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Nonlinear Relationship Between Body Mass Index and Esophageal Acid Exposure in the Extraesophageal Manifestations of Reflux
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:874 – 878
ALIMENTARY TRACT Nonlinear Relationship Between Body Mass Index and Esophageal Acid Exposure in the Extraesophageal Manifestations of Reflux MUHAMMAD ASLAM,* JAMES C. SLAUGHTER,‡ MARION GOUTTE,* C. GAELYN GARRETT,§ DAVID HAGAMAN,储 and MICHAEL F. VAEZI* *Division of Gastroenterology, Hepatology and Nutrition, ‡Department of Biostatistics, §Voice Center, 储Allergy, Sinus and Asthma Program, Vanderbilt University Medical Center, Nashville, Tennessee
BACKGROUND & AIMS: Obesity is believed to be an important etiologic factor in gastroesophageal reflux disease. However, it is not clear how obesity might affect esophageal acid exposure in patients with extraesophageal manifestations of reflux. METHODS: We conducted a cross-sectional study of 223 patients with extraesophageal symptoms suspected of being related to reflux. Participants underwent endoscopy and 48-hour wireless pH testing. The percentage of time at a pH of less than 4 (total, upright, and supine) was measured for each patient, and data were compared with corresponding body mass index (BMI), as continuous and categoric variables (normal, 18.5 to ⬍25; overweight, 25 to ⬍30; and obese, ⬎30). Multivariable linear regression was used to identify variables associated with percentage of total time at a pH less than 4. The primary predictor of interest was BMI; age, sex, esophagitis, and hiatal hernia status were considered potential confounders or precision variables. RESULTS: Esophageal acid exposure was associated significantly (P ⬍ .001) with BMI. The percentage of time at a pH less than 4 and total symptomatic reflux events increased significantly (P ⫽ .005) with increasing BMI. The relationship between percentage of time at a pH less than 4 and BMI was nonlinear and S-shaped. With BMI ranges, the percentage of time at a pH less than 4 increased by 0.23% (normal BMI), 0.75% (overweight), and 0.07% (obese) for every 1-kg/m2 increase in BMI (P ⬍ .001). CONCLUSIONS: Increases in esophageal acid exposure are greatest among overweight patients and plateau in obese patients. The findings have implications for benefit of weight loss in patients with suspected extraesophageal manifestations of gastroesophageal reflux disease.
the risk of GERD7–10 and its complications11–14 in a dose-dependent manner. Although the exact mechanism by which obesity promotes GERD remains unclear, recent data point to obesity increasing pressure stress on the esophagogastric junction with subsequent anatomic disruption through separation between the intrinsic lower esophageal sphincter (LES) and the extrinsic crural diaphragm.9,15,16 Extraesophageal manifestations of GERD represent an increasingly prevalent condition in which patients’ presentation is atypical of that for typical reflux disease. Patients with this clinically important entity often present with symptoms such as asthma, chronic cough, laryngitis, and dental erosions.17 Although the relationship between the extraesophageal symptoms and reflux disease varies, there are some common themes. In addition to the lack of the classic heartburn and regurgitation symptoms, esophagitis or Barrett’s esophagus usually is less prevalent in this group. Thus, physiologic testing with pH monitoring often is necessary to determine the presence, severity, and correlation of esophageal acid exposure to patients’ presenting symptoms. Although much attention in the past has focused on the association between obesity and typical GERD, currently there are no data on the relationship between obesity and esophageal acid exposure in those with extraesophageal symptoms. Thus, the aim of the present study was to systematically characterize the relationship between BMI and acid reflux in a cohort of patients presenting with the chief complaint of extraesophageal symptoms. We tested the hypothesis that increasing BMI in this group of patients may be different from that of typical GERD patients and is associated with a nonlinear increase in esophageal acid exposure.
Keywords: GERD; pH Monitoring; Esophagus; Stomach Acid.
Materials and Methods
O
besity continues to be a leading health concern in the United States.1 The prevalence of overweight and obese children, adolescents, and adults continues to increase, with doubling of the rates in adults aged 20 years or older and tripling in children and adolescents aged 6 to 19 years over the past decade.2– 4 Similar to the trends for obesity, the prevalence of gastroesophageal reflux disease (GERD) is increasing in the United States.4 – 6 The rapid and parallel increase in the prevalence of obesity and GERD during the past 3 decades has invoked much interest in defining the relationship between the 2 entities. Recent evidence suggests that an increase in body mass index (BMI) may increase
The study was performed in accordance with the Declaration of Helsinki, and good clinical practice and applicable regulatory requirements. The Vanderbilt Institutional Review Board approved this clinical trial (IRB #090814).
Abbreviations used in this paper: BMI, body mass index; CI, confidence interval; GERD, gastroesophageal reflux disease; IQR, interquartile range; LES, lower esophageal sphincter. © 2012 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2011.12.032
August 2012
Study Design and Patient Population The study population consisted of patients with suspected reflux-related extraesophageal symptoms referred to the Vanderbilt Center for Esophageal Disorders to undergo physiologic testing between 2006 and 2011. The following information was collected for all participants: presence, severity, and frequency of the chief complaints of extraesophageal symptoms (cough, hoarseness, throat clearing, sore throat, globus sensation, problem swallowing, chest pain, and discomfort to talk); concomitant typical GERD symptoms (heartburn/regurgitation); current medications as well as information on subject demographics (age, sex, and race); history of smoking and alcohol use; and presence of voice/ throat and nose symptoms. Patients with mechanical antireflux procedures, esophageal motility disorders, pregnancy, and those unable to provide informed consent were excluded from the study. Patients with typical GERD symptoms such as heartburn and regurgitation as the primary chief complaints also were excluded. All subjects underwent esophagogastroduodenoscopy followed by prolonged ambulatory 48-hour wireless pH testing 7–10 days off acid suppression. The National Health and Nutrition Examination Survey protocols18 were followed for height and weight measurements for all patients. Body weight was measured to the nearest 0.05 kg with a monthly calibrated digital scale (Detecto-Medic; Detecto Scales, Inc, Northbrook, IL). Height was measured using a stadiometer (Perspective Enterprises, Portage, MI). World Health Organization BMI categories were used to group the patients as follows: normal weight, BMI of 18.5 to less than 25; overweight, BMI of 25 to less than 30; and obese, BMI of 30 or greater.
