The overlap between gastroesophageal reflux disease and irritable bowel syndrome: an updated systematic review

INTRODUCTION

The definition of functional gastrointestinal disorders (FGIDs) includes a variety of chronic symptoms and signs that affect the gastrointestinal tract which usually occur in combinations and does not necessarily alter any biochemical and structural components in the physiology of the intestine, according to the Rome IV criteria.¹ Evidence shows that the overall prevalence of these disorders affects around one-third of the global general population.² As previously stated, FGIDs include a variety of gastrointestinal clinical pictures. These can affect multiple areas of the tract. Moreover, evidence shows that multiple comorbidities can simultaneously occur at different intestinal regions within the same patient.³ Disorders causing functional dyspepsia (FD), like GERD, and irritable bowel syndrome are the commonest FGIDs.

GERD is a common disorder of the upper gastrointestinal tract with a high prevalence rate in the general population.⁴ Previous reports showed that around 40% of the United States population frequently complain about relevant esophageal symptoms, and around 10-20% of them complain from these symptoms on a weekly basis.⁵ It also impact the quality of life of those affected patients and the elevated cost-related to care and management. The pathophysiology behind GERD development is mainly attributable to the mucosal damage secondary to the abnormal passage of gastric contents through an incompetent gastroesophageal junction. This leads to the development of many symptoms such as retrosternal heartburn and food regurgitation. The clinical diagnosis of this condition is built on the history of these symptoms, in addition to the characteristic relief after administration of proton pump inhibitors (PPIs).^6,7

Many studies have been published that have investigate the association between the different varieties of FGIDs, with many of them focusing on the correlation between IBS and GERD, specifically.^8-10 Jung et al even reported that the rate of co-occurrence of these conditions is probably more common than the expected rates.⁹ This phenomenon can be explained by the presence of a general sensory and motor function in the gastrointestinal tract. Consequently, evidence suggests that these disorders probably have common risk factors and pathophysiological mechanisms that need further investigations. Despite many reviews reporting this, none of it have recently investigated the growing evidence regarding the association of GERD and IBS within the last decade.^9,11 Therefore, the present study aims at collecting and updating new evidence from the current studies in the literature that reported the correlation between GERD and IBS.

Search strategy

We have conducted a thorough search strategy to include all of the relevant articles based on our inclusion criteria. The search term included all of the following key-words and their synonyms to find all the relevant articles: ("Irritable bowel syndrome" or "functional diarrhea" or "functional constipation" or "spastic colon" or IBS) and ("gastroesophageal reflux" or GERD or "gastro-esophageal reflux" or "gastro-oesophageal reflux" or GORD or reflux or "24-hour pH"). We used this term in the relevant databases including PubMed, web of science, scopus, google scholar, the international standard randomised controlled trial number, the Cochrane library, and the world health organization virtual health library. We included studies that published their results in English and article that were published from 2011 up to the date this study was conducted (January 2021). Searching the references of the included studies and the relevant reviews were also conducted to include any study that we might have missed using our systematic search strategy. The manual search was also done according to our inclusion and exclusion criteria.

Inclusion and exclusion criteria

We targeted all study designs that investigated the association between GERD and IBS that was published from 2011 up to January 2021 and assessed their outcomes on human subjects. Moreover, for a study to be included, a clear definition of GERD and IBS should be included within the literature of the study. We aimed to assess the prevalence and associated factors between the two disorders from the included studies. Therefore, we excluded studies that overlapped the above information and did not investigate the association between the two disorders or did not clearly state the prevalence rate of either of the two modalities within a population of patients that had the other modality at baseline. We also excluded articles that were published in non-English languages, abstract-only articles, incomplete and non-original studies as reviews, thesis, protocols, and editorials.

Screening and data extraction

This step was conducted following the previously published and widely-known preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.¹² After we finished searching the relevant databases, we imported these results into a unified endnote library to identify and exclude all the possible duplicated citations. The grouped results were then exported to an excel sheet that was prepared for the next step: title and abstract screening. The excel sheet included information about the reference of the included study as ID, authors, title, publication year, DOI, URL, journal, and abstracts. If an abstract was missing, members had to search the relevant journals to retrieve the study abstract. The screening was done by two authors who were blinded to each others’ results to achieve the best outcomes from the process. After finishing their screening, four authors compared their results in a public group discussion under the senior author’s supervision. Full-texts of the included articles were then retrieved to presume the screening process to include the potential studies.

