|Year : 2017 | Volume
| Issue : 6 | Page : 311-317
|Association between gastroesophageal reflux disease and nonalcoholic fatty liver disease: A meta-analysis
Karn Wijarnpreecha1, Panadeekarn Panjawatanan2, Charat Thongprayoon1, Veeravich Jaruvongvanich3, Patompong Ungprasert4
1 Department of Internal Medicine, Bassett Medical Center, Cooperstown, New York, USA
2 Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
3 Department of Internal Medicine, University of Hawaii, Honolulu, USA
4 Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA; Division of Rheumatology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok
Click here for correspondence address and email
|Date of Web Publication||4-Dec-2017|
| Abstract|| |
Background/Aim: The relationship between gastroesophageal reflux disease (GERD) and nonalcoholic fatty liver disease (NAFLD) has been demonstrated in recent epidemiologic studies although the results were inconsistent. This meta-analysis was conducted to summarize all available data and to estimate the risk of NAFLD among patients with GERD.
Materials and Methods: Comprehensive literature review was conducted using MEDLINE and EMBASE database from inception through November 2016, to identify studies that compared the risk of NAFLD among patients with GERD versus those without GERD. Effect estimates from each study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird.
Results: Eight studies (four cross-sectional studies and four case–control studies) with 31,322 participants met the eligibility criteria and were included in the meta-analysis. The risk of NAFLD among patients with GERD was significantly higher than those without GERD with the pooled odds ratio of 2.07 (95% confidence interval, 1.54–2.79). The statistical heterogeneity was high with an I2 of 87%.
Conclusions: A significantly increased risk of NAFLD among patients with GERD was observed in this meta-analysis.
Keywords: Erosive esophagitis, gastroesophageal reflux, meta-analysis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis
|How to cite this article:|
Wijarnpreecha K, Panjawatanan P, Thongprayoon C, Jaruvongvanich V, Ungprasert P. Association between gastroesophageal reflux disease and nonalcoholic fatty liver disease: A meta-analysis. Saudi J Gastroenterol 2017;23:311-7
|How to cite this URL:|
Wijarnpreecha K, Panjawatanan P, Thongprayoon C, Jaruvongvanich V, Ungprasert P. Association between gastroesophageal reflux disease and nonalcoholic fatty liver disease: A meta-analysis. Saudi J Gastroenterol [serial online] 2017 [cited 2022 Aug 8];23:311-7. Available from: https://www.saudijgastro.com/text.asp?2017/23/6/311/219809
| Introduction|| |
Nonalcoholic fatty liver disease (NAFLD) is a common hepatic disorder characterized by macrovesicular fat accumulation in the liver of individuals with no history of excessive alcohol consumption. Insulin resistance and chronic inflammation are closely linked to the pathogenesis of NAFLD  and are often considered as the liver manifestation of metabolic syndrome. With the pandemic of obesity, NAFLD is estimated to affect over 64 million people in the United States.,, Risk factors of NAFLD include obesity, hypertension, dyslipidemia, hyperuricemia, lack of sleep, and physical inactivity.,,,,
Gastroesophageal reflux disease (GERD) is one of the common gastrointestinal ailments characterized by the reflux of stomach contents into esophagus causing symptoms of heartburn, regurgitation, and dysphagia. It is more common in Western countries with the estimated prevalence of 20% compared with <5% in Asian countries. GERD is a risk factor for esophageal adenocarcinoma and several extraesophageal diseases including laryngitis, reflux asthma syndrome, interstitial lung disease, and recurrent otitis media.
Recent studies have suggested that GERD could also be a risk factor for NAFLD although the results were inconsistent.,,,,,,,, To summarize all available data, we conducted this systematic review and meta-analysis of observational studies, which compared the risk of NAFLD among patients with GERD versus those without GERD.
| Materials and Methods|| |
Information sources and search strategy
A systematic literature search of MEDLINE and EMBASE database was carried out from inception to November 2016 to identify all original studies that investigated the association between GERD and NAFLD. The systematic literature review was independently conducted by three investigators (K.W., P.P., and P.U.) using the search strategy that included the terms for “gastroesophageal reflux” and “nonalcoholic fatty liver disease” as described in online supplementary data 1. No language limitation was applied. A manual search for additional potentially relevant studies using references of selected included articles was also performed. This study was conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement, which is provided as online supplementary data 2.
