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Gastroesophageal reflux disease and non-digestive tract diseases Expert Rev. Gastroenterol. Hepatol. Early online, 1–8 (2015)

Ying Chen Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Ruijin Er Road 197, Shanghai, 200025, People’s Republic of China Tel.: +86 02 164 370 045 Fax: +86 02 164 370 045 [email protected]

Over the past decade, incidence of gastroesophageal reflux disease (GERD) showed an increasing trend resulting from factors, including lifestyle and dietary habits; however, both etiology and pathological mechanisms remain controversial. GERD occurs as a result of a variety of mechanisms and there is no single factor. Symptoms of GERD are often non-typical, with a likelihood of being overlooked by non-gastroenterology professionals. Therefore, improving GERD awareness in non-gastroenterology practitioners, along with early diagnosis and treatment, provide potential benefit to clinicians and patients alike. Increasing evidence suggests GERD has specific connections with a variety of non-digestive tract conditions, may contribute an aggravating compounding effect on other diseases, prolong hospitalization, and increase subsequent medical costs. This review considers and emphasizes the association between GERD and non-digestive tract conditions, including atrial fibrillation, chronic obstructive pulmonary disease, primary pulmonary fibrosis and energy metabolism related to diet. KEYWORDS: atrial fibrillation . atypical symptom . etiology . gastroesophageal reflux disease . non-digestive tract disease

Gastroesophageal reflux disease (GERD) refers to a range of symptoms and associated complications caused by the backflow of stomach contents (including gastric acid) into the esophagus [1]. In Western Europe and North America, the incidence of GERD is recorded between 10 and 20%, while the incidence in Singapore was reported as 10% in 1999. During the last 10 years, the incidence of GERD has shown an increasing trend, although specific causes of GERD remain complex; recent studies suggest an association with a variety of factors, including lifestyle, obesity, age, Helicobacter pylori infection, the gradient increase of gastroesophageal pressure, hiatal hernia and a reduction in lower esophageal sphincter (LES) pressure. The pathological mechanisms of reflux have a potential association with the relaxation of LES, a weakening in esophageal mucosal barrier and reduction in the ability of esophageal acid clearance. GERD has a variety of clinical manifestations; typical symptoms include acid reflux and heartburn, whereas atypical symptoms of pharyngeal foreign body sensation, belching


and retrosternal discomfort have been recorded. Therefore, diagnosis of GERD includes evaluations based on clinical symptoms combined with diagnostic techniques, including questionnaires, endoscopy, esophageal pH monitoring, empirical proton pump inhibitor (PPI) tests and endoscopy results (grading based on endoscopic esophageal mucosal integrity, pathological diagnosis of Barrett’s esophagus and the presence of dysplasia). Primarily located in the chest and extending through the diaphragm into the abdominal cavity, the esophagus connects throat and stomach cavities with the neighboring non-digestive tract organs of throat, heart and trachea. When stomach contents, including gastric acid, bile, pepsin and possibly even pancreatic juice, enter the esophagus via the stomach cavity, the specialized physiological structure renders clinical manifestations of GERD to be associated with disorders of adjacent, non-digestive tract organs. This article emphasizes the association between GERD and non-digestive tract disease, with additionally related pathophysiological mechanisms.

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GERD & atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmic diseases. Due to the close positioning of esophagus and atria, and similar nerve innervations, it has been proposed that AF development is associated with the occurrence of GERD. AF has been drawing increasing attention with respect to an association with GERD. The progression of a continuity of arrhythmia starting from paroxysmal AF and developing into persistent or permanent AF has been shown to be accompanied with GERD in research over the last 10 years. Kunz et al. found that patients with GERD have an AF occurrence probability as high as 5%, while the presence of GERD increases the AF likelihood to 40% [2]. However, the nature of the GERD to AF relationship remains controversial in that both share similarities in risk factors, such as age, sleep disorders, obesity and diabetes, and is further compounded by the number of clinical classifications in AF and the variety of diagnostic criteria for GERD. Consequently, a combination of these factors may lead to a limitation in experimental design, and subsequently may affect the consistency in results. Precise mechanisms of AF are uncertain, but their association with esophageal disorders has recently been proposed. A recent clinic-based review study indicates a significant correlation of GERD and AF: The multi-site questionnaire surveyed and classified 188 outpatients with GERD symptoms after excluding factors of gender, hypertension, coronary artery disease, using multivariate statistical analysis, with results showing that AF was significantly associated with GERD, suggesting that AF is an independent risk factor of GERD, after removing cardiovascular risk factors [3]. This questionnaire is composed of two parts, seven items related to reflux-like symptoms and five items related to dysmotility-like dyspeptic symptoms. The cutoff value for the total score was set at 8 points to diagnose GERD, which has been reported to yield a sensitivity of 62%, a specificity of 59% and a diagnostic accuracy of 60%. In AF patients, the reflux, dyspeptic and total scores of patients with permanent AF (n = 61) did not differ from the respective scores of patients with paroxysmal AF (n = 25). Univariate analysis exploring the relation between factors and high scores showed an age-independent incidence of GERD and demonstrated that only AF remained a significant (p < 0.001) factor contributing to GERD. Multivariate analysis was also performed by incorporating these factors. In conclusion, AF alone was an independent contributor to the occurrence of symptomatic GERD. Another study sampled from the Taiwan National Health Insurance database showed the same results [4]. The study cohort comprised 29,688 newly diagnosed adult GERD patients; 29,597 randomly selected age-, gender-, comobiditymatched subjects comprised the comparison cohort. GERD patients were diagnosed by either endoscopy or 24-h pH meter inspection before PPI was prescribed as treatment. The diagnoses of GERD were valid. During a maximum 3 years followup, a total of 351 patients experienced AF, including 184 (0.62%) patients in the GERD cohort and 167 (0.56%) doi: 10.1586/17474124.2015.1012495

