Festi D, Scaioli E, Baldi F, Vestito A, Pasqui F, Biase ARD, Colecchia A. Body weight, lifestyle, dietary habits and gastroesophageal reflux disease. World J Gastroenterol 2009; 15(14): 1690-1701
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Davide Festi, MD, Department of Clinical Medicine, S. Orsola-Malpighi Hospital, Via Massarenti 9, Bologna 40138, Italy. email@example.com
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World J Gastroenterol. Apr 14, 2009; 15(14): 1690-1701 Published online Apr 14, 2009. doi: 10.3748/wjg.15.1690
Body weight, lifestyle, dietary habits and gastroesophageal reflux disease
Davide Festi, Eleonora Scaioli, Fabio Baldi, Amanda Vestito, Francesca Pasqui, Anna Rita Di Biase, Antonio Colecchia
Davide Festi, Eleonora Scaioli, Fabio Baldi, Amanda Vestito, Francesca Pasqui, Anna Rita Di Biase, Antonio Colecchia, Department of Clinical Medicine, University of Bologna, Bologna 40138; Department of Pediatrics, University of Modena, Modena 41100, Italy
ORCID number: $[AuthorORCIDs]
Author contributions: Colecchia A, Baldi F, Festi D concepted and designed the manuscript; Vestito A, Pasqui F drafted the manuscript; Scaioli E, Di Biase AR acquired data.
Correspondence to: Davide Festi, MD, Department of Clinical Medicine, S. Orsola-Malpighi Hospital, Via Massarenti 9, Bologna 40138, Italy. firstname.lastname@example.org
Received: December 10, 2008 Revised: March 4, 2009 Accepted: March 11, 2009 Published online: April 14, 2009
While lifestyle modifications are currently used as first-line treatment for subjects with gastroesophageal reflux disease (GERD), the pathogenetic role of lifestyle factors and consequently, the efficacy of lifestyle measures is controversial. Our aim was to systematically review the pathogenetic link between overweight/obesity, dietary habits, physical activity and GERD, and the beneficial effect of specific recommended changes, by means of the available literature from the 1999 to the present. Obesity, in particular, abdominal obesity, plays a key role in determining GERD symptoms and complications through mechanical and metabolic effects. Controlled weight loss (by diet or surgery) is effective in improving GERD symptoms. No definitive data exist regarding the role of diet and, in particular, of specific foods or drinks, in influencing GERD clinical manifestations. Moderate physical activity seems to be beneficial for GERD, while vigorous activity may be dangerous in predisposed individuals. In conclusion, being obese/overweight and GERD-specific symptoms and endoscopic features are related, and weight loss significantly improves GERD clinical-endoscopic manifestations. The role of dietary behavior, mainly in terms of specific dietary components, remains controversial. Mild routine physical activity in association with diet modifications, i.e. a diet rich in fiber and low in fat, is advisable in preventing reflux symptoms.
Citation: Festi D, Scaioli E, Baldi F, Vestito A, Pasqui F, Biase ARD, Colecchia A. Body weight, lifestyle, dietary habits and gastroesophageal reflux disease. World J Gastroenterol 2009; 15(14): 1690-1701
Gastroesophageal reflux disease (GERD) is defined as an abnormal reflux of the gastric contents into the esophagus at least once a week, leading to symptoms, such as heartburn and/or acid regurgitation, and/or esophageal mucosal damage, which may also provoke long-term complications, such as Barrett’s esophagus. GERD represents a common disorder, particularly in the Western world (about 10%-20% in Western countries and under 5% in Asia) and its prevalence appears to be increasing. The incidence rate, reported by two longitudinal studies, was 4.5 and 5.4/1000 people per year, respectively.
GERD is a multifactorial disease in which anatomical and functional factors both play a pathogenetic role. The main pathogenetic mechanism of GERD is considered to be transient lower esophageal sphincter relaxation (TLESR) which may account for the majority of reflux episodes, in patients with esophagitis and in those with non-erosive reflux disease (NERD). An increased number of TLESR episodes, combined or not with an impaired LES basal tone or with gastric or esophageal motor dysfunction, may lead to GERD, but the underlying causes of these functional disorders are still partially unknown.
However, the role of genetic factors was suggested by twin studies wherein hereditability accounted for 31%-43% of the likelihood of reflux disease, which suggests that genetic and environmental factors both play an important role. Among the environmental factors, lifestyle factors, in particular being overweight/obese, incorrect dietary habits, the lack of regular physical activity and smoking have frequently been suggested to be possible GERD risk factors. However, the exact pathogenetic role of these factors is still under debate and the beneficial effect of specific recommended changes in lifestyle habits is also controversial.
A comprehensive search of the literature (Medline/PubMed databases 1999-June 2008, using the following keywords singly and in different combinations: GERD, food intake, food questionnaire, energy intake, motor activity, exercise, obesity, abdominal obesity) was carried out and the evidence available was critically reviewed.
RELATIONSHIP BETWEEN OVERWEIGHT/OBESITY AND GERD
The observation of a consensual increase in the frequency of obesity and GERD in Western countries has suggested a possible pathogenetic link between these two diseases, and it has generated great interest in elucidating the mechanisms demonstrating this association. However, although the relationship between GERD and obesity has been the subject of several studies, conflicting results have been obtained.
In a meta-analysis of epidemiological studies regarding the association between obesity and GERD-related disorders, it was found that being overweight (BMI, 25-30 kg/m2) and being obese (BMI, > 30 kg/m2) were associated with GERD symptoms (OR, 1.43; 95% CI, 1.158-1.774 and OR, 1.94; 95% CI, 1.468-2.566, respectively), erosive esophagitis (OR, 1.76; 95% CI, 1.156-2.677 in overweight subjects) and esophageal adenocarcinoma (OR, 1.52; 95% CI, 1.147-2.009 and OR, 2.78; 95% CI, 1.850-4.164, respectively). A cross-sectional study on 206 consecutive patients not on acid-suppressing medications who underwent 24-h pH measurement showed a significant (P < 0.005) association between a BMI > 30, a high waist circumference and acid reflux episodes. An additional meta-analysis of clinical studies on the relationship between obesity and reflux symptoms, esophagitis or GERD-related hospitalization documented a positive association between BMI (OR, 1.57; 95% CI, 1.36-1.80 in overweight and OR, 2.15; 95% CI, 1.89-2.45 in obese subjects) and GERD in studies carried out in the USA, but the results were heterogeneous in those carried out in Europe.
Different explanations have been proposed in order to interpret these geographical differences. In fact, the relationship between BMI and the percentage of body fat differs between ethnic groups.
Since there are probably multiple pathogenetic mechanisms of GERD (TLESR, esophageal and gastric motor function, and gastric secretion), it is possible that not all of them are related to, or influenced by, the presence of obesity. Furthermore, different definitions of GERD (endoscopic, symptom reports by self-administered or validated questionnaires) have been utilized in the different studies, as well as different measures of obesity (BMI, central adiposity).
RELATIONSHIP BETWEEN BEING OVERWEIGHT/OBESE AND GERD: SUGGESTED PATHOGENETIC MECHANISMS
The exact pathophysiological mechanisms that demonstrate the association/relationship between being overweight/obese and GERD have not been fully identified, but some hypotheses have been suggested.
