Elevated Body Mass Disrupts the Barrier to Gastroesophageal Reflux

PAPER Elevated Body Mass Disrupts the Barrier to Gastroesophageal Reflux

Shahjehan A. Wajed, FRCS; Christopher G. Streets, MRCS; Cedric G. Bremner, MD; Tom R. DeMeester, MD

Hypothesis: Obesity impairs the antireflux function of quantified using the DeMeester score, and body mass in- a structurally intact barrier. dex was calculated.

Design: Retrospective analysis of body mass index in Results: There was a strong correlation between body patients with normal esophageal manometric findings but mass index and severity of gastroesophageal reflux. Pa- with symptomatic and objectively confirmed gastro- tients who were overweight had significantly higher dis- esophageal reflux. tal esophageal acid exposure. No significant difference in manometric findings was demonstrated between pa- Setting: Specialist esophageal center. tients with normal weight and those who were overweight. Patients: Patients symptomatic and diagnostic for gastroesophageal reflux, referred between October 1, 1998, Conclusion: The barrier to gastroesophageal reflux is and June 30, 2000. Exclusion criteria were a defective rendered insufficient in patients who are overweight. barrier, motility disorders, or previous surgery.

Main Outcome Measures: Reflux was defined and Arch Surg. 2001;136:1014-1019

XPOSURE OF the distal esopha- fat deposition could interfere directly with gus to pathologic levels of re- the LES esophageal body complex, pre- fluxed gastric juices causes venting it from functioning effectively, or the clinical phenomenon it could change the intra-abdominal pres- of gastroesophageal reflux sure dynamics and render the barrier in- Edisease (GERD) and its sequelae. Reflux competent. We investigated the effect of is prevented by a mechanically compe- body mass index (BMI), a standard marker tent lower esophageal sphincter (LES), for obesity and body fat content, as a pos- which provides a barrier between the sible factor in the generation of GERD in gastric and esophageal compartments, these individuals. and a proper clearance activity of the esophageal body by appropriate LES RESULTS relaxation and peristaltic contractions on swallowing.1,2 Patient demographics, esophageal char- Despite the presence of a structur- acteristics, and disease variables are sum- ally normal LES and effective esophageal marized in the Table. The mean age of the clearance, excessive gastroesophageal re- entire cohort was 48.6 years (range, 19-85 flux and consequent esophageal damage years), with 41 men and 29 women. The may still occur. In these patients, other fac- primary presenting complaint was heart- tors must therefore exist that override the burn in 37 patients, with dysphagia and standard barrier to reflux. regurgitation representing another 15, to- A possible simple explanation for the taling 52 with typical symptoms. The re- existence of GERD in this subgroup of pa- mainder presented with atypical symp- tients might be a local impairment of the toms still attributable to GERD. Body mass normal barrier mechanism. This may be index was abnormally high in 55 pa- From the Department of caused by an external alteration in the ana- tients, and no patient within this cohort Surgery, University of Southern tomical and physiological characteristics qualified as being underweight. Of the 55 California, Los Angeles. of the LES or esophageal body. Excessive patients who were overweight, 37 were

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 PATIENTS AND METHODS illary level. Before each test, the pressure transducers were calibrated using a mercury-filled manometer, so that a change in pressure of 1 mm Hg corresponded to 0.5 mm PATIENTS on the recording paper. A belt pneumograph was positioned around the chest to record respiratory excursions. A retrospective analysis of data obtained between October A piezoelectric transducer was taped on the neck at the level 1, 1998, and June 30, 2000, was made of patients referred of the cricoid cartilage to record pharyngeal swallows. Ma- to the esophageal laboratory, Department of Surgery, Uni- nometry was performed in the fasted state, and all medi- versity of Southern California, Los Angeles, for assessment cations were discontinued 24 hours before the test. The sub- of clinically suspected GERD. Patients with symptoms or ject was placed in the supine position and encouraged to a history strongly suggestive of GERD and with objective relax. The recording catheter was passed through an anes- evidence of increased distal esophageal acid exposure on thetized nostril into the stomach and withdrawn at 1-cm 24-hour ambulatory pH monitoring were identified. Those increments every 20 seconds back into the esophagus. with any structural abnormality of the LES, incomplete The 3 manometric