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Lower esophagus in dyspeptic Iranian patients: A prospective study Article in Journal of Gastroenterology and Hepatology · April 2003 DOI: 10.1046/j.1440-1746.2003.02969.x · Source: PubMed
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Blackwell Science, LtdOxford, UK JGHJournal of Gastroenterology and Hepatology0815-93192003 Blackwell Publishing Asia Pty Ltd 18 2969 Lower esophagus in dyspeptic Iranian patients S Nasseri-Moghaddam et al. 10.1046/j.0815-9319.2002.02969.x Gerd and Barrett’s Esophagus315321BEES SGML
Journal of Gastroenterology and Hepatology (2003) 18, 315–321
GERD AND BARRETT’S ESOPHAGUS
Lower esophagus in dyspeptic Iranian patients: A prospective study SIAVOSH NASSERI-MOGHADDAM, REZA MALEKZADEH, MASOUD SOTOUDEH, MOHAMMAD TAVANGAR, KOUROSH AZIMI, AMIR-ALI SOHRABPOUR, PARDIS MOSTADJABI, HOSNIEH FATHI AND MINA MINAPOOR
Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
Abstract Background: Gastroesophageal junction cancer has increased over time in Western countries. Gastroesophageal reflux disease (GERD) is considered to be a major risk factor. We prospectively studied the prevalence of clinical, histological and endoscopic GERD, and premalignant changes among dyspeptic Iranian patients referred for upper gastrointestinal endoscopy (UGIE). Methods: Consenting patients referred for UGIE to our clinic were enrolled. Their symptoms were recorded, UGIE was conducted, and biopsies from all suspicious lesions and across the Z-line were taken. Results: Of the 344 enrolled patients, 269 (135 women, 134 men; mean age: 41.6 years) were evaluated. One major GERD symptom (heart burn, acid regurgitation, dysphagia and chest pain) was seen in 209 (77.6%) patients, and 207 patients (76.1%) had endoscopic esophagitis. Thirteen patients (5%) had specialized intestinal metaplasia at the gastrointestinal junction (SIM-GEJ), and three had glandular dysplasia (two low-grade, one high-grade). No symptom could predict the presence of histological or endoscopic findings. Patients with dysplasia had more advanced degrees of endoscopic esophagitis. Conclusion: Gastroesophageal reflux disease is common among Iranian patients referred for diagnostic endoscopy. The prevalence of SIM-GEJ among this population was comparable to that reported in Western countries. © 2003 Blackwell Publishing Asia Pty Ltd Key words: Barrett’s esophagus, gastroesophageal junction, gastroesophageal reflux disease, Helicobacter pylori, specialized intestinal metaplasia, symptoms.
INTRODUCTION Lower esophageal adenocarcinoma has increased significantly in Western countries over the past few decades.1–3 This once rare problem, the existence of which had even been questioned, is now responsible for almost half of all esophageal tumors.2,3 Gastroesophageal reflux disease (GERD) and its complication, Barrett’s esophagus, are considered to be the main culprits for this change in prevalence of lower esophageal adenocarcinoma.2–14 Over the past decade, it has been shown that specialized intestinal metaplasia (a potentially precancerous lesion and the hallmark of Barrett’s esophagus) and dysplasia can occur in apparently normal-looking esophageal mucosa, or in short segments (less than 3 cm) of Barrett’s esophagus.5,6,12,15–23 Therefore, the concept of Barrett’s esophagus (2–3 cm or more of columnarlined epithelium above the gastroesophageal junction
(GEJ)) has changed, and has now included even shorter segments of columnar metaplasia if they contain foci of specialized intestinal metaplasia (characterized by the presence of Goblet cells).10,11,24,25 The exact etiology and natural history of specialized intestinal metaplasia (SIM) at the GEJ (SIM-GEJ) are not well understood, but there are reports that indicate this may be another cause of the increasing prevalence of esophageal adenocarcinoma.5,6,12,15–23 Some authors suggest that biopsies may be warranted in normal-looking GEJ to detect these potentially harmful lesions.5,6 Specialized intestinal metaplasia at the junction may be etiologically different to the same pathology within the tubular esophagus, the former being linked to Helicobacter pylori and chronic carditis rather than to GERD,8,12,19,22 although the issue remains unclear. Gastroesophageal reflux disease and its complications are considered to be infrequent in Asia.20,26
Correspondence: Dr S Nasseri-Moghaddam, Assistant Professor of Medicine and Gastroenterology, No. 1, Sharifi Street, Behrooz Avenue, Mohseni circle, Mirdamad Boulevard, Tehran 19119, Iran. Email:
[email protected] Accepted for publication 2 October 2002.
