Occurrence and Risk Factors for Autoimmune Thyroid Disease in Patients with Atrophic Body Gastritis

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1 CLINICAL RESEARCH STUDY Occurrence and Risk Factors for Autoimmune Thyroid Disease in Patients with Atrophic Body Gastritis Edith Lahner, MD, a Marco Centanni, MD, b Giacoma Agnello, MD, a Lucilla Gargano, MD, b Lucy Vannella, MD, a Carlo Iannoni, MD, a Gianfranco Delle Fave, MD, a Bruno Annibale, MD a a Department of Digestive and Liver Disease, University La Sapienza, Second Medical School, Ospedale Sant Andrea, Rome, Italy; b Endocrinology Unit, Department of Experimental Medicine, University La Sapienza, Polo Pontino, Latina, Italy. ABSTRACT PURPOSE: To investigate the occurrence of and risk factors for autoimmune thyroid disease in atrophic body gastritis patients. METHODS: Cross-sectional study on 401 consecutive outpatients with atrophic body gastritis. Diagnostic work-up of thyroid disease was completed in 319 atrophic body gastritis patients (225 women, median age 55.5 years [range years]). Data on anagraphics, lifestyle, family history, and biochemical and histological items were obtained at baseline, and associations between atrophic body gastritis and autoimmune and nonautoimmune thyroid diseases were explored through descriptive statistics and logistic regression analyses. RESULTS: Of the 319 atrophic body gastritis patients, 169 (53%) had an associated thyroid disorder, and 89 (52.7%) of these were unaware of it. The thyroid disease was autoimmune in 128 patients (75.7%) and nonautoimmune in 41 patients. Logistic regression showed that risk factors for having autoimmune thyroid disease in atrophic body gastritis patients were female sex (odds ratio [OR] 5.6, 95% confidence interval [CI], ), presence of parietal cell antibodies (OR 2.5, 95% CI, ), and presence of metaplastic atrophy (OR 2.2, 95% CI, ). CONCLUSIONS: Autoimmune thyroid disease and atrophic body gastritis occur in a closely linked fashion, suggesting that atrophic body gastritis patients should be investigated for an occult autoimmune thyroid disease, in particular women and those with positive parietal cell antibodies Elsevier Inc. All rights reserved. The American Journal of Medicine (2008) 121, KEYWORDS: Atrophic body gastritis; Autoimmune thyroid disease; Intrinsic factor antibodies; Parietal cell antibodies; Pernicious anemia Atrophic body gastritis is a chronic, often symptomless disorder affecting the corporal mucosa. It is characterized by disappearance of the oxyntic glands, leading to loss of production of chlorhydric acid and intrinsic factor. 1 Hypochlorhydria causes loss of feedback on gastrin production, thus, hypergastrinemia together with low pepsinogen I levels is a well-established biochemical marker for atrophic body gastritis. 2,3 Atrophic body gastritis is epidemiologically and biologically linked to the development of the intestinal-type gastric adenocarcinoma and gastric carcinoid This study was funded by grants from the Italian Ministry for University and Research PRIN Requests for reprints should be addressed to Bruno Annibale, MD, Department of Digestive and Liver Disease, University La Sapienza, Ospedale Sant Andrea, Via di Grottarossa 1035, Roma 00189, Italy. address: bruno.annibale@uniroma1.it type I, 4-6 and frequently presents clinically with pernicious anemia. Atrophic body gastritis, in particular when associated with pernicious anemia, is often considered an autoimmune disorder, supported by the frequent presence of parietal cell and intrinsic factor autoantibodies as well as by its association with other autoimmune diseases. 7 Recent data give evidence that Helicobacter pylori infection, which is able to induce atrophy of the gastric mucosa, 8,9 may be the trigger of gastric autoimmunity, 10,11 but, as recently reported, a clear distinction between autoimmune atrophic gastritis and H. pylori-induced atrophic gastritis is difficult. 12,13 The association of atrophic body gastritis with thyroid disorders has been described since the early 1960s, long before routine gastroscopy and a histological consensus classification of gastritis were introduced. 