Abstract
OBJECTIVE: To provide a basis for the clinical identification of true and false reflux, integrated traditional Chinese and Western medicine, and psychosomatic treatment, we conducted a retrospective study of the etiology and epidemiological and Traditional Chinese Medicine (TCM) syndrome characteristics of patients with reflux/heartburn symptoms.
METHODS: The 210 10 patients with reflux/heartburn treated at Tianjin Nankai Hospital from January 1, 2016, to December 31, 2019, were divided into four groups according to their pathogenesis. Sex, age, course of disease, incidence rate, gastroscopy, 24-h pH-impedance, esophageal manometry, Hamilton Anxiety Scale (HAMA) / Hamilton Depression Scale (HAMD) score, 8-week proton pump inhibitor (PPI) treatment effect, and TCM syndrome characteristics were statistically analyzed.
RESULTS: A total of 21010 patients (8864 men and 12146 women), with reflux/heartburn symptoms were screened, including 6284 (29.9%) patients with reflux esophagitis (RE), 10427 (49.6%) patients with non-erosive reflux esophagitis (NERD), 2430 (11.6%) patients with reflux hypersensitivity (RH), and 1870 (8.9%) patients with functional heartburn (FH). The incidence of the disease was higher in women than in men (P <0.0001). The ranking of the incidence of anxiety and depression in these four groups was FH>RH>NERD>RE (P < 0.0001). There were more women than men in the groups with anxiety and more men than women in the groups with depression (P < 0.0001), and there was no significant difference in the distribution of anxiety and depression between men and women (P = 0.5689). There were significant differences in TCM syndrome characteristics between NERD, RE, and functional esophageal diseases (P < 0.01). The highest proportion of functional esophageal disease TCM symptoms was Qistagnation and phlegm obstruction syndrome (36.16%), and there was no significant difference between RH and FH. The effective rates of PPI treatment at 8 weeks in patients in the RE, NERD, RH, and FH groups were 89%, 72%, 54%, and 0%, respectively. RE was classified into grades A, B, C, and D according to the Los Angeles grading system. The ranking of the incidence of these four grades was A>B>C>D (P < 0.0001). The effective rates of PPI treatment at 8 weeks were 91%, 81%, 69%, and 63% in patients with grade A, B, C, and D RE, respectively (P < 0.0001). The highest proportion of TCM syndrome types of NERD and RE was the stagnated heat syndrome in the liver and stomach syndrome, 38.99% and 33.90%, respectively.
CONCLUSION: Reflux/heartburn symptoms are relatively common in middle-aged women, and NERD is the most common etiology, followed by RE, RH, and FH. The most common TCM syndrome characteristics in NERD and RE were stagnated heat syndrome in the liver and stomach syndrome, and Qistagnation and phlegm obstruction syndrome in functional esophageal diseases. Most patients with reflux/heartburn symptoms also experienced anxiety and depression.
Keywords: gastroesophageal reflux; esophagitis, peptic; hypersensitivity; heartburn; proton pump inhibitors; emotional disorders; syndrome complex
1. INTRODUCTION
Gastroesophageal reflux disease (GERD) refers to the reflux of gastroduodenal contents into the esophagus causing heartburn. According to whether it leads to esophageal mucosal erosion and ulcer, it is divided into reflux esophagitis (RE) and non-erosive reflux esophagitis (NERD). Heartburn and reflux are the most common and typical symptoms of GERD. The incidence rate of this disease is higher in Europe and America than in China. With the changes of diet and living habits, the rate of reflux heartburn symptoms is gradually increasing in China. Reflux symptoms are common in clinical settings. If patients have symptoms such as heartburn or retrosternal pain, it is easy to diagnose gastroesophageal reflux disease and prescribe acid suppression treatment.1 However, in some patients, even the most standardized dosages and courses of acid inhibitors are ineffective. Some patients can achieve partial alleviation of symptoms, but repeated bouts can be protracted and difficult to heal. In addition, clinical findings show that these patients often have different degrees of anxiety, depression, and other emotional disorders, which seriously affect the treatment and quality of life of the patients.2 Functional esophageal diseases account for a certain proportion of refractory reflux symptoms, but they are easily neglected. Differential clinical diagnoses require not only gastroscopy but also 24-h pH-impedance detection, esophageal manometry, and experimental proton pump inhibitor (PPI) therapy. For this reason, we retrospectively summarized the outpatients and inpatients who complained of reflux/heartburn symptoms in our hospital over the past three years, analyzed the possible causes and epidemiological characteristics, and evaluated the efficacy of standardized acid suppressants. To obtain clinical mastery of the identification of these diseases, identify true and false cases of reflux, improve psychosomatic treatment, and provide a basis for treatment, we utilized an anxiety and depression scale to explore the impact of psychological factors on these diseases.