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Gastroesophageal reflux disease is exacerbated by a number of factors including heavy meals, particularly if spicy and fatty, obesity, alcohol and tobacco use. Epidemiological studies in Iran are lacking, but some data indicate increasing prevalence of GERD.27 If this holds true, then GERD-related cancerous and precancerous lesions may become a major problem in our area in the near future. In addition, data from both uncontrolled observations and expert opinion holds that the incidence of esophageal adenocarcinoma is rising in Iran. The GEJ has not been prospectively evaluated in the Iranian population. To assess the situation, we decided to systematically evaluate the lower esophagus and the GEJ among Iranian dyspeptic patients referred for upper gastrointestinal endoscopy (UGIE).
METHODS Patients All patients 18 years of age and older scheduled for UGIE in a private subspecialty clinic from February to May 2000 were enrolled. Patients were excluded from the study if any of the following were present: (i) unwillingness to participate; (ii) being a known case of Barrett’s esophagus or upper gastrointestinal (GI) cancer; (iii) being highly suspect to harbor an upper GI cancer; (iv) being known to have esophageal varices; (v) having a bleeding tendency either because of disease or medication; (vi) having any comorbid illness making safe biopsy taking impossible; or (vii) taking proton pump inhibitors over the past 2 weeks, or H-2 blockers within the past week. All patients were asked to sign a consent form, indicating informed consent. If a patient declined to consent, this did not affect his/her medical management.
Clinical data The patients were then systematically interviewed for the following items: (i) demographic data (including name, age, sex, weight, and height); (ii) symptoms of GERD, peptic ulcer disease and any other symptoms referable to the upper GI tract; (iii) duration of these symptoms; (iv) severity of the symptoms according to a visual analog scale (those marking halfway or more on the scale were considered to have a more severe symptom); (v) habits such as smoking and drinking tea or coffee; (vi) medication; and (vii) past or family history of GI disease or malignancy. Acid regurgitation, heartburn, chest pain not attributable to cardiac events, and dysphagia were considered as major GERD symptoms. Other symptoms queried in the questionnaire are shown in Table 1. The body mass index (BMI) was calculated according to the following equation: BMI (kg/m2) = weight (kg)/height2 (m2).
Table 1
Other symptoms covered in the questionnaire
Morning nausea Frequent eructation Upper epigastric pain Epigastric burning sensation Sore mouth Sore throat Odynophagia Globus sensation Hoarseness Cough
Study protocol The patients then underwent a standard UGIE under a local anesthetic with a 10% lidocaine spray. All endoscopies were conducted by a single experienced endoscopist (RM). The entire esophagus, the GEJ, and the stomach and the duodenum down to its second portion were scrutinized; any abnormality seen was recorded and any suspicious lesion was biopsied. The esophagus was carefully evaluated for the location of the Z-line (level of transition of the pale squamous epithelium of the esophagus to the velvety red columnar epithelium of the stomach), evidence of esophagitis (Los Angeles criteria and classification),28 location of the GEJ (defined as the most proximal part of the gastric folds), shortsegment Barrett’s esophagus (SSBE, defined as columnar-lined mucosa extending less than 2 cm above the GEJ either as tongue-like projections, islands or circumferentially), long-segment Barrett’s esophagus (LSBE, defined as the Z-line identified more than 2 cm above the most proximal end of the gastric folds or tongues of columnar-lined mucosa extending 2 cm or more above the GEJ), mass lesions, and hiatus hernia (defined as the gastric folds seen above the diaphragmatic hiatus). All suspicious esophageal lesions were biopsied. In addition, two biopsies across the Z-line, regardless of its location, were obtained. All biopsy specimens were spread, oriented on filter paper, fixed in 10% neutral buffered formalin, routinely processed, embedded in paraffin, sectioned and stained with hematoxylin and eosin. The specimens were then examined for evidence of esophagitis (defined as the presence of polymorphonuclear leukocytes, eosinophils or an increased number of lymphocytes in the esophageal epithelium, degeneration of the basal cell layers of the squamous epithelium with exocytosis of inflammatory cells, or inflammation in the lamina propria), intestinal metaplasia (defined as the presence of specialized absorptive columnar epithelium with Goblet cells and/or paneth cells) (Fig. 1), dysplasia, cancer, and H. pylori by two pathologists independently. Both pathologists were blinded to the endoscopic findings.
