Distinct Clinical Characteristics Between Patients With Nonerosive Reflux Disease and Those With Reflux Esophagitis

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5:690 – 695

Distinct Clinical Characteristics Between Patients With Nonerosive Reflux Disease and Those With Reflux Esophagitis JUSTIN C. Y. WU, CARRIAN M. Y. CHEUNG, VINCENT W. S. WONG, and JOSEPH J. Y. SUNG Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong

Background & Aims: It has been postulated that nonerosive reflux disease (NERD) and erosive reflux disease (ERD) are 2 distinct entities of gastroesophageal reflux disease. The aim of this study was to compare the clinical characteristics between patients with NERD and those with ERD. Methods: We prospectively recruited consecutive patients presenting with weekly attacks of heartburn or acid regurgitation. Exclusion criteria included gastric surgery, recent use of nonsteroidal anti-inflammatory drug or proton pump inhibitor, and peptic ulcer disease. Concomitant functional dyspepsia, irritable bowel syndrome, and psychological disorders were documented. Endoscopy, esophageal manometry, acid perfusion test, and 24-hour ambulatory pH monitoring were performed. Risk factors of NERD were determined by multivariate analysis. Results: Two hundred fourteen patients (NERD, 113; ERD, 111) were studied. NERD patients were characterized by higher prevalence of Helicobacter pylori (36.3% vs 18%, P ⴝ .005), functional dyspepsia (64.6% vs 42.3%, P ⴝ .003), irritable bowel syndrome (44.2% vs 15.3%, P < .001), psychological disorders (9% vs 0.9%, P ⴝ .04), and positive acid perfusion test (40.7% vs 19.8%, P ⴝ .004). ERD patients had more hiatal hernias (35.1% vs 17.1%, P ⴝ .009), higher esophageal acid exposure (total time esophageal pH <4, 4.2% ⴞ 2.1% vs 5.9% ⴞ 2.3%; P ⴝ .01), and esophageal dysmotility (P < .05). With multivariate analysis, H pylori (odds ratio, 1.8; 95% confidence interval [CI], 1.1–3.2), irritable bowel syndrome (odds ratio, 2.8; 95% CI, 1.6 –5.3), and positive acid perfusion test (odds ratio, 1.9; 95% CI, 1.4 –2.8) were independent risk factors for NERD. Conclusions: Patients with NERD and ERD have distinct differences in clinical characteristics. NERD is characterized by higher prevalence of functional gastrointestinal disorders and esophageal acid hypersensitivity.

G

astroesophageal reflux disease (GERD) is a chronic relapsing acid-peptic disorder of the esophagus. It is one of the most common gastrointestinal conditions that affects up to 42% of adults in the United States.1,2 GERD has traditionally been considered a “spectrum disease,” which consists of a variety of conditions ranging from nonerosive reflux disease (NERD), erosive esophagitis, peptic stricture, Barrett’s esophagus, and adenocarcinoma. It is generally believed that NERD is the mildest form of GERD, in which NERD patients have lower esophageal acid exposure than patients with reflux esophagitis and Barrett’s esophagus. However, it has been shown that severity of reflux symptoms correlates poorly with esophageal acid exposure and esophageal mucosal damage.3 NERD pa-

tients often reported comparable severity of symptom and impaired quality of life as compared with patients with erosive esophagitis.4 Symptomatic relapse occurs in a similar proportion of patients with and without esophagitis after discontinuation of medical treatment.5 From these clinical aspects, NERD does not seem to behave as a mild form of GERD. Studies on the natural course of NERD, in particular the disease progression along the spectrum of GERD, have yielded conflicting results. Whereas some studies reported a considerable proportion of NERD patients who progressed to erosive esophagitis,6,7 other long-term cohort studies reported that none of the NERD patients developed any complication of GERD.8 As a result, the concept of GERD being a spectrum disease has been questioned in recent years. It has been postulated that NERD comprises a heterogeneous group of patients with different clinical characteristics and pathophysiologic mechanisms. Under the conglomeration of GERD, diseases can be categorized into 3 unique groups: NERD, erosive reflux disease (ERD), and Barrett’s esophagus.9 To date, there is a lack of data on direct comparison of risk factors, and the clinical and physiologic characteristics between NERD and ERD. The objective of this study was to compare the clinical characteristics including demographics, comorbidities, and physiologic features of patients with NERD and ERD. The inter-relationships among these factors were also evaluated.