It has long been hypothesized[17–20] that visceral adiposity, expressed by an increased abdominal waist circumference, could be associated with increased intra-abdominal pressure which would, in turn, promote GERD by increasing intragastric pressure (IGP).
Using high-resolution manometry, it was found that IGP as well as the gastroesophageal pressure gradient (GEPG), during expiration and inspiration, was significantly higher (P < 0.0001) in obese and overweight patients, as compared to those with a normal BMI. This showed an IGP increase of 0.3 mmHg per unit of increase in BMI and the association was stronger in men than in women. Similar results were obtained in a recent retrospective analysis in patients with typical GERD symptoms who underwent pH-monitoring and esophageal manometry. By means of multiple regression analysis, an increase of BMI was independently associated with IGP and with an increase of GEPG during inspiration; furthermore, BMI, IGP and GEPG were strong independent predictors of hiatal hernia, and IGP and GEPG were not independently associated with abnormal acid exposure or esophagitis.
A further pathogenetic mechanism has been suggested by Pandolfino et al who observed that obesity was associated with a separation between LES and the extrinsic crural diaphragm, a disruption which could predispose obese subjects to hiatal hernia. It is known that hiatal hernia is commonly associated with symptomatic GERD, and patients with abnormal esophageal acid exposure have a significantly higher prevalence of hiatal hernia. Furthermore, in patients with hiatal hernia, esophagitis or abdominal low distal esophageal pH are more common than in those without hiatal hernia. In a retrospective case-control study on 1389 patients, obesity was found to represent an independent risk factor for hiatal hernia. Therefore, it is possible that obesity, through alteration of normal IGP and separation between LES and the extrinsic crural diaphragm, predisposes to hiatal hernia and consequently, to GERD.
Another plausible mechanism for the association between obesity and GERD is represented by slower esophageal acid clearance, as shown by Quiroga et al in a case-control study using esophageal manometry in normal weight and obese patients with GERD and in healthy subjects. All subjects with GERD showed altered esophageal motility and obese patients also had impaired esophageal acid clearance.
In obese patients, other esophageal motor abno-rmalities, such as hypotensive LES pressure, nutcracker esophagus and non-specific motility disorders[26–29] have been observed.
However, the most important reflux mechanism in obese subjects seems to be TLESR. The main stimulus for generating TLESR episodes is gastric distension, which leads to intense stimulation of both stretch and tension mechanoreceptors in the proximal stomach. In fact, in a recent study, three groups of subjects without GERD (28 obese, 28 overweight and 28 normal) underwent BMI measurements, upper endoscopy, manometry and pH recordings for both the fasting and the postprandial period and were given a symptom questionnaire. During the 2-h postprandial period, both overweight and obese individuals showed a significantly (P < 0.001) higher rate of TLESR episodes, and a higher proportion of TLESR episodes accompanied by acid reflux and total acid exposure than normal weight subjects. A direct correlation between increasing BMI, an increased number of TLESR episodes, and an increased number of TLESR episodes associated with acid reflux was identified. Therefore, it seems that obese subjects have a higher postprandial IGP, which provokes more postprandial TLESR episodes.
Another mechanism by which obesity can cause GERD is related to the visceral component of abdominal obesity. In fact, visceral fat is metabolically active and it has been associated with low serum levels of protective cytokines, such as adiponectin, and high levels of inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. An increase in these inflammatory cytokines in patients with erosive esophagitis and Barrett’s esophagus has also been observed.
In conclusion, although conflicting and non-definitive results exist, it is likely that GERD and obesity are in some way linked; in particular, abdominal obesity seems to play a key role in determining GERD symptoms and complications through mechanical and metabolic effects. Consistent with this evidence, it is possible to hypothesize that GERD may be a curable condition through the control of body weight and, in particular, by reducing abdominal obesity.
OBESITY AND GERD-RELATED SYMPTOMS
Different studies have analyzed the possible relationship between obesity and GERD by evaluating the clinical manifestation of the disease since reflux symptoms (mainly, heartburn and acid regurgitation) represent the main target for diagnostic evaluation and treatment in GERD patients. However, the factors responsible for the generation of symptoms, in normal or overweight subjects, have not been clearly identified.
Sensitization of esophageal chemoreceptors, either directly by intermittent exposure to refluxed acid or indirectly through esophagitis-associated inflammatory mediators, is thought to be one of the most important mechanisms responsible for symptom generation in GERD.
Several authors have evaluated the relationship between obesity and the symptoms of GERD, both to confirm the association between obesity and GERD and to find potential risk factors for symptom generation (Table 1). In all the studies available, only typical GERD symptoms (i.e. heartburn and regurgitation) have been taken into account, with the use of interviews or structured questionnaires.
Table 1 Association between being overweight/obese and GERD-related symptoms.
In a large cross-sectional study on abdominal obesity, GERD symptoms and ethnicity performed on 80110 members of an health organization, it was found that increased abdominal diameter, adjusted for BMI, was an independent risk factor for reflux symptoms (OR, 1.85; 95% CI, 1.55-2.21) in the white population but not among blacks and Asians, and this aspect was not influenced by gender.
A recent large cohort study in 10 545 women reported a significant (P < 0.001) dose-dependent relationship between increasing BMI and frequent reflux symptoms; this relationship was present even in the normal range of BMI.
Two large population studies and a case-control study have found a positive association between BMI and reflux symptoms. The same results were previously obtained in a large population-based study carried out in Norway; the authors found a stronger association among women, especially premenopausally, and that the use of hormone therapy strengthened the association, which suggested that estrogens may play an important role in the etiology of reflux disease. Another recent study performed in Sweden on a large number of twins, confirmed that BMI seems to be a risk factor for GERD symptoms in monozygotic twins.
However, the association between obesity and GERD symptoms was not confirmed in subjects with benign esophageal disease. Furthermore, a cohort study from New Zealand found no association between BMI and reflux symptoms but, as its authors noted, the cohort consisted of young adults, and GERD symptoms do not usually appear until middle age. The same results were produced by a nationwide case-control study in Sweden and by a recent population-based epidemiological study in Italy.
No data are available yet about the possible correlation between obesity and atypical GERD symptoms.
In conclusion, although further studies are probably needed, most of the available evidence suggests a relationship between obesity, mainly abdominal obesity, and GERD-related typical symptoms.
OBESITY AND REFLUX ESOPHAGITIS
Endoscopic investigation, alone or combined with information regarding specific symptoms obtained by means of structured questionnaires, has been carried out in order to evaluate the possible correlation between GERD-related disorders, such as esophagitis, and obesity (Table 2).
Table 2 Association between overweight/obesity and reflux esophagitis.
The above mentioned meta-analysis by Hampel et al has documented the association between a BMI ≥ 25 kg/m2 and erosive esophagitis. This association was confirmed by Nocon et al using a symptomatic questionnaire and upper endoscopy in 6215 patients and by Kim et al who observed, in 27 319 subjects, an association between an increasing BMI and abnormal endoscopic findings, such as erosive gastritis, gastric ulcer, duodenal ulcer (OR, 1.31; 95% CI, 1.22-1.40; P < 0.0001 for overweight subjects; OR, 1.40; 95% CI, 1.14-1.72; P < 0.001 for obese patients) and reflux esophagitis (OR, 1.61; 95% CI, 1.42-1.83; P < 0.001 for overweight subjects, OR, 2.23; 95% CI, 1.59-3.11; P < 0.001 for obese patients). In a long-term follow-up study (median 18.5 years) on 12 349 subjects, increased hospitalization rates for esophagitis and hiatal hernia were documented in patients with a BMI > 25 kg/m2. Other population-based studies have also confirmed the correlation between obesity, mainly abdominal obesity, and erosive esophagitis.