17 The term thy /$ -see front matter 2008 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 Lahner et al Atrophic Body Gastritis and Autoimmune Thyroid Disease 137 rogastric syndrome has been used to define the presence of thyroid autoantibodies or autoimmune thyroid disease in patients with pernicious anemia, 15,18-20 which, in turn, was considered synonymous with atrophic body gastritis. 21 However, many of these older studies assessed the association between gastritis and thyroiditis only on the basis of gastric or thyroid autoantibodies, without a complete diagnostic work-up of the stomach or the thyroid. 14,15,18,19 To our knowledge, recent studies assessing the frequency of autoimmune thyroid disease in patients with atrophic body gastritis are lacking, and the entity of the association between these 2 disorders is not known. Thus, the aim of the present study was to investigate the occurrence of and risk factors for autoimmune thyroid disease in atrophic body gastritis patients. MATERIALS AND METHODS CLINICAL SIGNIFICANCE More than half of patients with atrophic body gastritis were found to have thyroid disease. Half of the thyroid disease cases were previously undiagnosed, and most (76% of cases) were autoimmune. Autoimmune thyroid disease was associated with female sex and parietal cell antibodies, but not with pernicious anemia. Patients with atrophic body gastritis should be assessed for occult autoimmune thyroid disease. Patients As the result of a screening program for atrophic body gastritis, we consecutively diagnosed this condition in 401 outpatients (269 women; median age 55 years [range years]) who presented to our gastroenterology department for long-standing dyspepsia (n 86) or were referred from the hematological department for anemia (n 302) or from the endocrinology department for autoimmune thyroid disease (n 13). 22,23 At the time of diagnosis, a structured questionnaire comprising anagraphical, lifestyle, and family history items was filled in for each patient. The diagnosis of atrophic body gastritis was based on histologic confirmation of gastric body mucosal atrophy, fasting hypergastrinemia, and low pepsinogen I levels. 22,23 All patients underwent gastroscopy with antral (n 3) and corporal (n 3) biopsies stained with hematoxylin and eosin for conventional histological evaluation and with Giemsa stain for H. pylori determination. 22,23 The degree of gastritis was assessed according to the updated Sydney System. 24 Atrophy of the body and antral mucosa was defined as focal or complete replacement of oxyntic or pyloric glands by metaplastic pyloric or intestinal glands, respectively. 22,23 All patients underwent serological studies: fasting gastrin levels by a specific radioimmunoassay (normal value 40 pg/ml); 22,23 pepsinogen I levels by a commercial radioimmunoassay kit (Pepsik, Sorin, Saluggia, Italy) (normal value 20 ng/ml); 23 parietal cell antibodies by a commercial kit (Autostat, Cogent Diagnostic Ltd, Edinburgh, UK); 22,23 intrinsic factor antibodies by an indirect enzymelinked immunosorbent assay (ELISA); 25 and H. pylori immunoglobulin G antibodies by a commercial ELISA kit (Bio Rad, Milan, Italy). 9,22 The diagnosis of pernicious anemia was defined as a hemoglobin concentration 14 g/dl for men and 12 g/dl for women, mean corpuscular volume 100 fl, low levels of vitamin B 12 (normal values pg/ml), response to vitamin B 12 therapy, and histological confirmation of gastric body mucosa atrophy. 26 None of the patients included in the study was on treatment with proton pump inhibitors or H 2 receptor antagonists. All patients gave written informed consent to the study, which was approved by the local Ethics Committee. Evaluation of Thyroid Status A careful clinical history for thyroid disease was collected in all atrophic body gastritis patients. Those with a positive clinical history were referred for endocrinological evaluation at a single center in order to confirm the diagnosis of thyroid disease; those with a negative clinical history were invited to undergo a biochemical/immunological (serum iodothyronines, basal thyrotropin, and serum antiperoxidase antibodies) and ultrasonographic evaluation of the thyroid status (Figure). Thyroid hormones and autoantibodies were determined by commercial kits: free triiodothyronine and free thyroxine levels by radioimmunoassay (Ares-Serono, Milan, Italy); basal thyrotropin levels by immunoradiometric