The effects of a weakly acidic meal on gastric buffering and postprandial gastro-oesophageal reflux

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1 Alimentary Pharmacology and Therapeutics The effects of a weakly acidic meal on gastric buffering and postprandial gastro-oesophageal reflux K. Ravi*, D. L. Francis*, J. A. See, D. M. Geno* & D. A. Katzka* *Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester MN, USA. Department of Nutrition, Mayo Clinic, Rochester MN, USA. Correspondence to: Dr D. A. Katzka, Division of Gastroenterology & Hepatology, Mayo Clinic, 2 First Street SW, Rochester, MN 5595, USA. katzka.david@mayo.edu Publication data Submitted 17 May 211 First decision 12 June 211 Resubmitted 16 June 211 Accepted 18 June 211 EV Pub Online 5 July 211 SUMMARY Background Exclusion of the meal during ambulatory ph monitoring presumes that a meal completely buffers gastric acid and reflux of acidic food content cannot be distinguished from gastric acid. However, the ability of a meal to completely buffer gastric acid remains unclear. Aim To determine the effect of a weakly acid meal on gastric buffering and oesophageal acid exposure. Methods Patients undergoing multichannel intraluminal impedance ph studies were given a standard weakly acidic meal (ph = 5.9). Gastric and oesophageal ph was measured during the meal and in 15 min intervals for 2 h postprandially. Results The study included 3 patients, with pathological acid reflux detected in 18 patients. Complete gastric buffering occurred in seven patients (23%) and was lost in all patients within 75 min of the meal. Oesophageal acid was detected in 33% of patients within 3 min of the meal and 81% of patients during the 2 h postprandial period. Postprandial oesophageal acid exposure was greater in patients with pathological acid reflux (9 2.7% vs % P =.5) with a trend towards more incomplete gastric acid buffering and significant differences when measuring weak acid reflux (ph 4 5). Acid reflux rarely occurred in the absence of gastric acid, with gastric acid present in 74 of 79 (94%) fifteen minute postprandial intervals with acid reflux. Conclusions The ability of a meal to buffer gastric acid is poor. Early postprandial oesophageal acid reflux occurs in a substantial proportion of patients. Addition of a weakly acidic or ph neutral meal to ambulatory ph monitoring may unmask early postprandial acid reflux and provide data on gastric acid buffering. Aliment Pharmacol Ther 211; 34: ª 211 Blackwell Publishing Ltd doi:1.1111/j x

2 Postprandial buffering and GERD INTRODUCTION Standard clinical practice with an ambulatory ph monitor is to exclude the meal period when measuring acid exposure in the oesophagus. This approach is largely based on several assumptions. First, most meals contain acidic foods such as tomato sauce, coffee or cola and reflux of these contents into the oesophagus, when measured by a ph catheter, cannot be distinguished from gastric hydrochloric acid. This practice is also based on the assumption that an ingested meal completely buffers gastric acid such that true reflux of gastric hydrochloric acid should not occur until after the stomach has emptied the principal if not entire portion of its food content. However, efficacy of the gastric buffering provided by a meal with respect to gastric ph remains largely unexplored. In fact, recent data have challenged the concept that postprandial stomach content is uniform in ph. 1, 2 For example, when ph probes are placed in the cardia and the gastric body simultaneously, they do not always mirror the same ph. More specifically, there may be times when the ph in the gastric cardia reflects an acidic environment while the ph in the gastric body is neutral. This in turn suggests some degree of acid pooling and separation in the gastric cardia. 2, 3 This is theorised to have important implications in acid gastro-oesophageal reflux where the first step towards reflux might be this sequestered proximal gastric pool of acid, termed the acid pocket, rather than continuous reflux from the more distal stomach. 