Ambulatory Esophageal pH Monitoring Ambulatory pH monitoring was performed for 48 hours in all participants using wireless pH monitors (Given Imaging, Inc, Duluth, GA) after stopping acid-suppression therapy for at least 14 days. During this time, patients kept diaries of meal times, symptoms, and supine position. Wireless capsules were activated and calibrated by submersion in buffer solutions at pH 7.0 and pH 1.0 (Medtronic), and then activated by magnet removal. Patients underwent esophagogastroduodenoscopy with conscious intravenous sedation for visual anatomic inspection and distance measurements from the incisors to the squamocolumnar junction. Capsules then were placed using the manufacturer’s delivery system at 6 cm above the squamocolumnar junction, and attached with vacuum suction of 600 mm Hg. Capsule placement was confirmed at endoscopy. After successful placement, patients were given wireless pH recorders to wear about their waists or to keep within 3 to 5 feet at all times. Recording devices receive pH data sampling transmitted by the capsule at 433 Hz with 6-second sampling intervals. Patients were instructed to perform their normal daily activities and dietary practices. After completion of the study, data were downloaded from recording devices to dedicated computers using Datalink software (Given Imaging, Inc). Patient diary information was entered manually into the computer-based record. The acid pH data (% time pH ⬍ 4) were analyzed in the total, upright, and supine periods. Abnormal reflux parameters were defined by values exceeding the 95th percentile values for each of the reflux parameters (total, ⬎4.2%; upright, ⬎6.3%; and supine, ⬎1.2%).19
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Statistical Analysis Data were collected and stored at the secure web-based Vanderbilt Digestive Disease Center Research Electronic Data Capture (grant 1 UL1 RR024975 NCRR/NIH). Research Electronic Data Capture is an application designed to support data capture for research studies providing the following: (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources. There was strict control and supervision of the data entry and access for this study. The total percentage of time the pH was less than 4 was used as our primary end point to describe the association between BMI and esophageal acid exposure. For descriptive analyses only, acid reflux abnormality was defined as when the total time pH was less than 4 was more than 4.2%. Unadjusted associations between BMI and pH parameters were tested using either the Wilcoxon ranksum test (continuous outcomes) or the Pearson chi-square test (binary outcomes). In the main analyses, multivariable linear regression was used to evaluate the association of BMI with the percentage of time the pH was less than 4 while adjusting for esophagitis status, presence of hiatal hernia, age, and sex. BMI was modeled as a continuous covariate using regression splines with 3 degrees of freedom to allow the relationship with pH to vary smoothly over the range of BMI. Results are presented as the expected change in the percentage of time the pH was less than 4 owing to a 1-kg/m2 change in BMI with accompanying 95% confidence intervals (CIs). Similar analyses were performed for upright and supine pH parameters. Statistical analysis was conducted using the R software package using robust standard error estimates. Continuous variables were summarized using the median, 25th, and 75th percentiles, and results were considered significant if the P value was less than .05.
Results Demographics and Body Mass Index Distribution The study population consisted of 223 patients (median age, 53 y; interquartile range [IQR], 42– 61 y; 76% female; 91% Caucasian; median BMI, 28; IQR, 24 –32). The primary symptom complaints included the following: cough (52%), asthma (19%), hoarseness (15%), sore throat (6%), sinusitis/ rhinitis (5%), and globus (3%). A secondary complaint of heartburn and/or regurgitation was present in 40% of patients. Hiatal hernia was present in 28% of patients (80% with ⬍2 cm). Esophagitis was present in 15% of subjects (Los Angeles grade A, 50%; grade B, 27%; grade C, 16%; and grade D, 7%). The following were the BMI distributions for the study population: 66 of 223 (30%) subjects were in the normal weight category (BMI, 18.5 to ⬍25), 82 of 223 (37%) subjects were in the overweight category (BMI, 25 to ⬍30), and 75 of 223 (34%) subjects were in the obese category (BMI, ⱖ30).
Acid Reflux Parameters The median percentage of time that pH was less than 4 on day 1 and day 2 was as follows: total, 9.0% (IQR, 6.5%– 12.4%); upright, 10.0% (IQR, 7.8%–16.2%); and supine, 2.4% (IQR, 1.2%– 8.1%). A total of 177 of 223 (79%) patients had
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Table 1. Association Between Esophageal Acid Exposure and BMI BMI Acid exposure
18.5 to ⬍25 (n ⫽ 66)
25 to ⬍30 (n ⫽ 82)
ⱖ30 (n ⫽ 75)
P
% Time pH ⬍4a Total Upright Supine % Abnormal acid exposure Total symptomatic reflux events
6.2 (3.0–8.2) 7.9 (4.2–12.1) 1.15 (0.05–3.77) 70 123 (55–178)
6.9 (4.3–10.5) 8.5 (5.2–14.4) 2.33 (0.20–5.94) 76 155 (96–216)
9.8 (6.9–12.8) 13.0 (8.4–7.2) 4.15 (1.17–8.30) 92 163 (125–229)
⬍.001 ⬍.001 ⬍.001 .003 .005
aMedian
(IQR).
abnormal esophageal acid exposure, with 70% of this group having esophageal acid exposure (% total time pH ⬍4) of less than 10%. Esophageal acid exposure increased significantly (P ⬍ .001) with increasing BMI both as a continuous and as a categoric variable. The median percentage of total time the pH was less than 4 was 6.2% (IQR, 3.0%– 8.2%), 6.9% (IQR, 4.3%–10.5%), and 9.8% (IQR, 6.9%–12.8%) in the normal, overweight, and obese groups, respectively (Table 1). The latter group had the highest prevalence of abnormal esophageal acid exposure at 92% compared with the overweight or normal weight populations. In parallel, the number of symptomatic reflux events increased significantly from the normal to obese groups (Table 1). Holding BMI constant, subjects with esophagitis experienced a 2.3% increase in the percentage of time the pH was less than 4 compared with subjects without esophagitis (95% CI, 0.2%– 4.4%). Independent of esophagitis or hiatal hernia status or the presence of concomitant typical symptoms, the increase in acid exposure was steepest in the BMI zone of 25 to 30, with a minimal increase for a BMI of greater than 30 (Figure 1). The increase in the total percentage of time the pH was less than 4
per 1-kg/m2 BMI increase is listed in Table 2. The largest increase in the percentage of time the pH was less than 4 per unit BMI occurred in the overweight, but not obese, category. For a BMI of 25 to less than 30, the percentage of time the pH was less than 4 increased by 0.75% per unit BMI (P ⬍ .01) as compared with only a 0.07% change per unit BMI for the obese category (Table 2). The relationship between acid reflux and BMI was nonlinear for all 3 reflux parameters: percentage total, upright, and supine time with a pH of less than 4.