2. MATERIALS AND METHODS
2.1. Patients
Patients were admitted to the digestive outpatient and inpatient departments of Tianjin Nankai Hospital from January 2016 to December 2018.
2.2. Inclusion criteria
Patients fulfilled all the following conditions were eligible for inclusion: (a) typical heartburn/reflux symptoms, (b) gastroscopy examination, (c) 8 weeks of standard PPI treatment, (d) Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD) scores; and (e) 24-h esophageal pH-impedance monitoring and/or pressure measurement for endoscopy-negative patients.
2.3. Exclusion criteria
Patients with any of the following conditions were excluded from the study: (a) patients with organic digestive tract lesions, including peptic ulcers, eosinophilic esophagitis, esophageal hiatal hernia, or gastrointestinal cancer; (b) patients with primary esophageal motility disorders, such as achalasia, distal esophageal spasm, and jackhammer esophagus; (c) patients with Helicobacter pylori infection; (d) patients who had undergone abdominal surgery; (e) patients with severe systemic diseases or cancer and patients with systemic malignant tumors; (f) pregnant or lactating women; (g) patients who had used PPI drugs and/or anti-anxiety or anti-depressive drugs in the last two weeks; (h) patients with metabolic diseases or systemic diseases such as polymyositis and scleroderma.
2.4. Inclusion criteria of RE, NERD, reflux hypersensitivity (RH), and functional heartburn (FH)
For the RE and NERD inclusion criteria were based on the 2015 ASGE Guidelines: the Role of Endoscopy in GERD Management3 and the Montreal Consensus Guidelines;4 the inclusion criteria for RH and FH were based on the Rome IV criteria.5
Inclusion criteria for RE were as follows: reflux/ heartburn symptoms and gastroscopic mucosal lesions of the lower esophagus; RE was classified as A, B, C, or D according to the Los Angeles Standard Classification system.6
The inclusion criteria for NERD were as follows: reflux/heartburn symptoms, no esophageal mucosal damage based on gastroscopy results, and 24-h esophageal pH-impedance monitoring, which indicated a DeMeester score>14.72.
The inclusion criteria for RH were as follows:7 reflux/heartburn symptoms for more than 6 months, no esophageal mucosal damage visible under gastroscopy, and a 24-h esophageal pH-impedance monitoring DeMeester score<14.72. Weak acid reflux (pH 4-7) and/or heartburn symptoms were associated with acid reflux events in more than 50% of patients. PPI treatment for eight weeks was effective.
The inclusion criteria for FH were as follows: reflux or heartburn symptoms for more than 6 months, no esophageal mucosal lesions visible under gastroscopy, 24-h pH-impedance monitoring of the esophagus DeMeester score<14.72, no weak acid reflux or alkali reflux, and ineffective 8-week PPI treatment.
2.5. Data collection
The age, sex, course of disease, gastroscopic manifestations, 24-h pH impedance, esophageal manometry, HAMA/HAMD score, and 8-week PPI treatment results of all patients who met the inclusion criteria were recorded.