4 6 If postprandial gastric acid buffering is not complete, unbuffered gastric acid may have important clinical implications. Free gastric hydrochloric acid may result in postprandial gastro-oesophageal reflux and may precipitate oesophageal injury. It may also be the site of acid that primes and or fills the proximal acid pocket. Consequently, it is important to gain a better understanding of the amount of free gastric hydrochloric acid that exists after a meal and determine the ability for pure gastric hydrochloric acid to occur early in the postprandial period. METHODS The study was approved by the Mayo Foundation Institutional Review Board. All adult patients between 18 and 65 years of age referred to the motility testing laboratory at the Mayo Clinic Rochester for combined multichannel intraluminal impedance and ph monitoring studies (MII-pH) between June of 21 and April of 211 were eligible for study inclusion. Study subjects were prospectively recruited by a single investigator (DMG). All study subjects had acid suppressive medical therapy discontinued at least 7 days prior to undergoing MII-pH testing. All patients underwent MII-pH testing using a dual channel MII-pH catheter with impedance data gathered from electrodes located 3 cm, 5 cm, 7 cm, 9 cm, 15 and 17 cm proximal to the lower oesophageal sphincter (LOS) as well as two ph electrodes located 1 cm below and 5 cm above the proximal LOS (Sandhill Scientific, Highland Ranch, CO, US). After an overnight fast, patients reported to the General Clinical Research Center for placement of the catheter with the electrodes positioned as described above. The patients were then given a standard meal consisting of hamburger, potatoes, ice cream and milk (1126 calories, 53 g fat, 46 g protein, 89 g carbohydrates, ph = 5.9) under direct supervision to ensure completion of the meal within 3 min. Gastric and oesophageal ph was monitored during the meal and in 15 min intervals for up to 12 min postprandially. Thereafter standard practice and data analysis was completed for the 24 h study period. Data are reported as mean standard error of the mean unless otherwise indicated. Gastric and oesophageal acid exposure was assessed in the entire patient population as well as in those with pathological acid reflux and normal 24 h ph studies independently. Group comparisons of binomial data were performed using Fisher s exact test while student s t-test was used for continuous data. Correlation of gastric and oesophageal acid exposure was assessed using Pearson s correlation coefficient. RESULTS Demographics and clinical features A total of 5 patients undergoing clinically indicated MII-pH studies were identified for the 11 month study period. After excluding patients who either did not have gastric ph monitoring, discontinued the study due to probe intolerance, consumed a nonstandard meal immediately before or after ingesting the standard ph neutral meal, had inadequate studies because of probe dysfunction, and those in whom the time of standard meal ingestion was not recorded, a total of 3 patients meeting eligibility criteria were included. Pathological acid reflux was identified in 18 of the 3 patients (6%), with similar demographical and clinical characteristics compared with those with normal ph studies (Table 1). Prandial gastric acid buffering The ability of the meal to buffer gastric acid during the meal period was determined. Patients with pathological Aliment Pharmacol Ther 211; 34: ª 211 Blackwell Publishing Ltd

3 K. Ravi et al. Pathological acid reflux Normal ph study Number of patients Females 11 (61%) 8 (67%) 1. Age (years) Body mass index (kg m 2 ) Presence of hiatal hernia 7 (%) 8 (%) 1. * Categorical data assessed using Fisher s exact test with student s t-test used for continuous data. P value* Table 1 Demographics and clinical features oesophageal acid reflux maintained ph >4 for % (Range = %). Patients with normal 24 h oesophageal acid exposure, maintained a ph >4 of % (Range = 99.9%) during the meal period. These differences were not significant (P =.9). Postprandial gastric acid buffering Gastric and oesophageal ph were measured for 6 min after ingestion of the standard meal in all patients and for 12 min in 21 of the 3 patients. Postprandially gastric acid buffering was incomplete, with absence of gastric acid observed in only 7 of 3 (23%) patients within the first 15 min of the meal. The appearance of an acidic ph increased steadily over the next 6 min until 6 75 min postprandially, when all subjects registered an acidic ph