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Keywords:

  • abdominal circumference;
  • body mass index;
  • pH-impedance;
  • proximal extent

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgment
  9. References

Background  Increased body weight is associated with higher intragastric pressure. Proximal extent of reflux is a determinant of symptoms in patients with gastro-esophageal reflux disease (GERD). We aimed to investigate the association between body mass index (BMI) and abdominal circumference on the incidence and proximal extent of reflux.

Methods  A total of 95 patients [37 men, age 51(16–82) years] with typical and/or atypical GERD symptoms underwent 24 h impedance-pH monitoring. Forty-nine patients were studied ‘off’ and 46 ‘on’ proton pump inhibitors (PPI) treatment. Reflux was classified as acid (pH < 4) or weakly acidic (pH 4–7). Proximal extent was defined as the number of reflux events reaching ≥15 cm above the lower esophageal sphincter. Body mass index and abdominal circumference (cm) were assessed.

Key Results  In patients ‘off’ PPI, there was a correlation between BMI and esophageal acid exposure (ρ = 0.53, < 0.001), volume exposure (ρ = 0.48, < 0.001), total number of reflux events (ρ = 0.47, < 0.001) and number of acid reflux events (ρ = 0.49, < 0.001). In patients ‘on’ PPI there was a correlation between BMI and esophageal acid exposure (ρ = 0.32, = 0.03), volume exposure (ρ = 0.46, < 0.01) and total number of reflux events (ρ = 0.33, = 0.03). Similar correlations were found between abdominal circumference and reflux. A correlation between BMI and proximal extent of reflux was present in patients ‘off’ PPI (ρ = 0.32, = 0.03). In patients ‘on’ PPI, we found a correlation between abdominal circumference and proximal extent (ρ = 0.31, = 0.03).

Conclusions & Inferences  Body mass index and abdominal circumference may contribute to GER and its proximal extent, in patients ‘on and ‘off’ PPI. Further studies investigating the role of weight reduction in the control of GERD symptoms are warranted.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgment
  9. References

Gastro-esophageal reflux disease (GERD) is a prevalent condition which is affecting up to 20% of the Western population.1 Gastro-esophageal reflux disease can present itself through a variety of both typical (heartburn/regurgitation) and atypical (chest pain, cough, wheezing,…) symptoms. Over the last decade, the prevalence of GERD has significantly increased. The reason for this steady increase remains unknown, but increasing body weight has been implicated as a contributing factor.2,3 An increase in body weight may lead to an increase in intragastric pressure, which in turn might provide a driving force for reflux. An increase in one unit of body mass index (BMI) has been associated with a 10% increase in intragastric pressure.4 The relationship between BMI and intragastric pressure is likely to be due to the presence of abdominal fat which exerts mechanical pressure on the stomach. Hence, abdominal circumference might be a relevant factor in determining the relationship between increasing body weight, intragastric pressure and the prevalence of reflux.

Previous studies have shown that an increase in BMI is associated with an increased prevalence of acid reflux, identified by 24 h esophageal pH monitoring.5 Although acid reflux is important, non-acid reflux events may also occur in conditions during which the gastric content is neutralized, in particular during the postprandial period or in patients treated with proton pump inhibitors (PPI). Impedance recordings allow detection of all types of reflux independent of the pH. In addition to an increased sensitivity of reflux detection, impedance monitoring allows to analyze the characteristics of the refluxate including composition (liquid/mixed or gas) and proximal extent of reflux.6 Using impedance monitoring it has been demonstrated that a high proximal extent of reflux is associated with an increased likelihood of symptom perception.7–9 The factors that determine the proximal extent of reflux are not fully elucidated. Esophageal motility, volume and viscosity of the refluxate have been proposed.10–12 The role of intragastric pressure as a determinant of proximal extent remains unknown.