For data extraction to take place, a standardized excel sheet was needed. Consequently, two of the authors collaborated to design a suitable sheet that suits our criteria and intended outcomes. At first, a pilot sheet was performed based on the outcomes of some of the included studies. After that, the sheet was rigorously modified multiple times based on the designs and outcomes from all of the included studies. The sheet was designed to extract the articles IDs, last author name, title, sample size, study design, the country where the study was conducted, and the assessed outcomes including the prevalence of overlap between IBS and GERD and the associated factors.

Assessment of bias

For cross-sectional studies, the adjusted Newcastle-Ottawa scale NOS for cross-sectional studies was used, by which all studies were graded out of 10 according to the estimated quality (Newcastle-Ottawa 2011).¹³ The tool was divided into three main categories including (1) the methodological quality of studies using five grades, (2) comparability of each study using two grades, (3) and the outcomes and statistical analysis using three grades. On the other hand, for randomized studies, the Cochrane Collaboration’s proposal for the assessment of the risk of bias, by which, the following domains were assessed: selection, detection, performance, reporting, and attrition to classify studies as having low, some concerns, or high risk of bias. This step was done by two reviewers and disagreements were resolved by discussion.¹⁴

Search results

The total number of citations that were obtained by the thorough search strategy have reached 3,451. Using endnote, we excluded 1,972 duplicate articles and the remaining ones were prepared for the title and abstract screening. Among these articles, only 125 articles were eligible for full-text screening which resulted in the inclusion of 13 articles that met our inclusion criteria. We also managed to add another three articles to the overall list by manual search. The details of the search strategy and reasons for the excluded articles are presented in our flow diagram in Figure 1.

Q; symptom questionnaire; Endo; Endoscopy; RCT: Randomized controlled trial; NS; Non-specified; IBS: Irritable bowel syndrome; GERD: Gastroesophageal reflux disease; UK: United Kingdom.

Risk of bias

The risk of bias assessment showed that ten of our studies had good results having a total score of 7-8 while the other studies had satisfactory results (total=5-6) with none of the studies having non-satisfactory results (total= 0-4). The detailed assessment and scores of all cross-sectional studies are presented in Table 1. Assessment of bias for two randomized controlled trials (RCTs) showed that both of them also had a low risk of bias totally and within all domains, except for reporting of the intended outcomes which had some concerns.

Included studies characteristics

The total sample size that investigated the overlap between IBS and GERD in this study was 146,156 patients. The largest sample size was recorded by the registry-based study by Rasmussen et al (n=95,253) and the two cross-sectional studies conducted by Pourhoseingholi et al (n=18,180, each).^15-17 On the other hand, the smallest size was recorded by Funaki et al (n=37), Martinucci et al (n=46), and Baran et al (n=55).¹⁸²⁰ At baseline, three studies included patients with GERD, six included patients with IBS, while seven included patients with non-specified GERD or IBS to study the correlation as to their primary outcome.^15-18,21-30 Almost all studies were cross-sectional in design while only two studies were RCTs.^27,30 All of the studies were published between 2011 and 2020 as presented in Table 2, together with other baseline characteristics and outcomes.

DISCUSSION

IBS and GERD diagnostic approaches

All of the included studies have reported the simultaneous occurrence of IBS and GERD patients. Almost all of the included studies assessed the presence of either of these disorders based on the clinical pictures that were obtained from their included patients by prepared questionnaires. Moreover, endoscopy, including the various types like esophagogastroduodenoscopy and colonoscopy, was also used to assess the status of the esophagus and stomach, in addition to the status of the bowel, for confirmation of GERD and IBS related lesions. Only three of the included studies used the 24-h pH monitoring for the assessment of gastric juice activity.^19,20,25 This test was previously considered the most sensitive laboratory test in diagnosing GERD and related gastro-esophageal lesions. Blood tests and H. pylori infection were also assessed by some studies for further confirmation of the diagnosis.^21,27,30 On the other hand, assessment and identification of IBS patients were based on Rome III criteria, while only one study depended on questionnaire-based diagnosis, one used the ReQuest questionnaire, one used the Manning approach, while only one study depended on the Rome II criteria.^16,21 The variability between the included studies in terms of the methods of diagnosis is probably due to the nature of data collection in some studies which depended on retrospective data, however, almost all recent studies use the Rome III criteria almost exclusively. The effect of the applied diagnostic approach on the estimated overlap rates was clearly shown in a meta-analysis by Lovell et al who reported that the degree overlap was reduced to 14.2% when the Rome II criteria were used, from 26.7% when the Manning criteria were used for IBS patients.³¹