in the gastric probe (Figure 1). Among patients where complete buffering was achieved early in the postprandial period, the effect was transient, with only three patients displaying complete gastric acid buffering by 6 min (Figure 1). Gastric acid exposure time was substantial throughout the postprandial period with a gastric ph <4 for 53% of the time between 15 and 3 min, 75% of the time between 45 and 6 min and 95% of the time from 15 to 12 min postprandially. While postprandial gastric acid buffering was poor overall, it appeared to be more transient and incomplete in patients with pathological acid reflux compared with those with normal ph studies, although these differences did not reach statistical significance (Figure 2). Postprandial oesophageal acid exposure Postprandial oesophageal acid reflux was not an uncommon event in this patient population. Overall, oesophageal acid reflux occurred in 2 of 3 (67%) patients in the first 6 min postprandially and 17 of 21 (81%) patients in the 12 min following the standard meal % Subjects Time postprandial (min) Figure 1 Proportion of subjects with complete gastric acid buffering. 57 Aliment Pharmacol Ther 211; 34: ª 211 Blackwell Publishing Ltd

4 Postprandial buffering and GERD 1 9 % Time ph < Esophageal acid exposure time (abnormal ph study) Esophageal acid exposure time (normal ph study) Esophageal weak acid exposure time (abnormal ph study) Esophageal weak acid exposure time (normal ph study) Gastric acid exposure time (abnormal ph study) Gastric acid exposure time (normal ph study) Meal Time postprandial (min) Figure 2 Postprandial acid and weak acid exposure time. Early postprandial oesophageal acid reflux occurred in a substantial proportion of patients, seen in 1 of 3 (33%) patients within the first 3 min following ingestion of the meal. Oesophageal acid reflux episodes were not trivial, with substantial oesophageal acid exposure time seen. Overall, acid was present in the oesophagus for 3.2% ( 22.8%) of the time in the first 6 min and for 6.2% ( 32.5%) in the first 12 min after the standard meal. Correlation of postprandial and 24 h oesophageal acid exposure Postprandial oesophageal acid and gastric acid exposure time appeared to be more prominent in patients with pathological acid reflux, defined by an oesophageal ph <4 for greater than 4.2% of the 24 h study period (Figure 2). Patients with pathological acid reflux had an oesophageal ph <4 for 9 2.7% of the 12 min following the standard meal compared with 1.7.8% for patients with normal 24 h ph studies (P =.5). This difference was most pronounced later in the postprandial period, with an oesophageal acid exposure time of % vs..2.1% from 6 to 9 min following the meal in patients with abnormal and normal 24 h ph studies, respectively, (P =.2). Among those patients with pathological acid reflux, seven patients were primarily upright refluxers. Overall, upright refluxers had greater oesophageal acid exposure time ( vs , P =.47) than supine refluxers, despite having similar gastric acid exposure time ( vs , P =.4). When plotting the changes in postprandial oesophageal weak acid exposure (ph between 4 and 5, Figure 2), patients with overall increased oesophageal acid exposure tended to have higher levels of oesophageal weakly acid exposure when compared with those with physiological acid exposure (Figure 2). Specifically, during the 2 h postprandial time period, patients with abnormal oesophageal acid exposure had 11.7% vs. 2.7% weak acid exposure (P =.3). There were also significant differences between these patient groups when calculating weakly acid exposure at time periods 6 12 min (P =.5) and 6 9 min (P =.2). To determine if these increased levels of acid exposure were a function of increased reflux episodes, the total number of postprandial episodes (both acid and non-acid) was determined (Table 2). As can be seen, the greatest number of reflux episodes occurred within the first 3 min of the meal and then decreased and remained generally stable. This was despite a progressive increase in postprandial oesophageal acid exposure. Correlation of postprandial gastric acid and oesophageal acid exposure Postprandial oesophageal acid exposure occurred almost exclusively in the presence of unbuffered gastric acid. Oesophageal and gastric acid exposure was assessed in a total of 217 fifteen minute postprandial intervals in the 3 patient cohort. Oesophageal acid reflux was detected in a total of 79 intervals with unbuffered gastric acid Aliment Pharmacol Ther 211; 34: ª 211 Blackwell Publishing Ltd