Eligible studies were required to be cross-sectional, case–control, or cohort studies that investigated the relationship between GERD and NAFLD. They were also required to provide the effect estimates [odds ratios (OR), relative risks (RR), hazard ratios (HR) or standardized incidence ratio (SIR)] with 95% confidence intervals (CI). Inclusion was not restricted by study size. When more than one article using the same database/cohort was available, the study with the most comprehensive data/analyses was included.
Retrieved articles were independently reviewed for their eligibility by the same three investigators (K.W., P.P., and P.U.). Disagreement was resolved by conference with all investigators. Newcastle-Ottawa quality assessment scale was used to appraise the quality of the study in three areas, including the recruitment of cases and controls, the comparability between the groups, and the ascertainment of the outcome of interest for cohort study and the exposure for case–control study. The modified Newcastle-Ottawa scale as described by Herzog et al. was used for cross-sectional study.
A structured data collection form was used to extract the following data from each study: title of the study, name of the first author, publication year, year of the study, country where the study was conducted, number of subjects, demographics of subjects, methods used to identify and verify GERD and NAFLD, adjusted effect estimates with 95% CI, and covariates that were adjusted in the multivariable analysis.
To ensure the accuracy, this data extraction process was independently performed by two investigators (K.W. and P.P.) and was reviewed by the senior investigator (P.U.).
Data analysis was performed using the Review Manager 5.3 software from the Cochrane Collaboration (London, UK). Adjusted point estimates from each study were combined by the generic inverse variance method of DerSimonian and Laird, which assigned the weight of each study for the pooled analysis based on its variance. As the outcome of interest was relatively uncommon, we planned to use RR and HR of cohort study as an estimate for OR to calculate the pooled effect estimates with OR of case–control study and cross-sectional study. In light of the high likelihood of between-study variance because of different study designs, populations, and methodologies, random-effect model was used. Cochran's Q test and I 2 statistic were used to determine the between-study heterogeneity. A value of I 2 of 0–25% represents insignificant heterogeneity, 26–50% represents low heterogeneity, 51–75% represents moderate heterogeneity, and >75% represents high heterogeneity.
| Results|| |
Using our search strategy, 962 potentially eligible articles were identified (350 articles from MEDLINE and 612 articles from EMBASE). After the exclusion of duplicated 320 articles, 642 articles underwent title and abstract review; 624 articles were excluded at this stage because they were case reports, case series, correspondences, review articles, in vitro studies, animal studies, or interventional studies, leaving 25 articles for full-text review. Twelve of them were excluded after the full-length review as they did not report the outcome of interest, while three articles were excluded as they were descriptive studies without comparative analysis. Ten studies met the eligibility criteria. However, four studies utilized the same database.,,, The Choi et al. and the Lee et al. studies used the same cohort of employees of three Korean universities from 2007 to 2009. Similarly, the studies by Kang et al. and Kim et al. used the same cohort recruited from Myongji Hospital, Goyang, Korea from 2004 to 2011. To avoid double-counting of the same data, only the studies by Lee et al. and Kang et al. were included. Those two studies were chosen over the studies by Choi et al. and Kim et al. as they provided more comprehensive data in the articles. Therefore, eight studies (four cross-sectional studies ,,, and four case–control studies ,,,) with 31,322 participants were included in the final analysis. The literature retrieval, review, and selection process are shown in [Figure 1]. The characteristics and quality assessment of the studies are shown in [Table 1]. It should be noted that the inter-rater agreement for the quality assessment using the Newcastle-Ottawa scale was high with the kappa statistics of 0.85.
We found a significantly increased risk of NAFLD among patients with GERD with the pooled OR of 2.07 (95% CI, 1.54–2.79), as demonstrated in [Figure 2]. The between-study heterogeneity was high with an I 2 of 87%. Subgroup analysis according to study design showed a significantly elevated risk in both cross-sectional (pooled OR 1.52; 95% CI, 1.15–2.00; I 2 86%) and case–control subgroup (pooled OR 3.04; 95% CI, 2.27–4.06; I 2 0%).
Because the statistical heterogeneity remained high in cross-sectional study subgroup, we have conducted a jack-knife sensitivity analysis by excluding one study at a time from the full analysis. Interestingly, we found that exclusion of the study by Chung et al. dramatically reduced I 2 to 1% and did not significantly alter the pooled effect estimate of this subgroup (pooled OR 1.24; 95% CI, 1.14–1.35).
Evaluation for publication bias
Funnel plot was used to assess publication bias [Figure 3]. The graph is asymmetric and, thus, suggests that publication bias in favor of positive studies might have been present.
| Discussion|| |
This study is the first systematic review and meta-analysis that summarizes all available data on the association between GERD and NAFLD. We found an approximately two-fold increased risk of NAFLD among patients with GERD compared with subjects without GERD.