characteristics of the distal esoph- LES relaxation, or any abnormality of esophageal body ageal sphincter measured were sphincter pressure, abdomi- function were excluded. Patients with a history of esopha- nal length, and overall length. The end respiratory gastric gogastric surgery were also excluded. Patients were re- baseline pressure was used as a zero reference for pressure quested to discontinue any antacid medication 2 weeks be- measurement. A persistent rise in pressure exceeding 2 fore esophageal investigations. The remaining patients formed mm Hg above the gastric baseline marked the distal bor- the study cohort and consisted of those with an apparently der of the sphincter. The proximal border was marked by structurally normal LES and functional esophageal body, but the point at which sphincter pressure dropped to end with objective evidence of increased acid exposure to the inspiratory esophageal baseline pressure. Five measure- esophagus. ments of the distance between these 2 points were averaged and represented the overall length of the sphincter. ESOPHAGEAL STUDIES The point at which the end inspiratory pressure changed from a positive to a negative deflection represented the res- Esophageal Manometry piratory inversion point. Five measurements of the distance between the respiratory inversion point and the Manometry was performed using a single-catheter assem- distal border of the sphincter, that is, the length of the pres- bly consisting of 8 fluid-filled, perfused polyvinyl tubes sure wave that reflected positive excursions with respira- bonded together with five 0.8-mm lateral openings placed tion, were averaged and represented the abdominal length 5 cm apart and radially oriented 120° from each other. The of the sphincter. The amplitude of the sphincter was mea- recording catheter was continuously perfused with dis- sured as the difference (in millimeters of mercury) be- tilled water using a low-compliance, pneumohydraulic cap- tween the gastric baseline and the pressure at the respira- illary infusion pump (Arndorfer Medical Specialties, Green- tory inversion point during the middle of the respiratory dale, Wis) at a rate of 0.5 mL/min. Each tube was connected to an external pressure transducer positioned at the midax- Continued on next page

classified as grade 1 overweight, 16 were grade 2 over- this difference was significant, with PϽ.001 for the weight, and 2 were grade 3 overweight. DeMeester score (Figure 2) and PϽ.01 for the total per- Manometric evidence of a hiatal hernia was present centage duration the pH was less than 4. Nearly half the in 35 patients. No significant differences in patient char- patients with a normal BMI had abnormal acid expo- acteristics, however, were noted between those with and sure during the postprandial period, while only a small without evidence of a hiatal hernia, including BMI and the number of the overweight group had the same problem, esophageal and reflux severity variables presented in the with 22 (40%) of these having upright reflux disease. Table. Similarly, subgrouping patients on the basis of sex Further subdivision of the overweight patients into or presenting symptoms (typical vs atypical) did not re- their respective WHO classification groups reflected the veal any significant differences among any variables. trend of increasing distal esophageal acid exposure with A strong and significant correlation between BMI and increasing BMI, although these did not distinguish them- DeMeester score was observed. Using Spearman ␳ analy- selves from each other statistically. Of note, it appeared sis, a coefficient of 0.38, with PϽ.001, was derived that weight alone, as opposed to weight and height, was (Figure 1). A similar relationship was also noted be- the major discriminating factor between the 2 groups. Both tween BMI and the total percentage duration the pH was groups had a similar mean height but contrasted mark- less than 4 (coefficient 0.26, P=.03). edly in weight. Dichotomizing the cohort into normal and over- No significant differences with regard to patient weight subgroups based on BMI confirmed the major dif- details or manometric features were noted between the ference in the objective severity of esophageal acid expo- normal and overweight groups. Lower esophageal sure. For patients with a normal BMI, the mean DeMeester sphincter lengths and pressures were almost identical. score was 21.5, and the total percentage duration the pH However, the difference in manometric esophageal was less than 4 was 6.2%. This compared with a mean score lengths, with a mean shorter value of 1.2 cm in patients of 34.7 and a percentage duration of 9.2% for the patients who were overweight, approached significance in this who were overweight. Using a Mann-Whitney analysis, study (P=.06).