assay (Radim Techland, Liege, Belgium); and antiperoxidase antibodies by a radioligand assay (Radim Techland). By ultrasonography, thyroid gland size, echogenicity of the parenchyma, and nodular lesions were evaluated. Patients in whom the biochemical/immunological or ultrasonographic evaluation gave abnormal results were referred for endocrinological evaluation at the same single center, in order to define the diagnosis of autoimmune or nonautoimmune thyroid disease. The diagnosis of autoimmune thyroiditis was based on the presence of antiperoxidase antibodies (antibody titers stably 200 U/mL in at least 2 separate measurements) and characteristic ultrasound features (ie, nonhomogeneous pattern with diffuse reduction of echogenicity), according to Rago et al, 27 in the presence, but even in the absence of mild or overt hypothyroidism. 28 Also, patients with the presence of only antiperoxidase antibodies but normal morphofunctional thyroid parameters were classified as having autoimmune thyroid disease. 27 Thyroid atrophy was diagnosed in the presence of reduced thyroid volume and ultrasound-detected diffuse fibrosis of the gland. Graves disease was diagnosed in patients with

3 138 The American Journal of Medicine, Vol 121, No 2, February 2008 Figure Study design. ABG atrophic body gastritis. clinical and biochemical hyperthyroidism presenting with antithyrotropin receptor antibodies (performed when needed by a radioreceptor assay, Ares-Serono). Nonautoimmune thyroid disease was assessed on the basis of the presence of ultrasonographic thyroid abnormalities (increased thyroid volume 25 ml, with the presence of one or more nodules) and the definite absence of antiperoxidase antibodies. Only atrophic body gastritis patients with definite normal morphofunctional and immunological parameters were assumed to have a healthy thyroid gland. A total of 319 (79.6%) of the 401 eligible atrophic body gastritis patients completed the evaluation of thyroid status and were included in the study. Fifty-five (13.7%) patients did not adhere to the protocol, 12 (3.0%) did not complete the thyroid diagnostic work-up, and 15 (3.7%) refused the endocrinological evaluation; therefore, 82 atrophic body gastritis patients (44 women) were excluded from the study due to incomplete thyroid evaluation. Statistical Evaluation Data were expressed as median (range), mean SEM or number/total (percentage, %), and differences between atrophic body gastritis patients with autoimmune thyroid disease, nonautoimmune thyroid disease, and those with a healthy thyroid gland were analyzed using an independent samples t test, chi-squared test, Fisher exact test, or Mann- Whitney test, as appropriate. Two-tailed P values.05 were considered statistically significant. The presence of risk factors for the occurrence of autoimmune thyroid disease in atrophic body gastritis patients was assessed by performing multivariate analyses by logistic regression models. The presence or absence of autoimmune thyroid disease was considered a dependent variable. In order to increase the possibility that the correct variables (risk factors and potential confounders) were included in the analysis, 2 logistic regression models were used (enter and stepwise method). Descriptive statistics and logistic regression were run on a dedicated software package (Med- Calc Software 9.2; Mariakerke, Belgium). RESULTS Overall, a total of 169 (53%) of the 319 atrophic body gastritis patients had associated thyroid disease, whereas in the remaining 150 patients, the thyroid gland was found to be healthy. Of these 169 atrophic body gastritis patients, 80 (47.3%) were aware of the thyroid disease before the diagnosis of atrophic body gastritis and had at least one criterion (ie, presence of goiter, palpable nodules, positive antibodies, suppressed or increased thyrotropin, free thyroxine levels out of normal range) suggestive of thyroid disease. The definite diagnosis was confirmed based on the criteria reported above. The remaining 89 (52.7%) subjects were unaware of the thyroid disease, which was diagnosed on the basis of complete thyroid evaluation after the diagnosis of atrophic body gastritis. Of the 169 patients with thyroid disease, 128 (75.7%) had an autoimmune thyroid disease (9 had atrophic thyroiditis and 2 