Why patients with NAFLD have a higher risk of NAFLD is not well-understood. There are several possible explanations.
First, the apparent association may not be causal but is a result of shared underlying risk factors. Central obesity is the key feature of metabolic syndrome and is linked to both NAFLD and GERD. It is well known that visceral fat plays an important role in insulin resistance, the prime factor in the pathogenesis of NAFLD., It has been demonstrated that increased abdominal pressure from the accumulation of visceral fat is a contributing factor to esophageal regurgitation and development of GERD. Moreover, visceral adipose tissue in human is known to produce several proinflammatory cytokines and increased level of these cytokines is associated with a lower esophageal sphincter tone, which could predispose to GERD.,, Increased oxidative stress associated with inflammation is also deleterious to the esophageal muscular layer., Unhealthy eating habit such as heavy meals before bedtime could lead to both GERD and obesity (and, thus NAFLD). Hypertriglyceridemia is another component of metabolic syndrome and, thus, is common among patients with NAFLD., Interestingly, studies have suggested that triglyceride could affect the lower esophageal sphincter's tone and could possibly be the shared underlying factor between NAFLD and GERD.,
Second, NAFLD may be linked to GERD via autonomic nervous system dysfunction. Studies have demonstrated that patients with NAFLD had a higher prevalence of autonomic disturbance.,, The cause of this increased autonomic abnormality is still not known. Studies have also shown that autonomic dysfunction could lead to abnormal gastric and esophageal motility and, thus, predispose to development of GERD.,,
Although the quality of included studies was high as reflected by the high Newcastle-Ottawa scores and the literature review process was comprehensive, we acknowledge that this study has some limitations and the results should be interpreted with caution.
First, statistical heterogeneity was high in the meta-analysis. We believe that the difference in study design was the main source of the between-study variation as subgroup analysis of only case–control studies showed an I 2 of 0%. Nonetheless, the statistical heterogeneity remained high in cross-sectional study subgroup. The I 2 decreased dramatically after the exclusion of the only study  that used transient elastography to diagnose NAFLD (other cross-sectional studies used ultrasonography), which may suggest that the difference in the methods used to diagnose NAFLD was also responsible for the high between-study variation. Second, all of the included studies were cross-sectional and case–control studies. There is no longitudinal study that investigates this association. Therefore, the temporal relationship between GERD and NAFLD could not be clearly established. Third, the funnel plot of this meta-analysis was asymmetric. Therefore, publication bias in favor of positive study may have been present. Fourth, almost all of the included studies were conducted in Asian countries, which have a lower prevalence for both GERD and NAFLD. Therefore, generalizability of the results to other populations could be limited.
| Conclusion|| |
In summary, this study demonstrated a significantly increased risk of NAFLD among patients with GERD. However, it is not known whether this association is causal or is a result of shared underlying risk factors. Further investigations are required to characterize the underlying pathogenesis.
The authors have no commercial associations that might be a conflict of interest about this article. No funding support for this article.
All authors had access to the data and a role in writing the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: From steatosis to cirrhosis. Hepatology 2006;43:S99-112.
Byrne CD, Targher G. NAFLD: A multisystem disease. J Hepatol 2015;62:S47-64.
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease: Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73-84.
Sayiner M, Koenig A, Henry L, Younossi ZM. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world. Clin Liver Dis 2016;20:205-14.
Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, et al
. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 2016;64:1577-86.
Wijarnpreecha K, Panjawatanan P, Lekuthai N, Thongprayoon C, Cheungpasitporn W, Ungprasert P. Hyperuricemia and risk of nonalcoholic fatty liver disease: A meta-analysis. Liver Int 2017;37:906-18.
Wijarnpreecha K, Thongprayoon C, Edmonds PJ, Cheungpasitporn W. Associations of sugar- and artificially sweetened soda with nonalcoholic fatty liver disease: A systematic review and meta-analysis. QJM 2016;109:461-6.
Wijarnpreecha K, Thongprayoon C, Panjawatanan P, Ungprasert P. Short sleep duration and risk of nonalcoholic fatty liver disease: A systematic review and meta-analysis. J Gastroenterol Hepatol 2016;31:1802-7.
Wijarnpreecha K, Thongprayoon C, Ungprasert P. Coffee consumption and risk of nonalcoholic fatty liver disease: A systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2017;29:e8-12.
Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus G. The Montreal definition and classification of gastroesophageal reflux disease: A global evidence-based consensus. Am J Gastroenterol 2006;101:1900-20.
Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut 2005;54:710-7.
Catanzaro R, Calabrese F, Occhipinti S, Anzalone MG, Italia A, Milazzo M, et al
. Nonalcoholic fatty liver disease increases risk for gastroesophageal reflux symptoms. Dig Dis Sci 2014;59:1939-45.
Chung HC, Lee H, Park JC, Shin SK, Lee YC, Kim SU, et al
. Hepatic steatosis is associated with increased risk and severity of erosive esophagitis. Gastroenterology 2014;146:S-751.
Fujikawa Y, Tominaga K, Fujii H, Machida H, Okazaki H, Yamagami H, et al
. High prevalence of gastroesophageal reflux symptoms in patients with non-alcoholic fatty liver disease associated with serum levels of triglyceride and cholesterol but not simple visceral obesity. Digestion 2012;86:228-37.
Hung WC, Wu JS, Yang YC, Sun ZJ, Lu FH, Chang CJ. Nonalcoholic fatty liver disease vs. obesity on the risk of erosive oesophagitis. Eur J Clin Invest 2014;44:1143-9.
Kang BD, Choi JS, Choi JY, Kim YJ, Cho JH, Han KJ, et al
. Fatty liver diagnosed by ultrasonography is associated with the risk of erosive reflux esophagitis. J Gastroenterol Hepatol 2012;27:142-3.
Kim P, Jeong SH, Kim HM. Fatty liver is associated with the increased risk of erosive reflux esophagitis, not minimal change esophagitis. J Gastroenterol Hepatol 2016;31:117-8.
Miele L, Cammarota G, Vero V, Racco S, Cefalo C, Marrone G, et al
. Non-alcoholic fatty liver disease is associated with high prevalence of gastro-oesophageal reflux symptoms. Dig Liver Dis 2012;44:1032-6.
Sangheun Lee HMK, Kim YJ. Moon CM, Cho JH, Han KJ. Erosive esophagitis is associated with fatty liver in school workers. Gastroenterology 2011;140:S-256.
Yamamoto SK, Nishiyama M, Fukuoka M, Kudo S, Maesaka K, Shirai K, et al
. Features of upper gastrointestinal abnormalities in non-alcoholic steatohepatitis (NASH) patients. United European Gastroenterology Journal 2014;2:A450.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603-5.
Herzog R, Alvarez-Pasquin MJ, Diaz C, Del Barrio JL, Estrada JM, Gil A. Are healthcare workers' intentions to vaccinate related to their knowledge, beliefs and attitudes? A systematic review. BMC Public Health 2013;13:154.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.
Choi HK, Lee SH, Kim YJ, Cho JH, Han KJ. Fatty liver is associated with increased risk for erosive esophagitis in school workers. J Gastroenterol Hepatol 2011;26:16-288.
Chung YE, Lee H, Park JC, Shin SK, Lee YC, Kim SU, et al
. Hepatic steatosis is associated with increased risk and severity of erosive esophagitis. Gastroenterology 2014;146:S-751.
Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 2003;278:45777-84.
El-Serag HB, Tran T, Richardson P, Ergun G. Anthropometric correlates of intragastric pressure. Scand J Gastroenterol 2006;41:887-91.
Cao W, Cheng L, Behar J, Fiocchi C, Biancani P, Harnett KM. Proinflammatory cytokines alter/reduce esophageal circular muscle contraction in experimental cat esophagitis. Am J Physiol Gastrointestinal Liver Physiol 2004;287:G1131-9.
Nam SY, Choi IJ, Ryu KH, Park BJ, Kim HB, Nam BH. Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women. Gastroenterology 2010;139:1902-11.
Tilg H, Moschen AR. Visceral adipose tissue attacks beyond the liver: Esophagogastric junction as a new target. Gastroenterology 2010;139:1823-6.
Erbil Y, Turkoglu U, Barbaros U, Balik E, Olgac V, Kaya H, et al
. Oxidative damage in an experimentally induced gastric and gastroduodenal reflux model. Surg Innov 2005;12:219-25.
Oh TY, Lee JS, Ahn BO, Cho H, Kim WB, Kim YB, et al
. Oxidative stress is more important than acid in the pathogenesis of reflux oesophagitis in rats. Gut 2001;49:364-71.
Matsuzaki J, Suzuki H, Iwasaki E, Yokoyama H, Sugino Y, Hibi T. Serum lipid levels are positively associated with non-erosive reflux disease, but not with functional heartburn. Neurogastroenterol Motil 2010;22:965-70.