in the control group. The log-rank test showed that patients with GERD had significantly higher incidence of AF than those without GERD (p = 0.024). After Cox proportional hazard regression model analysis, GERD was independently associated with the increased risk of AF (hazard ratio: 1.31; 95% CI: 1.06–1.61, p = 0.013). Pathological mechanisms behind the association of AF with GERD remain unclear, although it is generally accepted that an enhancement in vagus nerve impulses augments the onset and sustenance of AF, while vagus stimulation reduces the regional atrial refractory period, thereby increasing its dispersion and reducing the re-entry loop. Meanwhile, vagal acetylcholine release acting on parietal cell receptors leads to increased gastric acid secretion and vagus control can also induce LES relaxation, facilitating the acidic stomach contents entering the esophagus. Efficient adjuvant therapy in the treatment of tachyarrhythmia and GERD is through modulation of the parasympathetic system by such drugs as antianxietics. It seems, therefore, that both GERD and AF are two disease outcomes produced by one mechanism, the actions of the vagus nerve; however, it remains unclear if there exists a causal relationship. Since 2010, a number of studies have shown a relationship between AF and inflammatory cytokines. C-reactive protein (CRP) is an important inflammatory marker [5]; Bruins et al. were the first to study the correlation and suggest the presence of a particular relationship between inflammation and AF [6]. Pepys et al. speculated that CRP may directly affect atrium structure via the activation of serum complement [7]. Other than serum CRP, other inflammatory cytokines such as IL-6 and TNF-a have also been associated with AF. Boos et al. showed that patients with AF have higher serum levels of IL-6 and TNF-a than patients with sinus rhythm [8]. Therefore, inflammation plays a crucial role in the occurrence and maintenance of AF. In the case of sustained acid reflux, esophageal epithelium stimulation can produce inflammation and secretion of a wide variety of inflammatory cytokines, such as IL-1 and IL-6 [9,10], the latter stimulating parasympathetic nerves leading to disorders in atrial electrical transmission. Moreover, a number of studies found that the inflammatory cytokines produced by the esophageal epithelium in patients with GERD were highly consistent with those cytokines detected near the tissues of pulmonary vein and atrium in AF patients [11]. In addition, the inflammatory response can facilitate thrombosis increasing the probability of embolism as a complication of AF: the inflammatory cytokine hypothesis. Isomoto et al. studied endoscopy-negative GERD, erosive reflux esophagitis and epithelial dysplasia esophagitis and found that levels of IL-8 were significantly higher in the epithelial cells, which were also found to express a high level of TNF-a [12]. IL-8 and associated inflammatory factors mediate the migration and activity of peripheral blood leukocytes, producing oxygen radicals and aggravating tissue necrosis and cellular apoptosis [13]. Expert Rev. Gastroenterol. Hepatol.

