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Does Sleeve Gastrectomy expose the distal Esophagus to Severe Reflux? A Systematic Review & Meta-analysis

Kai Tai Derek Yeung BMBS MRCS, Nicholas Penney MBBS MRCS, Leanne Ashrafian PhD MRCS, Ara Darzi MD FRCS FACS FMedSci FRS and Hutan Ashrafian PhD MRCS MBA

Department of Surgery and Cancer, Imperial College London, London, UK.

Correspondence and Reprints:

Dr Hutan Ashrafian

Academic Surgical Unit,

10th Floor, QEQM Wing, St Mary’s Hospital

Praed Street, London

United Kingdom, W2 1NY

Tel: (+44)2075895111

Email: h.ashrafian@imperial.ac.uk

Source of Support: Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC).

INTRODUCTION

The proportion of Laparoscopic Sleeve Gastrectomies (SG) being performed as a primary bariatric procedure around the globe continues to increase. The International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) report that SG accounts for 43.6% of all primary bariatric procedures performed globally between 2013-20171. In nation states with high rates of morbid obesity such as the United States or those in the Middle East, SG is the most common bariatric procedure accounting for up to 60% of all recorded cases2.

This increase in the surgical popularity of SG particularly when compared to the long-established and so-called ‘gold-standard’ Roux-En-Y Gastric Bypass is multifactorial. It is a relatively simpler procedure, which does not involve anatomical re-arrangement or surgical anastomoses, entails no risk of internal hernia and is widely accepted to carry shorter operative times. SG is also accepted in high risk patients, including those who are liver and renal transplant candidates and elderly3. Importantly, several long-term studies have also shown that those who undergo SG have weight loss and metabolic outcomes comparable to RYGB4, 5.

However, as SG’s popularity continues to increase, one major drawback is the potential development or worsening of Gastro-esophageal reflux disease (GERD) post operatively. GERD is a co-morbidity common amongst those with obesity and the impact of surgery is yet to be fully quantified. There is disparity in current literature, with some reporting SG can worsen pre-existing or cause ‘de novo’ GERD6-8 while others report an improvement in GERD9, 10. There is also a widespread variation and discrepancy in pre-operative criteria with some centres not offering SG to those with GERD and some who do. In the Fifth International Consensus Conference for Sleeve Gastrectomy, only 23.3% of expert surgeons questioned felt that GERD was an absolute contraindication. 80% however, felt that the presence of Barrett’s esophagus (BE) was an absolute contraindication3. Long-term clinical trials comparing RYGB to SG showed that while internal hernias were the primary cause of re-operations in patients after RYGB, severe reflux resistant to medical treatment was the leading cause for those who underwent SG4, 5.

GERD is the primary risk factor for Barret’s Esophagus. The practice of routine pre and post-operative endoscopic screening for Esophagitis and BE is also very varied. Although patients are consented for the risk of GERD, the same cannot be said of Esophagitis and BE. We found one case report in the current literature where a 46 year patient presented with Esophageal adenocarcinoma 5 years post sleeve gastrectomy despite having endoscopic investigations to exclude GERD, hiatus hernia and H.pylori pre-operatively11. The demographic of those who undergo bariatric surgery tend to be between 30-50 years. If SG leads to worsening GERD there may be severe unintended consequences for patient outcomes and implications for long-term GERD-related complications.

The aim of this study was to systematically appraise and meta-analyse all existing published data to assess the effect of sleeve gastrectomy on GERD, esophagitis, BE in order to clarify the long-term clinical sequelae of this procedure.

METHODS

This systematic review was conducted in accordance with the guidelines for the “Preferred Reporting Items for Systematic Reviews and Meta-analyses” (PRISMA)12. All stages of literature search, study selection, data extraction and quality assessment were performed independently by 2 authors (KTDY and NP). Any disagreement was resolved by discussion and consensus with a third reviewer (HA).

Literature Search

A systematic search was performed using electronic searches in EMBASE, Medline, Cochrane Library and Psychinfo. The appropriate MESH terms and free text all field search was performed for “Sleeve Gastrectomy”, “Bariatric Surgery”, “Obesity”, “Gastrectomy”, “Gastric Sleeve”, “Stomach Stapling”, “Gastro-esophageal Reflux”, “Gastro-oesophageal Reflux”, “Reflux”, “Metaplasia” “Barrett’s Esophagus” and “Barrett’s Oesophagus”. The search included all study designs, with further studies not captured by the search identified via bibliographic cross referencing. Titles and abstracts were screened independently for full text review by two reviewers (KTDY and NP).