Furthermore, an association between the metabolic syndrome and reflux esophagitis has recently been documented in a cross-sectional case-control study on 7078 subjects. In particular, it was observed that, among the single components of the metabolic syndrome, abdominal obesity (in particular visceral fat) and elevated serum triglycerides represented independent risk factors for reflux esophagitis (OR, 1.60; 95% CI, 1.03-2.48). Furthermore, it has been demonstrated that only visceral adipose tissue, evaluated by cross-sectional computed tomography, was an independent risk factor for reflux esophagitis. This tissue, in fact, is recognized to be metabolically active and it has been associated with elevated serum levels of pro-inflammatory adipokines (IL-6, TNF-α and adiponectin), compounds which may play a role in GERD development. It seems that visceral adipose tissue plays a key role in increasing lipolysis and free fatty acid, leading to insulin resistance, which is considered the major pathophysiological factor for the development of the metabolic syndrome[3355–57]. It has been suggested that these substances might alter the LES pressure or affect the esophageal clearance of refluxate.
However, the association between BMI and esophagitis has not been confirmed in a recent Japanese prospective study, as well as in an epidemiological survey and a multicenter Italian observational study. The different percentages of body fat in different ethnic groups may represent a possible explanation for these different results.
In conclusion, as occurs for specific GERD symptoms, most of the evidence available also suggests a positive correlation for the association between being overweight/obese and GERD-related morphological lesions.
WEIGHT CHANGES AND GERD-RELATED SYMPTOMS
The observed relationship between weight gain and an increase in GERD-related symptoms, as well as that between weight reduction and a decrease in GERD-related symptoms[62–64], represents additional evidence of the close relationship between obesity and GERD. However, results from studies of weight loss for the control of GERD-related symptoms in obese subjects are not conclusive.
In an uncontrolled study on selected patients with a BMI > 25 kg/m2, Fraser-Moodie et al found that weight loss, induced by general dietary advice, had a beneficial effect on GERD symptoms, as evaluated by a structured questionnaire. Different results were obtained in obese patients with reflux disease who were on a very-low-calorie diet, in which no reduction in reflux symptoms or changes in reflux episodes measured by 24 h pH-monitoring were documented. However, these studies have presented important limitations since they included patients with hiatal hernia, which represents an irreversible condition that contributes to the occurrence of GERD despite the weight loss, and they were carried out on very small numbers of patients, 20 and 15, respectively.
The effect of weight loss induced by endoscopic or surgical procedures has been evaluated. A significant reduction in esophageal acid exposure was documented during weight loss induced by an intragastric balloon in a randomized, double-blind, sham-controlled study. An improvement in GERD symptoms was also found after weight loss induced by bariatric surgery. In particular, the Roux-en-Y gastric bypass seems to represent the surgical procedure that is most effective in improving GERD symptoms in obese subjects[68–72]. Roux-en-Y gastric bypass may be successful at reducing GERD symptoms by diverting bile away from the esophagus, eliminating acid production in the gastric pouch, and reducing the volume of acid refluxate. This hypothesis is supported by the observation of rapid symptom improvement after the surgical procedure; long-term symptom improvement is likely to be the result of weight loss.
Studies evaluating other types of bariatric surgery, such as laparoscopic gastric banding or vertical banded gastroplasty, have produced conflicting results[2674–78]. In particular, laparoscopic adjustable gastric banding has no, or minimal, effect on GERD-related symptoms but, over time, symptoms increase toward baseline or beyond. This effect is likely caused by slippage of the band distally, which results in more stomach above the band. Therefore, the impact of laparoscopic adjustable gastric banding on GERD is independent of weight loss; instead, it is the direct anatomical alteration of the band that impacts on GERD symptoms.
However, these studies are still limited by small sample sizes, lack of randomization, failure to use control groups, use of retrospective data and inconsistent timing of postoperative re-evaluation. Furthermore, it has yet to be clarified whether the surgical technique itself, and/or weight loss, represents the mechanism of action for symptom improvement.
In obese subjects undergoing weight loss, the effect of changes in meal composition on reflux symptoms has also been investigated, although in small studies. In a study on eight obese volunteers, a lower carbohydrate diet reduced reflux symptoms and reflux episodes, which was evaluated by means of 24-h pH monitoring. A higher frequency of reflux symptoms with a high-fat diet as compared to a low-fat diet has also been demonstrated, using four different calorie/fat composition diets, in 15 patients with GERD. Furthermore, esophageal acid exposure was higher with the high-calorie diet as compared to the low-calorie diet.
Together, these data indicate an effective role for weight loss in improving GERD symptoms as well as the effect of differing meal compositions on reflux disease.
DIET AND GERD
It is a common belief that some foods may induce or worsen GERD symptoms; in fact, in daily clinical practice, this belief leads to advising patients to avoid the suspect foods. Furthermore, since GERD symptoms are most commonly reported postprandially, the role of diet components in inducing symptoms has been suggested. However, different and conflicting results exist in the literature for identifying the most “refluxogenic” foods (Table 3).
Table 3 Dietary intake and GERD-related clinical manifestations.
Old experimental and clinical studies have shown a decrease in LES pressure and an increase in esophageal acid exposure in response to the ingestion of food rich in fats, chocolate and carminatives[82–85]. Nebel et al have demonstrated that fried foods, spicy foods and alcohol are the most common precipitating factors of heartburn; however, this study had no control group and did not quantify the intake of dietary items.
In order to elucidate the association of different nutrients with the risk for GERD, El-Serag et al carried out a cross-sectional study on 915 employers, using a dietary questionnaire to estimate the average food consumption over the previous year, and a GERD questionnaire together with an upper endoscopy for assessing GERD severity. A positive association between high fat intake, and GERD symptoms and erosive esophagitis was observed, while a high-fiber diet seemed to reduce reflux symptoms. However, the effects of fat on GERD symptoms and erosive esophagitis were dependent on BMI since this is statistically significant only in overweight individuals. Furthermore, a higher daily intake of fats and proteins was observed in those participants with erosive esophagitis.
More recently, Shapiro et al observed in 58 subjects with typical heartburn symptoms that increased consumption of cholesterol, saturated fatty acids and an higher percentage of calories from fats was significantly associated with an increased likelihood of having reflux events. The role of fats in symptom generation has been confirmed by some[89–91], but not by others. Ruhl et al failed to document an association between dietary fat intake and erosive esophagitis and reflux symptoms, although higher reflux disease hospitalization rates were associated with an increased BMI. These results are consistent with those produced by Nandurkar et al, who analyzed potential risk factors for reflux among 211 community subjects and concluded that only BMI, and not diet, may influence symptomatic GERD.
Also Pehl et al did not find differences in reflux parameters comparing a high-fat meal with a low-fat meal; similar results were obtained by Colombo et al, although they found that a caloric load increased esophageal acid exposure.