Methods Patients This was a consecutive case series study. We prospectively recruited consecutive patients who were referred for weekly attacks of heartburn and/or acid regurgitation as the dominant complaint in the Gastroenterology Clinic of the Prince of Wales Hospital, a university medical center for secondary and tertiary medical care. The study design was reviewed and approved by the hospital ethics committee, and informed written consent was obtained from all recruited patients. All patients had prior symptomatic relief by proton pump inhibitor or H2 receptor antagonist to confirm that the reflux symptoms were acid-related. Patients were excluded from the study if they had previous gastric surgery, achalasia, secondary Abbreviations used in this paper: BMI, body mass index; CI, confidence interval; ERD, erosive reflux disease; GERD, gastroesophageal reflux disease; LES, lower esophageal sphincter; NERD, nonerosive reflux disease. © 2007 by the AGA Institute 1542-3565/07/$32.00 doi:10.1016/j.cgh.2007.02.023

June 2007

causes of GERD such as scleroderma, use of nonsteroidal antiinflammatory drug or proton pump inhibitor in last 4 weeks, or concomitant peptic ulcer disease.

Symptom Assessment All eligible patients were then invited to complete a validated self-administered questionnaire for assessment of reflux symptoms, dyspepsia, abdominal pain, and bowel disturbance. Duration of reflux symptoms was recorded. Severity of heartburn and acid regurgitation was rated by using 4-point Likert scale (0, asymptomatic; 1, mild, only recall on questioning and does not affect daily activity; 2, moderate, constantly aware of the symptom but does not affect daily activity; 3, severe, interferes with daily activity). Concomitant functional dyspepsia and irritable bowel syndrome were diagnosed as defined by Rome II criteria.10 Functional dyspepsia was further classified into dysmotility-like (belching, early satiety, postprandial fullness), ulcer-like (pain and burning sensation at epigastrium), or nonspecific. Irritable bowel syndrome was classified into diarrhea-predominant, constipation-predominant, or alternating-type. Psychological disorders including generalized anxiety disorder, panic disorder, and depression were diagnosed by a face-to-face interview with a diagnostic questionnaire according to the Diagnostic and Statistical Manual [of Mental Disorders], Fourth Edition criteria.

Endoscopy Endoscopy was performed for assessment of erosive esophagitis and hiatal hernia by a single endoscopist (J.W.). The severity of erosive esophagitis was graded by Los Angeles classification. Grade A esophagitis referred to the presence of mucosal break(s) less than 5 mm long that did not extend between the tops of 2 mucosal folds; grade B referred to mucosal break(s) more than 5 mm long that did not extend between the tops of 2 mucosal folds; grade C referred to mucosal break(s) that was continuous between the tops of 2 or more mucosal folds and involved less than 75% of the circumference; and grade D referred to mucosal break(s) that involved at least 75% of the esophageal circumference.11 Patients without endoscopic esophagitis as defined by Los Angeles classification were considered to have NERD, whereas those patients with erosive esophagitis were classified as having ERD. Diagnosis of Helicobacter pylori infection was confirmed if both biopsy urease test and histology results were positive. Two biopsy specimens were obtained from antrum and corpus for histologic assessment by a single pathologist who was blinded to the status of esophagitis.

Esophageal Manometry All patients underwent esophageal function test after endoscopic examination by an investigator (C.C.) who was unaware of the status of esophagitis. Patients were instructed to stop anti-secretory and prokinetic agents for at least 10 days before the study except for the use of antacid. After an overnight fast, stationary esophageal manometry was performed with a 10-channel silicon rubber low-compliance, pneumohydraulic perfused manometric assembly with sleeve sensor (Dentsleeve International Ltd, Mississauga, Ontario, Canada). The manometric assembly was inserted through the anesthetized nostril, and position of LES was determined by using

DISTINCT CHARACTERISTICS OF NERD

691

station pull-through technique on 0.5-cm intervals. Basal LES pressure was determined by sleeve sensor with reference to baseline gastric pressure. Esophageal peristalsis was examined by using ten 5-mL aliquots wet swallows followed by five 20-mL air bolus injection for assessment of secondary peristalsis. Esophageal motility dysfunction included (1) weak LES, which was defined as LES pressure below 10 mm Hg; (2) ineffective esophageal motility, which was defined as failed primary peristalsis in more than 30% of wet swallowing sequence; and (3) impaired secondary peristalsis, which was defined as failed secondary peristalsis in more than 60% of air bolus insufflations. The acid sensitivity of esophagus was then evaluated by acid perfusion test, which involved esophageal perfusion with 0.1 N hydrochloric acid and normal saline for up to 20 minutes in a random order. The acid perfusion test was considered positive if the acid perfusion provoked symptoms that were similar to those experienced by patients.