Evidence of IBS and GERD overlap

Among the studies that reported the presence of GERD among IBS patients, pourhoseingholi et al reported the highest prevalence rate, being 74.7% GERD patients among 18,180 patients with IBS.¹⁶ On the other hand, the lowest prevalence rate of patients with GERD among an IBS population was found to be 20.6%, however, the sample size was limited being 102 only as reported by Morozova et al.²⁵ Another four studies have also reported the prevalence of GERD symptoms among patients with IBS. A large study by El Slahy et al reported that 66% of their 1489 IBS patients were diagnosed with GERD.²⁴ A similar rate of 64.9% was also reported by Funaki et al, however, the sample size was too small which may have magnified the results.¹⁸ The other two studies by Baran et al and Martinucci et al also reported similar rates, but lower than the previous two studies, as being 41.8%, and 41.3% for the two studies, respectively.^19,20

On the other hand, the reported overlap rates were lower when IBS was investigated either in GERD or a non-specified population. Wu et al conducted a cross-sectional study to investigate the effect of the overlap of IBS and non-erosive reflux disease (NERD) when associated with inflammatory bowel diseases on the quality of life of the affected patients.²³ The reported overlap between NERD and IBS was 39.9%. In another study that was conducted by Ford et al, the authors reported that IBS occurred in 15.8% of their 4003 GERD population.²¹ On the other hand, Lei et al reported a prevalence rate of 9.5% only.²² In the studies which investigated the overlap between IBS and GERD with no baseline identification of neither of the disorders, the overlap prevalence rate ranged between 1.7% and 34%. It is worth mentioning that two of these studies were RCTs, and although investigating the overlap was not mainly among the study outcomes, we managed to obtain overlap results from the two studies' data being 15% and 13.3% in the two studies.^27,30 We have also noticed the lowest prevalence rate among the non-specified sample size studies was in the study where the largest sample size was estimated in our review.¹⁵ So, this might raise questions about the potential effect of sample size on the reported outcomes, however, this was out of our review scope. We also noticed that studies with IBS baseline populations recorded the highest prevalence overlap rates which might also raise questions about whether IBS has a role in developing GERD more than GERD does on IBS, however, this also was not within the scope of this review and further studies are needed.^{16,18-20,24,25}

Risk factors and pathophysiology for IBS and GERD overlap

Although the diagnosis of this condition is mainly based on the clinical pictures of the affected patients, endoscopy and hematological examinations can aid in diagnosis indication, in addition to excluding the differential diagnoses.^19,32 Nam et al reported that somatization and anxiety were as significant risk factors for IBS as to NERD.²⁸ These factors, in addition to age, H. pylori infection, and smoking, significantly contributed to the development of GERD-related symptoms when they were in IBS patients. Fujiwara et al reported that female gender and cigarette smoking was associated with IBS and GERD overlap in their cross-sectional study.²⁶ In the study by Martinucci et al the authors noticed that IBS overlaps more frequently with functional heartburn than erosive and non-erosive reflux diseases.¹⁹ In another study by Garros et al, who studied the overlap between IBS and patients receiving PPI for GERD, the authors reported a positive correlation between IBS and not responding to PPI treatment as the overlap rate was higher among these patients.³³ Baran et al also reported that treating functional constipation was associated with resolve in reflux symptoms in children that suffered from GERD and functional constipation overlap.²⁰ The meta-analysis by Lovell et al has also supported this as they showed that GERD symptoms were more likely to occur fourfold in IBS patients than other non-IBS patients.³¹ These results might partially explain the possible association between IBS and GERD which might be attributable to the abnormal generalized motility of the digestive system and the harmful effect of gastric acid.^34,35 This is supported by the previous studies which reported a state of visceral hypersensitivity to a large number of stimuli as chemical, anatomical, and physical stimuli in both GERD and IBS.^36,37 Costantini et al has indicated this by showing that GERD symptoms increased in IBS patients when esophageal provocative tests were introduced, as compared to the control group.³⁸ Our reported results about the degree of GERD and IBS overlap are also sonsistent with the results by the previous reviews in 2013, and 2006.^39,40 The latter review has even demonestrated that IBS alone is not common and GERD increases the prevalence of the condtion.

