Characteristics of patients with erosive and nonerosive GERD in high-helicobacter-pylori prevalence region

Diseases of the Esophagus (2004) 17, 223 227 2004 ISDE Blackwell Publishing, Ltd. Original article Characteristics of patients with erosive and nonerosive GERD in high-helicobacter-pylori prevalence region L. V. Jonaitis, G. Kiudelis, L. Kupcinskas Department of Gastroenterology, Kaunas University of Medicine, Kaunas, Lithuania SUMMARY. It is still not known whether there are differences between erosive and nonerosive GERD. The aim of the present study is to evaluate the prevalence of Helicobacter pylori (HP) infection, and other differences between erosive and nonerosive gastroesophageal reflux disease (NERD) patients. One-hundred and four consecutive GERD patients (mean age: 41.6 ± 12.3 years) were interviewed, endoscoped and tested for HP. Erosive GERD was defined according to the Los Angeles classification. Patients who had no erosions in the esophagus but complained of heartburn or/and acid regurgitation at least twice a week and for whom these symptoms had a negative impact on daily activities were considered to be NERD patients. Erosive GERD was identified in 53 (51%) patients (mean age: 41.0 ± 12.7 years) and NERD in 51 (49.0%) patients (mean age: 42.2 ± 11.9 years). HP infection was found in 32 (60.4%) erosive GERD patients, and 41 (80.4%) NERD patients, P < 0.05. Multivariate analysis revealed that there were two statistically significant prediction factors for NERD: female sex with odds ratio (OR) of 6.34 (95% CI: 2.41 16.64; P = 0.0002) and HP infection with odds ratio (OR) of 3.28 (95% CI: 1.26 8.58; P = 0.015). The presence of HP and female sex are found to be statistically significant predictors of NERD. KEY WORDS: gastroesophageal reflux disease (GERD), Helicobacter pylori, nonerosive gastroesophageal reflux disease (NERD). INTRODUCTION There is a decreasing prevalence of Helicobacter pylori (HP) around the world and at the same time the incidence and prevalence of GERD increases. 1 In developed Western countries GERD has become the leading gastrointestinal pathology, with the majority of patients requiring long-term treatment. It has been reported that the breakthrough in the incidence of GERD is accompanied by a dramatically decreased prevalence of HP infection and peptic ulcer disease. 2 At the same time, the increase in the incidence of precancerous Barrett s esophagus and esophageal adenocarcinoma has been proven. 3 5 The latter is the one of a few gastrointestinal cancers, the incidence of which is increasing. The negative correlation of these conditions with the prevalence of HP has been reported in some areas and a possible Address correspondence to: Professor Limas Kupcinskas, Chairman of Lithuanian Helicobacter Pylori Study Group, Head of the Department of Gastroenterology, Kaunas University of Medicine, Mickeviciaus 9, 3000 Kaunas, Lithuania. Tel: + 370 8640575: Fax: + 370 7734508, + 370 7220733; Email: likup@kmu.lt role of HP in protecting against GERD and esophageal adenocarcinoma are proposed, especially stressing the protective role of caga-positive HP strains. 6 8 However there are no evidence-based explanations of this phenomena and further investigations are needed. During the last decade the nosological entity of nonerosive gastroesophageal reflux disease (NERD) has emerged. 9 11 The definition of this disease is still under some discussion, but most have already defined it as severe symptoms of GERD (heartburn and acid regurgitation) significantly interfering with normal daily activity without endoscopically detected erosions in lower esophagus. 12 The pathogenesis of NERD is still not fully understood and some researchers speculate that this condition is a part of non-ulcer dyspepsia and may be related not only to gastroesophageal reflux events, but also to the presence of regulatory abnormalities and HP-induced gastritis. 13 15 There is a lot of discussion regarding whether or not the prevalence of HP is different among erosive versus nonerosive GERD patients and whether or not HP is important in the pathogenesis of the disease. 16 18 The prevalence of HP infection is still high in Eastern European countries, especially in the olderaged population. 19,20 The incidence of GERD is 223