had Graves disease) and the remaining 41 patients had a nonautoimmune thyroid disease: 21 patients had a multinodular goiter with or without autonomous functioning nodules, 13 had a previously diagnosed subacute thyroiditis, and 7 patients had undergone complete thyroidectomy before the diagnosis of atrophic body gastritis (3 for thyroid cancer and 4 for large multinodular goiter). Table 1 shows the clinical, biochemical, and histological features of atrophic body gastritis patients with respect to the thyroid status. The female sex was highly prevalent not only among atrophic body gastritis patients with autoimmune thyroid disease (83.6%), but also among those with nonautoimmune thyroid disease (85.4%), compared with patients with a healthy thyroid gland (55.3%, P.001). The percentages of females and males excluded from the study

4 Lahner et al Atrophic Body Gastritis and Autoimmune Thyroid Disease 139 Table 1 Clinical, Biochemical, and Histological Features in Atrophic Body Gastritis (ABG) Patients with Respect to the Thyroid Status ABG Patients with Autoimmune Thyroid Disease n 128 ABG Patients with Nonautoimmune Thyroid Disease n 41 ABG Patients with a Healthy Thyroid Gland n 150 Age, years, median (range) 54 (20-76) a 57 (30-80) 56.5 (17-95) Female sex, % 83.6 b 85.4 b 55.3 Presence of pernicious anemia, % Active smokers, present/absent Fasting gastrin, pg/ml, mean SEM Pepsinogen I, ng/ml, mean SEM Positivity of intrinsic factor antibodies, % Positivity of parietal cell antibodies, % 86.7 a Presence of extrathyroid autoimmune diseases d, % 17.2 c Presence of active H. pylori infection e, % Clinical history of peptic ulcer, % First degree family history for peptic ulcer, % First degree family history for gastric cancer, % Presence of corpus-restricted atrophic gastritis f, % Presence of multifocal atrophic gastritis g, % Presence of metaplastic atrophy, % a Compared with ABG patients with a healthy thyroid gland, P.01. b Compared with ABG patients with a healthy thyroid gland, P.001. c Compared with ABG patients with a healthy thyroid gland, P.03. d Autoimmune diseases other than autoimmune thyroid disease. e ABG patients were defined as having active H. pylori infection when both histology and ELISA serology were positive. 13 f Presence of mucosal atrophy only in the gastric body. g Presence of mucosal atrophy in the gastric body and in the antrum. due to lack of compliance (n 82) were similar (53.6% females and 46.4% males). For all other features, patients with nonautoimmune thyroid disease and those with a healthy thyroid gland were similar. Unadjusted comparison between atrophic body gastritis patients with autoimmune thyroid disease and those with a healthy thyroid gland showed that the former were slightly younger (median age 54 years vs 56.5 years, P.0151) and had more frequently positive parietal cell antibodies (86.7% vs 72%, P.0104), whereas the positivity to intrinsic factor antibodies was similarly distributed among the 2 groups (39.8% vs 46.7%, P.2759). The presence of extrathyroid autoimmune diseases (eg, vitiligo, insulin-dependent diabetes mellitus, alopecia) was significantly more associated with the presence of autoimmune thyroid disease than with its absence (17.2% vs 8.0%, P.0318). In contrast, the classical features of autoimmune gastritis, that is, the presence of pernicious anemia (48.4% vs 49.3%, P.9772) and corpus-restricted atrophic gastritis (76.6% vs 73.3%, P.6315), were similarly associated with both groups. As for the presence of active H. pylori infection and the personal clinical and family history for peptic ulcer, no differences were observed between the 2 groups (Table 1). Adjusted analyses indicated that the variables associated with the presence of autoimmune thyroid disease were female sex, presence of parietal cell antibodies, and presence of metaplastic atrophy, as shown in Table 2, independently from the method used for the selection of input variables. In contrast to unadjusted analyses, the significant association with extrathyroid autoimmune diseases in atrophic body gastritis patients with autoimmune thyroid disease was not confirmed (odds ratio [OR] of 2.1, 95% confidence interval [CI], , P.1287). However, a relevant number of these patients included in the univariate analyses (7 of 22 in the