Esophageal pH Monitoring A monocrystalline antimony pH catheter (Medtronic, Kista, Sweden) was passed transnasally after manometry, and the electrode was positioned at 5 cm above the proximal margin of LES for 24-hour ambulatory pH monitoring. Patients were instructed to take meals and work according to their daily routine except that coffee, fruit juice, and antacids were avoided. The exact time of reflux symptoms was recorded by using a diary provided to the patients. Data acquisition was performed with a portable data logger (Microdigitrapper MK III; Medtronic). Semiautomated analysis was performed with the aid of commercially available software (EsopHogram; Medtronic). Any reflux episode, defined as pH ⬍4, with duration less than 5 seconds was considered an artifact. Total esophageal acid exposure time (expressed as percentage of time esophageal pH ⬍4) was determined. Esophageal pH study was considered abnormal if percentage of time esophageal pH ⬍4 was more than 4%. The diagnosis of NERD in patients with normal esophageal acid exposure was determined by a strong correlation between symptom and acid reflux episode, which was defined as symptom index of 75% or above. Patients with functional heartburn, which referred to reflux symptoms that were not caused by acid reflux, were therefore excluded from this study.

Statistical Analysis Patient characteristics were compared. Age was categorized into 3 groups (⬍40 years, 40 – 60 years, and ⬎60 years). Body mass index (BMI) was dichotomized as obese (⬎25) and non-obese according to the World Health Organization definition.12 Univariate analyses were performed with two-tailed t test for continuous variables, and ␹2 tests were used for dichotomous or categorical variables. In the multivariate analysis, potential predictor variables including age, gender, severity of heartburn, disease duration, obesity, smoking, alcohol, functional dyspepsia, irritable bowel syndrome, psychological disorders, hiatal hernia, H pylori, esophageal dysmotility, positive acid perfusion test result, and abnormal esophageal pH study were evaluated with a logistic regression model. Two-tailed P value of less than .05 was regarded as significant.

692

WU ET AL

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 6

Table 1. Comparison of Clinical Characteristics Between NERD and ERD Patients NERD

ERD

P value

N 113 111 Female (%) 68 (60.2) 51 (45.9) .03 Mean age, y (SD) 45.2 (16.3) 56.1 (18.6) .03 Smoking (%) 15 (13.3) 10 (9) .31 Alcohol (%) 8 (7.1) 6 (5.4) .61 Mean BMI (SD) 22.1 (3.2) 21.7 (3.6) .67 Disease duration (%) .44 ⬍1 y 20 (17.7) 15 (13.5) 1–5 y 63 (55.8) 71 (64.0) ⬎5 y 30 (26.5) 25 (22.5) Median symptom score (range) 2 (1–3) 2 (1–3) .89 H pylori infection (%) 41 (36.3) 20 (18) .005 Hiatal hernia (%) 20 (17.7) 39 (35.1) .009 Functional dyspepsia (%) 73 (64.6) 47 (42.3) .003 Irritable bowel syndrome (%) 50 (44.2) 17 (15.3) ⬍.001 Psychological disorder (%) 10 (9) 1 (0.9) .04 Esophageal dysmotility (%) LES pressure ⬍ 10 mm Hg 12 (10.8) 32 (28.8) .002 Ineffective esophageal motility 15 (13.3) 29 (26.1) .03 Impaired secondary peristalsis 22 (19.5) 42 (37.8) .002 Mean acid exposure time (SD) Total 4.2 (2.1) 5.9 (2.3) .01 Upright 5.9 (4.7) 9.2 (4.3) .01 Supine 0.6 (0.7) 2.1 (2.2) ⬍.001 Abnormal pH study (%) 68 (60.2) 91 (82.0) ⬍.001 Positive acid perfusion test (%) 46 (40.7) 22 (19.8) .004

