INTRODUCTION
Celiac disease (CD) is a systemic autoimmune disease triggered by gluten, a special protein in cereals, mostly affecting the proximal small intestine in people with genetic predisposition [1]. CD affects 0.6% to 1% of the population worldwide [2]. It can cause many extraintestinal symptoms such as anemia, osteoporosis, infertility and peripheral neuropathy, as well as manifestations such as diarrhea, steatorrhea, abdominal distension, weight loss, and malabsorption [3].
CD causes crypt hyperplasia and villous atrophy accompanied by an increase in intraepithelial lymphocytes, leading to mucosal damage in the proximal small intestines [4, 5]. Duodenal intraepithelial lymphocytosis, characterized by an increase in intraepithelial lymphocytes in the duodenum, may be an early sign of CD as well as non-gluten-related diseases such as Helicobacter pylori (HP), giardia infection, IgA deficiency and Crohn’s disease [6–8].
HP is held responsible for many diseases such as chronic gastritis, peptic ulcer, MALT lymphoma, intestinal metaplasia, and adenocarcinoma [9]. The relationship between HP and CD has not been fully explained. Some previously published studies suggest an inverse relationship between CD and HP and argue that HP may play a protective role against the development of CD [10–14].
AIM
In this study, we aimed to evaluate the prevalence of HP infection in CD and its relationship with the clinical course of the disease.
MATERIAL AND METHODS
The files of 946 patients over the age of 18 who underwent upper gastrointestinal system endoscopy in our tertiary health center between 2017 and 2019 were retrospectively reviewed after the local ethics committee approval (decision number 2011-KAEK-25 2020/11-06). Biopsy results and serological tests requested for the diagnosis of CD were noted. Duodenal biopsy specimens stained with hematoxylin-eosin (H&E) were classified according to Marsh-Oberhuber criteria. Marsh 0, 1, 2 and 3 were grouped as normal morphology, normal morphology with high intraepithelial lymphocytes, high intraepithelial lymphocytes with crypt hyperplasia and villous atrophy, respectively. Anti-tissue transglutaminase (anti-tTG), anti-endomysium (EMA), and anti-gliadin (AGA) antibody test results requested for the diagnosis of CD in patients with suspicious and specific clinical signs were recorded.
The diagnosis of HP infection was made by staining the biopsy samples taken from the antrum and corpus with H&E and Giemsa. HP activity was evaluated with Sydney classification. Disease activity was classified as 1, 2, or 3 according to mild, moderate, and severe activity, respectively.
One-hundred and sixty-eight patients with a Marsh score of 0 and negative serological tests for CD were determined as the non-CD group and 155 patients with a histopathological evaluation of 1 and above according to the Marsh classification and/or positive serological tests for CD were determined as the CD group. Age and gender of both groups were recorded. Histopathological evaluations for HP were scanned. 623 patients, whose histological and/or serological evaluations were outside the criteria of CD and non-CD groups were not included in the study.
STATISTICAL ANALYSIS
NCSS (Number Cruncher Statistical System) program was used for statistical analysis. Descriptive statistical methods (mean, standard deviation, median, frequency, percentage, minimum, maximum) were used while evaluating the study data. The conformity of the quantitative data to the normal distribution was tested with the Shapiro-Wilk test. The Mann-Whitney U test was used for the comparisons between two groups of quantitative variables that did not show normal distribution, and the Kruskal-Wallis test was used for comparisons between more than two groups of quantitative variables that did not show normal distribution. Pearson χ2 test and Fisher-Freeman-Halton tests were used to compare qualitative data. For statistical significance, p < 0.05 was accepted.
RESULTS
A total of 323 cases (218 (67.5%) females, 105 (32.5%) males) aged 39.08 ±14.83 years (min.–max.: 18–87) were included in the study. There was no significant difference between the groups in terms of gender (p = 0.994) and age (p = 0.742). The presence of HP (p = 0.015) and severity (p = 0.001) were found to be lower in the CD group than in the non-CD group (Table 1).
Table 1
Comparison of data by presence of celiac disease
While no significant difference was observed between the severity of inflammation and age, gender, biopsy results, and serological tests, only the difference between the severity of inflammation and anti-tTG IgG levels reached statistical significance (Table 2).