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 cycle. Five measurements of resting sphincter pressure were Mississauga, Ontario) was positioned to lie 5 cm proximal obtained and averaged to obviate the variation of pressures to the manometric upper border of the LES. Using a digi- at each orifice due to the radial asymmetry of the sphincter. tal data recording device (MK III; Medtronic, Shoreview, Normal values for the overall length of the sphincter, Minn), pH in the distal esophagus was monitored for 24 abdominal length of the sphincter, and resting sphincter hours, during which a test refluxogenic meal was given to pressure were defined as greater than 2 cm, greater than 1 induce postprandial reflux. To assess positional reflux, the cm, and 6 to 26 mm Hg, respectively, with values outside patients were asked to maintain a diary to record activ- these limits representing the 2.5th percentile of a normal ity. Calculation of a composite (DeMeester) score was population distribution.1 used to assess severity of the reflux disease,3,4 and the The presence of a “double hump” profile of the lower total duration that the esophageal pH was less than 4 esophageal high pressure zone signified manometric evi- was recorded and expressed as a percentage of total dence of a hiatal hernia, and measurements of the LES were ambulatory duration. made at the start of the most proximal hump, in these cases. Relaxation of the LES was determined by positioning 4 EVALUATION OF OBESITY radially placed channels at the level of the respiratory inversion point, and the activity at this level and the channel 5 cm Body mass index was calculated as weight in kilograms proximal to it (within the distal esophagus) was recorded in divided by the square of height in meters. Using the response to 5 separate swallows of 5-mL water boluses. Nor- World Health Organization (WHO) classification,5 a mal relaxation was recorded if the pressure in the LES fell to normal BMI was defined as a value between 18.5 and gastric baseline during the swallows. 24.9. Values of 25.0 to 29.9 were defined as grade 1 Esophageal body motility was investigated by plac- overweight, 30.0 to 39.9 as grade 2 overweight (obese), ing the 5 recording channels along the length of the esopha- and 40.0 or higher as grade 3 overweight (morbidly gus. The most proximal channel was located at a point 1 obese). cm distal to the lower border of the upper esophageal sphincter, and pressure activity was assessed in response to 10 STATISTICAL ANALYSIS separate swallows each of a 5-mL water bolus. Normal esophageal motility was recorded only if normal peristal- Data were reported as mean±SEM. Correlation between vari- sis in the total absence of simultaneous or interrupted waves ables was assessed using Spearman ␳ analysis. Nonpara- occurred, and if the pressure at each level was within nor- metric testing between 2 groups of variables was carried mal 95th percentile limits for that level. out using a Mann-Whitney analysis, and a Fisher exact test was used for comparison between 2 sets of distinct sub- Distal Esophageal Acid Exposure groups. All tests were 2-tailed, with significance defined as PϽ.05. Analysis was performed using standard commer- This was determined by 24-hour ambulatory pH monitor- cially available biomedical software (SPSS, version 10.0; SPSS ing. A 1-channel bipolar pH probe (Ingold; MUI Scientific, Inc, Chicago, Ill).