Results From October 2001–September 2005, 256 patients were recruited. Forty-two patients were excluded from the study because of peptic ulcer (30 patients), recent use of NSAID (8 patients), functional heartburn (3 patients), and secondary causes of GERD (1 patient). Two hundred fourteen patients were eligible for study. One hundred thirteen patients had NERD, and 111 patients had ERD. Among patients with ERD, 65 (58.6%) had grade A disease and 28 (25.2%) had grade B disease. Fourteen (12.6%) and 4 (3.6%) patients had grade C and D disease, respectively. On univariate analysis, both groups of patients had comparable BMI, disease duration, and symptom severity. However, NERD patients were significantly younger (P ⫽ .03) and had higher prevalence of female gender (P ⫽ .03) and H pylori infection (P ⫽ .005), whereas sliding hiatal hernia was more prevalent in patients with ERD (P ⫽ .009) (Table 1). They also differed in the prevalence of comorbidities. NERD patients had a significantly higher prevalence of functional dyspepsia (P ⫽ .003), irritable bowel syndrome (P ⬍ .001), and psychological disorders (P ⫽ .04). Nonspecific dyspepsia and diarrhea-predominant IBS were the most common forms of functional dyspepsia and IBS in both groups of patients, respectively (Table 2). All the patients with psychological disorders were female. Three NERD patients had panic disorder, and the other patients had generalized anxiety disorder. On the other hand, patients with ERD had more severe esophageal motility dysfunction as diagnosed by manometry. They also had significantly higher esophageal acid exposure (P ⫽ .01) than NERD patients. Abnormal esophageal acid exposure time was noted in 91 (82.0%) of ERD and 68 (60.2%) of NERD patients, respectively (P ⬍ .001). All the remaining 45 NERD

patients with normal esophageal acid exposure had positive symptom reflux correlation. On the contrary, acid perfusion test was positive in a significantly higher proportion of NERD patients (P ⫽ .004) (Table 1). NERD patients were divided into 2 subgroups according to esophageal acid exposure. Although there was an insignificant trend of higher positive rate of acid perfusion test (51.1% vs 33.8%, P ⫽ .07) and psychological disorders (15.6% vs 4.4%, P ⫽ .09) in patients with normal esophageal acid exposure, there was no difference in concomitant functional gastrointestinal disorders, endoscopic and manometric findings (Table 3). ERD patients were further divided into low-grade (grades A and B) and high-grade (grades C and D) esophagitis for subgroup analysis (Table 4). Compared with low-grade disease, patients with high-grade esophagitis were characterized by older age (P ⫽ .01), higher esophageal acid exposure (P ⫽ .02), and higher prevalence of hiatal hernia (P ⬍ .001) and esophageal dysmotility (P ⬍ .001). There was no difference in prevalence of H pylori infection, functional gastrointestinal and psychological disorders, and positive rate of acid perfusion test. The risk factors for NERD and ERD were evaluated with multivariate analysis. The independent risk factors for ERD were hiatal hernia (odds ratio, 2.3; 95% confidence interval [CI], 1.6 – 4.8), abnormal esophageal pH study (odds ratio, 2.1; 95% CI, 1.2– 4.9), and esophageal dysmotility (odds ratio, 2.6; 95% CI, 1.7– 4.3), whereas H pylori (odds ratio, 1.8; 95% CI,: 1.1–3.2), irritable bowel syndrome (odds ratio, 2.8; 95% CI, 1.6 –5.3), and positive acid perfusion test (odds ratio, 1.9; 95% CI, 1.4 –2.8) were associated with NERD. Age, gender, and functional dyspepsia were not significantly associated with NERD or ERD in multivariate analysis. In both NERD and ERD groups, advanced age was significantly associated with hiatal hernia (age ⬍40 vs 40 – 60 vs ⬎60: 15.4% vs 19.7% vs 50.9%; P ⬍ .001) and esophageal dysmotility (age ⬍40 vs 40 – 60 vs ⬎60: 17.9% vs 31.8% vs 81.1%; P ⬍ .001), whereas female gender (IBS positive vs IBS negative: 71.6% vs 45.2%; P ⬍ .001) and functional dyspepsia (IBS positive vs IBS negative: 89.6 % vs 38.2%; P ⬍ .001) were significantly associated with irritable bowel syndrome.