Discussion This study objectively assessed the relationship between BMI and GERD in patients suspected of having extraesophageal manifestations of reflux. Similar to prior reports in patients with typical GERD,7,8,10,20,21 we found that esophageal acid exposure increased significantly with increasing BMI as a continuous as well as categoric variable. However, our data suggest that the increase in acid exposure per unit increase in BMI is not linear, unlike as previously reported in typical GERD. The most marked increase in acid reflux occurred in the BMI zone of 25 to 30 with a minimal increase for a BMI of greater than 30. The nonlinear S-shaped association in our study population was independent of age, sex, and esophagitis status. Table 2. Association Between BMI and Total Percentage of Time pH Was Less Than 4 Adjusted for Esophagitis Status, Age, Presence of Hiatal Hernia, and Sex Change in % total time pH ⬍4 Effecta Lower 2.5b Upper 97.5b BMI category, kg/m2 18.5 to ⬍25 25 to ⬍30 ⬎30 Esophagitis Age (every 10-y increase) Hiatal hernia Male
Figure 1. Graphic representation of multivariable linear regression model controlling for esophagitis status, presence of hiatal hernia, age, and sex in patients with extraesophageal symptoms. There is an Sshaped relationship between increasing BMI and the percentage of time the pH was less than 4. The largest increase in acid exposure occurred between a BMI of 25 to 30 independent of esophagitis.
aEffects
0.23 0.75 0.07 2.32 0.02 0.72 1.36
⫺0.17 0.26 ⫺0.37 0.20 ⫺0.42 ⫺0.97 ⫺0.39
0.62 1.20 0.09 4.40 0.46 2.40 3.10
P
.27 ⬍.01 .12 .03 .94 .40 .13
are the expected change in the percentage of time the pH was less than 4 for every 1-kg/m2 increase in BMI (within each specified range), a 10-year increase in age, and the presence of esophagitis, hiatal hernia, and male sex. bThe lower 2.5 and upper 97.5 columns represent the 2.5th to 97.5th percentile of the data.
August 2012
Ayazi et al20 evaluated a large group of GERD patients and reported that for every unit increase in BMI, the percentage of total time the pH was less than 4 increased by 0.35% (95% CI, 0.42– 0.46). They observed that the relationship between the BMI and the percentage of total time the pH was less than 4 was constant, without a BMI threshold above or below which the positive relationship between BMI and esophageal acid exposure ceased to exist. Similarly, El-Serag et al,21 in their crosssectional study of anthropometric correlates of intragastric pressure in 322 patients, noted an approximate 10% increase in intragastric pressure per each unit increase in BMI. However, Crowell et al10 in their study of 157 patients with typical GERD reported a significant linear trend between esophageal acid exposure and BMI; however, acid exposure time was not significantly different between the overweight and obese groups. Our data agree with the latter findings, suggesting saturation of the obesity effect on esophageal acid exposure. The mechanism by which obesity promotes GERD is not yet defined, but some competing hypotheses have been proposed. The intra-abdominal pressure theory suggests that obesity in general and abdominal obesity in particular disrupts the integrity of lower esophageal sphincter through increasing the intragastric pressure,9,21,22 inducing separation between LES and the extrinsic crural diaphragm9 or enhancing frequency of its transient relaxations.23 In contrast, the dietary habits theory suggests that dietary intake and habits may be the common denominator for the concurrent increase in the incidence of both obesity and GERD.24 Both theories are based on reasonable assumptions, and it is possible that both intra-abdominal pressure changes and dietary habits play important roles. Our finding of saturation of the obesity effect on esophageal acid exposure appears to be more physiological in the context of the intra-abdominal pressure theory. It is well reported that BMI is related more strongly to body and subcutaneous fat than to visceral fat in both sexes.25–27 Oka et al25 reported a quadratic relationship between visceral fat and BMI in their male participants (n ⫽ 1432); the increase in visceral fat was greater at lower levels of BMI and leveled off at higher levels of BMI in a quadratic fashion. In a smaller cohort of 16 females and 9 males with a BMI greater than 35, Springer et al28 observed that above a certain BMI level (⬎35 to 40), in contrast to subcutaneous fat, visceral adipose tissue no longer correlated with BMI and, thus, may have reached a sex-dependent plateau. Furthermore, in this study population, the LES pressure was not different among the 3 obesity categories (BMI, 35– 40, 40 –50, and ⬎50). These studies lend further support to the nonlinear relationship between acid reflux and BMI similar to the results in our study. However, the exact nature of the relationship between BMI, visceral adipose tissue, and acid reflux needs further study. The clinically important implications of our findings are that the level of increase in esophageal acid exposure is more substantial when patients gain weight and are not yet in the obese category. In the obese group the esophageal acid exposure levels off and further weight gain does not mean more severe reflux. This finding coincides with the clinical observation of increasing patient complaints when they only gain small amounts of weight. More importantly, an intriguing speculation based on our findings relates to the potential reflux-related benefit of weight loss in the obese but more importantly in the overweight group of patients with suspected GERD-related
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extraesophageal symptoms. Although the results of prior studies on weight loss and GERD symptom improvements are mixed,29 –31 a recent meta-analysis concluded that dietary and lifestyle intervention improves GERD symptoms in obese patients with bariatric surgery; Roux-en-Y gastric bypass in particular yields the most favorable results.32 In addition, a recent trial reported the reduction and discontinuation of reflux medication with weight loss in patients with gastroesophageal reflux disease.33 In this trial 64% of the 100 severely obese patients who lost 59 kg in 45 weeks were able to discontinue their medications compared with only 18% of the 83 obese patients who lost 19 kg in 20 weeks. Although beyond the scope of the present study, future studies are needed to assess if esophageal acid exposure can be reduced in those who lose weight, especially from the overweight to normal BMI category because this represented the steep part of the curve in our study (Figure 1). Our report had some limitations. The study was from a tertiary care facility and