autoimmune thyroid disease group and 3 of 12 in the healthy thyroid gland group) were excluded from multivariate analyses due to missing data. Moreover, adjusted analyses did not confirm the association of younger age with the presence of autoimmune thyroid disease in atrophic body gastritis patients (OR 0.98, 95% CI, , P.98), but confirmed the lack of association between the presence of autoimmune thyroid disease and pernicious anemia (OR 1.65, 95% CI, , P.1757), corpus-restricted atrophic gastritis (OR 1.18, 95% CI, , P.6540), and the presence of intrinsic factor antibodies (OR 1.7, 95% CI, , P.2257). DISCUSSION This study provides data demonstrating that a thyroid disorder is associated in more than half (53%) of patients with histologically diagnosed atrophic body gastritis. In Western countries, the frequency of autoimmune thyroid disease can be estimated at between 5% and 15%, 28 and in Europe that of nonautoimmune thyroid disease is around 15% due to the presence of iodine deficiency. 29 In our series, autoimmune

5 140 The American Journal of Medicine, Vol 121, No 2, February 2008 Table 2 Variables Significantly Associated with the Presence of Autoimmune Thyroid Disease (ATD) in Atrophic Body Gastritis (ABG) Patients: Logistic Regression Models Variable Model 1 a OR (95% CI) Model 2 b OR (95% CI) Female sex 5.6 ( ) 4.7 ( ) Presence of parietal cell 2.5 ( ) 2.6 ( ) antibodies Presence of metaplastic atrophy 2.2 ( ) 2.1 ( ) In both models, the significance level of the overall model fit was P a Sample for analysis consisted of 224 patients. Fifty-four patients were excluded because data on one or more input variables were missing. All independent variables that may be hypothesized on theoretical grounds to be potential confounders of the relationship between ABG and ATD were included in the model (enter method). Input variables were: age, sex, onset of disease, presence of pernicious anemia, presence of other autoimmune diseases, presence of metaplastic atrophy, presence of corpus-restricted atrophic gastritis, active H. pylori infection, presence of parietal cell antibodies and intrinsic factor antibodies, fasting gastrin, and pepsinogen I. b Sample for analysis consisted of 220 patients. Fifty-eight patients were excluded because data on one or more input variables were missing. Independent variables were entered into the model according to the stepwise method. In this model, all available input variables were initially included (those of model 1 plus hemoglobin, mean corpuscular volume, clinical history for peptic ulcer, clinical history for neoplasia, family history for peptic ulcer, family history for gastric neoplasia, and smoking habit). The model excluded all variables except for the 3 significant ones (associated significance level.05: female sex, presence of parietal cell antibodies, and presence of metaplastic atrophy). thyroid disease represented the vast majority of cases (76%) of thyroid disease associated with atrophic body gastritis. Therefore, among atrophic body gastritis patients, the frequency of nonautoimmune thyroid disease reflects that of the general population, whereas the occurrence of autoimmune thyroid disease is 3 to 8 times more prevalent. 28 The association of pernicious anemia and thyroid disease was first described more than 40 years ago, and the term thyrogastric syndrome was introduced in the early 1960s, but has fallen into desuetude. 15,18-20 These older studies assessed the association between pernicious anemia and thyroiditis on the basis of gastric or thyroid autoantibodies and found an association ranging from 2.6% to 32%. 14,15,18,19 A more recent report highlighted the need to assess the coexistence of these 2 apparently unrelated autoimmune diseases. 