High resolution esophageal manometry and life exposure factors in non-cardiac chest pain patients with refractory gastroesophageal reflux disease

Background: Refractory gastroesophageal reflux disease (RGERD) is defined by the presence of troublesome GERD symptoms despite proton pump inhibitors (PPIs) treatments for 8-12 weeks. Non-cardiac chest pain (NCCP) is the most common atypical presentations. This study was aimed at clarifying the features of High Resolution Esophageal Manometry (HREM) and life exposure factors of NCCP in RGERD patients for guiding further therapeutic strategies. Methods: 83 RGERD patients were enrolled, in which 44 patients afflicted with NCCP as P group and 39 patients without NCCP as NP group. According to the endoscopy results, P group was further divided into reflux esophagitis group (RE group), non-erosive reflux disease group (NERD group) and Barrett’s esophagus group (BE group). HREM was performed to assess esophageal motility. Diverse questionnaires were conducted to evaluate severity of symptoms, quality of life, risk factors, degrees of anxiety and depression and so on. Results: a)Average resting pressures of the lower esophageal sphincter (LES), residual pressures of the LES and the esophageal distal contractile integral (DCI) score in P group were significantly lower than those in NP group (p<0.05). b)Average resting pressures of the upper esophageal sphincter (UES), residual pressures of the UES, lengths of the LES and the UES showed no difference between the two groups (p>0.05). c)Compared with NP group, the patients in P group had higher exposure to alcohol, coffee, sweets, overeating and stress (p<0.05). d)Anxiety and depression status of patients in P group were remarkably severer than those in NP group (p<0.05). e)The pain intensity in RE group and BE group was higher than NERD group (P<0.05), while there was no difference between RE group and BE group (P>0.05). Conclusions: Esophageal motility related anti-reflux barriers are much weaker in the RGERD patients with NCCP


Background
Gastroesophageal reflux disease (GERD) refers to one of the common clinical digestive diseases caused by stomach and duodenal contents flowing back into the esophagus and characterized by heartburn and acid reflux [1]. Because of the improvements of living standards and the changes of lifestyles, GERD is prevalent worldwide with its incidence increasing year by year [2]. Although the uncomfortable symptoms of GERD patients can be mostly relieved by conventional proton pump inhibitors (PPIs), there are still 10% -40% GERD patients whose symptoms such as reflux, chest pain etc. cannot be obviously relieved after double dose of PPI treatment for 8-12 weeks, which is named refractory gastroesophageal reflux disease (RGERD) [3,4]. When those troublesome symptoms can't be improved with GERD therapy, High Resolution Esophageal Manometry (HREM) are often performed to assess peristalsis and to detect alternative major motor disorders in the setting of GERD.
GERD is associated with a broad spectrum of symptoms, which can be split into the typical symptoms such as heartburn and acid regurgitation and the atypical symptoms such as non-cardiac chest pain (NCCP), chronic cough, hoarseness, and asthma [5]. It's reported that presence of GERD was strongly associated with NCCP in the community [6]. The average annual prevalence of NCCP in the general population is approximately 25%, making NCCP the most common atypical presentation of GERD [7]. At present, the reports on RGERD are not adequate, what's more, they mainly display the differences of overall symptoms between RGERD and non-RGERD patients, whereas the investigation of a certain symptom of RGERD has been rarely reported. With the objective of further

Questionnaires
The questionnaires were conducted under the guidance of the same doctor who was present to confirm that the participants understood the forms clearly. However, the doctor was prohibited from using any suggestive words regardless of any questions.