the patient population comprised those who were either partially or nonresponsive to proton pump inhibitor therapy. Thus, the relationship between esophageal acid exposure and BMI may be different in other groups. However, it is not uncommon that patients with continued symptoms despite proton pump inhibitor therapy are referred to specialty centers such as those in this study. Further, the enrolled patient group in our study is in line with the current indications of pH testing for those unresponsive to an initial empiric trial of acid suppression.34,35 Given the cross-sectional design of our study, we could only compare BMI and pH among the subjects as a whole; an ideal study would be a prospective study in which patients could serve as their own control with pH parameters tested before and after either weight loss or weight gain. Such a study has been designed and is in the implementation phase by our group. Finally, the high prevalence of abnormal esophageal acid exposure in our group of 79% may be population specific, but does not change the primary outcome of the study regarding the association of reflux and obesity. In conclusion, we found that BMI is associated significantly and nonlinearly with esophageal acid exposure in patients with suspected GERD-related extraesophageal symptoms, and the net increase in acid exposure was most pronounced between a BMI range of 25 to 30. These findings may have important implications with respect to future studies for goals of weight loss in this group of patients. References 1. El-Serag H. Role of obesity in GORD-related disorders. Gut 2008; 57:281–284. 2. Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999 – 2002. JAMA 2004;291:2847–2850. 3. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999 –2004. JAMA 2006;295: 1549 –1555. 4. El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol 2007;5:17–26. 5. Murray L, Johnston B, Lane A, et al. Relationship between body mass and gastro-oesophageal reflux symptoms: the Bristol Helicobacter project. Int J Epidemiol 2003;32:645– 650. 6. Friedenberg FK, Xanthopoulos M, Foster GD, et al. The association between gastroesophageal reflux disease and obesity. Am J Gastroenterol 2008;103:2111–2122.
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7. El-Serag HB, Ergun GA, Pandolfino J, et al. Obesity increases oesophageal acid exposure. Gut 2007;56:749 –755. 8. Herbella FA, Sweet MP, Tedesco P, et al. Gastroesophageal reflux disease and obesity. Pathophysiology and implications for treatment. J Gastrointest Surg 2007;11:286 –290. 9. Pandolfino JE, El-Serag HB, Zhang Q, et al. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology 2006;130: 639 – 649. 10. Crowell MD, Bradley A, Hansel S, et al. Obesity is associated with increased 48-h esophageal acid exposure in patients with symptomatic gastroesophageal reflux. Am J Gastroenterol 2009;104: 553–559. 11. 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. 12. Corley DA. Obesity and the rising incidence of oesophageal and gastric adenocarcinoma: what is the link? Gut 2007;56:1493– 1494. 13. Corley DA, Kubo A, Levin TR, et al. Abdominal obesity and body mass index as risk factors for Barrett’s esophagus. Gastroenterology 2007;133:34 – 41; quiz, 311. 14. 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. 15. Wajed SA, Streets CG, Bremner CG, et al. Elevated body mass disrupts the barrier to gastroesophageal reflux. Arch Surg 2001; 136:1014 –1019. 16. de Vries DR, van Herwaarden MA, Smout AJ, et al. 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. 17. Moore JM, Vaezi MF. Extraesophageal manifestations of gastroesophageal reflux disease: real or imagined? Curr Opin Gastroenterol 2010;26:389 –394. 18. Center for Diseases Control. Anthropometry procedures manual. Atlanta, GA: Center for Diseases Control, 2000. 19. Johnson LF, Demeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974;62:325–332. 20. Ayazi S, Hagen JA, Chan LS, et al. Obesity and gastroesophageal reflux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of patients with reflux symptoms. J Gastrointest Surg 2009;13:1440 –1447. 21. El-Serag HB, Tran T, Richardson P, et al. Anthropometric correlates of intragastric pressure. Scand J Gastroenterol 2006;41: 887– 891. 22. de Vries D, van Herwaarden M, Smout A, et al. 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. 23. Wu JC, Mui LM, Cheung CM, et al. Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology 2007;132:883– 889.
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24. Tutuian R, Castell DO. Pressure details from the weight-challenged gastroesophageal junction: more than the usual suspects. Gastroenterology 2006;130:988 –989. 25. Oka R, Miura K, Sakurai M, et al. Comparison of waist circumference with body mass index for predicting abdominal adipose tissue. Diabetes Res Clin Pract 2009;83:100 –105. 26. Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham heart study. Circulation 2007;116:39 – 48. 27. Vega GL, Adams-Huet B, Peshock R, et al. Influence of body fat content and distribution on variation in metabolic risk. J Clin Endocrinol Metab 2006;91:4459 – 4466. 28. Springer F, Schwarz M, Machann J, et al. Quantitative assessment of visceral fat in morbidly obese patients by means of wide-bore MRI and its relation to lower esophageal sphincter pressure and signs of gastroesophageal reflux. Obes Surg 2010; 20:749 –756. 29. Jacobson BC, Somers SC, Fuchs CS, et al. Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med 2006;354:2340 –2348. 30. Fraser-Moodie CA, Norton B, Gornall C, et al. 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. 31. Kjellin A, Ramel S, Rössner S, et al. Gastroesophageal reflux in obese patients is not reduced by weight reduction. Scand J Gastroenterol 1996;31:1047–1051. 32. De Groot NL, Burgerhart JS, Van De Meeberg PC, et al. Systematic review: the effects of conservative and surgical treatment for obesity on gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2009;30:1091–1102. 33. Anderson J, Jhaveri M. Reductions in medications with substantial weight loss with behavioral intervention. Curr Clin Pharmacol 2010;5:232–238. 34. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association institute technical review on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:1392–1413. e1–5. 35. DeVault KR, Castell DO, American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005;100:190 – 200.
Reprint requests Address requests for reprints to: Michael F. Vaezi, MD, PhD, MSc (Epi), Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 1660 TVC, 1301 22nd Avenue South, Nashville, Tennessee 37232-5280. e-mail: michael.vaezi@vanderbilt. edu; fax: (615) 322-8525. Conflicts of interest The authors disclose no conflicts.