Inclusion Criteria

Studies published that contained outcome data for primary sleeve gastrectomy associated with the primary and secondary outcomes listed below were included. If studies contained multiple cohorts, data for primary sleeve gastrectomy were included only. Study participants were adults over the age of 18 years. Date range was from 2000 and the last search was performed in August 2018.

Exclusion Criteria

Only studies published in English were included in the systematic review. Abstracts, conference articles, opinion pieces, editorial letters, case studies, reviews and meta-analysis were excluded from the final review. Non-human studies were not included. Those without appropriate data published related to the primary and secondary outcomes of this study were also excluded.

Quality Assessment

The Newcastle-Ottawa Scale13 was used to assess the quality of the studies included in this study. Each study was assessed independently by two investigators for study selection, comparability and outcomes. Eight items with three subscales contribute to a maximum total score of 9. We considered a study scoring 3 to be of poor quality, between 4-6 as fair quality and 7 as good quality.

Data Extraction

The primary outcome was prevalence of esophagitis and Barrett’s Esophagus after primary laparoscopic sleeve gastrectomy. Secondary outcomes included: Change in Reflux; De Novo Reflux; Hiatus Hernia rate; Proton Pump Inhibitor (PPI) use; Body Mass Index (BMI) change; Excess Weight Loss (EWL); Diabetes Resolution and Percentage of patients requiring revision to Roux-En-Y Gastric bypass for severe reflux. Data for study numbers and length of follow up was also recorded.

Statistical Analysis

Statistical analysis was performed using Stata Software, Version 15.1. StataCorp LCC, Texas, USA. Random mass effects analysis was used to calculate weighted mean differences and mass effect. All studies were analysed if data availability allowed. Studies reporting outcomes after 24 months or more were considered long-term and a separate subgroup analysis was performed. Data was pooled using a random effects model and statistical heterogeneity was calculated using I2. We considered an I2 of 30 or less as low, between 30 and 60 to be moderate, and 60 or over as high heterogeneity.

RESULTS

Study Characteristics

A total of 951 citations were retrieved by literature searches.10 additional articles were found from bibliography cross referencing. Full text review was performed on 77 full text articles with 46 meeting the final inclusion criteria for this meta-analysis. All 46 studies included were retrospective or cohort studies. There were no randomised control trials. A total of 10718 patients were included in the meta-analysis. Study follow up ranged from 3 to 132 months.

Studies reporting outcomes over 24 months were considered long-term and a separate long-term subgroup analysis was performed for each outcome. The relevant PRISMA flow diagram and checklist is included as supplementary digital content.

[Table 1]

Table 1. All studies included in this study with follow up percentage, follow up (months) and quality score using the Newcastle-Ottawa Scale. * Indicates the use of direct physiological testing or imaging.

Change in Reflux - 35 studies were included, pooled random effects analysis of the change in the percentage of patients reported to have reflux between pre and post-operative groups demonstrated an increase of 19% following SG (95% CI 15%-22% p<0.0001). Subgroup analysis of 26 long-term studies also showed an increase of 19% post-operatively (95% CI 15%-23% p<0.0001). There was high heterogeneity in both analyses with I2 = 95.4% and 95.7% respectively.

[Figure 1]

Figure 1. Forest plot of Change in Reflux for all studies

De Novo Reflux- 30 studies were included, pooled random effects analysis of the reported rates of new onset or de novo reflux after SG was 23% (95% CI 17%-29% p<0.0001). Subgroup analysis of 24 long-term studies demonstrated a result of 20% (95% CI 14%-27% p<0.0001). There was high heterogeneity in both analyses with I2 = 98.9% and 99.0% respectively.

[Figure 2]

Figure 2. Forest plot showing De Novo Reflux of all studies

Oesophagitis- 13 studies were included, pooled random effects analysis of the reported rates of oesophagitis after SG was 30% (95% CI 3%-58% p<0.0001). Subgroup analysis of 8 long-term studies demonstrated a result of 28% (95% CI -9%-66% p<0.0001). There was high heterogeneity in both analyses with I2 = 99.8% and 99.9% respectively.

[Figure 3]

Figure 3. Forest plot showing Oesophagitis of all studies

Barrett’s Esophagus- 6 studies were included, pooled random effects analysis of the reported rates of Barrett’s Esophagus after SG was 6% (95% CI 3%-9% p<0.0001). Subgroup analysis of 5 long-term studies showed a result of 8% (95% CI 4%-13% p<0.0001). There was high heterogeneity in both analyses with I2 = 92.9% and 94.1% respectively.