Statistical analysis The chi-squared and Fisher’s exact tests at a significance level of 0.05, and the SPSS program for Windows,
Lower esophagus in dyspeptic Iranian patients
317 Table 2
Figure 1 Specialized intestinal metaplasia. Goblet cells are clearly evident in the surface epithelium and the mucosal crypts. H&E ¥200.
version 10.0 (SPSS Inc., Chicago, IL, USA), were used for statistical analyses. Patients with LSBE were not included in the analysis for histological findings and SIM. In appropriate instances, logistic regression analysis was performed to assess relationships.
RESULTS Patient characteristics and clinical findings Three hundred and forty-four patients underwent an UGIE during the study period. Seventy-five of these did not meet the inclusion criteria. Two hundred and sixty-nine eligible consenting patients (135 women and 134 men) were enrolled. The mean age was 41.6 ± 13.9 years (range 18–80 years). The mean weight was 68.26 ± 13.72 kg and the mean BMI was 24.42 ± 5.05 kg. There were no differences between men and women regarding their age range, bodyweight or BMI. All were systematically interviewed as mentioned previously. Eighty-five (31.6%) complained of heartburn, 68 (25.3%) of whom experienced it at least once a week. One hundred and fifty-three (56.9%) had acid regurgitation, 108 of whom (40.0%) suffered from it at least once a week. Forty-five patients (16.7%) reported dysphagia. Fifteen of these (5.5%) had heartburn more than half the times they ate, and six others (2.2%) suffered from it all the time. Two hundred and nine patients (77.6%) had experienced one of the above reflux symptoms at least once over the past month. There was no sex difference for experiencing any of the symptoms. Major symptoms were not more common among patients with sliding hiatal hernias. The mean BMI was 24.2 in women and 24.6 in men (P = NS). Patients with a BMI of 25 or more complained of acid regurgitation more frequently (P = 0.047). There was no correlation between other symptoms and increasing BMI. Dysph-
Endoscopic findings
Esophagitis grade A Esophagitis grade B Esophagitis grade C Esophagitis grade D Esophageal stricture Hiatal hernia CLO-test positive Total
Shortsegment Barrett’s esophagus
Longsegment Barrett’s esophagus
Alone
Total
36
1
102
139
19
7
30
56
3
1
5
9
0
1
2
3
0
2
3
5
45 37
8 7
98 114
151 158
58
10
139
agic patients reported hoarseness and chronic cough more often (P < 0.0001, P = 0.015, respectively) and were more likely to have experienced sore throat for more than 1 year (P = 0.03). Fifty-three of our patients (19.7%) smoked cigarettes. Patients who smoked had a higher chance of experiencing acid regurgitation (P = 0.05). Smokers also had a trend toward experiencing more heartburn, but this did not reach statistical significance (P = 0.077). Overall, smokers did not experience more severe symptoms than non-smokers.
Endoscopic findings Patients underwent UGIE as described above. Endoscopic findings are summarized in Table 2. Endoscopic esophagitis was seen in 207 patients (76.9%) and was significantly more common among men than women (P < 0.05). Most patients had either grade A or B esophagitis (67.1% and 27.0%, respectively). Seventy-one patients (26.4%) had columnar metaplasia (Barrett’s esophagus) on endoscopy, 10 of whom had LSBE. Sliding hiatal hernias (SHH) were found in 151 subjects (56.5%). One hundred and forty (92.7%) patients with SHH had endoscopic esophagitis, while only 102 (67.7%) patients with endoscopic esophagitis had SHH. There was no correlation between increasing age and the presence of esophagitis, Barrett’s esophagus, or SHH. No tumors or masses were found in the study population. Two patients had gastric ulcers (0.7%) and 75 had duodenal ulcers (27.9%). Patients with endoscopic esophagitis were more likely to suffer from more prolonged globus sensation (more than 1 year, P = 0.003), more severe epigastric burning sensation (P = 0.009), more severe heartburn (P = 0.027), and more severe bloating sensed in the epigastrium (P = 0.021). These patients also complained of
318 chronic cough more often than patients without endoscopic esophagitis (P = 0.007). Patients having a sore mouth for more than 2 years were more likely to harbor higher grades of endoscopic esophagitis (grades C, D, and strictures, P = 0.033). This association became even stronger when patients reported a sore mouth for 5 years or more (P = 0.005). Patients with grades B, C or D esophagitis reported odynophagia more frequently (P = 0.045), while those harboring grades C or D esophagitis were even more likely to suffer from odynophagia (P < 0.0001). Patients who had experienced heartburn for more than 10 years or belching for more than 2 years were more likely to have endoscopic Barrett’s esophagus (P = 0.035 and P = 0.038, respectively). Likewise, patients who suffered from chronic cough were more likely to have endoscopically apparent Barrett’s esophagus (P = 0.045).