5 K. Ravi et al. Interval (min) Pathological acid reflux Normal ph study P value Acid reflux episodes ( 2).2.1 ( 1) ( 3).3.2( 2) ( 3).4.2 ( 2) ( 2).2.2 ( 2) ( 2).3.1( 1) ( 2).2.2 ( 1) ( 2).4.2 ( 2) ( 2).4.2 ( 1).6 Non Acid Reflux Episodes ( 6) ( 3) ( 5) ( 2) ( 4).7.3 ( 3) ( 3).2.2 ( 2) ( 2).3.1 ( 1) ( 3).8.4 ( 3) ( 2).3.2 ( 2) ( 4).5.2 ( 1).8 * Values expressed as mean SEM (range) Table 2 Postprandial reflux episodes* Table 3 Number of postprandial intervals with oesophageal and gastric acid 15 min Intervals with gastric acid present 15 min Intervals with no gastric acid present 15 min Intervals with oesophageal acid present min Intervals with no oesophageal acid present present during the same interval in 74 of 79 (94%) episodes (Table 3). Early postprandial oesophageal acid reflux followed a similar pattern, with unbuffered gastric acid present in 13 of 14 (93%) and 31of 35 (89%) of intervals with oesophageal acid detected within 3 and 6 min of the standard meal, respectively. However, the correlation between oesophageal and gastric acid exposure time was poor (Figure 3). The Pearson correlation coefficient for these two factors in the first 6 and 12 min after the standard meal were r =.1 and r =.3, respectively. The correlation between postprandial oesophageal and gastric acid exposure time was negative in patients with abnormal 24 h ph, suggesting that patients with more complete buffering of gastric acid within the distal stomach were more likely to have prolonged oesophageal acid exposure (Figure 4). DISCUSSION The pathophysiology of gastro-oesophageal reflux is complex, with multiple aetiological factors implicated. While abnormalities in peristalsis, body position and epithelial defence factors have been considered compounding factors, lower oesophageal sphincter function is believed to play the most important role. In particular, the frequency of transient lower oesophageal sphincter relaxations (TLOSRs) and the presence of hiatal hernias have garnered a great deal of attention. However, the LOS pressure is not always a precise determinant of acid reflux and not all patients with a hiatal hernia have GERD. Furthermore, while TLOSRs are the major mechanism for acid reflux, studies have shown that they occur at a similar frequency in GERD and healthy volunteers. This was corroborated in our study demonstrating a decrease in total reflux episodes as the postprandial period progresses despite an increase in oesophageal acid exposure. Instead, the primary difference in oesophageal acid exposure 572 Aliment Pharmacol Ther 211; 34: ª 211 Blackwell Publishing Ltd

6 Postprandial buffering and GERD Proportion of time with esophageal acid.2.15 to 6 Min postprandial Proportion of time with esophageal acid to 12 Min postprandial.1.15 R =.1.1 R = Proportion of time with gastric acid Proportion of time with gastric acid Figure 3 Correlation of postprandial oesophageal and gastric acid exposure. to 6 min postprandial.25 Normal ph study.25 Pathologic acid reflux Proportion of time with esophageal acid to 12 min postprandial Proportion of time with gastric acid Figure 4 Oesophageal and gastric acid exposure correlation for subjects with normal and abnormal 24 h ph studies. appears to relate to a greater likelihood for TLOSRs to be associated with acid reflux in patients with GERD. 7 9 Consequently, additional factors need to be considered in the pathophysiology of GERD. Historically, variations in gastric function are considered to play little to no role in GERD. However, recent studies have challenged this concept. Several studies have now suggested that gastric acid secretion, particularly in the postprandial period, may be increased in patients with GERD. 1, 11 Similarly, it has been suggested that gastric motility may be altered in patients with GERD. 12, 13 The traditional concept of a uniform distribution of food and secretions in the postprandial stomach with a resultant complete buffering of gastric acid has also come under greater scrutiny in recent years. Discrepancies in the T2 weighted images of the postprandial stomach with echo planar MRI based on polysaccharide concentrations have suggested that postprandial mixing of gastric contents is poor. 1 Aliment Pharmacol Ther 211; 34: ª 211 Blackwell Publishing Ltd