Discussion NERD has been postulated to be a distinct entity of GERD for nearly a decade.13 In this study, we have observed differences in clinical and physiologic profiles between NERD and ERD in a large prospective consecutive case series.

Table 2. Subtypes of Functional Dyspepsia and Irritable Bowel Syndrome in NERD and ERD Patients

Functional dyspepsia (%) N Ulcer-like Dysmotility Nonspecific Irritable bowel syndrome N Diarrhea-predominant Constipation-predominant Alternating

NERD

ERD

73 12 (16.4) 27 (37) 34 (46.6)

47 9 (19.1) 18 (38.3) 20 (42.6)

P value .89

.10 50 22 (44) 9 (18) 19 (38)

17 9 (52.9) 6 (35.3) 2 (11.8)

June 2007

DISTINCT CHARACTERISTICS OF NERD

693

Table 3. Comparison of Clinical Characteristics Between NERD Patients With Normal and Abnormal Esophageal Acid Exposure

N Female (%) Mean age, y (SD) Smoking (%) Alcohol (%) Mean BMI (SD) Disease duration (%) ⬍1 y 1–5 y ⬎5 y Median symptom score (range) H pylori infection (%) Hiatal hernia (%) Functional dyspepsia (%) Irritable bowel syndrome (%) Psychological disorder (%) Esophageal dysmotility (%) LES pressure ⬍10 mm Hg Ineffective esophageal motility Impaired secondary peristalsis Positive acid perfusion test (%)

Abnormal pH study

Normal pH study

P value

68 43 (63.2) 44.6 (16.1) 7 (10.3) 6 (8.8) 22.3 (3.2)

45 25 (55.6) 46.1 (16.4) 8 (17.8) 2 (4.4) 21.8 (2.9)

.41 .12 .25 .47a .16

12 (17.6) 38 (55.9) 18 (26.5) 2 (1–3) 28 (41.2) 14 (20.6) 47 (69.1) 26 (38.2) 3 (4.4)

8 (17.8) 25 (55.6) 12 (26.7) 2 (1–3) 13 (28.9) 6 (13.3) 26 (57.8) 24 (53.3) 7 (15.6)

9 (13.2) 8 (11.8) 16 (23.5) 23 (33.8)

3 (6.7) 7 (15.6) 6 (13.3) 23 (51.1)

1.00

.64 .18 .32 .22 .11 .09 .36a .56 .18 .07

SD, standard deviation. exact test.

aFisher

Table 4. Comparison of Clinical Characteristics Between Patients With Low-Grade (LA Grade A or B) and High-Grade (LA Grade C or D) Esophagitis Low-grade

High-grade P value

N 93 18 Female (%) 42 (45.2) 9 (50) Mean age, y (SD) 54.4 (14.3) 64.9 (18.2) Smoking (%) 9 (9.7) 1 (5.6) Alcohol (%) 4 (4.3) 2 (11.1) Mean BMI (SD) 21.9 (3.1) 20.7 (2.5) Disease duration (%) ⬍1 y 13 (14) 2 (11.1) 1–5 y 61 (65.6) 10 (55.6) ⬎5 y 19 (20.4) 6 (33.3) Median symptom score (range) 2 (1–3) 2 (1–3) H pylori infection (%) 19 (20.4) 1 (5.6) Hiatal hernia (%) 21 (22.6) 18 (100) Functional dyspepsia (%) 39 (41.9) 8 (44.4) Irritable bowel syndrome (%) 16 (17.2) 1 (5.6) Psychological disorder (%) 1 (1.1) 0 (0) Esophageal dysmotility (%) LES pressure ⬍10 mm Hg 14 (15.1) 18 (100) Ineffective esophageal motility 17 (18.3) 12 (66.7) Impaired secondary peristalsis 24 (25.8) 18 (100) Mean acid exposure time (SD) Total 5.6 (2.7) 7.5 (3.9) Upright 8.8 (4.4) 11.3 (5.3) Supine 1.7 (1.1) 4.2 (2.6) Abnormal pH study (%) 73 (78.5) 18 (100) Positive acid perfusion test (%) 20 (21.5) 2 (11.1) SD, standard deviation. aFisher exact test.