Histological findings Histological findings were as follows (LSBE patients excluded): Thirteen patients (5.0%) had SIM at the Zline, and SIM was more common among patients older than 40 years of age (8.7% compared with 1.4%, P = 0.006). Specialized internal metaplasia was seen in 9.1% of patients without any of the major GERD symptoms, and in 2.9% of those with at least one of the four major symptoms (P = 0.055). Of the 13 patients with SIM, 12 had endoscopic esophagitis (92.3%) and five had short segments of Barrett’s esophagus (38.5%). The other, a 48-year-old woman with a history of heartburn for more than 10 years had a completely normallooking Z-line. Smokers were more likely to develop SIM, either in SSBE or at a normally located Z-line (P = 0.049). Glandular dysplasia (Fig. 2) was found in
Figure 2 Glandular dysplasia. The nuclear changes including enlargement, rounding, irregularity, abnormal mitoses and nucleoli, as well as loss of polarity and structural abnormalities, are diagnostic for dysplasia.
S Nasseri-Moghaddam et al. three subjects (1.2%); two of whom had low-grade dysplasia and the other high-grade dysplasia. Fifteen other patients had reactive glandular atypia (Fig. 3) in a background of reflux esophagitis (5.7%). Whether these patients have dysplasia remains to be determined after adequate treatment of esophagitis and repeating the biopsies. None of the patients with dysplasia had endoscopic or histological Barrett’s esophagus, but all three had endoscopic esophagitis; two grade B and one grade C. Dysplasia was no more common in patients with GERD symptoms. Two of the three patients with dysplasia had SHH (66.7%). Specialized internal metaplasia and dysplasia were equally seen among patients with endoscopic esophagitis or with a normal-looking esophagus. The presence of SSBE could not predict the presence of SIM or dysplasia. Helicobacter pylori was found in 131 (48.7%) of GEJ tissues examined. There was no correlation between the presence of endoscopic GERD or SIM-GEJ and H. pylori. Patients having dysplasia were more likely to harbor H. pylori than those without dysplasia (P = 0.009). There was also no correlation between any of the major reflux symptoms and H. pylori.
Figure 3 Reactive glandular atypia. Some of the cells in the glandular structures and part of the surface epithelium show nuclear enlargement, hyperchromasia and some structural irregularities. These changes, however, are not striking enough to be called dysplasia. Numerous inflammatory cells infiltrate the lamina propria.
Lower esophagus in dyspeptic Iranian patients
DISCUSSION The lower esophagus and the cardia have been the focus of extensive research over the past decade. This is mostly because of a dramatic increase in the incidence of adenocarcinoma of the GEJ over the past decade in Western countries.1–3,14,20 This has occurred alongside a parallel increase in the incidence of GERD and its complication Barrett’s esophagus.10,14,20 Some reports indicate a 10-fold increased incidence of Barrett’s esophagus in Western countries over the past few decades.14,20 As a result of this coincidence and the well-known potential of the columnar-lined esophagus to turn into malignant tissue, GERD and Barrett’s esophagus have been considered as major risk factors for the increase in the incidence of adenocarcinoma of the lower esophagus.1,2,10,14,24 In 1994, Spechler et al. reported the existence of SIM in a normal-looking GEJ or SSBE.5 They found that 18% of 142 patients undergoing UGIE for various reasons had SIM either in short segments of columnar-lined esophagus or at a normallooking Z-line. Since then, several other reports have appeared confirming their data, albeit with varied frequency.6–13,15 Most of these investigators could not show any correlation between the presence of SIM at the junction and any of the clinical and endoscopic findings of their patients. It has also been shown that the intestinalized epithelium in SSBE and that from a normal-looking GEJ have a proliferative activity similar to that of LSBE, and significantly higher than a normal esophagus and GEJ.29 This raises the possibility of increased potential for malignant transformation of this type of tissue. Dysplasia associated with Barrett’s esophagus is also considered a premalignant lesion. However, dysplasia is reported in 2–5% of SIM found at the GEJ, but its precise significance is not well understood.12 Hirota et al. found that 13.2% of 889 patients referred for UGIE had SIM (1.6% LSBE, 6% SSBE, and 5.6% SIM-GEJ). They reported dysplasia or cancer in 31% of LSBE, 10% of SSBE and 6.4% of SIMGEJ.12 They concluded that, although the prevalence of dysplasia or cancer is much lower in SSBE and SIM found at a normal looking GEJ, because of the higher prevalence of these latter lesions, the overall impact of these lesions in the epidemiology of the lower esophageal and cardia cancer may be substantial.12 Here we report on the clinical characteristics and the endoscopic and histological findings of the lower esophagus and the GEJ of 269 Iranian patients undergoing UGIE for various reasons. Seventy-one (26.8%) of our patients had grossly columnar-lined epithelium on endoscopy, 61 (23%) of whom had less than 2 cm tongues or islands (i.e. SSBE). None of the SSBE patients found on endoscopy had dysplasia. This may be because of the few biopsies taken. Five per cent of our patients had SIM-GEJ. Western reports indicate prevalence rates of 5–19% in similar populations.5–13,15 As we took only two biopsies across the Z-line, it can be concluded that with the most conservative estimate the prevalence of SIM at the Z-line in Iran is just at the lower limit of that in Western countries,8 and almost similar to that of the normal Western population.12,13,15 Although SIM was more prevalent among older smok-