ALIMENTARY TRACT Nonlinear Relationship Between Body Mass Index and Esophageal Acid Exposure in the Extraesophageal Manifestations of Reflux MUHAMMAD ASLAM,* JAMES C. SLAUGHTER,‡ MARION GOUTTE,* C. GAELYN GARRETT,§ DAVID HAGAMAN,储 and MICHAEL F. VAEZI* *Division of Gastroenterology, Hepatology and Nutrition, ‡Department of Biostatistics, §Voice Center, 储Allergy, Sinus and Asthma Program, Vanderbilt University Medical Center, Nashville, Tennessee
BACKGROUND & AIMS: Obesity is believed to be an important etiologic factor in gastroesophageal reflux disease. However, it is not clear how obesity might affect esophageal acid exposure in patients with extraesophageal manifestations of reflux. METHODS: We conducted a cross-sectional study of 223 patients with extraesophageal symptoms suspected of being related to reflux. Participants underwent endoscopy and 48-hour wireless pH testing. The percentage of time at a pH of less than 4 (total, upright, and supine) was measured for each patient, and data were compared with corresponding body mass index (BMI), as continuous and categoric variables (normal, 18.5 to ⬍25; overweight, 25 to ⬍30; and obese, ⬎30). Multivariable linear regression was used to identify variables associated with percentage of total time at a pH less than 4. The primary predictor of interest was BMI; age, sex, esophagitis, and hiatal hernia status were considered potential confounders or precision variables. RESULTS: Esophageal acid exposure was associated significantly (P ⬍ .001) with BMI. The percentage of time at a pH less than 4 and total symptomatic reflux events increased significantly (P ⫽ .005) with increasing BMI. The relationship between percentage of time at a pH less than 4 and BMI was nonlinear and S-shaped. With BMI ranges, the percentage of time at a pH less than 4 increased by 0.23% (normal BMI), 0.75% (overweight), and 0.07% (obese) for every 1-kg/m2 increase in BMI (P ⬍ .001). CONCLUSIONS: Increases in esophageal acid exposure are greatest among overweight patients and plateau in obese patients. The findings have implications for benefit of weight loss in patients with suspected extraesophageal manifestations of gastroesophageal reflux disease.
the risk of GERD7–10 and its complications11–14 in a dose-dependent manner. Although the exact mechanism by which obesity promotes GERD remains unclear, recent data point to obesity increasing pressure stress on the esophagogastric junction with subsequent anatomic disruption through separation between the intrinsic lower esophageal sphincter (LES) and the extrinsic crural diaphragm.9,15,16 Extraesophageal manifestations of GERD represent an increasingly prevalent condition in which patients’ presentation is atypical of that for typical reflux disease. Patients with this clinically important entity often present with symptoms such as asthma, chronic cough, laryngitis, and dental erosions.17 Although the relationship between the extraesophageal symptoms and reflux disease varies, there are some common themes. In addition to the lack of the classic heartburn and regurgitation symptoms, esophagitis or Barrett’s esophagus usually is less prevalent in this group. Thus, physiologic testing with pH monitoring often is necessary to determine the presence, severity, and correlation of esophageal acid exposure to patients’ presenting symptoms. Although much attention in the past has focused on the association between obesity and typical GERD, currently there are no data on the relationship between obesity and esophageal acid exposure in those with extraesophageal symptoms. Thus, the aim of the present study was to systematically characterize the relationship between BMI and acid reflux in a cohort of patients presenting with the chief complaint of extraesophageal symptoms. We tested the hypothesis that increasing BMI in this group of patients may be different from that of typical GERD patients and is associated with a nonlinear increase in esophageal acid exposure.
Keywords: GERD; pH Monitoring; Esophagus; Stomach Acid.
Materials and Methods
O
besity continues to be a leading health concern in the United States.1 The prevalence of overweight and obese children, adolescents, and adults continues to increase, with doubling of the rates in adults aged 20 years or older and tripling in children and adolescents aged 6 to 19 years over the past decade.2– 4 Similar to the trends for obesity, the prevalence of gastroesophageal reflux disease (GERD) is increasing in the United States.4 – 6 The rapid and parallel increase in the prevalence of obesity and GERD during the past 3 decades has invoked much interest in defining the relationship between the 2 entities. Recent evidence suggests that an increase in body mass index (BMI) may increase
The study was performed in accordance with the Declaration of Helsinki, and good clinical practice and applicable regulatory requirements. The Vanderbilt Institutional Review Board approved this clinical trial (IRB #090814).
Abbreviations used in this paper: BMI, body mass index; CI, confidence interval; GERD, gastroesophageal reflux disease; IQR, interquartile range; LES, lower esophageal sphincter. © 2012 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2011.12.032
August 2012
Study Design and Patient Population The study population consisted of patients with suspected reflux-related extraesophageal symptoms referred to the Vanderbilt Center for Esophageal Disorders to undergo physiologic testing between 2006 and 2011. The following information was collected for all participants: presence, severity, and frequency of the chief complaints of extraesophageal symptoms (cough, hoarseness, throat clearing, sore throat, globus sensation, problem swallowing, chest pain, and discomfort to talk); concomitant typical GERD symptoms (heartburn/regurgitation); current medications as well as information on subject demographics (age, sex, and race); history of smoking and alcohol use; and presence of voice/ throat and nose symptoms. Patients with mechanical antireflux procedures, esophageal motility disorders, pregnancy, and those unable to provide informed consent were excluded from the study. Patients with typical GERD symptoms such as heartburn and regurgitation as the primary chief complaints also were excluded. All subjects underwent esophagogastroduodenoscopy followed by prolonged ambulatory 48-hour wireless pH testing 7–10 days off acid suppression. The National Health and Nutrition Examination Survey protocols18 were followed for height and weight measurements for all patients. Body weight was measured to the nearest 0.05 kg with a monthly calibrated digital scale (Detecto-Medic; Detecto Scales, Inc, Northbrook, IL). Height was measured using a stadiometer (Perspective Enterprises, Portage, MI). World Health Organization BMI categories were used to group the patients as follows: normal weight, BMI of 18.5 to less than 25; overweight, BMI of 25 to less than 30; and obese, BMI of 30 or greater.