The aim of this study was to evaluate the relationship between BMI or abdominal circumference and the prevalence and proximal extent of reflux (acid and non-acid) both in patients ‘on’ and ‘off’ PPI treatment.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgment
  9. References

Patients

A total of 95 patients [37 men, mean age 51(16–82) years] with GERD symptoms, referred from the university hospital outpatient clinic, were studied prospectively using 24 h esophageal impedance-pH monitoring. Forty-eight patients presented exclusively with typical GERD symptoms (heartburn and/or regurgitation), 41 patients with exclusively atypical symptoms (chest pain, cough, wheezing, and ENT symptoms) and six patients with both. Of the 95 patients included in the study, 46 were ‘on’ PPI (omeprazole 2 × 20 mg or equivalent) [22 men, mean age 52 (24–74), 21 patients with exclusively atypical GERD symptoms] whereas the remaining 49 were ‘off’ PPI [17 men, mean age 49 (16–82), 20 with exclusively atypical GERD symptoms]. Upper endoscopy data of the last 12 months were available in 35/95 patients of which 12 showed erosive esophagitis grade A, two grade B/C and two Barrett’s esophagus. Weight, height, and abdominal circumference were assessed on the study day. The BMI was calculated and considered increased if greater than 25.

24 h impedance-pH monitoring

Esophageal impedance-pH was recorded with a 2.1 mm diameter catheter that comprised six electrode pairs to measure intraluminal impedance and two antimony pH sensors (Sandhill Scientific, Inc., Highlands Ranch, CO, USA). The impedance-pH catheter was connected to an ambulatory recorder (Sleuth, Sandhill Scientific, Inc., Highlands Ranch, CO, USA). The impedance amplifier delivered ultra-low current in a range of 1–2 kHz with resulting current flow variations in response to intraluminal impedance changes. The impedance and pH signals were digitized at 50 Hz and stored in the data logger. Before the start of the recording, the pH electrodes were calibrated using pH 4.0 and 7.0 buffer solutions.

Study protocol

The study was performed as an outpatient procedure after an overnight fast. The catheter was passed transnasally. Esophageal pH was measured at 5 cm and impedance at 3, 5, 7, 9, 15, and 17 cm proximal to the lower esophageal sphincter (LES). The patients were encouraged to maintain normal activities, sleep schedule, and eat their usual meals at their normal times. They were asked to remain upright during the day and lie down only at their usual bedtime. Event markers on the data logger recorded meal times and posture changes. Between meals, patients abstained from snacks, beverages with a pH < 5, and were asked to avoid lozenges and gum chewing. Before the study, patients were instructed to keep a careful diary and trained to use a dedicated event marker in the data logger to record symptom episodes.

Data analysis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgment
  9. References

The impedance recording was analyzed using criteria described in a consensus report on detection and definitions of acid, non-acid, and gas reflux.6 Gastroesophageal reflux was defined as a sequential orally progressing drop in impedance to less than 50% of the baseline values starting distally and propagating retrograde to at least the next more proximal measuring segment. According to the corresponding pH change, impedance-detected reflux was classified as acid if pH fell below 4 for at least 4 s or, if pH was already below 4, as a decrease of at least 1 pH unit sustained for more than 4 s Weakly acidic reflux was defined as a pH drop of at least 1 pH unit sustained for more than 4 s with the basal pH remaining between 7 and 4.

The proximal extent of each reflux event was evaluated from the impedance tracings and the proximal extent in each patient was defined as the number of reflux episodes reaching ≥15 cm above the LES. For each patient, the total number of reflux events (acid and weakly acidic), the proximal extent of reflux and the exposure of the esophageal body to acid (% of time with esophageal pH < 4) and volume were calculated. Total volume exposure/24 h was obtained from the impedance tracing by adding the volume exposures during reflux measured at five above LES.13 The number of reflux events and the volume exposure were regarded as increased if these values were above the 95th percentile of normal data obtained in healthy subjects ‘off’ and ‘on’ PPI therapy.13

Symptom association analysis

A symptom was considered ‘induced’ by reflux if it occurred in the 2 min period after the start of the reflux event. In each patient the symptom association probability (SAP) was calculated as previously described and was considered significant if >95%.14

Statistical analysis

Statistical analysis was performed using GraphPad software (Prism; GraphPad Software, Inc., San Diego, CA, USA). Data are presented as median (25–75th percentile), unless otherwise stated. Correlations between GER and BMI/abdomninal circumerence were calculated using Spearman’s rho rank correlation coefficient (ρ). Fisher’s exact test was used to calculate SAP. Comparison between ‘on’ and ‘off’ PPI patients were performed using a non-parametric Mann–Whitney U-test. Statistical significance was accepted if < 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgment
  9. References