Furthermore, none of the dietary items evaluated (i.e. vegetables, fruits, fish, meat, rice, milk, grilled and fried food), including alcohol, was associated with the risk of GERD symptoms in the above-mentioned monozygotic co-twin study based on the Swedish Twin Registry, which investigated lifestyle factors that potentially cause GERD.
Considering the recommended advice of controlling alcohol drinking and reducing, or avoiding, coffee to prevent GERD symptoms, several studies investigated the role of alcohol and coffee in GERD. While some authors have suggested that alcohol is an independent risk factor for GERD-related symptoms[95–98], others have not found such a relationship[99–102]. In their study about the lifestyle habits and GERD symptoms of the participants in two consecutive public health surveys in Norway (> 40 000 people), Nilsson et al did not find that alcohol, coffee or tea were risk factors for reflux-related symptoms. Shapiro et al not only confirmed these results, but also documented that alcohol was associated with a reduced perception of intra-esophageal acid reflux events.
Despite the observation that the intraesophageal infusion of coffee in patients with acid sensitivity may induce heartburn, two large epidemiological studies have found no association between coffee drinking and GERD. Boekema et al have found that coffee does not alter postprandial acid reflux time or the number of acid reflux episodes, and others have noted that coffee consumption is lower in subjects with reflux symptoms. However, the latter result might reflect avoidance of coffee by those who suffer from reflux because the beverage aggravates symptoms.
Furthermore, in their recent study of twins, Zheng et al have found that coffee intake might be a protective factor for GERD symptoms in men, but not in women. The authors have suggested that the differences observed might be caused by sex differences regarding caffeine metabolism. In fact, it has been demonstrated that the conversion of caffeine to paraxanthine, which accounts for 84% of the primary degradation of caffeine in humans, is markedly inhibited by exogenous estrogen in women taking oral contraceptives or in postmenopausal women on hormone replacement therapy. Given the conflicting data reported, the relationship between coffee and GERD remains unclear; as a consequence, there is insufficient evidence to support the routine recommendation of avoiding such beverages for patients with GERD.
In conclusion, no definitive data exist regarding the role of diet and, in particular, of specific foods or drinks, in GERD clinical manifestations. Despite the insufficient evidence to support an association between dietary behavior and GERD, some dietary interventions continue to be recommended as first-line therapy. Larger prospective controlled trials are required to conclusively recommend dietary modifications in the treatment of GERD.
SMOKING AND GERD
Population-based and epidemiological studies have suggested that tobacco smoking may represent a risk factor for GERD[939108–113]. Studies using specific questionnaires have reported that smoking is significantly associated with GERD-related symptoms (OR, 1.35; 95% CI, 1.01-1.82)[114–116]. Furthermore, a recent monozygotic co-twin study has provided compelling evidence that tobacco smoking increases the risk for the occurrence of frequent GERD symptoms, and a case-control study on 3153 patients with severe GERD-related symptoms has shown that the duration of smoking was associated with increasing reflux symptoms (OR, 1.7; 95% CI, 1.5-1.9 in subjects who had smoked for > 20 years). Different mechanisms have been suggested to justify the association between smoking and GERD. Cigarette smoking can reduce the LES pressure[117–119] and decrease salivary bicarbonate secretion, thus reducing the physiological neutralizing effect of saliva on intraesophageal acid and prolonging acid clearance. Furthermore, abrupt increases in intra-abdominal pressure, as occur during coughing or deep inspiration, have been associated with reflux symptoms in smokers. However, studies that have examined acid perfusion using the Bernstein test or esophageal pH[123–125] have reported that smokers compared to non-smokers do not show an increased esophageal acid exposure time, despite having more “reflux episodes”. Furthermore, two old case-control studies evaluating, on very small samples, the effect of smoke cessation on GERD outcomes were unable to document an improvement in GERD symptoms after the cessation of tobacco use.
PHYSICAL ACTIVITY AND GERD
Since previous investigations have demonstrated that strenuous exercise may induce GERD[128–130] and that GERD symptoms are common among athletes, it has been suggested that physical activity represents another risk factor for GERD. However, available evidence indicates that a positive association between exercise and GERD is present in vigorous, but not in moderate, exercise. In fact, Clark et al have reported that running, cycling and weight lifting increase GERD in asymptomatic volunteers. Furthermore, these authors have found that specific types of exercise are more likely to induce reflux symptoms, with running and resistance exercises being more refluxogenic than cycling.
Similar results have been obtained by Peters, in addition, this author has found increased reflux using high-carbohydrate sport drinks with respect to water, which demonstrates a possible role of sport drinks in facilitating reflux symptoms. Therefore, it seems that a hierarchy of exercises in inducing reflux symptoms exists. However, there is no general agreement with respect to the mechanism by which vigorous exercise induces reflux. Exercise may alter esophageal motility and worsen symptoms of the upper gastrointestinal tract. Clark et al have speculated that “body agitation” may be important in inducing reflux. Soffer et al have focused on a decreased duration, amplitude and frequency of esophageal contractions with increasing exercise intensity. This suggestion has not been confirmed by Choi et al who reported increased frequency, but not duration or amplitude, of peristaltic contractions. Furthermore, Pandolfino et al have suggested that the anatomical compromise of the esophagogastric junction, as a consequence of frequent abdominal straining associated with strenuous exercise, may predispose to exercise-induced reflux. Other studies have suggested that GERD may be increased in athletes because of a decreased gastrointestinal blood flow, alterations of hormone secretion, changes in the motor function of the esophagus and the ventricle, and constrained body position during exercise.
All these studies suggest that a specific physical activity, i.e. an agonistic activity, plays a possible pathogenetic role in inducing GERD symptoms. However, these results should not be extended to normal physical activity, which has been demonstrated to have a protective effect against GERD (Table 4). In particular, in a large population-based study, a protective effect of physical activity was observed, documenting a correlation between the number of exercise sessions lasting at least 30 min and a decreased risk of GERD symptoms (OR, 0.5; 95% CI, 0.4-0.7). Therefore, a mechanism of an exercise-strengthened antireflux barrier, possibly constituted by striated muscle was suggested. The same results were produced by Nocon et al, who have also found that subjects with typical GERD symptoms are physically less active than those without symptoms.
Table 4 Physical activity and GERD-related clinical manifestations.
Furthermore, in their monozygotic co-twin study, Zheng et al have provided evidence that physical activity at work increases the risk of GERD symptoms, whereas physical activity at leisure time decreases this risk. The authors have suggested that physical activity at work might be linked with postprandial exercise, which has been found to be a risk factor for the development of GERD symptoms. Indeed, physical exercise at leisure time is predominantly performed at times without a feeling of stomach fullness and is, therefore, most unlikely to be a reflux-provoking postprandial exercise.
In conclusion, the relationship between exercise and GERD is also controversial. It may be a consequence of differences in the populations studied (age, race), evaluation of exercise (short-term, long-term), assessment of physical activity (different questionnaires) and diagnosis of the disease (symptom scale or pH-metry). However, mild routine physical activity in association with diet modifications, i.e. a diet rich in fiber and poor in fat, seems to be advisable to prevent reflux symptoms.