Ambulatory Esophageal pH Monitoring Ambulatory pH monitoring was performed for 48 hours in all participants using wireless pH monitors (Given Imaging, Inc, Duluth, GA) after stopping acid-suppression therapy for at least 14 days. During this time, patients kept diaries of meal times, symptoms, and supine position. Wireless capsules were activated and calibrated by submersion in buffer solutions at pH 7.0 and pH 1.0 (Medtronic), and then activated by magnet removal. Patients underwent esophagogastroduodenoscopy with conscious intravenous sedation for visual anatomic inspection and distance measurements from the incisors to the squamocolumnar junction. Capsules then were placed using the manufacturer’s delivery system at 6 cm above the squamocolumnar junction, and attached with vacuum suction of 600 mm Hg. Capsule placement was confirmed at endoscopy. After successful placement, patients were given wireless pH recorders to wear about their waists or to keep within 3 to 5 feet at all times. Recording devices receive pH data sampling transmitted by the capsule at 433 Hz with 6-second sampling intervals. Patients were instructed to perform their normal daily activities and dietary practices. After completion of the study, data were downloaded from recording devices to dedicated computers using Datalink software (Given Imaging, Inc). Patient diary information was entered manually into the computer-based record. The acid pH data (% time pH ⬍ 4) were analyzed in the total, upright, and supine periods. Abnormal reflux parameters were defined by values exceeding the 95th percentile values for each of the reflux parameters (total, ⬎4.2%; upright, ⬎6.3%; and supine, ⬎1.2%).19
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Statistical Analysis Data were collected and stored at the secure web-based Vanderbilt Digestive Disease Center Research Electronic Data Capture (grant 1 UL1 RR024975 NCRR/NIH). Research Electronic Data Capture is an application designed to support data capture for research studies providing the following: (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources. There was strict control and supervision of the data entry and access for this study. The total percentage of time the pH was less than 4 was used as our primary end point to describe the association between BMI and esophageal acid exposure. For descriptive analyses only, acid reflux abnormality was defined as when the total time pH was less than 4 was more than 4.2%. Unadjusted associations between BMI and pH parameters were tested using either the Wilcoxon ranksum test (continuous outcomes) or the Pearson chi-square test (binary outcomes). In the main analyses, multivariable linear regression was used to evaluate the association of BMI with the percentage of time the pH was less than 4 while adjusting for esophagitis status, presence of hiatal hernia, age, and sex. BMI was modeled as a continuous covariate using regression splines with 3 degrees of freedom to allow the relationship with pH to vary smoothly over the range of BMI. Results are presented as the expected change in the percentage of time the pH was less than 4 owing to a 1-kg/m2 change in BMI with accompanying 95% confidence intervals (CIs). Similar analyses were performed for upright and supine pH parameters. Statistical analysis was conducted using the R software package using robust standard error estimates. Continuous variables were summarized using the median, 25th, and 75th percentiles, and results were considered significant if the P value was less than .05.
Results Demographics and Body Mass Index Distribution The study population consisted of 223 patients (median age, 53 y; interquartile range [IQR], 42– 61 y; 76% female; 91% Caucasian; median BMI, 28; IQR, 24 –32). The primary symptom complaints included the following: cough (52%), asthma (19%), hoarseness (15%), sore throat (6%), sinusitis/ rhinitis (5%), and globus (3%). A secondary complaint of heartburn and/or regurgitation was present in 40% of patients. Hiatal hernia was present in 28% of patients (80% with ⬍2 cm). Esophagitis was present in 15% of subjects (Los Angeles grade A, 50%; grade B, 27%; grade C, 16%; and grade D, 7%). The following were the BMI distributions for the study population: 66 of 223 (30%) subjects were in the normal weight category (BMI, 18.5 to ⬍25), 82 of 223 (37%) subjects were in the overweight category (BMI, 25 to ⬍30), and 75 of 223 (34%) subjects were in the obese category (BMI, ⱖ30).
Acid Reflux Parameters The median percentage of time that pH was less than 4 on day 1 and day 2 was as follows: total, 9.0% (IQR, 6.5%– 12.4%); upright, 10.0% (IQR, 7.8%–16.2%); and supine, 2.4% (IQR, 1.2%– 8.1%). A total of 177 of 223 (79%) patients had
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Table 1. Association Between Esophageal Acid Exposure and BMI BMI Acid exposure
18.5 to ⬍25 (n ⫽ 66)
25 to ⬍30 (n ⫽ 82)
ⱖ30 (n ⫽ 75)
P
% Time pH ⬍4a Total Upright Supine % Abnormal acid exposure Total symptomatic reflux events
6.2 (3.0–8.2) 7.9 (4.2–12.1) 1.15 (0.05–3.77) 70 123 (55–178)
6.9 (4.3–10.5) 8.5 (5.2–14.4) 2.33 (0.20–5.94) 76 155 (96–216)
9.8 (6.9–12.8) 13.0 (8.4–7.2) 4.15 (1.17–8.30) 92 163 (125–229)
⬍.001 ⬍.001 ⬍.001 .003 .005
aMedian
(IQR).
abnormal esophageal acid exposure, with 70% of this group having esophageal acid exposure (% total time pH ⬍4) of less than 10%. Esophageal acid exposure increased significantly (P ⬍ .001) with increasing BMI both as a continuous and as a categoric variable. The median percentage of total time the pH was less than 4 was 6.2% (IQR, 3.0%– 8.2%), 6.9% (IQR, 4.3%–10.5%), and 9.8% (IQR, 6.9%–12.8%) in the normal, overweight, and obese groups, respectively (Table 1). The latter group had the highest prevalence of abnormal esophageal acid exposure at 92% compared with the overweight or normal weight populations. In parallel, the number of symptomatic reflux events increased significantly from the normal to obese groups (Table 1). Holding BMI constant, subjects with esophagitis experienced a 2.3% increase in the percentage of time the pH was less than 4 compared with subjects without esophagitis (95% CI, 0.2%– 4.4%). Independent of esophagitis or hiatal hernia status or the presence of concomitant typical symptoms, the increase in acid exposure was steepest in the BMI zone of 25 to 30, with a minimal increase for a BMI of greater than 30 (Figure 1). The increase in the total percentage of time the pH was less than 4
per 1-kg/m2 BMI increase is listed in Table 2. The largest increase in the percentage of time the pH was less than 4 per unit BMI occurred in the overweight, but not obese, category. For a BMI of 25 to less than 30, the percentage of time the pH was less than 4 increased by 0.75% per unit BMI (P ⬍ .01) as compared with only a 0.07% change per unit BMI for the obese category (Table 2). The relationship between acid reflux and BMI was nonlinear for all 3 reflux parameters: percentage total, upright, and supine time with a pH of less than 4.