The median BMI in our study population was 25.3 (22.2–27.1) of which 45 patients (47%) had an increased BMI. The mean abdominal circumference was 94.5[range (87–103) cm]. There was a strong correlation between BMI and abdominal circumference (ρ = 0.79, < 0.0001) (Fig. 1). Age and sex were unrelated to BMI and abdominal circumference (data not shown). Body mass index and abdominal circumference were similar in the patients studied ‘on’ and ‘off’ PPI (Table 1). Twenty-five patients had an increased esophageal acid exposure of which seven were patients ‘on’ PPI. Esophageal acid exposure and the number of acid reflux events were significantly higher in patients ‘off’ PPI vs those on PPI whereas the number of weakly acidic reflux events was significantly lower in those studied ‘off’vs those ‘on’ PPI patients. Volume exposure, total number of reflux events, and the proximal extent of reflux were similar in both groups (Table 1). Due to these significant differences in reflux characteristics, ‘off’ and ‘on’ PPI patients were analyzed separately.

image

Figure 1.  Correlation between the body mass index (BMI) and abdominal circumference (cm). There was a strong positive correlation between BMI and abdominal circumference in the patients included in the study (ρ = 0.79, P < 0.0001).

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Table 1.   Demographic and reflux characteristics of the patient population studies ‘off’ and ‘on’ proton pump inhibitor (PPI). Results are expressed as median (25–75th percentile)
 ‘off’ PPI‘on’ PPI
  1. BMI, body mass index.

  2. *Significant difference between patients ‘on’ and ‘off’ PPI.

BMI24.2 (20.4–27.2)25.4 (22.7–27.2)
Abdominal circumference (cm)94 (83.8–103.3)94.5 (89–100.8)
Acid exposure (%)3.2 (1.2–5.9)0.3 (0–1.6) *
Volume exposure (%)1.6 (0.6–2.1)0 (0–0.3)
Total nr of reflux events40 (31–62)37.5 (26.3–66.8)
No. of acid reflux events27 (12–37)5 (1–20) *
No. of non-acid reflux events14 (11–21)28 (18.5–42.8) *
% of mixed reflux58 (40–68)45.5 (34–69.7)
No. of reflux events with high proximal extent13 (6–29)13 (6.5–23.5)

Patients ‘off’ PPI

There was a significant positive association between BMI and the esophageal acid exposure, volume exposure, total number of reflux events, and the number of acid reflux events (Table 2). Moreover, we found a significant association between BMI and the proximal extent of reflux (Fig. 2). Similar associations were found during the upright and recumbent period (data not shown).

Table 2.   Correlation between body mass index (BMI) and different reflux parameters
BMI
 ‘off’ PPI‘on’ PPI
ρPρP
  1. PPI, proton pump inhibitor; LES, lower esophageal sphincter.

  2. Bold indicates significant correlation.

  3. *Remains significant after Bonferroni correction for multiple testing.

Total acid exposure0.530.0001*0.320.0336
Total volume exposure0.480.0006*0.460.0018*
No. of acid reflux events0.490.0005*0.240.1063
No. of weakly acidic reflux events0.080.58030.180.2365
Total no. of reflux events0.470.0009*0.330.0279
Proximal extent of reflux (no. of episodes ≥15 cm above LES)0.520.0002*0.290.0522
Proximal reflux% (%of episodes ≥15 cm above LES)0.490.0004*0.160.2894
image

Figure 2.  Figure displaying the correlation between body mass index (BMI) and reflux parameters in patients ‘off’ PPI. (A) shows the significant correlation between BMI and the total number of reflux events (ρ = 0.47, P = 0.0009) whereas (B) shows the positive correlation between BMI and the proximal extent of reflux (ρ = 52, P = 0.0002).

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Similar correlations were found between abdominal circumference and reflux parameters (Table 3).

Table 3.   Correlation between abdominal circumference and different reflux parameters
Abdominal circumference
 ‘off’ PPI‘on’ PPI
ρPρP
  1. LES, lower esophageal sphincter.

  2. Bold indicates significant correlation.

  3. *Remains significant after Bonferroni correction for multiple testing.