There is sufficient evidence to support the relationship between being obese/overweight and GERD, expressed as specific symptoms and endoscopic features. Furthermore, available evidence suggests that controlled weight loss (by diet or surgery) is able to induce a significant improvement in GERD symptoms and/or in GERD clinical-endoscopic manifestations. Definitive data still do not exist regarding the association between dietary behavior, mainly in terms of specific dietary components and GERD manifestations. Moderate physical activity seems beneficial, while vigorous activity may be dangerous in predisposed individuals. However, owing to the evidence that incorrect dietary habits and the absence of regular physical activity represent important risk factors for the development of the so-called “non-communicable diseases”, lifestyle changes are recommended in patients with or at high risk for GERD. According to the recent proposal by a panel of international experts of a new algorithm for GERD management, life-style factors (i.e. meal size and timing, not lying down after a meal or lying down where the head is in a non-elevated position, not smoking, not consuming alcohol, not eating heavily spiced or fatty food and having a physically active life) are important instruments for the overall management of GERD. Additional clinical studies are required.
Peer reviewer: Wallace F Berman, MD, Professor, Division of Pediatric GI/Nutrition, Department of Pediatrics, Duke University Medical Center, Duke University School of Medicine, Durham, Box 3009, NC27710, United States
Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus.Am J Gastroenterol. 2006;101:1900-1920; quiz 1943.
Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: a systematic review.Gut. 2005;54:710-717.
Ruigomez A, Garcia Rodriguez LA, Wallander MA, Johansson S, Graffner H, Dent J. Natural history of gastro-oesophageal reflux disease diagnosed in general practice.Aliment Pharmacol Ther. 2004;20:751-760.
Kotzan J, Wade W, Yu HH. Assessing NSAID prescription use as a predisposing factor for gastroesophageal reflux disease in a Medicaid population.Pharm Res. 2001;18:1367-1372.
El-Serag H. Role of obesity in GORD-related disorders.Gut. 2008;57:281-284.
Cameron AJ, Lagergren J, Henriksson C, Nyren O, Locke GR 3rd, Pedersen NL. Gastroesophageal reflux disease in monozygotic and dizygotic twins.Gastroenterology. 2002;122:55-59.
Mohammed I, Cherkas LF, Riley SA, Spector TD, Trudgill NJ. Genetic influences in gastroesophageal reflux disease: a twin study.Gut. 2003;52:1085-1089.
Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach.Arch Intern Med. 2006;166:965-971.
Nestle M. The ironic politics of obesity.Science. 2003;299:781.
Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004.JAMA. 2006;295:1549-1555.
Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.Ann Intern Med. 2005;143:199-211.
Corley DA, Kubo A. Body mass index and gastroesophageal reflux disease: a systematic review and meta-analysis.Am J Gastroenterol. 2006;101:2619-2628.
Fernandez JR, Heo M, Heymsfield SB, Pierson RN Jr, Pi-Sunyer FX, Wang ZM, Wang J, Hayes M, Allison DB, Gallagher D. Is percentage body fat differentially related to body mass index in Hispanic Americans, African Americans, and European Americans?Am J Clin Nutr. 2003;77:71-75.
Falk GW. Obesity and gastroesophageal reflux disease: another piece of the puzzle.Gastroenterology. 2008;134:1620-1622.
Pandolfino JE, El-Serag HB, Zhang Q, Shah N, Ghosh SK, Kahrilas PJ. Obesity: a challenge to esophagogastric junction integrity.Gastroenterology. 2006;130:639-649.
de Vries DR, van Herwaarden MA, Smout AJ, Samsom M. Gastroesophageal pressure gradients in gastroesophageal reflux disease: relations with hiatal hernia, body mass index, and esophageal acid exposure.Am J Gastroenterol. 2008;103:1349-1354.
Lambert DM, Marceau S, Forse RA. Intra-abdominal pressure in the morbidly obese.Obes Surg. 2005;15:1225-1232.
El-Serag HB, Tran T, Richardson P, Ergun G. Anthropometric correlates of intragastric pressure.Scand J Gastroenterol. 2006;41:887-891.
Iovino P, Angrisani L, Galloro G, Consalvo D, Tremolaterra F, Pascariello A, Ciacci C. Proximal stomach function in obesity with normal or abnormal oesophageal acid exposure.Neurogastroenterol Motil. 2006;18:425-432.
Iovino P, Angrisani L, Tremolaterra F, Nirchio E, Ciannella M, Borrelli V, Sabbatini F, Mazzacca G, Ciacci C. Abnormal esophageal acid exposure is common in morbidly obese patients and improves after a successful Lap-band system implantation.Surg Endosc. 2002;16:1631-1635.
Suter M, Dorta G, Giusti V, Calmes JM. Gastro-esophageal reflux and esophageal motility disorders in morbidly obese patients.Obes Surg. 2004;14:959-966.
Wilson LJ, Ma W, Hirschowitz BI. Association of obesity with hiatal hernia and esophagitis.Am J Gastroenterol. 1999;94:2840-2844.
Quiroga E, Cuenca-Abente F, Flum D, Dellinger EP, Oelschlager BK. Impaired esophageal function in morbidly obese patients with gastroesophageal reflux disease: evaluation with multichannel intraluminal impedance.Surg Endosc. 2006;20:739-743.
Suter M, Dorta G, Giusti V, Calmes JM. Gastric banding interferes with esophageal motility and gastroesophageal reflux.Arch Surg. 2005;140:639-643.
Koppman JS, Poggi L, Szomstein S, Ukleja A, Botoman A, Rosenthal R. Esophageal motility disorders in the morbidly obese population.Surg Endosc. 2007;21:761-764.
Jaffin BW, Knoepflmacher P, Greenstein R. High prevalence of asymptomatic esophageal motility disorders among morbidly obese patients.Obes Surg. 1999;9:390-395.
Hong D, Khajanchee YS, Pereira N, Lockhart B, Patterson EJ, Swanstrom LL. Manometric abnormalities and gastroesophageal reflux disease in the morbidly obese.Obes Surg. 2004;14:744-749.
Kahrilas PJ, Shi G, Manka M, Joehl RJ. Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distention in reflux patients with hiatal hernia.Gastroenterology. 2000;118:688-695.
Penagini R, Carmagnola S, Cantu P, Allocca M, Bianchi PA. Mechanoreceptors of the proximal stomach: Role in triggering transient lower esophageal sphincter relaxation.Gastroenterology. 2004;126:49-56.
Wu JC, Mui LM, Cheung CM, Chan Y, Sung JJ. Obesity is associated with increased transient lower esophageal sphincter relaxation.Gastroenterology. 2007;132:883-889.
Cnop M, Landchild MJ, Vidal J, Havel PJ, Knowles NG, Carr DR, Wang F, Hull RL, Boyko EJ, Retzlaff BM, Walden CE, Knopp RH, Kahn SE. The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations : distinct metabolic effects of two fat compartments..Diabetes. 2002;51:1005-1015.
Tselepis C, Perry I, Dawson C, Hardy R, Darnton SJ, McConkey C, Stuart RC, Wright N, Harrison R, Jankowski JA. Tumour necrosis factor-alpha in Barrett’s oesophagus: a potential novel mechanism of action.Oncogene. 2002;21:6071-6081.
Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia.Gastroenterology. 1994;107:271-293.
Fass R, Naliboff B, Higa L, Johnson C, Kodner A, Munakata J, Ngo J, Mayer EA. Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans.Gastroenterology. 1998;115:1363-1373.
Corley DA, Kubo A, Zhao W. Abdominal obesity, ethnicity and gastro-oesophageal reflux symptoms.Gut. 2007;56:756-762.