224 Diseases of the Esophagus noticeably increasing in this area, although there are no serious epidemiological data confirming it. 21 Therefore we conducted the study of consecutive GERD patients with the aim of finding any differences in demographic and clinical characteristics and in the prevalence of HP between two forms of GERD: erosive esophagitis and NERD. METHODS We investigated 104 consecutive GERD patients (mean age: 41.6 ± 12.3 years) who had not used proton pump inhibitors, bismuth compounds or antibiotics for at least 4 weeks before testing, H 2 -blockers for at least 7 days before testing, antacids for at least 48 h before testing and were not NSAIDs users. We also excluded patients with any severe accompanying diseases. After thorough interviewing of patients using a gastrointestinal symptom rating scale (GSRS) questionnaire a videoendoscopy was performed. During endoscopies, four biopsy specimens from the antrum and four from the corpus were taken for urease testing and histological examination. A single pathologist, who was blinded to any clinical and demographic data, performed histological evaluations of biopsies from the antrum and corpus of the stomach according to the Sydney system. 22 At least 2 h after endoscopy, validated C 14 -urea breath tests (UBT; Heliprobe, Noster System AB, Stockholm) were performed. 23 Helicobacter pylori was investigated using rapid urease test, Giemsa-stained histological specimens and C 14 -UBT. HP positivity established if at least two of these tests were positive. Erosive GERD was defined and evaluated according to the Los-Angeles classification. 24 Non-erosive GERD patients were those who had no erosions in the esophagus (during present investigation and in whom erosions had never been found in the past), but complained of heartburn or/and acid regurgitation at least twice a week with these symptoms having a negative impact on daily activities (Genval consensus). 12 Statistical analysis was performed using SPSS for Windows. The obtained data were analyzed and compared using χ 2 or Student s t-test, and logistic regression. Values of P < 0.05 were considered significant. The study was approved by Ethics Committee of Kaunas University of Medicine. RESULTS Of 104 patients, erosive GERD was found in 53 (51%) patients, (mean age: 41.0 ± 12.7 years) and NERD in 51 (49.0%; mean age: 42.2 ± 11.9 years). In the erosive GERD group there were 27 (50.9%) Fig. 1 Relationship of mean body mass index (BMI) to different degrees of gastroesophageal reflux disease.(nerd, nonerosive GERD.) men and 26 (49.1%) women. In the NERD group there were eight (15.7%) men and 43 (84.3%) women, P < 0.005. In the erosive GERD group the mean age of men was 35.0 ± 10.2 years, for women it was 47.3 ± 12.1 years, P < 0001. In NERD group mean age of the men was 37.7 ± 18.1 years and of women was 43.0 ± 10.4 years, P > 0.05. According to the Los-Angeles classification in the erosive GERD group there were 21 cases (39.6%) of esophagitis A, 27 cases (50.9%) of esophagitis B, four cases (7.5%) of esophagitis C and one case (1.9%) of esophagitis D. For the convenience of further calculations we joined esophagitis C and D cases into one group the C + D esophagitis group. The mean body mass index (BMI) was 26.23 ± 4.03. The mean BMI of erosive GERD patients was 26.83 ± 4.02 and for NERD patients it was 25.62 ± 3.99, P > 0.05. But there were significant differences in mean BMIs between the groups with NERD and esophagitis B, and an obvious trend of higher mean BMIs in patients with esophagitis C + D (significance level not reached due to the small number of patients with severe esophagitis) (Fig. 1). In the erosive GERD group endoscopic hiatus hernia was documented in 48 (90.6%) patients, in the NERD group it was found in 40 patients (78.4%), P = 0.086. In the esophagitis A group, hernias were found in 16 patients (76.2%); in the esophagitis B group, in 27 patients (100%); and in the esophagitis C + D group in five (100%) patients (according to χ 2 tests, P < 0.05). It is obvious that hiatus hernia is almost always present in severe GERD. In the erosive GERD group there were 18 smokers (34%), in the NERD group there were 10 smokers (19.6%), P = 0.099. There were six smokers (28.6%) in the esophagitis A group, 10 (37%) in the esophagitis B group and two (40%) in the esophagitis C + D group (according to χ 2 tests, P > 0.05). Frequencies of smokers are nor significantly different, but there is a trend for higher a frequency of smokers in more severe grades of GERD.

