Caucasian ethnicity as a risk factor for more severe mucosal damage in gastroesophageal reflux disease
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- Horiki, N., Omata, F., Ninomiya, K. et al. Esophagus (2012) 9: 153. doi:10.1007/s10388-012-0324-x
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Background and aims
In the Western world, 10–20 % of patients with GERD complain of at least weekly episodes of heartburn and/or acid regurgitation, while the corresponding value for GERD patients in Asia is <5 %. Reports of the risk factors for mucosal damage in patients with GERD are scarce. The aim of this study was to compare the severity of mucosal damage according to the Los Angeles system in Japanese and Caucasian residents of Japan who have GERD.
We conducted a retrospective cross-sectional study using 537 patients who visited St. Luke’s International Hospital and Mie University Hospital in Japan with symptoms of heartburn from January 2003 through December 2011. We divided the participants into two ethnic groups: 116 Caucasians (84 males and 32 females), mean age (SD) 43.8 (13.2) years old; and 375 Japanese (192 males and 183 females), mean age (SD) 53.2 (15.5) years old. Patients with a history of previous abdominal surgery or Helicobacter pylori eradication were excluded from the analysis. All patients were examined by esophagogastroduodenoscopy (EGD) to evaluate the severity of mucosal injury and hiatal hernia before medical treatment.
With multivariate ordinal logistic regression analysis, age (OR 1.03, 95 % CI 1.02–1.04, p < 0.001), male gender (OR 2.71, 95 % CI 1.84–4.01), Caucasian ethnicity (OR 1.65, 95 % CI 1.06–2.58, p = 0.0268), and the presence of hiatal hernia (OR 3.35, 95 % CI 2.06–5.46, p = 0.0012) were associated with more severe mucosal injury in GERD.
Patients with reflux symptoms tend to have more severe mucosal damage if they are male, older, Caucasian, or have a hiatal hernia. These patients should be evaluated by EGD more frequently.
KeywordsReflux esophagitisGastroesophageal reflux diseaseHeartburn
Gastroesophageal reflux disease (GERD) is a spectrum of diseases with symptoms of heartburn and acid regurgitation, and GERD does not necessarily involve mucosal injury by definition. The literature suggests that heartburn is the most relevant outcome measure for patients with endoscopy-negative GERD , that reflux symptoms aid with diagnosis but they lack sensitivity , and that the severity of GERD symptoms does not correlate well with mucosal damage. In the Western world, 10–20 % of patients with GERD complain of at least weekly episodes of heartburn and/or acid regurgitation, while the corresponding value for GERD patients in Asia was <5 % . It is important to evaluate mucosal damage, not only because it is a more objective hallmark of GERD, but also because it may be associated with the development of esophageal adenocarcinoma . However, there are only a few reports of the risk factors for mucosal damage in patients with GERD. The aim of this study was to investigate the risk factors for mucosal damage according to the Los Angeles system in a mixed population including Asian and Caucasian residents of Japan with GERD.
Patients and methods
Study design and population
Five hundred thirty-seven patients [mean age (SD), 50.2 (15.5); male, 56 %] visited St. Luke’s International Hospital [n = 394, 94 Caucasian, 291 Japanese, mean age (SD) 49.0 (15.0)] and Mie University Hospital [n = 143, 22 Caucasian, 84 Japanese, mean age (SD) 53.5 (16.4)] in Japan with symptoms of heartburn from January 2003 through December 2011. We divided the patients into two ethnic groups, as follows: (1) 116 Caucasian (84 males and 32 females; 65 American, 10 English, 8 French, 8 Spanish, 7 Canadian, 5 German, 4 Austrian, 3 Italian, 2 Irish, 1 Polish, 1 Dutch, 1 Swiss, 1 Norwegian), mean age (SD) 43.8 (13.3) years old; and (2) 375 Japanese (192 males and 183 females), mean age (SD), 53.2 years-old. Nationality was determined from passports. Ethnicity was determined by a self-assessment performed by each patient on their ethnic background. All patients, including the Caucasians, had been living in Japan for more than 6 months and were neither travelers nor short-term visitors. Patients who received medical treatment for heartburn, previous abdominal surgery, or Helicobacter pylori eradication were excluded from the analysis.
All patients were examined by esophagogastroduodenoscopy (EGD) (Olympus Optical Co., Ltd., Tokyo, Japan) to evaluate the severity of esophagitis and hiatal hernia before medical treatment for heartburn. EGD was carried out by an endoscopic specialist who had at least 10 years of experience. Informed consent was obtained from all patients. The degree of mucosal damage was assessed according to the Los Angeles system [5, 6], which classifies as follows: grade A: one (or more) mucosal break confined to the mucosal folds, each no longer than 5 mm, that does not extend between the tops of two mucosal folds; grade B: one (or more) mucosal break more than 5 mm long that does not extend between the tops of two mucosal folds; grade C: one (or more) mucosal break that is continuous between the tops of two or more mucosal folds but which involves less than 75 % of the circumference; grade D: one (or more) mucosal break which involves at least 75 % of the esophageal circumference. Hiatal hernia was graded according to Hill’s gastroesophageal flap valve (GEFV) classification as follows: grade I: presence of a prominent fold of tissue along the lesser curvature that is closely apposed to the endoscope; grade II: the fold is present but with periods of opening and rapid closing around the endoscope; grade III: the fold is not prominent and the endoscope is not tightly gripped by the tissue; grade IV: there is no fold and the lumen of the esophagus gapes open . In this study, grades III and IV of GEFV were considered positive for hiatal hernia.