Table 2
Comparison of various data according to the HP inflammation degree in celiac patients
There was no significant difference between the presence of HP and the histopathological severity of the disease in the CD group (p = 0.960, Table 3).
Table 3
Comparison of biopsy results according to HP status in celiac patients
DISCUSSION
Although the origin of CD goes back to the 2nd century, it is thought that gluten sensitivity started with the transition of humanity to agricultural society [15]. CD is a disease that develops after exposure to dietary gluten in genetically susceptible individuals and causes inflammation of the small intestine.
CD is a chronic disease with a worldwide prevalence of approximately 1% and its prevalence increasing in the last 50 years [16]. However, there are still undiagnosed cases. The increase in industrial food consumption and the difficulties in accessing healthy food are shown as the main reasons for the increase in prevalence. It is thought that the intense consumption of processed foods containing high amounts of gluten triggers the emergence of the disease with increased gluten exposure.
It appears that some patients with lymphocytic duodenosis, an often reversible clinical condition, are misdiagnosed as CD. In a prospective study on the etiology of lymphocytic duodenosis, it was emphasized that it was associated with irritable bowel syndrome in patients without an obvious cause, and the number of intraepithelial lymphocytosis became normal at a rate of 76% on repeat biopsy [17]. Lymphocytic duodenosis is rarely associated with CD. Serological markers can be used to differentiate CD from other causes of lymphocytic duodenosis.
Lebwohl et al. [18] showed an inverse relationship between the presence of HP and CD, and they proposed the “Hygiene hypothesis” that autoimmunity is triggered by decreased exposure to bacterial antigens. According to this study, it has been suggested that T-regulatory lymphocytes may also play a role in the pathogenesis of CD, since the cellular response mediated by T-regulatory lymphocytes in the intestinal wall is decreased or lost in CD. HP can reduce gluten immunogenicity by affecting its digestion through gastric pH modification or proteases.
In a study by Villanacci et al. [19], severe villous atrophy was observed in 96% of HP-negative CD patients, while this rate was reported as 76% in HP-positive patients. In our study, the incidence of HP in CD cases was found to be significantly lower than in non-CD cases (41.3% vs. 54.8%, p = 0.015). However, the difference between the presence of HP and the severity of inflammation in CD cases could not reach statistical significance (Table 3).
However, in a study conducted in the pediatric patient population, it was reported that no significant relationship was observed between HP and CD [20]. In another study, it was reported that the inflammatory response was lower in HP-positive children than adults [21]. When the population in which the study was conducted and the number of cases is evaluated together, it can be considered that the validity of these data in the chronic disease process are doubtful.
Konturek et al. [22] showed that there was a significantly higher seroprevalence of low virulent HP infection among CD compared to healthy controls; they reported that they reached results suggesting that infection with more virulent HP strains could protect from CD.
In a meta-analysis reported in 2020 in which 24 clinical studies were reviewed, a significant negative association between HP colonization and CD (OR = 0.58; 95% CI: 0.45–0.76; p < 0.001) was demonstrated without any bias [23].
When the results of our study were evaluated, it was observed that although HP infection was less common in CD, it had a more severe course (Table 1). Moreover, higher antibody titer (anti-tTG IgG) was found in CD with lower HP infection severity (Table 2). Basyigit et al. [24] in their study, which emphasized that HP is one of the bacterial species most likely to trigger autoimmunity, failed to reveal a relationship between HP and CD and attributed this failure to the low number of cases (n = 240). In our current study, in which we evaluated the data of 323 patients, we were able to detect a negative correlation between HP and CD. While the serological evaluations performed simultaneously with endoscopic biopsy were assessed in the aforementioned study, we evaluated positive test results at any time from patient files as positive in our current study. Since serological test results can be affected by gluten-free diet, we can say that negative serology does not exclude CD, and positive serology detected at any time may suggest CD [25].
The fact that it was not taken into account whether the patients received HP eradication therapy can be considered as a limitation. The reason for this is the high prevalence of HP (> 50%) in Türkiye [26]. In our study, the incidence of HP was observed as 54.8% in non-CD cases (Table 1). Another limitation of our study is that the IgA levels of a small number of patients could be reached. No significant deficiency was found in the achieved IgA levels.