Wu P, Ma L, Dai GX, Chen Y, Tong YL, Wang C, et al
. The association of metabolic syndrome with reflux esophagitis: A case-control study. Neurogastroenterol Motil 2011;23:989-94.
Ledeboer M, Masclee AA, Biemond I, Lamers CB. Effect of medium-and long-chain triglycerides on lower esophageal sphincter pressure: Role of CCK. Am J Physiol 1998;274:G1160-5.
Shapiro M, Green C, Bautista JM, Dekel R, Risner-Adler S, Whitacre R, et al
. Assessment of dietary nutrients that influence perception of intra-oesophageal acid reflux events in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2007;25:93-101.
Liu YC, Hung CS, Wu YW, Lee YC, Lin YH, Lin C, et al
. Influence of non-alcoholic fatty liver disease on autonomic changes evaluated by the time domain, frequency domain, and symbolic dynamics of heart rate variability. PLoS One 2013;8:e61803.
Sabath E, Baez-Ruiz A, Buijs RM. Non-alcoholic fatty liver disease as a consequence of autonomic imbalance and circadian desynchronization. Obes Rev 2015;16:871-82.
Sun W, Zhang D, Sun J, Xu B, Sun K, Wang T, et al
. Association between non-alcoholic fatty liver disease and autonomic dysfunction in a Chinese population. QJM 2015;108:617-24.
Chen CL, Orr WC. Autonomic responses to heartburn induced by esophageal acid infusion. J Gastroenterol Hepatol 2004;19:922-6.
Devendran N, Chauhan N, Armstrong D, Upton AR, Kamath MV. GERD and obesity: Is the autonomic nervous system the missing link? Crit Rev Biomed Eng 2014;42:17-24.
Lee YC, Wang HP, Lin LY, Lee BC, Chiu HM, Wu MS, et al
. Heart rate variability in patients with different manifestations of gastroesophageal reflux disease. Auton Neurosci 2004;116:39-45.
One Atwell Road, Cooperstown, New York
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
|This article has been cited by|
||Updates in interaction of gastroesophageal reflux disease and extragastroesophageal digestive diseases
| ||Yanqiu Li, Zhijun Duan |
| ||Expert Review of Gastroenterology & Hepatology. 2022; : 1 |
|[Pubmed] | [DOI]|
||Incidence of different types of irritable bowel syndrome in patients with nonalcoholic fatty liver
| ||Divna Popovic, Stefan Rošic, Snežana Lukic |
| ||Medicinski podmladak. 2022; 73(2): 6 |
|[Pubmed] | [DOI]|
||Helicobacter pylori, Sleeve Gastrectomy, and Gastroesophageal Reflux Disease: Is There a Relation?
| ||Michael Doulberis, Apostolis Papaefthymiou, Stergios A. Polyzos, Georgios Kotronis, Dimitra Gialamprinou, Maria Tzitiridou-Chatzopoulou, Maria Touloumtzi, Jannis Kountouras |
| ||Obesity Surgery. 2021; 31(4): 1839 |
|[Pubmed] | [DOI]|
||NAFLD Associated Comorbidity
| ||L. B. Lazebnik, S. V. Turkina |
| ||Experimental and Clinical Gastroenterology. 2021; (10): 5 |
|[Pubmed] | [DOI]|
||Association between Gastroesophageal Reflux Disease and Elastographic Parameters of Liver Steatosis and Fibrosis: Controlled Attenuation Parameter and Liver Stiffness Measurements
| ||Ivana Mikolasevic, Goran Poropat, Tajana Filipec Kanizaj, Nadija Skenderevic, Marko Zelic, Marija Matasin, Luka Vranic, Andrea Kresovic, Goran Hauser, Geoffrey Williams |
| ||Canadian Journal of Gastroenterology and Hepatology. 2021; 2021: 1 |
|[Pubmed] | [DOI]|
||Hepatoprotective properties of glycyrrhizic acid
| ||S. V. Okovity, K. L. Raikhelson, A. V. Volnukhin, D. A. Kudlai |
| ||Experimental and Clinical Gastroenterology. 2020; (12): 96 |
|[Pubmed] | [DOI]|
||Associations between gastro-oesophageal reflux disease and a range of diseases: an umbrella review of systematic reviews and meta-analyses
| ||JinJing Tan, Liqun Li, Xiaoyan Huang, Chengning Yang, Xue Liang, Yina Zhao, Jieru Xie, Ran Chen, Daogang Wang, Sheng Xie |
| ||BMJ Open. 2020; 10(12): e038450 |
|[Pubmed] | [DOI]|