Discussion This study objectively assessed the relationship between BMI and GERD in patients suspected of having extraesophageal manifestations of reflux. Similar to prior reports in patients with typical GERD,7,8,10,20,21 we found that esophageal acid exposure increased significantly with increasing BMI as a continuous as well as categoric variable. However, our data suggest that the increase in acid exposure per unit increase in BMI is not linear, unlike as previously reported in typical GERD. The most marked increase in acid reflux occurred in the BMI zone of 25 to 30 with a minimal increase for a BMI of greater than 30. The nonlinear S-shaped association in our study population was independent of age, sex, and esophagitis status. Table 2. Association Between BMI and Total Percentage of Time pH Was Less Than 4 Adjusted for Esophagitis Status, Age, Presence of Hiatal Hernia, and Sex Change in % total time pH ⬍4 Effecta Lower 2.5b Upper 97.5b BMI category, kg/m2 18.5 to ⬍25 25 to ⬍30 ⬎30 Esophagitis Age (every 10-y increase) Hiatal hernia Male
Figure 1. Graphic representation of multivariable linear regression model controlling for esophagitis status, presence of hiatal hernia, age, and sex in patients with extraesophageal symptoms. There is an Sshaped relationship between increasing BMI and the percentage of time the pH was less than 4. The largest increase in acid exposure occurred between a BMI of 25 to 30 independent of esophagitis.
aEffects
0.23 0.75 0.07 2.32 0.02 0.72 1.36
⫺0.17 0.26 ⫺0.37 0.20 ⫺0.42 ⫺0.97 ⫺0.39
0.62 1.20 0.09 4.40 0.46 2.40 3.10
P
.27 ⬍.01 .12 .03 .94 .40 .13
are the expected change in the percentage of time the pH was less than 4 for every 1-kg/m2 increase in BMI (within each specified range), a 10-year increase in age, and the presence of esophagitis, hiatal hernia, and male sex. bThe lower 2.5 and upper 97.5 columns represent the 2.5th to 97.5th percentile of the data.
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Ayazi et al20 evaluated a large group of GERD patients and reported that for every unit increase in BMI, the percentage of total time the pH was less than 4 increased by 0.35% (95% CI, 0.42– 0.46). They observed that the relationship between the BMI and the percentage of total time the pH was less than 4 was constant, without a BMI threshold above or below which the positive relationship between BMI and esophageal acid exposure ceased to exist. Similarly, El-Serag et al,21 in their crosssectional study of anthropometric correlates of intragastric pressure in 322 patients, noted an approximate 10% increase in intragastric pressure per each unit increase in BMI. However, Crowell et al10 in their study of 157 patients with typical GERD reported a significant linear trend between esophageal acid exposure and BMI; however, acid exposure time was not significantly different between the overweight and obese groups. Our data agree with the latter findings, suggesting saturation of the obesity effect on esophageal acid exposure. The mechanism by which obesity promotes GERD is not yet defined, but some competing hypotheses have been proposed. The intra-abdominal pressure theory suggests that obesity in general and abdominal obesity in particular disrupts the integrity of lower esophageal sphincter through increasing the intragastric pressure,9,21,22 inducing separation between LES and the extrinsic crural diaphragm9 or enhancing frequency of its transient relaxations.23 In contrast, the dietary habits theory suggests that dietary intake and habits may be the common denominator for the concurrent increase in the incidence of both obesity and GERD.24 Both theories are based on reasonable assumptions, and it is possible that both intra-abdominal pressure changes and dietary habits play important roles. Our finding of saturation of the obesity effect on esophageal acid exposure appears to be more physiological in the context of the intra-abdominal pressure theory. It is well reported that BMI is related more strongly to body and subcutaneous fat than to visceral fat in both sexes.25–27 Oka et al25 reported a quadratic relationship between visceral fat and BMI in their male participants (n ⫽ 1432); the increase in visceral fat was greater at lower levels of BMI and leveled off at higher levels of BMI in a quadratic fashion. In a smaller cohort of 16 females and 9 males with a BMI greater than 35, Springer et al28 observed that above a certain BMI level (⬎35 to 40), in contrast to subcutaneous fat, visceral adipose tissue no longer correlated with BMI and, thus, may have reached a sex-dependent plateau. Furthermore, in this study population, the LES pressure was not different among the 3 obesity categories (BMI, 35– 40, 40 –50, and ⬎50). These studies lend further support to the nonlinear relationship between acid reflux and BMI similar to the results in our study. However, the exact nature of the relationship between BMI, visceral adipose tissue, and acid reflux needs further study. The clinically important implications of our findings are that the level of increase in esophageal acid exposure is more substantial when patients gain weight and are not yet in the obese category. In the obese group the esophageal acid exposure levels off and further weight gain does not mean more severe reflux. This finding coincides with the clinical observation of increasing patient complaints when they only gain small amounts of weight. More importantly, an intriguing speculation based on our findings relates to the potential reflux-related benefit of weight loss in the obese but more importantly in the overweight group of patients with suspected GERD-related
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extraesophageal symptoms. Although the results of prior studies on weight loss and GERD symptom improvements are mixed,29 –31 a recent meta-analysis concluded that dietary and lifestyle intervention improves GERD symptoms in obese patients with bariatric surgery; Roux-en-Y gastric bypass in particular yields the most favorable results.32 In addition, a recent trial reported the reduction and discontinuation of reflux medication with weight loss in patients with gastroesophageal reflux disease.33 In this trial 64% of the 100 severely obese patients who lost 59 kg in 45 weeks were able to discontinue their medications compared with only 18% of the 83 obese patients who lost 19 kg in 20 weeks. Although beyond the scope of the present study, future studies are needed to assess if esophageal acid exposure can be reduced in those who lose weight, especially from the overweight to normal BMI category because this represented the steep part of the curve in our study (Figure 1). Our report had some limitations. The study was from a tertiary