Jacobson BC, Somers SC, Fuchs CS, Kelly CP, Camargo CA Jr. Body-mass index and symptoms of gastroesophageal reflux in women.N Engl J Med. 2006;354:2340-2348.
Nocon M, Labenz J, Willich SN. Lifestyle factors and symptoms of gastro-oesophageal reflux -- a population-based study.Aliment Pharmacol Ther. 2006;23:169-174.
Nocon M, Labenz J, Jaspersen D, Meyer-Sabellek W, Stolte M, Lind T, Malfertheiner P, Willich SN. Association of body mass index with heartburn, regurgitation and esophagitis: results of the Progression of Gastroesophageal Reflux Disease study.J Gastroenterol Hepatol. 2007;22:1728-1731.
Nandurkar S, Locke GR 3rd, Fett S, Zinsmeister AR, Cameron AJ, Talley NJ. Relationship between body mass index, diet, exercise and gastro-oesophageal reflux symptoms in a community.Aliment Pharmacol Ther. 2004;20:497-505.
Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms.JAMA. 2003;290:66-72.
Zheng Z, Nordenstedt H, Pedersen NL, Lagergren J, Ye W. Lifestyle factors and risk for symptomatic gastroesophageal reflux in monozygotic twins.Gastroenterology. 2007;132:87-95.
Andersen LI, Jensen G. Risk factors for benign oesophageal disease in a random population sample.J Intern Med. 1991;230:5-10.
Talley NJ, Howell S, Poulton R. Obesity and chronic gastrointestinal tract symptoms in young adults: a birth cohort study.Am J Gastroenterol. 2004;99:1807-1814.
Lagergren J, Bergstrom R, Nyren O. No relation between body mass and gastro-oesophageal reflux symptoms in a Swedish population based study.Gut. 2000;47:26-29.
Zagari RM, Fuccio L, Wallander MA, Johansson S, Fiocca R, Casanova S, Farahmand BY, Winchester CC, Roda E, Bazzoli F. Gastro-oesophageal reflux symptoms, oesophagitis and Barrett’s oesophagus in the general population: the Loiano-Monghidoro study.Gut. 2008;57:1354-1359.
Kim HJ, Yoo TW, Park DI, Park JH, Cho YK, Sohn CI, Jeon WK, Kim BI. Influence of overweight and obesity on upper endoscopic findings.J Gastroenterol Hepatol. 2007;22:477-481.
Ruhl CE, Everhart JE. Overweight, but not high dietary fat intake, increases risk of gastroesophageal reflux disease hospitalization: the NHANES I Epidemiologic Followup Study. First National Health and Nutrition Examination Survey.Ann Epidemiol. 1999;9:424-435.
Lee HL, Eun CS, Lee OY, Jeon YC, Sohn JH, Han DS, Yoon BC, Choi HS, Hahm JS, Lee MH. Association between GERD-related erosive esophagitis and obesity.J Clin Gastroenterol. 2008;42:672-675.
Kang MS, Park DI, Oh SY, Yoo TW, Ryu SH, Park JH, Kim HJ, Cho YK, Sohn CI, Jeon WK. Abdominal obesity is an independent risk factor for erosive esophagitis in a Korean population.J Gastroenterol Hepatol. 2007;22:1656-1661.
Chung SJ, Kim D, Park MJ, Kim YS, Kim JS, Jung HC, Song IS. Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.Gut. 2008;57:1360-1365.
Watanabe S, Hojo M, Nagahara A. Metabolic syndrome and gastrointestinal diseases.J Gastroenterol. 2007;42:267-274.
Barak N, Ehrenpreis ED, Harrison JR, Sitrin MD. Gastro-oesophageal reflux disease in obesity: pathophysiological and therapeutic considerations.Obes Rev. 2002;3:9-15.
Bosello O, Zamboni M. Visceral obesity and metabolic syndrome.Obes Rev. 2000;1:47-56.
Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM, Brunzell JD, Shofer JB, Fish BE, Knopp RH, Kahn SE. Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome.Diabetes. 2004;53:2087-2094.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.J Clin Invest. 2003;112:1821-1830.
Furukawa N, Iwakiri R, Koyama T, Okamoto K, Yoshida T, Kashiwagi Y, Ohyama T, Noda T, Sakata H, Fujimoto K. Proportion of reflux esophagitis in 6010 Japanese adults: prospective evaluation by endoscopy.J Gastroenterol. 1999;34:441-444.
Rey E, Moreno-Elola-Olaso C, Artalejo FR, Locke GR 3rd, Diaz-Rubio M. Association between weight gain and symptoms of gastroesophageal reflux in the general population.Am J Gastroenterol. 2006;101:229-233.
Cremonini F, Locke GR 3rd, Schleck CD, Zinsmeister AR, Talley NJ. Relationship between upper gastrointestinal symptoms and changes in body weight in a population-based cohort.Neurogastroenterol Motil. 2006;18:987-994.
Mathus-Vliegen EM, van Weeren M, van Eerten PV. Los function and obesity: the impact of untreated obesity, weight loss, and chronic gastric balloon distension.Digestion. 2003;68:161-168.
Mathus-Vliegen EM, Tygat GN. Gastro-oesophageal reflux in obese subjects: influence of overweight, weight loss and chronic gastric balloon distension.Scand J Gastroenterol. 2002;37:1246-1252.
Fraser-Moodie CA, Norton B, Gornall C, Magnago S, Weale AR, Holmes GK. Weight loss has an independent beneficial effect on symptoms of gastro-oesophageal reflux in patients who are overweight.Scand J Gastroenterol. 1999;34:337-340.
Friedenberg FK, Xanthopoulos M, Foster GD, Richter JE. The association between gastroesophageal reflux disease and obesity.Am J Gastroenterol. 2008;103:2111-2122.
Kjellin A, Ramel S, Rossner S, Thor K. Gastroesophageal reflux in obese patients is not reduced by weight reduction.Scand J Gastroenterol. 1996;31:1047-1051.
Frederiksen SG, Johansson J, Johnsson F, Hedenbro J. Neither low-calorie diet nor vertical banded gastroplasty influence gastro-oesophageal reflux in morbidly obese patients.Eur J Surg. 2000;166:296-300.
Frezza EE, Ikramuddin S, Gourash W, Rakitt T, Kingston A, Luketich J, Schauer P. Symptomatic improvement in gastroesophageal reflux disease (GERD) following laparoscopic Roux-en-Y gastric bypass.Surg Endosc. 2002;16:1027-1031.
Nelson LG, Gonzalez R, Haines K, Gallagher SF, Murr MM. Amelioration of gastroesophageal reflux symptoms following Roux-en-Y gastric bypass for clinically significant obesity.Am Surg. 2005;71:950-953; discussion 953-954.
Smith SC, Edwards CB, Goodman GN. Symptomatic and clinical improvement in morbidly obese patients with gastroesophageal reflux disease following Roux-en-Y gastric bypass.Obes Surg. 1997;7:479-484.
Clements RH, Gonzalez QH, Foster A, Richards WO, McDowell J, Bondora A, Laws HL. Gastrointestinal symptoms are more intense in morbidly obese patients and are improved with laparoscopic Roux-en-Y gastric bypass.Obes Surg. 2003;13:610-614.