319 ers, none of the clinical symptoms could predict its presence. Dysplasia was seen in 1.2% of our patients. All three cases of dysplasia were found among patients with endoscopic esophagitis of more severe degrees (two grade B and one grade C). Although all cases of dysplasia and most cases of SIM (12 out of 13) were found among patients with endoscopic esophagitis or SSBE, there was no statistical correlation between the pathological and the endoscopic findings. Interestingly, H. pylori infection was the only variable being significantly more common among patients with dysplasia. Weston et al. have reported that 24.4% of patients with LSBE and 8.1% of those with SSBE harbor dysplasia.17,18 Whether the dysplasia at the normal-looking junction is related to GERD or H. pylori is not well known.30–35 Hence, as no single or group of findings (either endoscopic or clinical) could predict the presence of SIM or dysplasia, biopsy taking from a normallooking GEJ may be warranted to detect SIM and dysplasia. These lesions have been proven to have malignant potential, although at a much lower rate than the classical Barrett’s esophagus.12,18 Among various clinical symptoms sought in our patients, prolonged globus and chronic cough were more likely to be associated with endoscopic esophagitis. In addition, severe heartburn, epigastric burning sensation and epigastric bloating were more likely to predict the presence of endoscopic esophagitis. This is in accord with the findings of Lagergren et al.,36 and contrary to the traditional belief that neither the duration nor the severity of symptoms correlate with endoscopic findings. An interesting finding in our study was that patients experiencing a sore mouth for more than 2 years (and particularly those experiencing it for more than 5 years) were more likely to harbor more severe degrees of esophagitis. If this is confirmed in other studies, a prolonged sore mouth can be counted as an index of the severity of GERD. Although patients with a BMI more than 25 kg/m2 were more likely to experience acid regurgitation, there was no correlation between increasing BMI and endoscopic esophagitis. To the best of our knowledge this is the first report examining the GEJ histologically and seeking its relation to endoscopic and clinical GERD among Iranian patients. Our work suffers from some shortcomings. First, we took only two biopsies. Had we taken more biopsies and from other sites (e.g. the gastric cardia, normal-looking esophagus and the gastric antrum) we may have arrived at different results (e.g. different frequencies of dysplasia, SIM and occult cancer). In addition, if the sections examined were stained with Alcian blue, then SIM could have been diagnosed with more sensitivity and specificity. Despite this, we conclude that endoscopic reflux is prevalent among Iranian patients referred for UGIE, and that at the most conservative estimate the prevalence of SIM at the junction is just similar to some Western countries. This is an alarming sign, for if GERD is not diagnosed and treated appropriately because of the common belief that it is not prevalent in Eastern countries, then we may face significant increases in the prevalence of GERD-related complications, and probably esophageal adenocarcinoma in our region in the future. A recent report from Ardabil, a
320 north-western Iranian province with a very high incidence of gastric cancer, has shown that the most common type of gastric cancer in the region is adenocarcinoma of the cardia.37 An endoscopic screening of apparently asymptomatic subjects in the same area also revealed a very high incidence (37.8%) of endoscopic reflux esophagitis.38 According to our data and those of other investigators,27,37,38 we conclude that GERD is the major and the most common cause of dyspepsia among patients referred for UGIE in Iran. The more westernized diet, which includes more fast foods (more spicy and fatty), the increased prevalence of cigarette smoking, and decreased physical activity may partially explain this increased frequency of GERD. Taking biopsies from the Z-line, even in the normal-looking GEJ, may be warranted among Iranian patients undergoing UGIE. Further studies with more biopsies of the GEJ are warranted to make various aspects of the problem clearer.
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