8,9 COMMENT lelithiasis, and malignancy. The etiology of its role in each of these conditions is complex and varied, but re- The key question in understanding the pathophysiol- sults in altered local and general anatomy or in changes ogy of GERD is what causes an overriding of the normal in physiological and metabolic body function. In es- valve mechanism. Structural defects in the LES or esoph- sence, the body is forced to deal with the storage of in- ageal body dysfunction predispose to disease evolution creased quantities of fat, resulting in the visceral depo- in most cases.6,7 In this study, we identified a cohort of sition of adipose tissue within the upper body. The intra- patients who shared the same manometric LES and esoph- abdominal compartment and regions around the thoracic ageal body characteristics as 97.5% of the normal, asymp- cage are favored locations, and this gives rise to the phe- tomatic general population, but whose distal esophagus nomenon of upper body obesity, which in itself com- was not protected from excessive gastric juice expo- prises a risk factor for disease.10 sure. Fifty-five (79%) of these patients had an elevated Barrier function could be modulated in several ways, BMI, and the increasing level of their obesity strongly cor- resulting from the consequences of obesity. Wide- related with the severity of the gastroesophageal reflux. spread deposition of adipose tissue within the mesen- This overweight subgroup of patients had a greater de- teries, omentum, and preperitoneal regions and viscera, gree of reflux, as measured by pH probe, than the small as well as around the gastroesophageal junction itself, may number with a normal BMI. Patients with a normal BMI interfere with the complex local anatomical and physi- in this study had a mild level of increased distal esoph- ological factors that contribute to valve competency, or ageal acid exposure, predominantly during the postpran- it may cause a global change in the intra-abdominal en- dial period. vironment. Obesity is now regarded as a worldwide disease of The presence of excess fat in and around the gas- epidemic proportions, which may induce ill health troesophageal junction could alter the anatomical struc- through several means. It is strongly associated with a ture and, hence, the geometry of the cardia, placing the wide spectrum of medical diseases, including diabetes sphincter at a mechanical disadvantage to counter gas dis- mellitus, cardiovascular and respiratory disorders, cho- tension forces attempting to pull it open. The acute angle

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Patient, Esophageal, and Reflux Variables* 90 Normal Overweight 80 Normal All Patients Weight Overweight 70 (N = 70) (n = 15) (n = 55) 60 Patient Details 50 Age, y 48.6 ± 1.8 49.5 ± 5.2 48.4 ± 1.8 Sex 40 Male 41 (59) 9 (60) 32 (58) DeMeester Score Female 29 (41) 6 (40) 23 (42) 30 Weight, kg 85.0 ± 2.1 68.5 ± 3.2 89.7 ± 2.2 20 Height, m 1.72 ± 0.01 1.72 ± 0.03 1.71 ± 0.01 2 Body mass index, kg/m 28.8 ± 0.7 22.9 ± 0.4 30.5 ± 0.7 10 Symptoms 15 20 25 30 35 40 45 50 55 60 Typical 52 (75) 10 (67) 42 (76) Body Mass Index, kg/m2 Atypical 18 (25) 5 (33) 13 (24) Figure 1. Scatterplot of body mass index against DeMeester score. Esophageal Characteristics Correlation coefficient, 0.38; significance, PϽ.001. LES overall length, cm 3.2 ± 0.1 3.0 ± 0.1 3.2 ± 0.01 LES abdominal length, cm 1.9 ± 0.1 1.8 ± 0.1 1.9 ± 0.01 LES resting pressure, mm Hg 15.4 ± 0.6 15.5 ± 0.8 15.4 ± 0.8 40 Esophageal length, cm 20.9 ± 0.3 21.9 ± 0.6 20.7 ± 0.3 Hiatal hernia 35 Absent 35 (50) 5 (33) 30 (55) Present 35 (50) 10 (67) 25 (45) 30 Reflux Disease DeMeester score† 31.9 ± 1.9 21.5 ± 1.8 34.7 ± 2.2 Percentage duration pH Ͻ4† 8.5 ± 0.5 6.2 ± 0.6 9.2 ± 0.6 25 Position DeMeester Score Upright 24 (34) 2 (13) 22 (40) 20 Supine 18 (26) 3 (20) 15 (27) Bipositional 15 (21) 3 (20) 12 (22) Postprandial 12 (17) 7 (47) 5 (9) 15 None 1 (1) 0 1 (1) n=15 n=55 Normal Overweight Body Mass Index, kg/m2 *Values are mean ± SEM. Figures in parentheses denote percentage for column. LES indicates lower esophageal sphincter. Some percentages do not Figure 2. Mean±SEM DeMeester scores for patients with normal weight