Hiatus Hernia Rates- 6 studies were included, pooled random effects analysis of the reported rates of Hiatus Hernias after SG was 41% (95% CI 21%-96 p<0.0001). There was high heterogeneity with I2 = 94.9%.

PPI use- 15 studies were included, pooled random effects analysis of the reported rate of PPI use after SG was 38% (95% CI 27%-49% p<0.0001). Subgroup analysis of 11 long-term studies demonstrated a result of 36% (95% CI 22%-50% p<0.0001). There was high heterogeneity in both analyses with I2 = 98.1% and 98.5% respectively.

Patients converted to RYGB due to severe reflux-16 studies were included, pooled random effects analysis of the reported rate of patients converted to RYGB for severe reflux was 4% (95% CI 2%-5% p<0.0001). Subgroup analysis of 15 long-term studies demonstrated a result of 4% (95% CI 2%-6% p<0.0001). There was high heterogeneity in both analyses with I2 = 95.6% and 95.9% respectively.

BMI Change- 25 studies were included, pooled random effects analysis of BMI change post operatively demonstrated a weighted mean difference reduction of 13.29kg/m2 (95% CI 11.00-15.58 p<0.0001). Subgroup analysis of 18 long-term studies demonstrated a result of 12.56kg/m2 (95% CI 10.46-14.70 p<0.0001). There was high heterogeneity in both analyses with I2 = 99.3% and 98.6% respectively.

Excess Weight Loss (%)- 33 studies were included, pooled random effects analysis of EWL demonstrated an effect size of 62% (95% CI 58%-61% p<0.0001). Subgroup analysis of 28 long-term studies demonstrated a result of 61% (95% CI 57%-65% p<0.0001). There was high heterogeneity in both analyses with I2 = 91.2% and 91.1% respectively.

Diabetic Resolution- 27 studies were included, pooled random effects analysis demonstrated 66% (95% CI 60%-70% p<0.0001) achieve diabetic resolution. Subgroup analysis of 23 long-term studies demonstrated a result of 66% (95% CI 58%-74% p<0.0001). There was high heterogeneity in both analyses with I2 = 98.0% and 98.3% respectively.

Subgroup analysis using objective GERD Lyon Consensus 2018 criteria- 6 studies fulfilled borderline GERD diagnostic criteria. Pooled random effects analysis of the change in the percentage of patients with GERD demonstrated an increase of 37% following SG (95% CI 23%-51% p<0.0001). Only 2 studies fulfilled conclusive GERD diagnostic criteria. Pool random effect analysis demonstrated an increase of 8.4% following SG (95% CL -5%-21% p<0.0001). There was high heterogeneity in both analyses with I2 = 96.1% and 94.8% respectively.

Results Summary

[Table 2]

Table 2. Summary of all study outcomes (p<0.0001 for all studies).

DISCUSSION

This meta-analysis provides evidence that Sleeve Gastrectomy (SG) leads to high rates of GERD after surgery. The prevalence of the additional unintended sequalae of esophagitis and Barrett’s esophagus (BE) following SG are also prominent. As a result, we feel that post-operative surveillance for these complications should be mandatory after SG.

There is still controversy in the literature regarding GERD after SG. Several long-term studies report an increased rate of GERD post-operatively19, 21-23, 51although there are conflicting studies suggesting symptomatic improvement9. There is also a disparity of surgical opinion regarding this issue. A survey at the Fifth International Consensus Conference for the current status of sleeve gastrectomy revealed that only 23.3% of expert bariatric surgeons felt that GERD was an absolute contraindication to SG3, whereas a higher proportion (52.6%) of general surgeons considered this as an absolute contraindication.

Post-operative GERD after Sleeve (POGAS) gastrectomy can be de-novo or result from an aggravation of pre-existing GERD. Our results demonstrate a 20% rate of long-term de-novo reflux, and an overall 19% increase in all reflux symptoms. These finding may be under-estimating the reflux rates after SG as the studies which actively investigated patients with physiological and invasive tests including pH manometry or UGI endoscopy regardless of symptoms found a much higher rate of both worsening and de novo GERD17, 22, 37, 49, esophagitis26, hiatus hernia33 and BE7, 51. Furthermore, there does not seem to be a correlation of symptoms7, 22, 51 with the prevalence of GERD, esophagitis and BE. As a result the use of symptomology alone as a screening tool for these complications is likely unreliable in clinical practice. We therefore feel that it may be time to reconsider the clinical post-operative follow-up of SG patients for these conditions. As the prevalence of POGAS, esophagitis and BE and revisional gastric bypass surgery after sleeve extend into a significant proportion of patients, there is an additional need to reconsider the consent process in SG patients to highlight these complications.