Mejia-Rivas MA, Herrera-Lopez A, Hernandez-Calleros J, Herrera MF, Valdovinos MA. Gastroesophageal reflux disease in morbid obesity: the effect of Roux-en-Y gastric bypass.Obes Surg. 2008;18:1217-1224.
Cobey F, Oelschlager B. Complete regression of Barrett’s esophagus after Roux-en-Y gastric bypass.Obes Surg. 2005;15:710-712.
Angrisani L, Iovino P, Lorenzo M, Santoro T, Sabbatini F, Claar E, Nicodemi O, Persico G, Tesauro B. Treatment of morbid obesity and gastroesophageal reflux with hiatal hernia by Lap-Band.Obes Surg. 1999;9:396-398.
Tolonen P, Victorzon M, Niemi R, Makela J. Does gastric banding for morbid obesity reduce or increase gastroesophageal reflux?Obes Surg. 2006;16:1469-1474.
de Jong JR, van Ramshorst B, Timmer R, Gooszen HG, Smout AJ. Effect of laparoscopic gastric banding on esophageal motility.Obes Surg. 2006;16:52-58.
Korenkov M, Kohler L, Yucel N, Grass G, Sauerland S, Lempa M, Troidl H. Esophageal motility and reflux symptoms before and after bariatric surgery.Obes Surg. 2002;12:72-76.
Gutschow CA, Collet P, Prenzel K, Holscher AH, Schneider PM. Long-term results and gastroesophageal reflux in a series of laparoscopic adjustable gastric banding.J Gastrointest Surg. 2005;9:941-948.
Austin GL, Thiny MT, Westman EC, Yancy WS Jr, Shaheen NJ. A very low-carbohydrate diet improves gastroesophageal reflux and its symptoms.Dig Dis Sci. 2006;51:1307-1312.
Fox M, Barr C, Nolan S, Lomer M, Anggiansah A, Wong T. The effects of dietary fat and calorie density on esophageal acid exposure and reflux symptoms.Clin Gastroenterol Hepatol. 2007;5:439-444.
DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease.Am J Gastroenterol. 2005;100:190-200.
Becker DJ, Sinclair J, Castell DO, Wu WC. A comparison of high and low fat meals on postprandial esophageal acid exposure.Am J Gastroenterol. 1989;84:782-786.
Hills JM, Aaronson PI. The mechanism of action of peppermint oil on gastrointestinal smooth muscle. An analysis using patch clamp electrophysiology and isolated tissue pharmacology in rabbit and guinea pig.Gastroenterology. 1991;101:55-65.
Nebel OT, Castell DO. Lower esophageal sphincter pressure changes after food ingestion.Gastroenterology. 1972;63:778-783.
Murphy DW, Castell DO. Chocolate and heartburn: evidence of increased esophageal acid exposure after chocolate ingestion.Am J Gastroenterol. 1988;83:633-636.
Nebel OT, Fornes MF, Castell DO. Symptomatic gastroeso-phageal reflux: incidence and precipitating factors.Am J Dig Dis. 1976;21:953-956.
El-Serag HB, Satia JA, Rabeneck L. Dietary intake and the risk of gastro-oesophageal reflux disease: a cross sectional study in volunteers.Gut. 2005;54:11-17.
Shapiro M, Green C, Bautista JM, Dekel R, Risner-Adler S, Whitacre R, Graver E, Fass R. Assessment of dietary nutrients that influence perception of intra-oesophageal acid reflux events in patients with gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2007;25:93-101.
Iwakiri K, Kobayashi M, Kotoyori M, Yamada H, Sugiura T, Nakagawa Y. Relationship between postprandial esophageal acid exposure and meal volume and fat content.Dig Dis Sci. 1996;41:926-930.
Holloway RH, Lyrenas E, Ireland A, Dent J. Effect of intraduodenal fat on lower oesophageal sphincter function and gastro-oesophageal reflux.Gut. 1997;40:449-453.
Meyer JH, Lembo A, Elashoff JD, Fass R, Mayer EA. Duodenal fat intensifies the perception of heartburn.Gut. 2001;49:624-628.
Pehl C, Waizenhoefer A, Wendl B, Schmidt T, Schepp W, Pfeiffer A. Effect of low and high fat meals on lower esophageal sphincter motility and gastroesophageal reflux in healthy subjects.Am J Gastroenterol. 1999;94:1192-1196.
Colombo P, Mangano M, Bianchi PA, Penagini R. Effect of calories and fat on postprandial gastro-oesophageal reflux.Scand J Gastroenterol. 2002;37:3-5.
Shaheen N, Ransohoff DF. Gastroesophageal reflux, Barrett esophagus, and esophageal cancer: clinical applications.JAMA. 2002;287:1982-1986.
Mohammed I, Nightingale P, Trudgill NJ. Risk factors for gastro-oesophageal reflux disease symptoms: a community study.Aliment Pharmacol Ther. 2005;21:821-827.
Wang JH, Luo JY, Dong L, Gong J, Tong M. Epidemiology of gastroesophageal reflux disease: a general population-based study in Xi’an of Northwest China.World J Gastroenterol. 2004;10:1647-1651.
O’Leary C, McCarthy J, Humphries M, Shanahan F, Quigley E. The prophylactic use of a proton pump inhibitor before food and alcohol.Aliment Pharmacol Ther. 2003;17:683-686.
Rosaida MS, Goh KL. Gastro-oesophageal reflux disease, reflux oesophagitis and non-erosive reflux disease in a multiracial Asian population: a prospective, endoscopy based study.Eur J Gastroenterol Hepatol. 2004;16:495-501.
Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J. Lifestyle related risk factors in the aetiology of gastro-oesophageal reflux.Gut. 2004;53:1730-1735.
Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J. Prevalence of gastro-oesophageal reflux symptoms and the influence of age and sex.Scand J Gastroenterol. 2004;39:1040-1045.
Stanghellini V. Relationship between upper gastrointestinal symptoms and lifestyle, psychosocial factors and comorbidity in the general population: results from the Domestic/International Gastroenterology Surveillance Study (DIGEST).Scand J Gastroenterol Suppl. 1999;231:29-37.
Talley NJ, Zinsmeister AR, Schleck CD, Melton LJ 3rd. Smoking, alcohol, and analgesics in dyspepsia and among dyspepsia subgroups: lack of an association in a community.Gut. 1994;35:619-624.
Price SF, Smithson KW, Castell DO. Food sensitivity in reflux esophagitis.Gastroenterology. 1978;75:240-243.
Boekema PJ, Samsom M, Smout AJ. Effect of coffee on gastro-oesophageal reflux in patients with reflux disease and healthy controls.Eur J Gastroenterol Hepatol. 1999;11:1271-1276.
Gender differences in the metabolic responses to caffeine. In: Tarnopolsky M, editor. Gender differences in metabolism. Boca Raton: CRC Press LLC; 1999;307.
Abernethy DR, Todd EL. Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives.Eur J Clin Pharmacol. 1985;28:425-428.
Pollock BG, Wylie M, Stack JA, Sorisio DA, Thompson DS, Kirshner MA, Folan MM, Condifer KA. Inhibition of caffeine metabolism by estrogen replacement therapy in postmenopausal women.J Clin Pharmacol. 1999;39:936-940.