30 Our study supports a relevant association between atrophic body gastritis with and without pernicious anemia and autoimmune thyroid disease on the basis of more updated and even criteria. In fact, the consistency of our findings stems from 2 reasons: our study population includes not only atrophic body gastritis associated with pernicious anemia, but also other clinical presentations, and it is based on appropriate diagnostic criteria for these 2 conditions, that is, histological diagnosis of atrophic body gastritis and increased accuracy of the immunomorphological diagnosis of autoimmune thyroid disease. It is noteworthy that more than half (52.7%) of atrophic body gastritis patients were diagnosed to have thyroid disease, following a complete thyroid evaluation after the diagnosis of gastritis. This finding may be important from a clinical point of view, because it shows how beneficial a thyroid diagnostic workup might be in this clinical setting. The subtle but detrimental effects of subclinical hypo- or hyperthyroidism may ensue to undiagnosed thyroid diseases and may be prevented by an early diagnosis. 30 Furthermore, a recent report pointed out that atrophic body gastritis patients with thyroid disease, who require oral thyroxine treatment, have definite thyroxine malabsorption as a major clinical feature. 31 Thus, in these patients the need for increased thyroxine dose should be kept in mind. The observed association between autoimmune thyroid disease and atrophic body gastritis suggests a common pathogenetic mechanism, such as autoimmune phenomena in both organs, probably due to an altered immune response in genetically predisposed individuals. 32,33 It is well known that thyroid disorders and other autoimmune diseases are highly prevalent among female patients, 34 as also shown by logistic regression analysis (female sex OR 5.6). Furthermore, these 2 autoimmune disorders often appear in familial clusters 34 and are associated with other endocrine and nonendocrine autoimmune disorders. 35,36 In this study, extrathyroid autoimmune disorders were observed 2 times more frequently in atrophic body gastritis patients with autoimmune thyroid disease than in those with a healthy thyroid gland. Another risk factor identified by multivariate analyses for having autoimmune thyroid disease associated with atrophic body gastritis was positivity to parietal cell antibodies (OR 2.5), well-known markers for gastric autoimmunity. 7 The results of this study thus suggest that positivity to parietal cell antibodies is indicative not only for gastric damage, but also for risk for thyroid autoimmunity. The presence of intrinsic factor antibodies was not associated with the presence of autoimmune thyroid disease in atrophic body gastritis patients. These antibodies are considered highly specific markers for the presence of pernicious anemia; 12 however, in this study, the presence of pernicious anemia was not indicative for having autoimmune thyroid disease associated with atrophic body gastritis (Table 1). Thus, the lack of association between pernicious anemia and autoimmune thyroid disease probably explains that intrinsic factor antibodies are not predictive for thyroid autoimmunity. Multivariate analyses also showed that intestinal metaplasia associated with gastric atrophy is a risk factor for the association of autoimmune thyroid disease with atrophic body gastritis. Intestinal metaplasia is an intermediate step in the temporal sequence of gastric mucosal changes eventually leading to gastric carcinoma and is considered a severity marker for atrophic gastritis. 37,38 It may be considered biologically reasonable that those patients with a more severe atrophic body gastritis, as indicated by the presence of intestinal metaplasia, are those mainly predisposed to

6 Lahner et al Atrophic Body Gastritis and Autoimmune Thyroid Disease 141 develop other autoimmune damage such as autoimmune thyroid disease. Although the logistic regression models were statistically significant (Table 2), univariate analyses showed no difference between the prevalence of metaplastic atrophy in all groups of atrophic body gastritis patients investigated (Table 1). Therefore, we feel that the interpretation of the significance of intestinal metaplasia as a risk factor for the association of autoimmune thyroid disease with atrophic body gastritis deserves caution. In conclusion, our study provides evidence that autoimmune thyroid disease and atrophic body gastritis occur in a closely linked fashion. The high prevalence of autoimmune thyroid disease in atrophic body gastritis patients (40%) suggests that these patients should be investigated for the presence of an occult autoimmune thyroid disease, in particular women and those with positive parietal cell antibodies. 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