7 K. Ravi et al. Furthering these observations, this study demonstrates that meal and after meal buffering of gastric hydrochloric acid is not complete in most patients. In this study cohort, the standard meal failed to provide complete gastric acid buffering in greater than half of subjects during the meal and in three quarters of subjects postprandially, reflected by a gastric ph measuring less than 4 within the first 15 min of completing the meal. Even among those patients with effective prandial buffering of gastric acid, the effect was transient, with buffering capacity of the meal lost in all patients within the first 75 postprandial minutes. Perhaps most striking, this poor buffering capacity was seen despite the large volume and high fat content of the provided meal. Simonian et al. previously demonstrated that a high volume fatty meal provided the greatest buffering effect on gastric acid. 2 Consequently, gastric acid buffering may be even more limited in normal circumstances when compared with that seen following the standard meal in this study. The frequency of postprandial acid reflux mirrored the presence of unbuffered gastric acid. Contrary to conventional thought, early postprandial acid reflux was a common occurrence in this study, with an oesophageal ph <4 seen in two-thirds of patients within the first hour and even seen within the first 3 min of the meal in one-third of the cohort. Oesophageal acid exposure time was significantly greater in patients with pathological acid reflux (9 2.7% vs % for 12 min following the standard meal, P =.5) and appeared to correlate with a trend towards more incomplete gastric acid buffering in these patients compared with those with normal ph studies. Furthermore, when measuring the degree of postprandial weak acid exposure (ph to 5) to the oesophagus, there were significant differences when comparing pathological to nonpathological acid refluxers. These findings suggest a direct role for unbuffered gastric acid precipitating postprandial oesophageal acid reflux and perhaps as an important determinant in GERD in total. Whether these differences would be more evident in patients with higher levels of overall oesophageal acid exposure remains to be determined. However, despite the apparent causative association between poor gastric acid buffering and postprandial acid reflux, the correlation between gastric and oesophageal acid exposure time was poor; demonstrated by a Pearson correlation coefficient of r =.3 for the 12 min postprandial period. This raises the obvious question of whether the measured oesophageal acid in this study reflects acidic food content rather than unbuffered gastric acid. The standard meal provided in this study not only had an overall ph of 5.9, but each individual component of the meal had a ph of 5.5 or greater and cannot explain an oesophageal ph <4. The precise mechanism by which the presence of poorly buffered postprandial gastric acid contributes to oesophageal acid exposure will be important to determine in future studies, although it did not appear to be related to differences in gastric acid buffering during the meal or the number of postprandial reflux episodes as demonstrated by our data. Several study limitations need to be acknowledged. First, the sample size is small and our results may be limited by type 2 error. Secondly, ph is only measured in the gastric body and 5 cm above the lower oesophageal body. The additional measurement of ph in the proximal stomach may offer more information both on the true nature of postprandial gastric acid buffering and the relationship between unbuffered distal gastric acid and the acid pocket. In addition, other factors that could influence postprandial gastric acid buffering, particularly gastric transit, are not assessed and may provide greater insight into variations in postprandial gastric acid buffering. Third, our ph measurements do not reflect gastric volume. As a result, we cannot determine if the gastric acid detected represents a relative large pool of fluid or a thin film adherent to mucosa and or coating the gastric food content. A