The finding of 36% long-term PPI use found in our study, suggests that either (i) pre-existing PPI’s were continued or (ii) they were commenced for symptomatic POGAS. The data available was not able to differentiate these results, although it is strongly suggestive of the latter as current reports on pre-existing PPI use before SG is generally reported to vary between 19% - 28%7, 27, 49, 51. Considering also that there is likely a subset of patients who have asymptomatic GERD or ‘silent’ GERD, there is an increased impetus to consider routine endoscopic or physiologic post-operative testing.

Multiple mechanisms are postulated to be contributory to reflux after SG: (i) Surgery causes a disruption to the normal ‘anti reflux’ anatomical architecture which relies on the correct anatomical orientation of the lower esophageal sphincter (LES), the angle of His, the diaphragm and associated gastric and esophageal-phrenic ligaments7, 55. (ii) Following dissection of the angle of His and potential damage to the sling fibres, the LES can be weakened56. (iii) The narrow and tubulised stomach has been shown to have increase intra-gastric pressure on manometric measurements57 which leads to a further increase in the gastro-esophageal pressure gradient. (iv) Residual stomach compliance is reduced due to the removal of the gastric fundus31 and there is a lower tolerance to the effect of oral intake on intra-gastric pressure. (v) Herniation of the gastric tube into the thoracic cavity also encourages reflux. This can be caused by the presence of a hiatus hernia and also disruption of the anchoring anatomical architecture after dissection. (vi) Vagus nerve damage also impacts on reflux. Vagus nerve damage during anti-reflux surgery has been shown to negatively impact long-term reflux control58. (vii) Poor surgical technique leading to twisting, kinking or strictures of the gastric tube also impacts outcomes.

Several factors are hypothesised to improve GERD post-operatively. Reduced BMI following surgery leads to a reduction in the gastro-esophageal pressure and there is accelerated gastric emptying following SG59. Furthermore, the residual stomach holds less volume and has a reduced production of acid. There is the potential of a reduced cylindrical radius of the stomach leading to lower wall tension (based on LaPlace’s law) potentially improving reflux, although this has not been found to be the case clinically. Overall our study reveals that SG results in an increased rate of post-operative reflux, lending some support to the traditional concept of physiological flap-valve mechanism (championed by Braune 1878 and Barrett 1954) where the angle of His offers a protective role against reflux60-63. Removal of the fundus and disruption of the components of this flap architecture may in turn contribute to increase in the demonstrated reflux after surgery.

This study found a 4% conversion rate of SG to RYGB for severe reflux. This is slightly higher than the 2.9% reported at the latest sleeve gastrectomy consensus meeting3. This number may be even higher in clinical practice as it may not have considered patients who were converted to RYGB for weight regain (also having coexistent POGAS).

We demonstrate long-term rates of 28% esophagitis and 8% of BE in this study. Those who reported rates of esophagitis and BE all performed endoscopic evaluation (see Table 1). Several studies report that symptoms did not necessarily correlate with endoscopic findings7, 33, 51, 52 and we therefore feel that these rates could potentially be even higher if all patients were to be investigated for these conditions formally.

Currently, IFSO and the American College of Gastroenterology (ACG) guidelines recommends RYGB for patients with severe GERD who wish to undergo surgery for morbid obesity64, 65. It is also the recommended option when obese patients present with recurrence of symptoms after traditional anti-reflux surgery65. The SM-BOSS 5 year RCT comparing SG to RYGB found resolution of reflux to be 25% and 60.4% respectively4. Another large scale study composed of 38,699 patients comparing SG to RYGB showed only 15.9% resolution of GERD after SG compared to 62.8% for those who underwent RYGB66. Some cases series of morbidly obese patients with concomitant GERD and BE have reported rates of BE regression after RYGB between 36%-43%,67, 68 although the mechanism and confirmation of this data in larger cohorts requires validation.

BE is a well-known precursor to esophageal adenocarcinoma; however, it is still not known which individuals with BE will progress to cancer. If an increased uptake of SG leads to an increased prevalence of BE, then there is a need to appraise, identify and stratify pre-cancer risk in SG patients. The 2017 IFSO global registry reported that 39,137 SG were performed worldwide between 2013-20171. Whilst bariatric surgery has demonstrated long-term beneficial anti-cancer effects 69, 70, an approximate prevalence of just under ten percent BE in the SG population may result in a significant increase of post-operative metaplasia at a population-level which may need directive surveillance and assessment.