Isolauri J, Laippala P. Prevalence of symptoms suggestive of gastro-oesophageal reflux disease in an adult population.Ann Med. 1995;27:67-70.
Locke GR 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ 3rd. Risk factors associated with symptoms of gastroesophageal reflux.Am J Med. 1999;106:642-649.
Haque M, Wyeth JW, Stace NH, Talley NJ, Green R. Prevalence, severity and associated features of gastro-oesophageal reflux and dyspepsia: a population-based study.N Z Med J. 2000;113:178-181.
Diaz-Rubio M, Moreno-Elola-Olaso C, Rey E, Locke GR 3rd, Rodriguez-Artalejo F. Symptoms of gastro-oesophageal reflux: prevalence, severity, duration and associated factors in a Spanish population.Aliment Pharmacol Ther. 2004;19:95-105.
Kennedy T, Jones R. The prevalence of gastro-oesophageal reflux symptoms in a UK population and the consultation behaviour of patients with these symptoms.Aliment Pharmacol Ther. 2000;14:1589-1594.
Wong WM, Lai KC, Lam KF, Hui WM, Hu WH, Lam CL, Xia HH, Huang JQ, Chan CK, Lam SK. Prevalence, clinical spectrum and health care utilization of gastro-oesophageal reflux disease in a Chinese population: a population-based study.Aliment Pharmacol Ther. 2003;18:595-604.
Watanabe Y, Fujiwara Y, Shiba M, Watanabe T, Tominaga K, Oshitani N, Matsumoto T, Nishikawa H, Higuchi K, Arakawa T. Cigarette smoking and alcohol consumption associated with gastro-oesophageal reflux disease in Japanese men.Scand J Gastroenterol. 2003;38:807-811.
Tibbling L, Gibellino FM, Johansson KE. Is mis-swallowing or smoking a cause of respiratory symptoms in patients with gastroesophageal reflux disease?Dysphagia. 1995;10:113-116.
Chattopadhyay DK, Greaney MG, Irvin TT. Effect of cigarette smoking on the lower oesophageal sphincter.Gut. 1977;18:833-835.
Dennish GW, Castell DO. Inhibitory effect of smoking on the lower esophageal sphincter.N Engl J Med. 1971;284:1136-1137.
Dua K, Bardan E, Ren J, Sui Z, Shaker R. Effect of chronic and acute cigarette smoking on the pharyngo-upper oesophageal sphincter contractile reflex and reflexive pharyngeal swallow.Gut. 1998;43:537-541.
Stanciu C, Bennett JR. Smoking and gastro-oesophageal reflux.Br Med J. 1972;3:793-795.
Trudgill NJ, Smith LF, Kershaw J, Riley SA. Impact of smoking cessation on salivary function in healthy volunteers.Scand J Gastroenterol. 1998;33:568-571.
Kahrilas PJ, Gupta RR. The effect of cigarette smoking on salivation and esophageal acid clearance.J Lab Clin Med. 1989;114:431-438.
Kahrilas PJ, Gupta RR. Mechanisms of acid reflux associated with cigarette smoking.Gut. 1990;31:4-10.
Smit CF, Copper MP, van Leeuwen JA, Schoots IG, Stanojcic LD. Effect of cigarette smoking on gastropharyngeal and gastroesophageal reflux.Ann Otol Rhinol Laryngol. 2001;110:190-193.
Berenson MM, Sontag S, Robinson MG, McCallum RM. Effect of smoking in a controlled study of ranitidine treatment in gastroesophageal reflux disease.J Clin Gastroenterol. 1987;9:499-503.
Pehl C, Pfeiffer A, Wendl B, Nagy I, Kaess H. Effect of smoking on the results of esophageal pH measurement in clinical routine.J Clin Gastroenterol. 1997;25:503-506.
Schindlbeck NE, Heinrich C, Dendorfer A, Pace F, Muller-Lissner SA. Influence of smoking and esophageal intubation on esophageal pH-metry.Gastroenterology. 1987;92:1994-1997.
Waring JP, Eastwood TF, Austin JM, Sanowski RA. The immediate effects of cessation of cigarette smoking on gastroesophageal reflux.Am J Gastroenterol. 1989;84:1076-1078.
Collings KL, Pierce Pratt F, Rodriguez-Stanley S, Bemben M, Miner PB. Esophageal reflux in conditioned runners, cyclists, and weightlifters.Med Sci Sports Exerc. 2003;35:730-735.
Pandolfino JE, Bianchi LK, Lee TJ, Hirano I, Kahrilas PJ. Esophagogastric junction morphology predicts susceptibility to exercise-induced reflux.Am J Gastroenterol. 2004;99:1430-1436.
Ravi N, Stuart RC, Byrne PJ, Reynolds JV. Effect of physical exercise on esophageal motility in patients with esophageal disease.Dis Esophagus. 2005;18:374-377.
Parmelee-Peters K, Moeller JL. Gastroesophageal reflux in athletes.Curr Sports Med Rep. 2004;3:107-111.
Schoeman MN, Tippett MD, Akkermans LM, Dent J, Holloway RH. Mechanisms of gastroesophageal reflux in ambulant healthy human subjects.Gastroenterology. 1995;108:83-91.
Jozkow P, Wasko-Czopnik D, Dunajska K, Medras M, Paradowski L. The relationship between gastroesophageal reflux disease and the level of physical activity.Swiss Med Wkly. 2007;137:465-470.
Clark CS, Kraus BB, Sinclair J, Castell DO. Gastroesophageal reflux induced by exercise in healthy volunteers.JAMA. 1989;261:3599-3601.
Peters HP, Wiersma WC, Akkermans LM, Bol E, Kraaijenhagen RJ, Mosterd WL, de Vries WR, Wielders JP. Gastrointestinal mucosal integrity after prolonged exercise with fluid supplementation.Med Sci Sports Exerc. 2000;32:134-142.
van Nieuwenhoven MA, Brouns F, Brummer RJ. The effect of physical exercise on parameters of gastrointestinal function.Neurogastroenterol Motil. 1999;11:431-439.
Soffer EE, Merchant RK, Duethman G, Launspach J, Gisolfi C, Adrian TE. Effect of graded exercise on esophageal motility and gastroesophageal reflux in trained athletes.Dig Dis Sci. 1993;38:220-224.
Choi SC, Yoo KH, Kim TH, Kim SH, Choi SJ, Nah YH. Effect of graded running on esophageal motility and gastroesophageal reflux in fed volunteers.J Korean Med Sci. 2001;16:183-187.
Jozkow P, Wasko-Czopnik D, Medras M, Paradowski L. Gastroesophageal reflux disease and physical activity.Sports Med. 2006;36:385-391.
Emerenziani S, Zhang X, Blondeau K, Silny J, Tack J, Janssens J, Sifrim D. Gastric fullness, physical activity, and proximal extent of gastroesophageal reflux.Am J Gastroenterol. 2005;100:1251-1256.
Daar AS, Singer PA, Persad DL, Pramming SK, Matthews DR, Beaglehole R, Bernstein A, Borysiewicz LK, Colagiuri S, Ganguly N. Grand challenges in chronic non-communicable diseases.Nature. 2007;450:494-496.
Tytgat GN, McColl K, Tack J, Holtmann G, Hunt RH, Malfertheiner P, Hungin AP, Batchelor HK. New algorithm for the treatment of gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2008;27:249-256.