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GERD & non-digestive tract diseases

Rieder F et al. conducted an in vitro culture of the esophageal mucosa tissues from esophagitis and non-esophagitis patients and found that IL-6 levels in patients with esophagitis were significantly increased, also noting that gastric acid stimulation caused cells to express more IL-6, which in turn decreased lower esophageal circular muscle contractility and increased gastroesophageal reflux. These inflammatory factors are the same cytokines involved in the occurrence and sustention of AF [14]. Other studies have provided alternative evidence for supporting the inflammatory cytokine hypothesis in AF and GERD. The PPI can prevent the exchange of hydrogen and potassium ions across a cell membrane thereby reducing glandular gastric acid secretion, hence its long-term use to relieve symptoms in patients with GERD or acid reflux. For patients with persistent AF and GERD, PPI shows a 78% treatment efficiency for AF [15]. Using 24-h esophageal pH examination and Holter electrocardiography monitoring, Gerson et al. [16], found that PPI could significantly reduce AF and acid reflux. It has been shown that GERD may induce AF through a particular mechanism: esophageal inflammation, pericarditis–myocarditis and vagus nerve damage induced by an increase in local inflammatory factors in blood and mediastinum; this is further supported by recent studies that suggest that PPI could reduce the inflammatory reaction by blocking oxidative stress. As a result of damage caused by factors such as inflammation, oxygen transfer in the mitochondrial oxidative respiratory chain was inhibited. Therefore, oxygen free radicals, produced by radical oxidative stress, can induce apoptosis leading to myocardial remodeling – a significant risk factor of AF. Reducing agents have been primarily used to remove oxygen free radicals in the body, including glutathione which provides hydrogen ions that bind to oxygen free radicals inhibiting oxidant damage. Pastoris et al. [17] found that esomeprazole is transformed into tetracyclic sulfonamide in the body, with the resulting thiolcontaining compound serving as a supplement to the reduction of glutathione caused by oxidative stress, thus reducing peroxide-accumulated mucosal damage. The two principle types of hiatal hernia are sliding and rolling hernia. Sliding hernia is where the gastroesophageal junction moves into the chest above the diaphragm; by using gastric endoscopy, a shift of the dentate line caused by gastric mucosa sliding into the chest is visible. In rolling hernia, the gastroesophageal junction remains located below the diaphragm, and an additional sac is developed from gastric tissue and retained in the lung intestinal cavity with no reflux of gastric contents. In the supine position, or with an elevation in intra-abdominal pressure, a sliding hernia can be induced with reflux, heartburn and other symptoms. More than half of the patients with sliding hernia experience accompanying gastroesophageal reflux. Given that stomach tissue moving into the chest can compress the left atrium, affecting sinus rhythm, the enlarged left atrium often oppresses the neighboring lower esophagus area resulting in a series of GERD symptoms. Therefore, in the presence of hiatal hernia, the probability of


combined GERD and AF is greatly increased due to the reinforcing effect on each other. Radiofrequency catheter ablation (RFCA), which has been developed in recent years, offers a surgical technique with the possibility of curing AF. Matin et al. evaluated the DeMeester scores among 31 patients prior to RFCA and found that 16.1% were diagnosed with GERD and, with use of lower esophageal pH monitoring, that 16.1% of patients with negative scores had gastroesophageal reflux. Comparing before and after RFCA, they confirmed that one patient (3.2%) had esophageal ulcers by endoscopy [18]. Esophageal ulcers induced during or after the RFCA can cause serious complications, atrial-esophageal fistula, with an incidence of 0.02% and a mortality rate between 50 and 80%, accounting for 6% mortality of radiofrequency ablation surgery [19]. The cause of RFCAassociated atrial fistula is not yet clear; however, a variety of factors, such as a high incidence of GERD with AF, stimulated vagus-induced gastric acid secretion, LES relaxation as well as heat generated by RFCA, are known to aggravate gastroesophageal reflux and esophageal ulcers in AF patients. A considerable number of studies suggest GERD and esophageal ulcers may play a role in the incidence and risk of atrial-esophageal fistula. Therefore, preventing esophageal ulcer development is particularly important and makes it necessary to understand a patient’s gastroesophageal reflux condition and esophageal ulcer state prior to RFCA. After RFCA, PPI treatment may be effective for AF patients with these associated risks [20,21]. GERD & chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a common, frequently occurring condition and currently ranks fourth among the causes of death worldwide with an expectation to be the third by 2020. Recent epidemiological surveys in China indicate that people over the age of 40 have a prevalence rate of 8%. In 2006, Global Initiative for Chronic Obstructive Pulmonary Disease considered COPD as a common but treatable and preventable disease with significant extra-pulmonary effects closely related to the severity of the patient’s condition. COPD, characterized by the presence of a limitation in airflow, is not fully reversible, and pulmonary function tests are considered the gold standard in diagnosis; with the use of a bronchodilator, forced expiratory volume in 1 s/forced vital capacity 50%, only 9% had GERD, suggesting that the degree of damage to lung function in COPD patients was significantly correlated with GERD. Therefore, COPD patients with GERD should receive early treatment for GERD in order to cut the influence of GERD on COPD and prevent deterioration in lung function. Expert Rev. Gastroenterol. Hepatol.

