Association between Helicobacter Pylori Infection and Barrett s Esophagus in Patients with Gastro-Esophageal Reflux Symptoms and Erosive Esophagitis

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1 Med. J. Cairo Univ., Vol. 82, No. 2, September: , Association between Helicobacter Pylori Infection and Barrett s Esophagus in Patients with Gastro-Esophageal Reflux Symptoms and Erosive Esophagitis EHSAN HASSAN, M.D.*; SAHAR MAKLAD, M.D.** and NOUR ABDEL MAKSOOD, M.D.*** The Departments of Pathology* and Hepatology & Gastroenterology**,***, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Kasr Al-Ainy Street, Fum El Khaleeg, Cairo, Egypt Abstract Objective: Barrett esophagus (BE) is considered to develop as a result of chronic gastroesophageal reflux disease (GERD) and to predispose to esophageal adenocarcinoma (EAC). Helicobacter pylori infection is said to play an etiological role in gastric carcinogenesis but possible role in Barret s esophagus remains uncertain. The aim of the study was to determine the correlation between helicobacter pylori infection in GERD patients and the development of Barret s esophagus and or esophageal carcinoma. Methods: Sixty patients complaining of recurrent upper gastrointestinal symptoms in the form of heart burn and reflux were included in the study. Endoscopic biopsies were taken for these patients and helicobacter pylori infection was confirmed by histopathological examination and Giemsa stain. Results: The study was conducted on 60 esophageal biopsies from patients complaining of various recurrent upper gastrointestinal symptoms. Esophageal H.pylori infection was found in 21 of 60 (35%) patients, 29/60 (48%) revealed chronic esophagitis with 12/29 positive H.pylori infection while 28/60 cases revealed Barrett s esophagitis with 8/28 positive H.pylori infection and 3/60 showed invasive esophageal carcinoma with 1/3positive H.pylori infection. Conclusion: We did not find a causal relationship between H.pylori and the development of chronic esophageal inflammation and Barret s esophagus. Other co factors need to be evaluated in this context as dietary factors, drug intake or others. Key Words: H.Pylori Barret s esophagus Histopathological changes Egyptian patients. Introduction THE esophagus is lined by stratified squamous epithelium with scattered mucous glands in the sub mucosa [1]. Barrett esophagus (BE) is defined as a change in the distal esophageal epithelium of any length characterized by columnar type mucosa during endoscopy and is confirmed to have intestinal metaplasia by biopsy [2]. Most Clinical and experimental evidence indicates that BE is consid- Correspondence to: Dr. Sahar Z. Maklad szmaklad@yahoo.com ered a complication of recurrent inflammation and ulceration as a consequence of chronic gastro esophageal reflux disease (GERD) and has the potential to develop into esophageal adenocarcinoma (EAC) [3,4]. Metaplastic epithelium could be of gastric or intestinal types. The large majority of patients are adults, however it has also been reported in children [5,6]. The mucosal extension of Barret s esophagus may be circumferential or in the form of finger like projections or islands that usually have the salmon pink color appearance [4]. Several etiological factors were blamed behind the occurrence of Barrret s esophagus are the dietary factors like nitrosamine, fungal toxins, hot food, smoking, alcohol, vit A, C or Zinc deficiency [7]. The etiology of inflammation below the normal Z line is an area of intense debate. Some suggest that it could be the earliest change of chronic gastro esophageal reflux disease, whereas other blame helicobacter pylori as the main cause. H pylori infection is a classical model with which we can study Cancer Development as a consequence of chronic inflammation [8]. Among the principle carcinogenic agents H.pylori is a considered a factor being responsible for 5% of all gastroesphageal malignancies. Formerly, H.pylori was classified as a type (1) carcinogen by the international agency for research on cancer in 1994 [9]. Various different reports were published regarding the role of H.pylori in predisposing to gastroesophageal reflux, Barrret s esophagus and carcinogenesis [10]. Weston et al., found the prevalence of H.pylori infection did not significantly differ among his study populations where; controls (42%), GERD (33%), and Barrret s esophagus (27%) [11] while Goldblum etal., reported that H pylori infection and not gastroesophageal reflux is the major cause of inflammation and intestinal metaplasia of cardiac mucosa [12]. On the contrary Watari et al., stated that according to many case-controlled studies, 169