Total acid exposure0.520.0002*0.380.0091
Total volume exposure0.430.0027*0.410.0060*
No. of acid reflux events0.440.0022*0.310.0338
No. of weakly acidic reflux events0.170.25410.210.1696
Total no. of reflux events0.470.0011*0.390.0071*
Proximal extent of reflux (no. of reflux events ≥15 cm above LES)0.460.0014*0.310.0355
Proximal extent of reflux (% of reflux events ≥15 cm above LES)0.370.01170.080.58

Patients ‘on’ PPI

In patients ‘on’ PPI we found a significant correlation between BMI and volume exposure and the total number of reflux events (Table 2). Similar correlations were found between abdominal circumference and reflux parameters (Table 3). A correlation between BMI and proximal extent of reflux was only borderline significant. However, we did find a significant correlation between abdominal circumference and proximal extent of reflux (Fig. 3). Similar associations between reflux parameters and BMI/abdominal circumference were found during the upright and recumbent period (data not shown).

image

Figure 3.  Correlation between the abdominal circumference and the total number of reflux event in patients ‘on’ PPI. (A) shows the correlation between the abdominal circumference and the total number of reflux events (ρ = 0.39, P = 0.0071). (B) shows the correlation between abdominal circumference and the proximal extent of reflux (ρ = 0.31, P = 0.0355).

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Symptoms

Overall, 1897 symptoms were reported during the study, of which 705 were typical symptoms and 1192 were atypical. Patients ‘off’ PPI reported significantly more symptoms compared with patients ‘on’ PPI [14 (2–37) vs 5 (1–11)/24 h, = 0.0089]. Patients that presented with atypical symptoms had a significantly higher BMI compared with patients with only typical symptoms [26.6 (23.9–28.4) vs 23.5 (20.2–26.3, = 0.004)].

Of the 1897 symptoms reported, 547 were associated with reflux. Overall, 38 patients had a positive SAP (26 patients ‘off’ PPI and 12 ‘on’ PPI). Patients with a positive SAP had a slightly higher number of proximal reflux events compared with patients with a negative SAP [14.5 (8.8–29.3) vs 11 (3.8–18) P = 0.05]. Body mass index and abdominal circumference were similar in patients with positive and negative SAP (data not shown).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgment
  9. References

Increasing body weight has been suggested as a contributing factor for the steady increase in the GERD prevalence over the last decade. The aim of our study was to evaluate the association between BMI, abdominal circumference and the prevalence, and proximal extent of reflux (acid and non-acid) in GERD patients ‘off’ and ‘on’ PPI treatment. Our results showed that BMI and abdominal circumference are associated with: (i) an increased incidence of acid and weakly acidic reflux both in patients ‘off’ and ‘on’ PPI treatment, and (ii) the proximal extent of reflux.

The prevalence of GERD has increased significantly over the last decade, affecting approximately 20% of the Western population.15 At the same time, body weight is increasing with approximately one billion adults worldwide being overweight.16 Several studies have suggested a link between both phenomena. A high BMI provides a risk factor for GERD and a dose–response relationship between bodyweight and GERD has been reported.2,17 Patients with a large BMI report a higher prevalence of weekly GERD symptoms compared with patients with a normal body weight. Moreover, several studies have demonstrated a relationship between BMI and severity of acid reflux.3,5,18

Our study showed a significant correlation between BMI and both the total esophageal acid exposure, and the number of acid reflux events, confirming these pervious findings. In contrast to some of the previous studies that included predominantly obese patients, our study showed that even including a large group of normal weight individuals (BMI < 25), a higher body weight is associated with more acid reflux.

Several mechanisms have been attributed to the high prevalence of GERD in overweight patients including LES pressure, changes in gastric emptying rate, increased rate of postprandial transient lower esophageal sphincter relaxations (TLESR’s), and an increase in intragastric pressure and gastroesophageal pressure gradient.4,19–23 An increase in intragastric pressure is predominantly related to central obesity, suggesting that abdominal circumference may be an important factor in the relationship between body weight and GERD. In addition to an increase in intragastric pressure, visceral fat is metabolically active and may provoke the release of adipokines which may affect gastroesophageal motility.24 In addition to BMI, we investigated the association between abdominal circumference and reflux parameters. Whereas, previous studies showed more important associations between abdominal circumference and reflux compared with BMI, we found a similar association between reflux on one hand and BMI or abdominal circumference on the other hand. The observation that in our patient population, BMI, and abdominal circumference were strongly correlated may explain this finding.