.71 .01 1.00 .25 .16

.49 .29 .19 ⬍.001 .84 .30 1.00 ⬍.001 ⬍.001 ⬍.001 .01 .01 ⬍.02 ⬍.04a .52

In this study, all patients had prior symptom relief by acid suppressive therapy before recruitment, and those with functional heartburn were excluded. As a result, only patients with acid reflux–related symptoms were studied. We have used a well-validated endoscopic classification system with high interobserver agreement to define NERD and ERD to avoid diagnostic confusion. In addition to demographic and endoscopic features, we also evaluated a wide range of physiologic parameters that might influence the severity of GERD. To study the relative importance of visceral hypersensitivity in the pathogenesis of NERD and ERD, we compared the prevalence of concomitant functional gastrointestinal disorders that might share the common etiology of visceral hypersensitivity. Acid perfusion test was used as a surrogate marker for esophageal acid sensitivity. We also evaluated the role of mechanical and motility factors by studying the prevalence of hiatal hernia and esophageal dysmotility in NERD and ERD patients. There were several studies comparing the esophageal motility function and acid exposure in NERD and ERD patients.14 –17 In general, ERD patients had lower LES pressure, amplitude of distal esophageal peristalsis, and higher rate of ineffective peristalsis. These manometric abnormalities were associated with high esophageal acid exposure. Most of these studies were, however, limited by small sample size and possible inclusion of patients with functional heartburn. In a recent large-scale series with clear definition of different entities of GERD, Frazzoni et al14 reported higher acid exposure in ERD patients than in NERD patients. Patients with advanced GERD complications were older than NERD patients. These pathophysiologic findings were in keeping with a spectrum model of GERD with increasing severity and duration of esophageal acid exposure. Yet, comparison of other clinical characteristics was not de-

694

WU ET AL

scribed in these studies. In our study, we also observed a similar difference in esophageal acid exposure between NERD and ERD patients. Patients with high-grade reflux esophagitis had the highest esophageal acid exposure, whereas NERD patients had lower acid exposure. Furthermore, the prevalence of hiatal hernia and esophageal dysmotility was substantially higher in ERD patients especially with high-grade esophagitis. These observations suggest that defective antireflux mechanism and high esophageal acid exposure play key roles in the pathogenesis of ERD.18,19 Overlapping between GERD and other functional gastrointestinal disorders has been reported in several studies.20 –22 However, the relative prevalence of these conditions in NERD and ERD patients has not been studied. In this study, we observed that functional dyspepsia and irritable bowel syndrome are far more common in NERD patients. Despite the absence of erosive esophagitis, a significantly higher proportion of NERD patients had positive acid perfusion test results as compared with ERD patients. The low rates of positive acid perfusion test results in ERD patients might be attributed to lower esophageal sensitivity with more advanced age in this group of patients,23 which decreases the awareness of severe acid reflux and its complication. All the aforementioned differences were not observed between patients with low-grade and high-grade esophagitis. These findings underscore the role of visceral hypersensitivity in pathogenesis of NERD.24 We also set out to compare NERD patients with abnormal and normal esophageal acid exposure in the subgroup analysis. A strong tendency of higher positive rate for acid perfusion test, albeit statistically nonsignificant, was observed in patients with normal esophageal acid exposure. This might signify a predominant role of esophageal acid hypersensitivity in pathogenesis of reflux symptoms in the subgroup of NERD patients with normal esophageal acid exposure, and a large-scale study is needed to confirm this postulation. Old age, male gender, disease duration, and obesity have been implicated as risk factors of GERD complications in many epidemiologic studies.25–29 In this study, however, there was no significant difference in BMI between NERD and ERD patients. Although the role of obesity as a major determining factor for erosive disease among GERD patients is not substantiated, its importance in pathogenesis of GERD should be further evaluated with non-reflux controls. Furthermore, old age and male gender were found to be significant only in univariate analysis but not in subsequent multivariate analysis as predictors of ERD. Further analysis revealed that prevalence of hiatal hernia and esophageal dysmotility increased with age, and female gender was significantly associated with irritable bowel syndrome. These observations suggest that age-related risk of GERD complications is confounded by higher prevalence of hiatal hernia and esophageal dysmotility in older patients,30 –33 and female-associated risk of NERD is confounded by concomitant functional gastrointestinal disorders. We postulate that visceral hypersensitivity plays a more important role in female patients, which might also account for the higher proportion of female gender in various functional gastrointestinal disorders.34 Another intriguing finding is the association between H pylori and NERD. The prevalence of H pylori observed in both NERD and ERD patients is lower than that of the general population as reported previously.35 This observation is compatible with

