
We investigated whether these HLA alleles and Hp infection might act as independent or combined risk factors in the development of ATD. The logistic model showed a significant interaction between HLA-DRB1*0301 and Hp infection in the total group of ATD (OR 2.00; 95% CI 1.2–3.4; P = 0.008) as well as the AT subgroup (OR 1.78; 95% CI 1.1–2.9; P = 0.02). No significant results were obtained between Hp antibodies and HLA-B8 or HLA-A1 alleles. No relationship was present between Hp antibodies titer and HLA alleles.

The OR relative to the HLA-DRB1*0301 effect in Hp-positive and Hp-negative ATD patients is reported in Table 3AGo; it shows that this effect is restricted to Hp-positive subjects with ATD and the subgroup with AT. In fact, the frequency of DRB1*0301 in Hp-negative patients was similar to that in controls; also the percentage of Hp-positive subjects in DRB1*0301-negative subjects was not statistically different between ATD or AT and controls, so it seems to be the contemporaneous presence of DRB1*0301 and Hp antibodies to give the higher ORs. In patients with GD, the interaction between Hp antibodies and HLA-DRB1*0301 did not have statistically significant results, probably due to the small number of patients.


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  		TABLE 3. Effect of presence or absence of HLA-DRB1*0301 allele and/or Hp antibodies in patients with ATD and controls (A) and in patients with AT and controls (B)

 
Turner patients

The effect of the simultaneous presence of the HLA-DRB1*0301 allele and Hp antibodies was independently retested in a sample of Turner patients through cross-sectional studies. In this sample we observed 22 subjects with Hp antibodies and nine subjects carrying the DRB1*0301 allele. All four patients (100%) with both HLA-DRB1*0301 and Hp antibodies developed AT, whereas only 26 of 61 (42.6%) without the copresence of these two factors developed AT (relative risk 2.35; P = 0.02); namely, eight were DRB1*0301 negative/HP positive and 18 were negative for both factors, whereas none of the five Turner patients DRB1*0301 positive/Hp negative developed AT (Table 4Go).


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  		TABLE 4. Effect of the presence or absence of HLA-DRB1*0301 allele and/or Hp antibodies in Turner patients with and without AT

 
Finally, the cumulative Mantel {chi}2 of the simultaneous presence of Hp antibodies and HLA-DRB1*0301 in the two samples of patients with autoimmune thyroid disease and Turner syndrome is shown in Table 5Go.


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  		TABLE 5. The cumulative Mantel {chi}2 of the simultaneous presence of HP antibodies and DRB1*0301 in the two samples

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
It is well known that gastric mucosa is the main target of H. pylori, which colonizes and damages surface epithelium and induces a chronic inflammatory response in the lamina propria. Gland atrophy and intestinal metaplasia are among the long-term consequences of this process (17, 18, 19). In some cases, H. pylori elicits antibodies cross-reacting with epithelial components (especially parietal cells) of the gastric mucosa, periglandular T cell infiltrates, and increased glandular cells apoptosis, which may cause diffuse, corpus-fundus restricted, atrophic gastritis of autoimmune type (6, 20, 21). Achlorhydria with secondary hypergastrinemia, with or without pernicious anemia, and increased risk for gastric enterochromaffin-like cell carcinoids and cancer are among the clinical consequences of this H. pylori-initiated autoimmune process (22, 23, 24, 25).

This study suggests that another target of Hp-elicited immune-inflammatory response might be the thyroid gland and that autoimmune thyroid disease may be a consequence. The significantly increased prevalence of Hp seropositivity we observed in patients with ATD, with or without associated Turner syndrome, in the absence of an association between HLA alleles and Hp-positive serology per se, supports the hypothesis that Hp may have a role in promoting autoimmune disease of the thyroid gland. In fact, the finding of antibodies against Hp at the time of first diagnosis of thyroid disease (ATD sample) or even before it (Turner sample) suggests that Hp infection preceded ATD and had a role in the induction of autoimmune processes against thyroid. It should be noted that in previous adult studies, Hp antibodies were assessed during and not at diagnosis of thyroid disease or before it, as in this study (11, 12, 13).

The lack of association between HLA alleles and Hp-positive serology per se, independently of thyroid disease, rules out a role of the HLA-A, -B, -C, -DRB1, and -DQB1 genes in predisposing to Hp infection. On the other hand, the significant association we found between ATD and the HLA-DRB1*0301 allele, a well-known marker of autoimmunity, strongly supports a role of this allele in sustaining thyroid disease. This conclusion is further supported by the fact that this allele has been specifically involved in both cellular and humoral reactions against self-structures such as hepatocytes, pancreatic insular cells, and thyrocytes (26, 27, 28, 29). Thus, it seems likely that, in children possessing the HLA-DRB1*0301 allele, H. pylori infection may activate an immune response directed against thyroid cells.

Guidelines for the management of Hp infection in children (30) identified gastric and duodenal ulcer disease and the rare cases of mucosa-associated lymphoid tissue lymphoma and atrophic gastritis with intestinal metaplasia as the only indications for therapy. In light of our results, the finding of Hp infection in children with ATD is intriguing and raises the possibility that Hp eradication might prevent or attenuate AT. In fact, a decrease of antithyroid antibodies titer has been recently observed in adult patients with ATD after eradication of Hp infection (31). In addition, Faller et al. (32) observed that antiparietal cell antibody prevalence decreased in patients with autoimmune gastritis after Hp eradication. These findings, coupled with the increased risk for other autoimmune diseases and especially the risk of cancer and carcinoids inherent to Hp-induced atrophic gastritis (5, 19, 24, 33), suggest the opportunity of trying Hp eradication in Hp-infected children with ATD and/or susceptible HLA alleles.

Careful clinical trials are needed on this issue.


   Footnotes
 
This work was supported by Ministero della Salute Ricerca Corrente Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo (Grant 34239/2000/gen.).

First Published Online November 1, 2005

Abbreviations: AT, Autoimmune thyroiditis; ATD, autoimmune thyroid disease; CI, confidence interval; GD, Graves’ disease; HLA, human leukocyte antigen; Hp, Helicobacter pylori; OR, odds ratio.

Received June 7, 2005.

Accepted October 24, 2005.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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