The classification of GERD was collapsed into three groups—nonerosive, mild (LA grades A, B), and severe (grades C, D)—for statistical analysis . Pearson’s chi-square test was applied to proportions. We performed bivariate ordinal logistic regression, including age, gender, ethnicity, and hiatal hernia, and constructed a multivariate model to calculate adjusted odds ratios. An α level of 0.05 was considered to be statistically significant. Analysis was performed using JMP® version 9 (SAS Institute Inc., Cary, NC, USA).
Caucasian (n = 116)
Japanese (n = 375)
Age [mean ± SD (median)]
44 ± 13 (69)
53 ± 16 (69)
84 (72.4)/32 (27.6)
192 (56.2)/183 (48.8)
Hiatal hernia [n (%)]
Erosive GERD [n (%)]
Severity of mucosal damage in GERD according to the Los Angeles system
Bivariate ordinal logistic regression
95 % CI
Multivariate ordinal logistic regression
95 % CI
Our study suggested that aging, male gender, hiatal hernia, and Caucasian ethnicity are independently associated with more severe mucosal damage as measured by the Los Angeles (LA) classification system in patients with symptomatic GERD.
The LA classification system for esophagitis was introduced in 1994, and was revised to improve its reliability in 1999. This revision uses mucosal folds to evaluate the circumferential extension of esophagitis. The k value (95 % CI), which represents the interobserver agreement, was reported to be 0.4 (0.22–0.51) in this revised classification . We applied the LA classification system to evaluate mucosal damage in GERD because this classification is the most widely accepted around the world.
A number of potential risk factors (for example, an immediate family history and obesity) and comorbidities (for example, respiratory diseases and chest pain) associated with GERD were identified . Heartburn as a symptom of GERD is extremely common, occurring weekly in approximately 20 % of adults in the United States . Heartburn is defined as a burning sensation rising from the stomach or lower chest towards the neck, and acid regurgitation as the spontaneous return of gastric or esophageal contents into the pharynx or the presence of an acid taste in the mouth [10, 11]. Patients with nonerosive GERD have no mucosal breaks in the esophagus, but occasionally have typical reflux symptoms . Symptomatic GERD is usually evaluated according to its severity and the frequency of heartburn. Severity of esophageal acid exposure is related to the severity of esophagitis, and pretreatment esophagitis grades were related to heartburn severity . In our study, to achieve a fair comparison, the inclusion criteria for symptom severity and frequency should have been standardized between the two ethnicities. However, we were not able to examine the frequency and severity of the symptoms because of a lack of data. It has been reported that the proportion of nonerosive GERD is higher among Asians than westerners [13–15]. However, in this study, the proportions of nonerosive GERD in the Japanese and the Caucasian populations were almost identical. One of the reasons for this may be that we excluded patients who were taking over-the-counter drugs (including Chinese medicine for heartburn) from the analysis, so the proportion of patients with nonerosive GERD dropped to a low level in both ethnic groups.
There have been several reports on the risk factors for mucosal damage in patients with GERD. Ryan et al.  found no significant increase in ulcerative reflux esophagitis with smoking, use of nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, or other factors related to lifestyle. Our study could not address these associations because of a lack of data.
Elderly patients with severe esophagitis were least likely to have severe heartburn. However, when elderly patients had severe heartburn, it appeared to be a good clinical indicator of the presence of severe mucosal damage. On the other hand, severe heartburn was a less reliable marker of severe esophagitis among younger patients . Our study also showed that aging is associated with more severe mucosal injury in patients with symptomatic GERD. Interestingly, severity of heartburn correlate with mucosal damage in patients with erosive esophagitis, especially in young adults . It was suggested that the trend for an increasing frequency of heartburn with age was more prominent in men (40.7 %) than in women (32.6 %) . There was no difference in the frequency of heartburn between city and rural dwellers, or between white- and blue-collar workers .
The prevalence of GERD differs among various ethnic populations. It is widely accepted that its prevalence is lower in Japanese than in Caucasians . The incidence of esophageal adenocarcinoma is also much lower in Japan than in Europe and USA, like GERD .
The incidence of esophageal adenocarcinoma is rapidly increasing. Its incidence is significantly high in males [21–23], especially Caucasians [24–27]. Adenocarcinoma of the esophagus is approximately eight times more frequent in white men than in white women, and five times more frequent in white men than in black men, indicating that white men are at the highest risk for this disease .
GERD was reported to be one of the risk factors for esophageal adenocarcinoma in Western countries , but data from Japan are limited . Reflux esophagitis, erosive GERD, has been also reported to be a risk factor for adenocarcinoma of the distal esophagus . The prevalence of reflux esophagitis among the young population is assumed to be associated with Barrett’s esophagus and esophageal adenocarcinoma. Therefore, we investigated the risk factors of erosive GERD.
We assume that Caucasian ethnicity leads to a higher prevalence of esophageal adenocarcinoma by way of mucosal damage.
In this study, we investigated the association between ethnicity and the degree of mucosal damage in GERD, although the study does have limitations, as follows. First, we could not investigate the association between mucosal damage and established risk factors such as body mass index (BMI) and eating habit because data were not available. Therefore, we cannot exclude the possibility that the association between Caucasian ethnicity and mucosal damage was erroneously influenced by BMI. Second, we have not validated our findings using other cohorts, so the possibility of selection bias is inevitable.
In conclusion, aging, male gender, hiatal hernia, and Caucasian ethnicity are associated with more severe mucosal damage in GERD. We should perform EGD more often to evaluate mucosal damage in patients with these characteristics. This may contribute to the prevention of esophageal neoplasm.