GERD & non-digestive tract diseases

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GERD & primary pulmonary fibrosis

Patti et al. [29] found that 66% of patients with primary pulmonary fibrosis (IPF) were also suffering from GERD. Rogha et al. [30] studied 46 cases of IPF patients using a 24-h pH test when discontinuing PPI; the resulting statistical analysis found that 68.6% of patients with IPF had an attributable risk percentage to acid exposure. IPF is a pulmonary fibrosis with unknown etiology and median survival after diagnosis of 2–3 years. Studies have shown that during an acute exacerbation period of IPF, pepsin can be detected in the bronchoalveolar lavage fluid, suggesting an inhalation of gastroesophageal contents [31]. Two recent retrospective cohort studies showed that during diagnosis, acid suppression therapy significantly prolonged survival time. Joyce S Lee et al. [32] conducted a randomized controlled, prospective study on 242 IPF patients and found that during the 30th week patients treated with PPI or H2 receptor antagonists had a significant reduction in forced vital capacity compared with the placebo patient control group. Forced vital capacity has a significant positive correlation with survival in IPF, suggesting that acid suppression therapy can lessen the deterioration in lung function, thereby delaying disease progression. Another case–control retrospective study lasting 7 years investigated 204 IPF patients over two hospital sites; after balancing influencing factors such as age, BMI, lung function and use of corticosteroid, it was found that patients with symptoms of gastroesophageal reflux diagnosed with GERD and using anti-reflux drugs for treatment had a longer survival time. Additionally, patients treated with GERD had a lower score of pulmonary fibrosis when examined by high-resolution computed tomography [33]. For the end-stage treatment of IPF, lung transplantation is needed to extend a patients’ life. Davis et al. conducted an analysis on 252 samples of bronchoalveolar lavage fluid from 100 cases of lung transplant patients from September 2009 to November 2011 and found that, when compared to other endstage lung transplant patients with cystic fibrosis or COPD, the bronchoalveolar lavage fluid of IPF transplant patients had higher concentrations of pepsin and higher incidence of acute rejection. Moreover, the concentration of pepsin in bronchoalveolar lavage fluid was inversely associated with LES pressure, suggesting the diagnosis of GERD to be an important factor in postoperative prognosis of IPF lung transplant patients and the potential benefit of a thoracic transplant while performing antireflux surgery [34]. GERD & energy metabolism

Nearly 20 years of one epidemiological survey found that the rising incidence of GERD, obesity and diabetes were surprisingly consistent; whether there is a correlation between these three factors has become a focus of research. In 2000, Jacobson et al. investigated the relationship of BMI and GERD among 10,545 female patients and then used questionnaires for scoring GERD; the results suggest that when


using BMI 20–22.4 as a benchmark, the occurrence of reflux was proportional to the BMI index. Meanwhile, for people with an average weight, a slight increase in weight aggravated reflux symptoms [35]. This large-scale population study provided a strong confirmation of the correlation between BMI and GERD. However, this study was conducted using a women only sample group limiting a greater generalization. Since then, studies of BMI and GERD have continued with two recent meta-analyses also drawing the same conclusion of a BMI association with GERD [36,37]. Obese patients often have a high intake of fat and sugar, and through pH monitoring study it was found that a high-fat diet, instead of high-sugar, was associated with typical GERD symptoms. Intake of fibrous food can reduce GERD symptoms [38]. For those with a BMI index reaching morbidly obese (>35), the intra-abdominal pressure is greatly increased [39], aggravating the pressure gradient in the abdominal cavity and facilitating the occurrence of gastroesophageal reflux. There is clinical evidence to show that after weight loss, a remission of GERD symptoms can occur. The Society of American Gastrointestinal Disease even suggested that for GERD patients with short-term weight gain or obesity, treatment of gastroesophageal reflux can be effected through weight loss [40]. Currently, the correlation of BMI and GERD symptoms and severity is widely recognized. Obesity includes the increase in both abdominal and peripheral fat, although there is a variance in the degree of impact each has on the onset and development of GERD. A case–control study of 688 subjects found that abdominal fat is more prone to produce Barrett’s esophagus. The trial suggested that abdominal fat increases the correlation of GERD with multiple factors, such as an increase in intra-abdominal pressure, elevation of the diaphragm, hiatal hernia, prolonged food removal time in the esophagus and LES relaxation [41]. At present, the pathogenesis for the correlation between abdominal obesity and GERD is not clear, but a currently accepted hypothesis is that due to the increase in abdominal circumference in central obesity, an increase in intra-abdominal pressure is caused and, therefore, both stomach and esophageal pressure gradients increase resulting in the occurrence of hiatal hernia or reflux [42–45]. In addition, it has been proved that active metabolism in visceral fat is a cytoprotective factor; accumulation in visceral fat and reduction in metabolism may result in a high level of inflammatory cytokines, TNF-a, IL-1 and IL-6b for instance, which aid gastroesophageal reflux-induced mucosal inflammation and thus develop reflux esophagitis and Barrett’s esophagus (BE) [46]. It is well established that obesity, insulin resistance and diabetes are closely related, and the correlation with GERD has been of question. In recent years, a number of relevant studies have been unable to find a consistent conclusion. In a large-scale population survey involving 65,333 people conducted in Norway, no significant correlation between GERD and diabetes mellitus (DM) was found [47]. After age and sex factors were balanced, another a large-scale population study in the UK even found doi: 10.1586/17474124.2015.1012495