GERD in high Helicobacter pylori prevalence region 225 Table 1 Mean scores of the histological gastritis characteristics according to Sydney classification in Helicobacter pylori (HP)-positive erosive gastroesophageal reflux disease (GERD) and nonerosive GERD (NERD) patients Antral mucosa Corpus mucosa HP density Gran. Lymph. Atrophy Int. met. HP density Gran. Lymph. Atrophy Int. met. Erosive GERD score (n = 32) 2.31 1.22 1.53 0.19 0.22 1.97 0.59 1.09 0.16 0.09 ± SD 0.82 0.83 0.62 0.40 0.55 0.82 0.76 0.64 0.45 0.39 NERD score (n = 41) 2.05 1.44 1.41 0.49 0.15 1.78 0.63 1.00 0.20 0 ± SD 1.00 0.78 0.55 0.71 0.42 0.91 0.92 0.63 0.46 0 P-value NS NS NS 0.04 NS NS NS NS NS NS Gran., granulocytes; Lymph., lymphocytes; Int. met., intestinal metaplasia; NS, not significant. Fig. 2 Helicobacter pylori (HP) prevalence in different grades of gastroesophageal reflux disease (GERD). (NERD, nonerosive GERD.) Altogether HP was established in 73 (70.2%) cases. HP was established in 32 patients (60.4%) in the erosive GERD group and 41 patients (80.4%) in the NERD group, P < 0.05. Interestingly, male erosive GERD patients were HP-positive in 19 (70.4%) cases and 13 female patients (50%) were HP-positive, P > 0.05. In contrast, in male NERD patients HP was found less frequently (six cases; 75%) than in women (35 cases; 81.4%), P > 0.05. There was an obvious trend for lower HP-positivity in the more severe grades of GERD (Fig. 2). We also applied a multivariate analysis model for the prediction of erosive or nonerosive GERD. Logistic regression revealed that there were two statistically significant prediction factors for NERD: female sex with an odds ratio (OR) of 6.34 (95% CI: 2.41 16.64), P = 0.0002 and HP infection with an odds ratio (OR) of 3.28 (95% CI: 1.26 8.58), P = 0.015. Smoking status, presence of hiatus hernia and a BMI of more than 24.9 (overweighed persons) did not reach statistical significance in the logistic regression model for prediction of the type of GERD. Based on the GSRS questionnaire we evaluated mean intensity scores of symptoms (epigastric pain, heartburn, acid regurgitation, hunger-like pain, nausea, burping, epigastric fullness, retching, abdominal bloating, constipation, diarrhea, urgency to defecate, incomplete defecation) in erosive GERD and NERD patients. We also evaluated the mean intensity scores of symptoms separately in HP-positive and HPnegative erosive GERD and NERD patients. Only the mean intensity of heartburn was significantly higher among NERD patients (2.92 ± 1.76 vs 3.63 ± 1.27, P = 0.026). We found that the intensity of heartburn remains statistically significantly higher only in HP-positive NERD patients (2.90 ± 1.83 vs 3.68 ± 1.23, P = 0.039). The mean scores of other symptoms were not different between the groups regardless of HP status. The histological characteristics of gastritis of HP-positive erosive and nonerosive GERD patients are presented in the Table 1. There are no significant differences in the gastritis scores in the antrum and corpus of the stomach between erosive GERD and NERD, and there is antrum-predominant gastritis in both erosive and nonerosive GERD patients. Only the mean atrophy score in the antrum was significantly higher (P = 0.04) in the NERD group. Based on endoscopic severity we also divided all GERD cases into mild GERD (NERD and esophagitis A cases) and severe GERD (esophagitis B, C and D). We applied a logistic regression model to find predictors for these two entities. Only two variables were found to be statistically significant predictors for severe GERD absence of HP, with OR 3.99 (95% CI: 1.46 10.87), P < 0.01; and male sex, with OR 6.17 (95% CI: 2.33 16.31), P < 0001. Smoking status, a BMI of more than 24.9 and the presence of hiatus hernia were not significant predictors. DISCUSSION In our consecutive GERD patients series almost half of the patients (49%) were NERD patients, it confirms data from other studies, that this entity accounts for approximately half of all GERD patients and that the patients without erosions are also negatively affected by GERD symptoms and searching medical care. The GSRS-based symptomatic pattern of our NERD patients revealed that their mean heartburn score is (statistically significantly) even higher than that of erosive GERD patients, but this difference was only between HP-infected patients. This could probably be explained by a higher