2 170 Association between Helicobacter Pylori Infection H.pylori infection may play a protective role in the development of reflux esophagitis (RE) [13]. However, the frequency of RE development does not increase following successful H.pylori treatment based on the previous studies including metaanalysis and systematic review. Even though some studies pointed to the fact that RE newly develops after H.pylori eradication, endoscopic findings reveal mild such as grade A or B according to the Los Angeles Classification System. With regard to BE, there is an inverse significant relationship. Since there are few studies indicating that BE increases after treatment of H.pylori, the eradication should be recommended for patients with H.pylori infection irrespective of the presence of RE or BE even in terms of the prevention of gastric cancer [14,15]. Patients and Methods Our study was conducted as a joint research work between Hepatology Department (endoscopy unit) and Pathology Department at the National Hepatology and Tropical Medicine Research Institute, Cairo, NHTMRI. Recruitment started from January 2013 to January 2014 for patients regularly attending endoscopy unit at the institute for symptoms including recurrent epigastric pain, heart burn, or gastroesphageal reflux disease. A total of 100 patients were included in the evaluation and 60 patients were included in our study. Patients with advanced hepatic disease, portal hypertensive gastropathy, esophageal varices were excluded. Also those with history of exposure to corrosives or esophageal dilatation were excluded. All patients were subjected to full history with special emphasis on previous exposure to medications as NSAIDS and Clinical examination. As by our routine at the endoscopy Department a written informed consent was signed by all patients before the procedure of upper endoscopy. Procedure technique: Patients are prepared by 12 hours fasting and were given Dormicum 5mg IV prior to endoscopy. The patient was connected to the monitoring device lying on the left lateral position. After adequate sedation was achieved, the scope was passed under direct vision and advanced to the duodenum. The color texture and integrity of the mucosa were examined. The scope was then retroflexed to evaluate the incisura and cardia. The patient was then subjected to biopsy using biopsy forceps. The patient was then extubated and transported to the recovery area. Biopsy specimens were transferred to Pathology Department where they were prepared and stained. H.pylori infection had to be confirmed by histopathological examination and Giemsa stain. The following sections were revealed from our cases. Our biopsies revealed the following specimens. Fig. (A): Section of esophageal biopsy showing severe chronic inflammation (H&E, x 200). Fig. (B): Section of esophageal biopsies with positive H.pylori infection (Giemsa, x 400). Fig. (C): Section of esophageal biopsies with positive H.pylori infection (Giemsa, x 400). Fig. (D): Section of esophageal biopsy showing intestinal metaplastic changes (HE x400).

3 Ehsan Hassan, et al. 171 Fig. (E): Section of esophageal biopsy showing Barrett s esophagus gastric type (HE x200). Fig. (F): Section of esophageal biopsy showing Barrett s adenocarcinoma (HE-X200). Results The mean age of our patients was 38.1 years old were the minimum age is 12 and max age is 70 years, with equal male to female ratio (30 males and 30 females). Fifty percent of our study population showed moderate inflammation while 22 cases (36.7%) showed mild inflammation and only 8 cases (13%) had evidence of severe inflammation. Regarding dysplasia only 10 percent of our cases showed any type of dysplasia were 3 cases showed low grade dysplasia, 2 cases showed squamous cell metaplasia and only 1 case showed Pathological evidence of adenocarcinoma. Barret s esophagus was detected in 25 cases (41.7%) of cases showing gastric metaplasia were only 3 cases with evidence of Cancer (Table 1). Regarding association between different parameters and H.pylori infection, it was found that infection showed statistical significance in the younger age group with a mean age of 24.6 if compared to the older age group with a mean of p-value <0.01 * (Table 2). H.pylori infection was encountered more in females in our study population if compared to males were it was identified in 71.4% of females if compared to only 28.6% in males. There was no direct correlation between H.pylori and chronic inflammation as only 47.6% were H.pylori positive in moderate inflammation cases and in 14.3% in cases with severe inflammation. Regarding gastric metaplasia, H.pylori was encountered in only 23.8% (5 cases) in cases with Barret s esophagus and in only 4.8% (1 case) in case of gastric Cancer (Table 3). Table (1): Description of the study group. Sex: Femal Male Frequency Percent Mean Age: 38.1 ±18.1 H.pylori: Negative Positive Chronic inflammation: Mild Moderate Severe Dysplasia: Negative Adenocarcinoma Low grade S_C_C Gastric metaplesia: Negative Barrett s SD Cancer Table (2): Association between age and H.pylori infection. H.pylori Mean Std. infection age Deviation Negative (n=39) Significance Positive (n=21) <0.01 *