General information
The general datas included patient's name, gender, age, height, weight, past disease history, history of medication, history of diagnosis and treatment, etc. Body mass index BMI was calculated by dividing the weight (in kg) by the height (in meters) squared.
Extra-esophageal manifestations questionnaire [5] The GERD related extra-esophageal symptoms questionnaire was used to record the incidence of chronic cough, hoarseness, pharyngeal discomfort and asthma.
The reflux diagnostic questionnaire (RDQ) [9] Statistics on the incidence of heartburn, acid reflux, antifeeding, chest pain, etc in the past 4 weeks. SF-36 quality of life scale [11] The questionnaire contains 36 items and eight dimensions, including physical functioning Life exposure factors questionnaire [12][13][14] In order to learn about the habits of diet and lifestyle, a self-designed life exposure factors questionnaire were conducted, including smoking, drinking, strong tea, coffee, sweets, greasy food, overeating, spicy food, high salt, staying up late, fatigue and stress.
Zung self-rating anxiety scale (SAS) [15] and Zung self-rating depression scale (SDS) [16] Subjects Esophageal motility measurement HREM studies were performed according to the standardized protocol as used previous studies in our center, using a 24-channel water-perfused catheter of 4.0 mm in diameter [17] (Ningbo Maida Medical Device Inc., Ningbo, China). The specific operational method is the same as the previous experiment [17]. The resting pressure, residual pressure and lengths of the upper esophageal sphincter (UES) and the low esophageal sphincter (LES), as well as the esophageal distal contractile integral (DCI) were recorded.

Statistical analysis
All data was input into SPSS 19.0 software package for processing. The count data was converted into a percentage and analyzed by the chi-square test. The measurement data were expressed as mean ± standard deviation (x ± s) and analyzed by t test. The significance level for all hypothesis testing (p-value) was 0.05.

Results
General data of subjects Comparison of extra-esophageal manifestations between P group and NP group The incidences of chronic cough, hoarseness and pharyngeal discomfort in P group were higher than those in NP group (p<0.05). No statistical difference was noted in the incidence of asthma between the two groups (p>0.05). (see Table 2).

Comparison of RDQ scores between P group and NP group
The RDQ scores of P group 22.55±3.454 were higher than those of NP group 17.64±3.048 . The difference was statistically significant (p<0.05, Fig. 1a).
Comparison of pain intensity between different types of endoscopy in P group In P group, 10 patients were in RE group, accounting for 22.7%, 29 patients in NERD group, accounting for 65.9%, 5 patients in BE group, accounting for 11.4%. The pain intensity among the three groups were compared (see Fig. 1b). The pain intensity in RE group and BE group were higher than NERD group (P<0.05), however, between RE group and BE group, there was no difference (P>0.05).

Comparison of quality of life
Between P group and NP group, there were significant differences in both physical health and mental health, which totally included eight dimensions (p<0.05, Fig.1c).

Analysis of life exposure factors
The exposure incidences of smoking, drinking, strong tea, coffee, overeating,sweets, greasy food, spicy food, high salt and stress in P group were higher than those of NP group. Among them, drinking, coffee, overeating, sweets, and stress between the two groups were significantly different (p<0.05), nevertheless, the remaining items were not statistically different.(see Table 3).

Analysis of anxiety and depression state
The incidences of anxiety and depression in P group were significantly higher than those in NP group(p< 0.05, Table 3).
Comparison of esophageal manometry results between P group and NP group Images of esophageal pressure measurements Typical images of esophageal motility measurements in P group and NP group were presented (see Fig. 2a, 2b).

Analysis of esophageal manometry data
The average resting and residual pressures of the LES and the esophageal DCI in P group were lower than those in NP group (p<0.05, Fig2f, 2g and 2i). The average resting and residual pressures of the UES and the lengths of the LES and the UES showed no difference between P group and NP group (P> 0.05, Fig. 2c-2e, and 2h).