The replacement of squamous cell epithelium by intestinal metaplasia in BE is reported to be caused by a cytokine mediated inflammatory response rather than the traditionally presumed acid causticity71. Some of the mechanistic pathways responsible for this process (based on animal and human models include) the activation of the hypoxia inducible factor (HIF)-2α gene. Pro-inflammatory cytokines are then amplified due to the enhanced transcriptional action of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)71.

 

Other transcriptional factors are also affected in this pathological pathway. SOX9 and FOXA2 is upregulated in the esophagus by acid reflux. These are transcription factors that characterize columnar cells. The NF-κB pathway also targets CDX2, which in turn guides the formation of intestinal epithelium. It is also hypothesised that acid reflux downregulates the squamous epithelial transcription factor SOX271. These factors all impact on gene regulation, cell growth, cell differentiation and cell apoptosis.

Further Study of SG and its’ associated long-term complications may represent an alternate opportunity to shed further insights into the understanding of mechanisms behind BE and its subsequent progression.

Most of the studies employed a wide variety of methods to diagnose and assess GERD, limiting the statistical comparability of our analysis. With the aim of providing a more objective view, we selected studies for subgroup analysis which fulfilled diagnostic criteria according to the 2018 Lyon Consensus54. Although the number of included studies were low, the results confirmed an increase in POGAS that was consistent with our overall results.

The beneficial effects of SG including weight loss, cardiovascular protection, anti-cancer effects69, 70 and metabolic enhancement have traditionally been considered to outweigh the potential risks associated with GERD72, 73. Several questions, however remain regarding the exact applications of SG distinct from other procedures with regard to appropriate inclusion criteria, methods and follow-up timeframe. We additionally suggest the significant contrition of POGAS, esophagitis and BE as important determinants in all future discussions for the consensus of SG in clinical practice.

Strengths and Limitations

This large integrated dataset of multiple studies has been able to clarify the prevalence of post-operative outcomes in SG patients. It demonstrates significant effect on post-operative prevalence of GERD, esophagitis and Barrett’s Esophagus. The findings should prompt reconsideration of current clinical practice and guidelines.

On the other hand, only a hand full of studies were of the highest quality. There was high heterogeneity and no data from randomized controlled trials. Different studies had variable selection criteria when offering surgery to those with and without GERD. There was a lack of data regarding standardisation of surgical technique. The range of follow up time was variable, and long-term sub-group analysis was performed in an attempt to offset this. Studies used a variety of methods to investigate and define reflux and its associated outcomes; this ranged from clinical notes to validated questionnaires to invasive and physiological investigations of pH manometry, upper GI endoscopy or a combination of the above. The subgroup analysis using the Lyon Consensus criteria was performed in an attempt to address this, although the numbers of studies applying these criteria was very low. Some studies aimed to investigate reflux specifically while others reported it as secondary outcomes. Studies using physiological and invasive techniques to investigate GERD found higher rates than those using symptomology alone. It is possible that the true rates of GERD are under reported here. Finally, there is a discrepancy in the number of studies included for each outcome. For example, 35 studies in change in reflux compared to only 6 in Barrett’s Esophagus. All of the above limits the interpretation of these datasets.

Future Work

Further work should investigate the effect of surgical technique and other factors such as bougie size and concomitant hiatus hernia repair on the rates of GERD post operatively. Large scale registry based, and randomized control trial studies designed to specifically investigate the long-term nature of SG complications using consensus criteria will also be helpful.

CONCLUSION

The post-operative prevalence of GERD, esophagitis and Barrett’s Esophagus following SG is significant. Symptoms do not always correlate with the presence of pathology. As the surgical uptake of SG continues to increase, there is a need to ensure that surgical decision-making and the consent process for this procedure considers these long-term complications whilst also ensuring their post-operative surveillance through endoscopic and physiological approaches. The long-term outcomes of this commonly performed bariatric procedure should be further investigated and considered alongside its weight-loss and metabolic effects.

ACKNOWLEDGEMNETS

Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC).

CONFLICT OF INTERETS

All Authors have no conflict of interests to declare for this study.

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Does Sleeve Gastrectomy expose the distal Esophagus to Severe Reflux? A Systematic Review & Meta-analysis