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 6

our previous findings of milder reflux disease in H pylori– infected GERD patients.36 There is marked geographical heterogeneity in the association between H pylori and GERD.37 A strong negative association has been observed in the Far East, but this association is not apparent in the Western population. This is probably attributed to higher prevalence of severe H pylori–related corpus gastritis with suppressed gastric acid secretion and gastric hypochlorhydria in the Asian population.38 There are some limitations in our study. First, this study was conducted with stringent frequency criteria for reflux symptoms. It might not represent patients with milder forms of the disease in the general population. Second, patients with non– acid-related heartburn symptoms were excluded from this study. So our results might not be extrapolated to the subset of patients with functional heartburn in which the symptoms are not relieved by acid suppression.39 Third, the difference in nonacidic regurgitation was not assessed by impedance monitoring in our patients. In conclusion, there are distinct differences in clinical and physiologic characteristics between NERD and ERD patients. Whereas ERD patients are characterized by typical features of GERD such as high esophageal acid exposure and defective antireflux mechanism, NERD is characterized by predominant features of functional gastrointestinal disorders such as concomitant functional dyspepsia, irritable bowel syndrome, and visceral hypersensitivity. Our findings favor the notion that NERD has distinct clinical characteristics and pathophysiologic mechanisms instead of representing a milder form of GERD. Further studies on the optimal management of NERD are warranted. References 1. Delaney BC. Review article: prevalence and epidemiology of gastrooesophageal reflux disease. Aliment Pharmacol Ther 2004; 20(Suppl 8):2– 4. 2. Locke GR, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997;112:1448 –1456. 3. Johansson KE, Ask P, Boeryd B, et al. Oesophagitis, signs of reflux, and gastric acid secretion in patients with symptoms of gastrooesophageal reflux disease. Scand J Gastroenterol 1986; 21:837– 847. 4. Tew S, Jamieson GG, Pilowsky I, et al. The illness behavior of patients with gastroesophageal reflux disease with and without endoscopic esophagitis. Dis Esophagus 1997;10:9 –15. 5. Carlsson R, Dent J, Watts R, et al. Gastrooesophageal reflux disease in primary care: an international study of different treatment strategies with omeprazole—International GORD Study Group. Eur J Gastroenterol Hepatol 1998;10:119 –124. 6. Schindlbeck NE, Klauser AG, Berghammer G, e al. Three year follow up of patients with gastrooesophageal reflux disease. Gut 1992;33:1016 –1019. 7. Pace F, Bollani S, Molteni P, et al. Natural history of gastrooesophageal reflux disease without oesophagitis (NERD): a reappraisal 10 years on. Dig Liver Dis 2004;36:111–115. 8. Isolauri J, Luostarinen M, Isolauri E, et al. Natural course of gastroesophageal reflux disease: 17-22 year follow-up of 60 patients. Am J Gastroenterol 1997;92:37– 41. 9. Fass R, Ofman JJ. Gastroesophageal reflux disease: should we adopt a new conceptual framework? Am J Gastroenterol 2002; 97:1901–1909. 10. Talley NJ, Stanghellini V, Heading RC, et al. Functional gastroduodenal disorders. Gut 1999;45(Suppl 2):II37–II42. 11. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of

June 2007

12.

13. 14.

15.

16.

17.

18. 19.

20.

21.

22.

23.

24.

25.

26.

oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999; 45:172–180. WWO expert consultation Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363:157–163. Quigley EM. Gastro-oesophageal reflux disease-spectrum or continuum? QJM 1997;90:75–78. Frazzoni M, Manno M, De Micheli E, et al. Pathophysiological characteristics of the various forms of gastro-oesophageal reflux disease: spectrum disease or distinct phenotypic presentations? Dig Liver Dis 2006;38:643– 648. Kasapidis P, Xynos E, Mantides A, et al. Differences in manometry and 24-h ambulatory pH-metry between patients with and without endoscopic or histological esophagitis in gastroesophageal reflux disease. Am J Gastroenterol 1993;88:1893–1899. Saraswat VA, Dhiman RK, Mishra A, et al. Correlation of 24-hr esophageal pH patterns with clinical features and endoscopy in gastroesophageal reflux disease. Dig Dis Sci 1994;39:199 – 205. Cadiot G, Bruhat A, Rigaud D, et al. Multivariate analysis of pathophysiological factors in reflux oesophagitis. Gut 1997;40: 167–174. Holloway RH. Esophageal body motor response to reflux events: secondary peristalsis. Am J Med 2000;108(Suppl 4a):20S–26S. Kahrilas PJ, Dodds WJ, Hogan WJ, et al. Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterology 1986;91: 897–904. Guillemot F, Ducrotte P, Bueno L. Prevalence of functional gastrointestinal disorders in a population of subjects consulting for gastroesophageal reflux disease in general practice. Gastroenterol Clin Biol 2005;29:243–246. Mohammed I, Nightingale P, Trudgill NJ. Risk factors for gastrooesophageal reflux disease symptoms: a community study. Aliment Pharmacol Ther 2005;21:821– 827. Kennedy TM, Jones RH, Hungin AP, et al. Irritable bowel syndrome, gastro-oesophageal reflux, and bronchial hyper-responsiveness in the general population. Gut 1998;43:770 –774. Fass R, Pulliam G, Johnson C, et al. Symptom severity and oesophageal chemosensitivity to acid in older and young patients with gastro-oesophageal reflux. Age Ageing 2000;29:125–130. Fass R, Naliboff B, Higa L, et al. Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans. Gastroenterology 1998;115:1363–1373. El-Serag HB, Graham DY, Satia JA, et al. Obesity is an independent risk factor for GERD symptoms and erosive esophagitis. Am J Gastroenterol 2005;100:1243–1250. Kulig M, Nocon M, Vieth M, et al. Risk factors of gastroesophageal reflux disease: methodology and first epidemiological results of the ProGERD study. J Clin Epidemiol 2004;57:580 –589.

DISTINCT CHARACTERISTICS OF NERD

695

27. Labenz J, Jaspersen D, Kulig M, et al. Risk factors for erosive esophagitis: a multivariate analysis based on the ProGERD study initiative. Am J Gastroenterol 2004;99:1652–1656. 28. Locke GR, Talley NJ, Fett SL, et al. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 1999;106: 642– 649. 29. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med 20052;143:199 –211. 30. Amano K, Adachi K, Katsube T, et al. Role of hiatus hernia and gastric mucosal atrophy in the development of reflux esophagitis in the elderly. J Gastroenterol Hepatol 2001;16:132–136. 31. Caskey CI, Zerhouni EA, Fishman EK, et al. Aging of the diaphragm: a CT study. Radiology 1989;171:385–389. 32. Grande L, Lacima G, Ros E, et al. Deterioration of esophageal motility with age: a manometric study of 79 healthy subjects. Am J Gastroenterol 1999;94:1795–1801. 33. Ferriolli E, Oliveira RB, Matsuda NM, et al. Aging, esophageal motility, and gastroesophageal reflux. J Am Geriatr Soc 1998;46: 1534 –1537. 34. Mayer EA, Naliboff B, Lee O, et al. Review article: gender-related differences in functional gastrointestinal disorders. Aliment Pharmacol Ther 1999;13(Suppl 2):65– 69. 35. Wu JC, Sung JJ, Ng EK, et al. Prevalence and distribution of Helicobacter pylori in gastroesophageal reflux disease: a study from the East. Am J Gastroenterol 1999;94:1790 –1794. 36. Wu JC, Sung JJ, Chan FK, et al. Helicobacter pylori infection is associated with milder gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2000;14:427– 432. 37. Raghunath A, Hungin AP, Wooff D, et al. Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease: systematic review. BMJ 20035;326:737. 38. Koike T, Ohara S, Sekine H, et al. Helicobacter pylori infection prevents erosive reflux oesophagitis by decreasing gastric acid secretion. Gut 2001;49:330 –334. 39. Barlow WJ, Orlando RC. The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis. Gastroenterology 2005;128:771–778.

Address requests for reprints to: Justin C. Y. Wu, Department of Medicine & Therapeutics, 9/F, Clinical Science Building, Prince of Wales Hospital, Shatin, Hong Kong. e-mail: [email protected]; fax: ⴙ852-2637-3852. Supported by a research grant from Hong Kong Society of Gastroenterology. The research work reported in this article was presented at Digestive Disease Week 2006.