Our results might be limited to the small sample size in some of the included studies and the poor evidence that supports the pathophysiology of IBS and GERD overlap and the effect of either of them over the other, despite the significant association that was found in the literature.

CONCLUSION

In this systematic review, we have found a strong correlation between IBS and GERD as indicated by the high prevalence rates of overlap by many of the included studies. However, the certain pathophysiology and risk factors behind this phenomenon remain non-clear and further studies are needed. The possible association indicates the need for a proper management plan for these patients for better care and quality of life.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

1. 1. Drossman DA, Hasler WL. Rome IV-Functional GI Disorders: Disorders of Gut-Brain Interaction. Gastroenterology. 2016;150(6):1257-61.
2. 2. Koloski NA, Talley NJ, Boyce PM. Epidemiology and health care seeking in the functional GI disorders: a population-based study. Am j gastroenterol. 2002;97(9):2290-9.
3. 3. Koloski NA, Talley NJ, Boyce PM. The impact of functional gastrointestinal disorders on quality of life. Am j gastroenterol. 2000;95(1):67-71.
4. 4. Vakil N, Van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am j gastroenterol. 2006;101(8):1900-2043.
5. 5. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63(6):871-80.
6. 6. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am j gastroenterol. 2013;108(3):308-28.
7. 7. Savarino E, Bredenoord AJ, Fox M, Pandolfino JE, Roman S, Gyawali CP. Expert consensus document: Advances in the physiological assessment and diagnosis of GERD. Nature reviews Gastroenterol hepatol. 2017;14(11):665-76.
8. 8. Kennedy TM, Jones RH, Hungin AP, O'Flanagan H, Kelly P. Irritable bowel syndrome, gastro-oesophageal reflux, and bronchial hyper-responsiveness in the general population. Gut. 1998;43(6):770-4.
9. 9. Jung HK, Halder S, McNally M. Overlap of gastro-oesophageal reflux disease and irritable bowel syndrome: prevalence and risk factors in the general population. Alimentary pharmacol therap. 2007;26(3):453-61.
10. 10. Quigley EM, Lacy BE. Overlap of functional dyspepsia and GERD--diagnostic and treatment implications. Nature reviews Gastroenterol hepatol. 2013;10(3):175-86.
11. 11. De Bortoli N, Tolone S, Frazzoni M. Gastroesophageal reflux disease, functional dyspepsia and irritable bowel syndrome: common overlapping gastrointestinal disorders. Ann Gastroenterol. 2018;31(6):639-48.
12. 12. Liberati A, Altman DG, Tetzlaff J. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.
13. 13. Celikten B, Uzuntas CF, Kurt H. Multiple idiopathic external and internal resorption: Case report with cone-beam computed tomography findings. Imaging Sci Dent. 2014;44(4):315.
14. 14. Higgins JPT, Altman DG, Gøtzsche PC. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
15. 15. Rasmussen S, Jensen TH, Henriksen SL. Overlap of symptoms of gastroesophageal reflux disease, dyspepsia and irritable bowel syndrome in the general population. Scandinavian j gastroenterol. 2015;50(2):162-9.
16. 16. Pourhoseingholi A, Pourhoseingholi MA, Moghimi-Dehkordi B. Epidemiological features of gastro-esophageal reflux disease in Iran based on general population. Gastroenterol hepatol bed to bench. 2012;5(1):54-9.
17. 17. Pourhoseingholi A, Vahedi M, Pourhoseingholi MA. Irritable bowel syndrome, gastro-oesophageal reflux disease and dyspepsia: overlap analysis using loglinear models. Arab j gastroenterol. 2012;13(1):20-3.
18. 18. Funaki Y, Kaneko H, Kawamura Y. Impact of Comorbid Irritable Bowel Syndrome on Treatment Outcome in Non-Erosive Reflux Disease on Long-Term Proton Pump Inhibitor in Japan. Digestion. 2017;96(1):39-45.
19. 19. Martinucci I, De Bortoli N, Fluri G. P.1.59: diagnosis of nerd in a population of patients with and without IBS: a PH-MII study. Dig liver dis. 2011;43.
20. 20. Baran M, Cagan Appak Y, Karakoyun M, Yalcinkaya S, Eliacik K, Dundar BN. The overlap of gastroesophageal reflux disease and functional constipation in children: the efficacy of constipation treatment. Eur j gastroenterol hepatol. 2017;29(11):1264-8.