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that the risk of diabetes was reduced in the first year after a diagnosis of GERD [48]. However, another small-sized study indicated a particular link seemed to exist between GERD and DM; the study measured the 24-h esophageal pH in 50 insulin-dependent DM patients who had no GERD symptoms and found that 28% of patients had an incidence of reflux that was significantly greater than the control group. This study also found this high incidence of GERD to be correlated with diabetes-related cardiovascular autonomic neuropathy [49]. Another 14,245 population-based case–control study indicated that BE patients showed a higher prevalence of Type 2 DM than the control group, with females showing higher gender relevance. After removing the BMI factors, it was considered that DM was an independent risk factor of BE [50,51]. One of the pathological mechanisms of Type 2 DM patients is insulin resistance, which increases insulin and insulin resistance factor-I (IGF-I) and decreases insulin-binding protein (IGFBP). A study investigated 135 BE, 135 GERD and 932 healthy colonoscopy controls and concluded that, compared to controls, GERD and BE had a higher level of insulin and high activity of IGF-I [52]. Rubenstein published an article in 2013 and postulated that male GERD patients with hyperinsulinemia had a positive correlation with BE, whereas leptin and ghrelin reduced hyperinsulinemia and decreased this correlation; this study indicates that metabolism-related hormones might effectively treat BE triggered by GERD, though BE is only an esophageal precancerous lesion [53]. Although this was an early study in its field, it has aroused great interest among related disciplines. As mentioned earlier, since BMI and GERD

have a definite relationship, targeting the energy metabolism of BMI may be a new approach to treating GERD. Another interesting in vitro study found that omeprazole can stimulate the expression of human insulin-like growth factor-binding protein [54]. However, it remains unknown as to whether PPI exerts its impact on the outcomes of GERD via IGF’s regulatory effect of fat metabolism. Expert commentary & five-year view

Due to factors such as lifestyle and dietary habits, the incidence of GERD has shown a rising trend in recent years. More and more evidence suggests that GERD has certain connections with a variety of non-digestive tract diseases and may even aggravate the condition and severity of other diseases, prolong hospitalization and increase medical costs. As GERD symptoms are often non-typical, the condition is easily overlooked by non-gastroenterological practitioners. Therefore, improving the awareness of non-gastroenterology professionals about GERD, along with early diagnosis and treatment, creates a beneficial and more medically efficient situation for both doctors and patients. Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues .

Gastroesophageal reflux disease (GERD) refers to a range of symptoms and associated complications that are caused by backflow of stomach contents (including gastric acid) into the esophagus.


Over the last 10 years, the correlation of atrial fibrillation and GERD has been an important research focus.


For the end-stage treatment of primary pulmonary fibrosis, lung transplantation is needed to extend a patients’ life.


Nearly 20 years of one epidemiological survey found that the rising incidence of GERD, obesity and diabetes is consistent.


The correlation of BMI and GERD symptoms and severity is widely recognized.


It remains unknown if proton pump inhibitor exerts its effect on the outcomes of GERD via insulin resistance factors’ regulatory effect of fat metabolism.

gastroesophageal reflux disease: a Multicenter Questionnaire Survey. Cardiology 2011;119:217-23

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Expert Rev. Gastroenterol. Hepatol.

Gastroesophageal reflux disease and non-digestive tract diseases.

Over the past decade, incidence of gastroesophageal reflux disease (GERD) showed an increasing trend resulting from factors, including lifestyle and d...
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