Discussion
GERD is the most common underlying mechanism of NCCP, with an estimated prevalence ranging from 30% to 60% [18][19][20]. In fact, RGERD-related NCCP also takes a large Etiological factors of GERD contain dysfunction of the esophagogastric junction (EGJ), which comprises ineffective acid and bolus clearance, increased intragastric pressure, and anatomical changes of the EGJ, such as a hiatal hernia, resulting in mucosal injury [21,22].
Insufficient inhibition of gastric acid secretion, ongoing weakly acidic or non-acid reflux and reflux sensitivity are the major causes of RGERD symptoms [3]. In addition, transient lower esophageal sphincter relaxations (TLESRs) are considered as a main mechanism behind acidic, weakly acidic, and weakly alkaline reflux episodes in both healthy populations and patients with GERD [23,24]. HREM is usually completed in order to evaluate the stucture and function of the EGJ, given its anti-reflux barrier property. The EGJ is a complex structure composed of the crural diaphragm and the LES [25]. As is shown in the study, the resting pressure and the residual pressure of the LES in P group were lower than those in NP group (P<0.05). Because of the low pressure of the LES, reflux is prone to happen. Thereby, it is speculated that reflux may play important roles in the occurrence of NCCP. The DCI itself represents the strength of the smooth muscle contraction wave at the distal end of the esophagus. When the peristaltic force is reduced, the ability to clear the bolus is worse [26]. In this study, the DCI of P group (2158.8±1154.3) was lower than that of NP group (3057.5±1729.9) (P<0.05). Although both were in the normal range, the difference was statistically significant. Consenquently, we speculated that the NCCP in RGERD patients may be related to ineffective acid and bolus clearance, owing to the decrease of DCI. Because CC v3.0 doesn't contain the TLESRs, we didn't take it into account at that time, which should be studied in the future research.
The RDQ scale is a retrospective statistic for the problems related to reflux symptoms to help diagnose GERD, with a high sensitivity and specificity [27]. It's generally assumed that the higher the score of RDQ is, the more serious the reflux is. Compared with NP group, the RDQ score of P group was relatively higher (P <0.05), indicating that the reflux might be the cause of NCCP. Because not all patients had performed the 24-hour PHmetry, for example, those patients with severe esophagitis (LA-C and LA-D) don't need to perform it to diagnose reflux. so we didn't analyse the data of 24-hour PH-metry owing to the limited data.
According to endoscopic results, GERD can be divided into RE, NERD and BE [3]. In the 44 patients with RGERD-related NCCP, the number of the RE group, the NERD group and the BE group accounted for 22.7%, 65.9%, 11.4%, respectively, which is accordance with the outcome of previous studies that NERD takes the largest proportion in GERD [28]. Studies have demonstrated that severity and/or frequency of GERD symptoms cannot predict the presence or absence of esophageal mucosal injury [29]. Nevertheless, the pain intensity of the RE group and the BE group were higher than the NERD group (P<0.05). And there was no significant difference in pain intensity between the RE group and the BE group (P>0.05). It's widely accepted that frequent and strong esophageal acid perfusion may trend to cause the occurrence of RE and BE, thereby it's speculated that the intensity of NCCP is closely related to the frequency and severity of acid reflux. The mechanisms of NCCP in RGERD patients are poorly understood. It has been suggested that the pain hypersensitivity within esophagus may be a factor in the generation of NCCP [30]. It has been reported that after the lower esophagus was acid-infused, the pain threshold of the upper esophagus and chest wall could be reduced [31]. Long-term reflux and repeated recurrence of inflammation may lead to destruction of the mucosal barrier, as well as the decline of pain threshold, making the symptoms of NCCP more serious.
It's reported that patients with GERD have a high probability of experiencing extraesophageal manifestations [5]. In this study, the incidences of chronic cough, hoarseness and pharyngeal discomfort in P group were higher than those in NP group P<0.05 . It appears that RGERD patients with NCCP are more possible to be accompanied by discomforts of chronic cough, hoarseness and pharyngeal discomfort, which indicates that these extra-esophageal manifestations may have the common pathogenesis.
Health consists of not only physiological health, but also mental health and social wellbeing. In this study, Chinese Version SF-36 Life Quality Scale was used to assess the impact of NCCP on patients' quality of life (QOL). The results showed that P group was in worse stage than NP group in both physical health and mental health (P<0.05). There were statistical differences in each dimension, suggesting that NCCP had negative effects on patients. Shelby et al [32] pointed out that for NCCP patients, chest pain, anxiety and fear of pain formed a vicious circle, resulting in physical and social psychological disorders, thereby reducing the QOL. Accordingly, improving the control of RGERD symptoms can improve QOL of patients.
Psychological state is closely related to the occurrence of GERD. Some investigations showed that anxiety and depression could cause the occurrence of GERD, especially NERD [33], and some studies showed that NERD patients often had poor effects on acid suppression owing to mental stress, anxiety and depression [34]. In this study, we found that the anxiety and depression states of P group were significantly worse than those of NP group, showing that there is a link between anxiety and depression states and RGERDrelated NCCP. Psychological factors are crucial for the occurrence and progression of RGERD, On the contrary, NCCP lead to or aggravate RGERD patients' symptoms, anxiety or depression, or both.
It's widely believed that lifestyle and dietary habits affect the occurrence of GERD.