21. 21. Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P. The natural history of gastro-oesophageal reflux symptoms in the community and its effects on survival: a longitudinal 10-year follow-up study. Alimentary pharmacol therap. 2013;37(3):323-31.
22. 22. Lei WY, Chang WC, Wen SH. Impact of concomitant dyspepsia and irritable bowel syndrome on symptom burden in patients with gastroesophageal reflux disease. Journal of the Formosan Medical Association = Taiwan yi zhi. 2019;118(4):797-806.
23. 23. Wu JC, Lai LH, Chow DK, Wong GL, Sung JJ, Chan FK. Concomitant irritable bowel syndrome is associated with failure of step-down on-demand proton pump inhibitor treatment in patients with gastro-esophageal reflux disease. Neurogastroenterol motility. 2011;23(2):155-60.
24. 24. El-Salhy M, Gilja OH, Hatlebakk JG. Overlapping of irritable bowel syndrome with erosive esophagitis and the performance of Rome criteria in diagnosing IBS in a clinical setting. Molecular med rep. 2019;20(1):787-94.
25. 25. Morozova YN, Pogromov AP, Mnatsakanyan MG, Tashchyan OV, Kolosova KY. Esophageal disorders in patients with irritable bowel syndrome. Terapevticheskii arkhiv. 2020;92(2):19-23.
26. 26. Fujiwara Y, Kubo M, Kohata Y. Cigarette smoking and its association with overlapping gastroesophageal reflux disease, functional dyspepsia, or irritable bowel syndrome. Internal med (Tokyo, Japan). 2011;50(21):2443-7.
27. 27. Mönnikes H, Schwan T, van Rensburg C. Randomised clinical trial: sustained response to PPI treatment of symptoms resembling functional dyspepsia and irritable bowel syndrome in patients suffering from an overlap with erosive gastro-oesophageal reflux disease. Alimentary pharmacol therap. 2012;35(11):1279-89.
28. 28. Nam SY, Ryu KH, Park BJ. Irritable bowel syndrome is associated with gastroesophageal reflux symptom but not erosive esophagitis. J neurogastroenterol motility. 2013;19(4):521-31.
29. 29. Al Saadi T, Idris A, Turk T, Alkhatib M. Epidemiology and risk factors of uninvestigated dyspepsia, irritable bowel syndrome, and gastroesophageal reflux disease among students of Damascus University, Syria. J epidemiol global health. 2016;6(4):285-93.
30. 30. Mönnikes H, Heading RC, Schmitt H, Doerfler H. Influence of irritable bowel syndrome on treatment outcome in gastroesophageal reflux disease. World j gastroenterol. 2011;17(27):3235-41.
31. 31. Lovell RM, Ford AC. Prevalence of gastro-esophageal reflux-type symptoms in individuals with irritable bowel syndrome in the community: a meta-analysis. Am j gastroenterol. 2012;107(12):1793-1801.
32. 32. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130(5):1377-90.
33. 33. Garros A, Mion F, Marjoux S, Damon H, Roman S. Factors associated with nonresponse to proton pump inhibitors therapy in patients referred for esophageal pH-impedance monitoring. J Int Society Dis Esophagus. 2016;29(7):787-93.
34. 34. Stanghellini V, Barbara G, Cogliandro R. Overlap between GERD and IBS - Irrefutable but subtle. J Clin Gastroenterol. 2007;41:S114-7.
35. 35. Jones R, Lydeard S. Irritable bowel syndrome in the general population. BMJ. 1992;304(6819):87-90.
36. 36. Elsenbruch S. Abdominal pain in Irritable Bowel Syndrome: a review of putative psychological, neural and neuro-immune mechanisms. Brain, behavior, immunity. 2011;25(3):386-94.
37. 37. Knowles CH, Aziz Q. Visceral hypersensitivity in non-erosive reflux disease. Gut. 2008;57(5):674-83.
38. 38. Costantini M, Sturniolo GC, Zaninotto G. Altered esophageal pain threshold in irritable bowel syndrome. Dig dis sci. 1993;38(2):206-12.
39. 39. de Bortoli N, Martinucci I, Bellini M. Overlap of functional heartburn and gastroesophageal reflux disease with irritable bowel syndrome. World j gastroenterol. 2013;19(35):5787-97.
40. 40. Nastaskin I, Mehdikhani E, Conklin J, Park S, Pimentel M. Studying the overlap between IBS and GERD: a systematic review of the literature. Dig dis sci. 2006;51(12):2113-20.