226 Diseases of the Esophagus sensitivity of the lower esophagus, especially if HP is present. 25 27 In a very recent systematic review of 20 studies by Raghunath et al. the prevalence of HP in GERD patients was assessed. 28 There was substantial heterogeneity between studies and this review confirmed that HP is less prevalent in GERD patients especially in Asian countries. There was no data about this topic from Eastern European countries, and our data could be the first published about the prevalence of HP in GERD patients in this geographic area. The overall prevalence of HP in Lithuania is still very high, so it is not surprising for us that HP was found in 70.2% of GERD cases. We found that the prevalence of HP is significantly higher among NERD patients and decreases with the severity of erosive GERD. This supports the theory that HP could be related to GERD, and that the absence of HP may be a risk factor for severe forms of erosive esophagitis, Barrett s esophagus and even esophageal adenocarcinoma. 29,30 In the study by Lagergren et al. it is undoubtedly shown that long-standing GERD is a risk factor for esophageal adenocarcinoma. 31 But it is still not clear which subgroups of GERD patients are at higher risk to esophageal adenocarcinoma probably HP-negative, erosive GERD patients. It is impossible to confirm that the absence of HP (or eradication of HP) is the most important factor for the development of erosive GERD, because a large proportion of erosive GERD patients is also infected by HP in our region. NERD may have significantly different pathogenesis, mainly related to hypersensitivity of the lower esophagus to comparably short-term reflux episodes, which are not able to damage the esophagus. The high proportion of HP-infected NERD patients in our region leads to speculation that this esophageal hypersensitivity may be stimulated by HP-induced inflammatory mediators. Also there still remains the possibility of subjectivity regarding the term heartburn and for the misdiagnosis of NERD. HPpositive patients are more likely to have functional dyspepsia (non-ulcer dyspepsia) and, due to an overlap of symptoms, some purely functional-dyspepsia patients may be regarded as NERD patients. So, it is probably reasonable to separate another group of patients from NERD patients, which could be defined as reflux-like dyspepsia (according to older dyspepsia definition). 32,33 It is well known that smoking status, BMI and the presence of hiatus hernia may be related to more severe GERD. 34 36 Although our data showed obvious trends and differences in these factors between erosive GERD and NERD, multivariate analysis did not show any statistically significant prognostic value. Logistic regression of our data revealed that HP and female sex are statistically significant predictors of NERD. The role of female predisposition to NERD was also stressed by other investigators. 37 We tried to elucidate whether the histological gastritis pattern of HP-infected patients is different between erosive and nonerosive GERD patients. Data have been found that show healing of corpus gastritis may be the main factor in the hypersecretion and development of GERD in the future. 38 40 In our series we found no significant differences in gastritis characteristics. The antrum-predominant gastritis was found in both erosive GERD and NERD patients. Only a higher mean score of atrophy in the antrum was found in erosive GERD patients, but overall atrophy scores were very low, therefore we think this finding is of no importance. So, in our high-hp-prevalent region we are not able to confirm that the type of gastritis is somehow related to erosive esophagitis or NERD. 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