and sum to 100 because of rounding. overweight. Significance, PϽ.001. †Significant difference between normal and overweight subgroups, PϽ.01, Mann-Whitney test. cally is not at fault in causing reflux in the patients who were overweight. It has been argued that a neural phe- of His, an important anatomical structure preventing gas- nomenon is primarily responsible for generating gastro- tric wall tension from pulling the LES apart,11,12 may be- esophageal reflux, through so-called transient LES re- come blunted, thus enabling moderate levels of gastric laxations.17 Therefore, by some unexplained mechanism, distension to more readily induce transient sphincter op- obesity invokes an increased frequency or duration of ening. Similarly, the potentiation effect on sphincter com- these events. There is no obvious evidence for this and petency derived from the diaphragmatic crural sling13 may no clear reason why progressive increases in BMI should be attenuated if this region is surrounded by cushions potentiate this effect. A direct, multifactorial mechani- of fatty tissue. cal process, interfering with the ability of the LES to pre- Obese individuals have a higher intra-abdominal rest- vent shortening or to offer adequate resistance to gastric ing pressure, and this relates to the sagittal abdominal pressure, is a more obvious explanation for the observa- diameter.14 Excess fat deposition in and around abdomi- tions in this study. nal viscera, in addition to elevating intra-abdominal pres- Observation of the association between obesity and sure, may interfere with and delay gastric emptying.15 This reflux disease, in general, has yielded conflicting con- promotes fundic distension, with corresponding sphinc- clusions among different studies; hence, the benefit of ter unfolding and length shortening, reducing its ability weight loss is also controversial. In a recent large, Swed- to function as an effective barrier.16 The restriction of free ish population interview-based study, Lagergren et al18 space within the peritoneal cavity is likely to result in re- concluded that the presence of gastroesophageal reflux duced pressure compliance within the abdominal com- symptoms occurred independently of BMI. However, this partment. Fluctuations in the intra-abdominal pres- group (with the addition of Lindgren)19 have previously sure, such as occurs with positional or postural change, linked the presence of gastroesophageal reflux as a risk coughing, or straining, are therefore exaggerated, with factor for esophageal adenocarcinoma, and Lagergren et sudden sharp rises in gastric pressure overcoming LES al20 have shown that this complication of GERD is, in fact, resistance. strongly associated with BMI. In a similar population- The finding of similar values for the LES character- based study, using a questionnaire among the residents istics in both groups suggests that the barrier intrinsi- of Olmstead County, Minnesota, BMI was indepen-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 dently associated with GERD.21 Studies of the massively 15. Maddox A, Horowitz M, Wishart J, Collins P. Gastric and oesophageal emptying obese22,23 and investigations of the effect of weight loss in obesity. Scand J Gastroenterol. 1989;24:593-598. 24,25 16. DeMeester TR, Ireland AP. Gastric pathology as an initiator and potentiator of therapy in symptomatic improvement have been con- gastroesophageal reflux disease. Dis Esophagus. 1997;10:1-8. tradictory in their conclusions. 17. Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroesophageal reflux in This study investigated patients with definitive symp- patients with reflux esophagitis. N Engl J Med. 1982;307:1547-1552. toms and proven disease and then specifically examined 18. Lagergren J, Bergstrom R, Nyren O. No relation between body mass and gastro- oesophageal reflux symptoms in a Swedish population based study. Gut. 2000; those in whom reflux would not normally be expected 47:26-29. to occur. This population will thus differ from more gen- 19. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesopha- eralized studies. Among these patients, those who have geal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999; a normal BMI have a mild form of disease and might 340:825-831. benefit therapeutically from simple conservative mea- 20. Lagergren J, Bergstrom R, Nyren O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann Intern Med. 1999;130: sures, including lifestyle changes. Patients who are over- 883-890. weight, however, have a more severe form of disease. 21. Locke, GR, Talley NJ, Fett SL. Risk factors associated with symptoms of gas- There may be some benefit achieved from simple weight troesophageal reflux. Am J Med. 1999;106:642-649. reduction, although compliance with this form of treat- 22. Lundell L, Ruth M, Sandberg N, Bove-Nielsen M. Does massive obesity pro- mote abnormal gastroesophageal reflux? Dig Dis Sci. 1995;40:1632-1635. ment is likely to vary considerably, depending on the in- 23. Fisher BL, Pennathur A, Mutnick JL, Little AG. Obesity correlates with gastro- dividual patient. There is also a potential role of surgical esophageal reflux. Dig Dis Sci. 1999;44:2290-2294. intervention. Because the barrier to reflux in these pa- 24. Kjellin A, Ramel S, Rossner S, Thor K. Gastroesophageal reflux in obese patients is rendered ineffective, augmentation of LES rest- tients is not reduced by weight reduction. Scand J Gastroenterol. 1996;31:1047- ing pressure and length could provide sufficient reserve 1051. 25. Fraser-Moodie CA, Norton B, Gornall C, Magnago S, Weale AR, Holmes GK. Weight to prevent the mechanistic overriding from taking place. loss has an independent beneficial effect on symptoms of gastro-oesophageal Simple endoscopic procedures or laparoscopic Nissen fun- reflux in patients who are overweight. Scand J Gastroenterol. 1999;34:337-340. doplication will prevent loss of length with gastric dis- 26. Mason RJ, DeMeester TR, Lund RJ, et al. Nissen fundoplication prevents short- tension26 and thus restore barrier competency. ening of the sphincter during gastric distention. Arch Surg. 1997;132:719-726.

Presented at the 72nd Annual Meeting of the Pacific Coast DISCUSSION Surgical Association, Banff, Canada, February 18, 2001. Carlos Pellegrini, MD, Seattle, Wash: As you know, primar- Corresponding author and reprints: Cedric G. Brem- ily because of the work done by the World Health Organiza- ner, MD, Department of Surgery, University of Southern Cali- tion, body mass index has emerged as the best proxy to mea- fornia, 1510 San Pablo St, Suite 514, Los Angeles, CA 90033 sure the effects of overweight on health. It has been clearly shown (e-mail: [email protected]). that several diseases, like hypertension, degenerative joint diseases, diabetes, and even small increases in BMI, significantly change health. The authors of this study examined the rela- REFERENCES tionship between the BMI and esophageal acid exposure in a group of 70 patients who had 24-hour pH monitoring demon- 1. Zaninotto G, DeMeester TR, Schwizer W, Johansson KE, Cheng SC. The lower stration of pathologic reflux and symptoms of abnormal gas- esophageal sphincter in health and disease. Am J Surg. 1988;155:104-111. troesophageal reflux. They found that in 55 of the 70 patients 2. Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esopha- who had BMIs greater than 25, and would therefore be con- geal volume clearance. Gastroenterology. 1988;94:73-80. sidered obese under the WHO classification, acid exposure was 3. Johnson LF, DeMeester TR. Twenty-four-hour pH monitoring of the distal esopha- greater than in the 15 patients who had a BMI in the normal gus: a quantitative measure of gastroesophageal reflux. Am J Gastroenterol. 1974; 62:325-332. range. They also found a direct correlation between BMI and 4. Jamieson JR, Stein HJ, DeMeester TR, et al. Ambulatory 24-h esophageal pH specific DeMeester score. Previous studies looking at obesity monitoring: normal values, optimal thresholds, specificity, sensitivity, and re- and the presence of abnormal gastroesophageal reflux have producibility. Am J Gastroenterol. 1992;87:1102-1111. yielded conflicting information. Some studies have shown that, 5. World Health Organization Expert Committee. Physical Status: The Use and In- indeed, there is a positive correlation, and some large studies terpretation of Anthropometry. Geneva, Switzerland: World Health Organiza- have failed to show that. What, then, is unique about the study tion; 1995. WHO Technical Report Series 854. you have heard today? 