care facility and the patient population comprised those who were either partially or nonresponsive to proton pump inhibitor therapy. Thus, the relationship between esophageal acid exposure and BMI may be different in other groups. However, it is not uncommon that patients with continued symptoms despite proton pump inhibitor therapy are referred to specialty centers such as those in this study. Further, the enrolled patient group in our study is in line with the current indications of pH testing for those unresponsive to an initial empiric trial of acid suppression.34,35 Given the cross-sectional design of our study, we could only compare BMI and pH among the subjects as a whole; an ideal study would be a prospective study in which patients could serve as their own control with pH parameters tested before and after either weight loss or weight gain. Such a study has been designed and is in the implementation phase by our group. Finally, the high prevalence of abnormal esophageal acid exposure in our group of 79% may be population specific, but does not change the primary outcome of the study regarding the association of reflux and obesity. In conclusion, we found that BMI is associated significantly and nonlinearly with esophageal acid exposure in patients with suspected GERD-related extraesophageal symptoms, and the net increase in acid exposure was most pronounced between a BMI range of 25 to 30. These findings may have important implications with respect to future studies for goals of weight loss in this group of patients. References 1. El-Serag H. Role of obesity in GORD-related disorders. Gut 2008; 57:281–284. 2. Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999 – 2002. JAMA 2004;291:2847–2850. 3. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999 –2004. JAMA 2006;295: 1549 –1555. 4. El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol 2007;5:17–26. 5. Murray L, Johnston B, Lane A, et al. Relationship between body mass and gastro-oesophageal reflux symptoms: the Bristol Helicobacter project. Int J Epidemiol 2003;32:645– 650. 6. Friedenberg FK, Xanthopoulos M, Foster GD, et al. The association between gastroesophageal reflux disease and obesity. Am J Gastroenterol 2008;103:2111–2122.
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7. El-Serag HB, Ergun GA, Pandolfino J, et al. Obesity increases oesophageal acid exposure. Gut 2007;56:749 –755. 8. Herbella FA, Sweet MP, Tedesco P, et al. Gastroesophageal reflux disease and obesity. Pathophysiology and implications for treatment. J Gastrointest Surg 2007;11:286 –290. 9. Pandolfino JE, El-Serag HB, Zhang Q, et al. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology 2006;130: 639 – 649. 10. Crowell MD, Bradley A, Hansel S, et al. Obesity is associated with increased 48-h esophageal acid exposure in patients with symptomatic gastroesophageal reflux. Am J Gastroenterol 2009;104: 553–559. 11. 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. 12. Corley DA. Obesity and the rising incidence of oesophageal and gastric adenocarcinoma: what is the link? Gut 2007;56:1493– 1494. 13. Corley DA, Kubo A, Levin TR, et al. Abdominal obesity and body mass index as risk factors for Barrett’s esophagus. Gastroenterology 2007;133:34 – 41; quiz, 311. 14. 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. 15. Wajed SA, Streets CG, Bremner CG, et al. Elevated body mass disrupts the barrier to gastroesophageal reflux. Arch Surg 2001; 136:1014 –1019. 16. de Vries DR, van Herwaarden MA, Smout AJ, et al. 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. 17. Moore JM, Vaezi MF. Extraesophageal manifestations of gastroesophageal reflux disease: real or imagined? Curr Opin Gastroenterol 2010;26:389 –394. 18. Center for Diseases Control. Anthropometry procedures manual. Atlanta, GA: Center for Diseases Control, 2000. 19. Johnson LF, Demeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974;62:325–332. 20. Ayazi S, Hagen JA, Chan LS, et al. Obesity and gastroesophageal reflux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of patients with reflux symptoms. J Gastrointest Surg 2009;13:1440 –1447. 21. El-Serag HB, Tran T, Richardson P, et al. Anthropometric correlates of intragastric pressure. Scand J Gastroenterol 2006;41: 887– 891. 22. de Vries D, van Herwaarden M, Smout A, et al. 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. 23. Wu JC, Mui LM, Cheung CM, et al. Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology 2007;132:883– 889.
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24. Tutuian R, Castell DO. Pressure details from the weight-challenged gastroesophageal junction: more than the usual suspects. Gastroenterology 2006;130:988 –989. 25. Oka R, Miura K, Sakurai M, et al. Comparison of waist circumference with body mass index for predicting abdominal adipose tissue. Diabetes Res Clin Pract 2009;83:100 –105. 26. Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham heart study. Circulation 2007;116:39 – 48. 27. Vega GL, Adams-Huet B, Peshock R, et al. Influence of body fat content and distribution on variation in metabolic risk. J Clin Endocrinol Metab 2006;91:4459 – 4466. 28. Springer F, Schwarz M, Machann J, et al. Quantitative assessment of visceral fat in morbidly obese patients by means of wide-bore MRI and its relation to lower esophageal sphincter pressure and signs of gastroesophageal reflux. Obes Surg 2010; 20:749 –756. 29. Jacobson BC, Somers SC, Fuchs CS, et al. Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med 2006;354:2340 –2348. 30. Fraser-Moodie CA, Norton B, Gornall C, et al. 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. 31. Kjellin A, Ramel S, Rössner S, et al. Gastroesophageal reflux in obese patients is not reduced by weight reduction. Scand J Gastroenterol 1996;31:1047–1051. 32. De Groot NL, Burgerhart JS, Van De Meeberg PC, et al. Systematic review: the effects of conservative and surgical treatment for obesity on gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2009;30:1091–1102. 33. Anderson J, Jhaveri M. Reductions in medications with substantial weight loss with behavioral intervention. Curr Clin Pharmacol 2010;5:232–238. 34. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association institute technical review on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:1392–1413. e1–5. 35. DeVault KR, Castell DO, American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005;100:190 – 200.
Reprint requests Address requests for reprints to: Michael F. Vaezi, MD, PhD, MSc (Epi), Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 1660 TVC, 1301 22nd Avenue South, Nashville, Tennessee 37232-5280. e-mail: michael.vaezi@vanderbilt. edu; fax: (615) 322-8525. Conflicts of interest The authors disclose no conflicts.