{'fraction_non_alphanumeric': 0.03947272061515928, 'fraction_numerical': 0.022116440864152324, 'mean_word_length': 5.101876675603217, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Association between gastroesophageal reflux disease and nonalcoholic fatty liver disease: A meta-analysis Systematic Review/Meta-analysis

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 I 2 of 87%. Conclusions: A significantly increased risk of NAFLD among patients with GERD was observed in this meta-analysis. Abstract


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. [1] Insulin resistance and chronic inflammation are closely linked to the pathogenesis of NAFLD [2] and are often considered as the liver manifestation of metabolic syndrome. [3] With the pandemic of obesity, NAFLD is estimated to affect over 64 million people in the United States. [3][4][5] Risk factors of NAFLD include obesity, hypertension, dyslipidemia, hyperuricemia, lack of sleep, and physical inactivity. [2,[6][7][8][9] 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. [10] It is more common in Western countries with the estimated prevalence of 20% compared with <5% in Asian countries. [11] GERD is a risk factor for esophageal adenocarcinoma and several extraesophageal diseases including laryngitis, reflux asthma syndrome, interstitial lung disease, and recurrent otitis media. [10] Recent studies have suggested that GERD could also be a risk factor for NAFLD although the results were inconsistent. [12][13][14][15][16][17][18][19][20] 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.

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.

Selection criteria
Eligible studies were required to be cross-sectional, casecontrol, 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. [21] The modified Newcastle-Ottawa scale as described by Herzog et al. was used for cross-sectional study. [22] Data abstraction 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.).

Statistical analysis
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. [23] 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. [24]

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 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. [26] 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. [2,27] 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. [28] 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. [29][30][31] Increased oxidative stress associated with inflammation is also deleterious to the esophageal muscular layer. [32,33] 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. [34,35] 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. [36,37] comparative analysis. Ten studies met the eligibility criteria. However, four studies utilized the same database. [16,17,19,25] The Choi et al. [25] and the Lee et al. [19] studies used the same cohort of employees of three Korean universities from 2007 to 2009. Similarly, the studies by Kang et al. [16] and Kim et al. [17] 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. [19] and Kang et al. were included. Those two studies were chosen over the studies by Choi et al. [25] and Kim et al. [17] as they provided more comprehensive data in the articles. Therefore, eight studies (four cross-sectional studies [15,16,19,26] and four case-control studies [12,14,18,20] ) 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   [19] Fujikawa et al. [14] Kang et al. [16] Miele et al. [ [20] Hung et al. [15] Chung et al. [26] Catanzaro et al. [12] Country Japan Taiwan  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. [38][39][40] 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. [41][42][43] [20] Hung et al. [15] Chung et al. [26] Catanzaro et al. [12] Diagnosis 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 [26] 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.

Disclosure
The authors have no commercial associations that might be a conflict of interest about this article. No funding support for this article.