6. Stein HJ, Barlow AP, DeMeester TR, Hinder RA. Complications of gastroesopha- There are 2 aspects of this study that make it unique. First, geal reflux disease: role of the lower esophageal sphincter, esophageal acid and the authors have an objective demonstration of gastroesopha- acid/alkaline exposure, and duodenogastric reflux. Ann Surg. 1992;216:35-43. geal reflux. Many of the previous studies have been based sim- 7. Stein HJ, Eypasch EP, DeMeester TR, Smyrk TC. Circadian esophageal motor function in patients with gastroesophageal reflux disease. Surgery. 1990;108: ply on questionnaires. Secondly, the authors limited the study 769-778. to a group of patients who have a structurally competent LES, 8. Kopelman PG. Obesity as a medical problem. Nature. 2000;404:635-643. that is, people who would normally not be expected to be re- 9. Willett WC, Dietz WH, Colditz GA. Guidelines for healthy weight. N Engl J Med. fluxing. That is what I want to focus on. Limiting the study to 1999;341:427-434. a group of patients with the structurally competent LES elimi- 10. Folsom AR, Kaye SA, Sellers TA, et al. Body fat distribution and 5-year risk of nates a number of potential confounding factors and allows one death in older women. JAMA. 1993;269:483-487. to look at the effects of BMI on acid exposure. On the other 11. Pettersson GB, Bombeck CT, Nyhus LM. The lower esophageal sphincter: mecha- hand, what concerns me is that if one is trying to determine nism of opening and closure. Surgery. 1980;88:307-314. the effects of obesity on reflux, limiting the study to just pa- 12. Marchand P. The gastro-oesophageal “sphincter” and mechanism of regurgitation. Br J Surg. 1955;42:504-513. tients with a structurally normal sphincter eliminates essen- 13. Mittal RK, Rochester DF, McCallum RW. Electrical and mechanical activity in the tially all patients with very severe reflux and eliminates, in fact, human lower esophageal sphincter during diaphragmatic contraction. J Clin In- most patients with abnormal gastroesophageal reflux. Thus, the vest. 1988;81:1182-1189. overall impact of obesity on acid exposure may be missed al- 14. Sugarman H, Windsor A, Bessos M, Wolfe L. Intra-abdominal pressure, sagittal together. Is it possible, for example, that obesity, by increases abdominal diameter and obesity comorbidity. J Intern Med. 1997;241:71-79. in intragastric pressure as they suggested, leads to the devel-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 opment of hiatal hernia or shortening of the sphincter? None My other experience is that it is very difficult to get pa- of these patients would have been included in the study. There- tients to lose weight when there is poor control of their reflux. fore, it would be important for the authors to tell us what the What are your strategies for weight loss in patients with sig- overall relationship is in their database between BMI and acid nificant GERD? exposure in all patients, not just those with structurally in- Ronald W. Busuttil, MD, Los Angeles, Calif: Although competent sphincter. the sphincter was hindered with obesity, was there a higher in- The second question would be, since they postulated cidence of esophagitis, ulcers, or Barrett’s disease in these pa- that increases in intra-abdominal pressure may be the result tients vs the nonobese? Secondly, did the proton-pump block- of an increase in BMI, was the intragastric pressure in these ers have any kind of effect, or was it blunted in these obese patients increased? Intragastric pressure is a good way to patients compared with the normal patients? measure intra-abdominal pressure. Did they look at the tran- Dr Bremner: Dr Pellegrini, your first question was what sient LES relaxation in these patients?...increases in fre- is the relationship of BMI to acid exposure overall, and there quency or duration? was, in fact, no relationship in our study. You asked about Lastly, from the point of view of a practical surgeon, is relaxation of the LES, and relaxation was normal in both decreasing