Whereas, previous studies using esophageal pH-metry were limited to the detection of acid reflux, esophageal impedance recordings now enable detection of all types of reflux, regardless of the pH of the refluxate. Proton pump inhibitor treatment is the first line treatment in patients with GERD. Although, PPI therapy significantly reduces acidity of the gastric content and the refluxate, the total amount of reflux is only slightly reduced and is converted into a non-acidic form.25 In patients with persistent symptoms ‘on’ PPI treatment, symptoms may be associated with persistent non-acidic reflux. Moreover, in particular in obese patients, the question has been raised whether the efficacy of PPI therapy is similar as in normal weight individuals.16 The current study included a group of patients with persistent symptoms ‘on’ PPI therapy. As expected, in the patients ‘on’ PPI we no longer found an association between BMI and acid reflux. However, we did find a significant relationship between BMI and total reflux (acid + non-acid), suggesting that even in patients treated with PPI’s, an increased body weight may be a risk factor for reflux.

In addition to an increased sensitivity of reflux detection, esophageal impedance recording provides a tool to asses reflux characteristics including composition (liquid, gas or mixed) and proximal extent. A high proximal extent of reflux is one of the factors which was shown to contribute to symptom perception in patients with GERD. Moreover, high proximal extent of the refluxate is the only factor associated with reflux perception in patients on double-dose PPI.7

What determines the proximal extent of reflux so far remains unclear, but besides viscosity of the refluxate, distensibility of the gastresophageal junction, and esophageal motility or tone, intragastric pressure is likely to play a role.10–12 In the current study, we showed that a higher BMI or abdominal circumference is associated with an increased rate of proximal reflux in patients ‘off’ PPI. These findings suggest that intragastric pressure may be a determinant of the proximal extent of reflux. Although, there was a trend towards a positive association between BMI and proximal extent of reflux in patients ‘on’ PPI, this was no longer significant. Nevertheless, we did find an association between abdominal circumference and proximal extent, suggesting that in particular central obesity may be a risk factor for symptoms that persist during PPI treatment. Why the relationship between proximal extent of reflux and BMI or abdominal circumference is less pronounced in patients ‘on’ PPI is unclear. Nevertheless, PPI treatment might modify the volume and viscosity of the refluxate, factors which in term might also affect the proximal extent of reflux. The role of proximal reflux may be further confirmed by the finding that patients with a significant association between reflux and symptoms (+SAP) had a significantly higher proximal extent of reflux compared with patients with a −SAP. Nevertheless, there was no difference in BMI or abdominal circumference between patients with +SAP and −SAP. The relationship between BMI, intragastric pressure, proximal extent, and symptom perception is complex as intragastric pressure is not the only determinant of the proximal extent of reflux. Moreover, although proximal extent of reflux may be important, other factors such as esophageal sensitivity, which are not related to abdominal obesity are also likely to play a role in symptom perception.

The current study has some limitations. We prospectively recruited patients with GERD symptoms referred for impedance-pH testing. This resulted in a heterogeneous study population including a range of patients with typical and/or atypical symptoms both ‘on’ or ‘off’ PPI therapy. The presence of erosive esophagitis may affect the proximal extent of reflux. Upper endoscopy data were only available in 35 patients of which 15 had erosive esophagitis and two had Barrett’s esophagus. Nevertheless, as we included patients ‘on’ PPI therapy and a group of patients with atypical GERD symptoms it is reasonable to assume that the impact of erosive esophagitis on our findings would be limited. The overall BMI in our study population was rather low. The effect of BMI and abdominal circumference on the prevalence and proximal extent of reflux in an obese population (BMI > 30) will need to be confirmed.

From our results we can conclude that a large BMI and/or abdominal circumference is a risk factor for GERD both in patients ‘on’ and ‘off’ PPI treatment. Moreover, our results suggest that central obesity is a risk for proximal reflux which might contribute to symptom perception, and which may persist during PPI therapy. Further studies will need to elucidate the role of changes in intragastric pressure on the proximal extent and symptom perception in patients with GERD.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgment
  9. References

Blondeau K, Van Oudenhove L and Farre R receive a grant from the Flanders research foundation (FWO).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Data analysis
  6. Results
  7. Discussion
  8. Acknowledgment
  9. References
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