4 172 Association between Helicobacter Pylori Infection Table (3): Association of different parameters with H.pylori infections. Variable Negative H.pylori Positive Total Significance Sex: Female 15 (38.5%) 15 (71.4%) 30 (50.0%) Male 24 (61.5%) 6 (28.6%) 30 (50.0%) * Chronic inflammation: Mild 14 (35.9%) 8 (38.1%) 22 (36.7%) Moderate 20 (51.3%) 10 (47.6%) 30 (50.0%) Severe 5 (12.8%) 3 (14.3%) 8 (13.3%) 0.96 Dysplasia: Negative 34 (87.2%) 20 (95.2%) 54 (90.0%) Adenonarcin 1 (2.6%) 0 (0.0%) 1 (1.7%) Low grade 3 (7.7%) 0 (0.0%) 3 (5.0%) Squamous Cell Carcinoma 1 (2.6%) 1 (4.8%) 2 (3.3%) 0.48 Gastric metaplasia: Negative 17 (43.6%) 15 (71.4%) 32 (53.3%) Barrett s 20 (51.3%) 5 (23.8%) 25 (41.7%) Cancer 2 (5.1%) 1 (4.8%) 3 (5.0%) 0.48 Abbreviations: BE : Barrett esophagus. NHTMRI : National Hepatology and Tropical Medicine Research Institute, Cairo. GERD : Gastroesophageal reflux disease. RE : Relux esophagitis. EAC : Esophageal adenocarcinoma. PAI : Cag pathogenicity island. HP : Helicobacter pylori. Discussion Helicobacter pylori, previously named Campylobacter pylori, are a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Australian scientists Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were not previously believed to have a microbial cause. It is also linked to the development of duodenal ulcers and stomach cancer. However, over 80 percent of individuals infected with the bacterium are asymptomatic and it has been postulated that it may play an important role in the natural stomach ecology [16]. More than 50% of the world s population harbor H.pylori in their upper gastrointestinal tract. Infection is more prevalent in developing countries, and incidence is decreasing in Western countries. H.pylori s helix shape (from which the generic name is derived) is thought to have evolved to penetrate the mucoid lining of the stomach [17,18]. Study of the H.pylori genome is centered on attempts to understand pathogenesis, the ability of this organism to cause disease. Approximately 29% of the loci are in the pathogenesis category of the genome database. Two of sequenced strains have an approximately 40-kb-long Cag pathogenicity island (a common gene sequence believed responsible for pathogenesis) that contains over 40 genes. This pathogenicity island is usually absent from H.pylori strains isolated from humans who are carriers of H.pylori but remain asymptomatic [19]. The caga gene codes for one of the major H.pylori virulence proteins. Bacterial strains that have the caga gene are associated with an ability to cause ulcers. The caga gene codes for a relatively long (1186 amino acid) protein. The cag pathogenicity island (PAI) has about 30 genes, part of which code for a complex type IV secretion system [20]. The low GC-content of the cag PAI relative to the rest of the Helicobacter genome suggests the island was acquired by horizontal transfer from another bacterial species [21]. Based on a casecontrol study, infection with H.pylori, particularly the caga + strain, is associated inversely with Barrett s esophagus. This was also observed by another study that suggested an inverse association with esophagitis, but not with GERD symptoms. H.pylori infection was associated inversely with Barrett s esophagus [22]. Helicobacter pylori has been implicated as a risk factor for precancerous lesions in the stomach which affect the acid producing parietal cells [23]. However, inconsistent evidence exists regarding the effect of H.pylori on gastroesophageal reflux disease, the primary putative risk factor for Barrett s

5 Ehsan Hassan, et al. 173 esophagus and esophageal adenocarcinoma, and the current evidence regarding the effect of H.pylori on Barrett s esophagus remains poorly understood. Some previous studies have reported that H.pylori is a risk factor for Barrett s esophagus, [24] while other studies have reported that H.pylori has no effect on Barrett s esophagus [25] and others still report a protective effect [26]. Previous metaanalyses, using small subsets of studies on this topic, failed to investigate sources of the heterogeneity of effects across studies. Watari studied the relationship between Helicobacter pylori status and the development of reflux esophagitis or Barrett s esophagus [13]. According to many case-controlled studies, H.pylori infection may play a protective role in the development of RE. However, the frequency of RE development does not increase following successful H.pylori treatment based on the previous studies including meta-analysis and systematic review. Even though RE newly develops after H.pylori eradication, endoscopic findings reveal mild such as grade A or B according to the Los Angeles Classification System. With regard to BE, there is an inverse significant relationship. Since there are few studies indicating that BE increases after treatment of H.pylori, the eradication should be recommended for patients with H.pylori infection irrespective of the presence of RE or BE even in terms of the prevention of gastric Cancer. In our study, there was no direct correlation between H.pylori infection and the development of esophagitis and or Barrret s esophagus. Esophageal H.pylori infection was only found in 21 of 60 (35%) patients, 29/60 revealed chronic esophagitis with 12/29 positive H.pylori infection while 28/60 cases revealed Barrett s esophagitis with 8/28 positive H. pylori infection and 3/60 showed invasive esophageal carcinoma with 1/3positive H.pylori infection (Table and Fig. A-F). 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