BMI and decreasing body weight really a cure for groups of patients. From a practical point of view, you asked gastroesophageal reflux? Have they had any experience mea- is decreasing the BMI effective in improving the LES? Studies suring acid exposure before and after losing significant previously suggest not, and we haven’t, in fact, had the oppor- amounts of weight? We have looked at symptoms and weight tunity to do that ourselves. This would make an excellent loss in a very small group of 6 patients who took the challenge study to assess whether obesity reduction restores barrier of losing a significant amount of weight and were surprised to competency. see that we did not see any decrease in symptoms or any de- Dr Finley, there was no difference in the relation of sex to crease in acid exposure, despite the loss of weight, suggesting reflux in our series. You asked a practical question: how could that, once a certain threshold is crossed in weight gain, in a we get these people to lose weight? Well, this is, as you know, certain individual, a certain damage occurs to the antireflux a tremendous problem today, and perhaps there will one day mechanism that cannot be repaired simply by losing weight. be an alternative to bariatric surgery, which is the way we are Richard J. Finley, MD, Vancouver, British Columbia: all pushing at the moment. There is a difference in distribution of fat between men and There was a question about esophagitis: was esophagitis women. Males tend to have a greater percentage of fat in their greater in the morbidly obese patients or the obese patients in peritoneal cavity than females, which may increase intra- our series? Our study was confined to manometric and pH stud- abdominal pressure. Did the authors notice a difference in re- ies alone, and we do not have the endoscopic details. All of these flux between the sexes? patients were off PPIs [proton-pump inhibitors] for the study.

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ARCHIVES OF INTERNAL MEDICINE Risk Factors for the Rising Rates of Primary Liver Cancer in the United States Hashem B. El-Serag, MD, MPH; Andrew C. Mason, MD Background: A recent increase in the incidence of hepatocellular carcinoma was reported in the United States. The cause of this witnessed rise remains unknown. Methods: We examined the temporal changes in both age-specific and age-standardized hospitalization rates of primary liver cancer associated with hepatitis C, hepatitis B, and alcoholic cirrhosis in the Department of Veterans Affairs Medical Cen- ter’s Patient Treatment File. Results: A total of 1605 patients were diagnosed with primary liver cancer between 1993 and 1998. The overall age-adjusted proportional hospitalization rate for primary liver cancer increased from 36.4 per 100000 (95% confidence interval [CI], 34.0-38.9) between 1993 and 1995 to 47.5 per 100000 (95% CI, 44.6-50.1) between 1996 and 1998. There was a 3-fold increase in the age-adjusted rates for primary liver cancer associated with hepatitis C virus, from 2.3 per 100000 (95% CI, 1.8-3.0) between 1993 and 1995 to 7.0 per 100000 (95% CI, 5.9-8.1) between 1996 and 1998. Concomitant with this rise, the age-specific rates for primary liver cancer associated with hepatitis C also shifted toward younger patients. During the same periods, the age-adjusted rates for primary liver cancer associated with either hepatitis B virus (2.2 vs 3.1 per 100000) or alcoholic cirrhosis (8.4 vs 9.1 per 100000) remained stable. The rates for primary liver cancer without risk factors also remained without a statistically significant change, from 17.5 (95% CI, 15.8-19.1) between 1993 and 1995 to 19.0 per 100000 (95% CI, 17.3-20.7) between 1996 and 1998. Conclusions: Hepatitis C virus infection accounts for most of the increase in the number of cases of primary liver cancer among US veterans. The rates of primary liver cancer associated with alcoholic cirrhosis and hepatitis B virus infection have remained stable. (2000;160:3227-3230) Reprints: Hashem B. El-Serag, MD, MPH, Houston VA Medical Center (152), 2002 Holcombe Blvd, Houston, TX 77030 (e-mail: [email protected]).

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