significant number of recruited patients were excluded from the study. However, the primary reason for exclusion was an MII-pH study without placement of a gastric ph probe. This was seen exclusively early in the recruitment period and was remedied following discussion with study personnel and therefore likely did not present a significant source of bias. The standard meal was weakly acidic with a ph of 5.9, potentially limiting its buffering capacity. However, previous studies investigating the buffering capacity of meals and the gastric cardia acid pocket have utilised meals with similar compositions, with reported lower meal ph ranging from 4.24 to , 5, 6, In addition, the high fat content of the meal served to maximise its buffering capacity. Despite these limitations, this study demonstrates that the ability of a high volume, high fat ph neutral meal to completely buffer gastric acid is poor. In addition, early postprandial acid reflux occurs in a substantial proportion of patients and cannot be explained by acidic food content alone. The mechanism by which this unbuffered acid contributes to oesophageal acid exposure is unclear. Finally, we suggest that the addition of a ph neutral meal during standard ambulatory ph monitoring should be considered as it may unmask early postprandial reflux 574 Aliment Pharmacol Ther 211; 34: ª 211 Blackwell Publishing Ltd

8 Postprandial buffering and GERD of gastric acid and may provide data on true gastric acid buffering. ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Marciani L, Gowland PA, Spiller RC, et al. Effect of meal viscosity and nutrients on satiety, intragastric dilution, and emptying assessed by MRI. Am J Physiol Gastrointest Liver Physiol 21; 28: G Simonian HP, Vo L, Doma S, et al. Regional postprandial differences in ph within the stomach and gastroesophageal junction. Dig Dis Sci 25; 5: Fletcher J, Wirz A, Young J, et al. Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal. Gastroenterology 21; 121: Clarke AT, Wirz AA, Seenan JP, et al. Paradox of gastric cardia: it becomes more acidic following meals while the rest of stomach becomes less acidic. Gut 29; 58: Beaumont H, Bennink RJ, de Jong J, et al. The position of the acid pocket as a major risk factor for acid reflux in healthy subjects and patients with GORD. Gut 21; 59: Pandolfino JE, Zhang Q, Ghosh SK. Acidity surrounding the squamocolumnar junction in GERD patients: acid pocket versus acid film. Am J Gastroenterol 27; 12: Trudgill NJ, Riley SA. Transient lower esophageal sphincter relaxations are no more frequent in patients with gastroesophageal reflux disease than in asymptomatic volunteers. Am J Gastroenterol 21; 96: Sifrim D, Holloway R. Transient lower esophageal relaxations: how many or how harmful? Am J Gastroenterol 21; 96: Iwakiri K, Hayashi Y, Kotoyori M, et al. Transient lower esophageal sphincter relaxations (TLESRs) are the major mechanism of gastroesophageal reflux but are not the cause of reflux disease. Dig Dis Sci 25; 5: Gardner JD, Sloan S, Miner PB Jr, et al. Meal-stimulated gastric acid secretion and integrated gastric acidity in gastrooesophageal reflux disease. Aliment Parmacol Ther 23; 17: Blonski WC, Shih GL, Brensinger CM, et al. Analysis of the acidity index and integrated intragastric acidity in 645 patients presenting with gastroesophageal reflux disease symptoms. Scand J Gastroenterol 26; 41: Penagini R, Hebbard G, Horowitz M, et al. Motor function of the proximal stomach and visceral perception in gastro-oesophageal reflux disease. Gut 1998; 42: Gonlachanvit S, Maurer AH, Fisher RS, et al. Regional gastric emptying abnormalities in functional dyspepsia and gastro-oesophageal reflux disease. Neurogastroenterol Motil 26; 18: Vo L, Simonian HP, Doma S, et al. The effect of rabeprazole on regional gastric acidity and the postprandial cardia gastro-oesophageal junction acid layer in normal subjects: a randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 25; 21: Hila A, Bouali H, Xue S. Postprandial stomach contents have multiple layers. J Clin Gastroenterol 26; 4: Bredenoord AJ, Weusten BL, Timmer R, et al. Gastro-oesophageal reflux of liquids and gas during transient lower oesophageal sphincter relaxations. Neurogastroenterol Motil 26; 18: Aliment Pharmacol Ther 211; 34: ª 211 Blackwell Publishing Ltd