2.6. Gastroscopy
Gastroscopy is the gold standard for diagnosing erosive esophagitis. The RE classifications are according to the Los Angeles Standard Classification system.6
2.7. 24-h pH-impedance monitoring8
This procedure can sensitively capture 24-h esophageal pH changes, identify acid reflux with a pH<4, and use impedance technology to accurately identify weak acids with a pH between 4 and 7, non-acid reflux with a pH>7,9 and the nature of the reflux (liquid, gas, or gas-liquid mixture). The procedure can be used in conjunction with pH monitoring to clarify the acid-alkalinity of the reflux and its relationship with reflux symptoms. The following are the 24-h pH-impedance monitoring indicators: (a) acid exposure time: total time (%) of pH<4 within 24 h and total time (%) of standing and lying pH<4; (b) acid exposure frequency: reflux times of pH<4; and (c) continuous acid exposure duration: reflux duration (>5 min) and longest reflux duration. The DeMeester score was calculated according to the above monitoring indicators: a total score>14.72 was positive, indicating abnormal acid exposure.
2.8. Measurement of esophageal pressure
According to the 2014 Chicago diagnostic criteria for esophageal dysfunction,10 by setting parameters, the results can exclude primary esophageal motility disorders (cardiac achalasia, distal esophageal spasm, and jackhammer esophagus) and secondary esophageal motility disorders (e.g., polymyositis and scleroderma).
2.9. HAMA/HAMD Task Scales
The HAMA and HAMD Task Scales11 were independently scored by two trained assessors through conversation and observation. The HAMA scale can better reflect the severity of anxiety symptoms. According to the information provided by the Chinese scale collaboration group, if the total score is more than 29 points, there may be serious anxiety symptoms; if the score is>21 points, there are obvious anxiety symptoms; if the score is>14 points, there are anxiety symptoms; if the score is more than 7 points, there may be anxiety symptoms; and if the score is less than 7 points, there are no anxiety symptoms. The HAMD scale can better reflect the severity of depressive symptoms. A total score greater than 35 points may indicate serious depression; a total score greater than 20 points may indicate mild or moderate depression, and a total score lower than 8 points indicates no depressive symptoms. In this study, patients with a HAMA score>14, HAMD score>20, and HAMA score>14 with a HAMD score>20 were considered to have anxiety, depression, and anxiety combined with depression, respectively.
2.10. Collection of Traditional Chinese Medicine (TCM) syndrome symptom
According to the ‘consensus opinions of experts on TCM diagnosis and treatment of gastroesophageal reflux disease’ formulated by the spleen and stomach disease branch of the Chinese Society of TCM in 2017 and the ‘guiding principles for clinical research of new TCM’ issued by the State Drug Administration in 2002. Heat stagnation in liver and stomach, heat gallbladder invading stomach, Qi depression and phlegm obstruction, blood stasis obstructing collaterals, deficiency of Qi and inverse and spleen deficiency, and dampness-heat syndrome were the main syndromes.
2.11. Evaluation of the efficiency of 8 weeks of PPI treatment
RE: rehabilitation: the symptoms were completely alleviated, and the esophageal mucosal lesions healed under gastroscopy examination. Improvement: The symptoms improved within 2 months after the withdrawal of drugs, and the damaged mucosa improved under endoscopic examination, but the mucosa was not completely healed. Invalid: The symptoms were not alleviated, and the damaged mucosa did not show improvement on gastroscopy examination.
NERD: rehabilitation: symptoms were completely alleviated, no recurrence for more than two months after the withdrawal of the drugs, improvement: complete remission of symptoms, recurrence within two months after the withdrawal of drugs, or delayed partial remission of symptoms. Invalid: no relief of symptoms.
RH: rehabilitation: symptoms were completely alleviated, no recurrence occurred for more than half a year after withdrawal; improvement: symptoms were completely alleviated, recurrence within half a year after the withdrawal of drugs, or delayed partial relief of symptoms. Invalid: no relief of symptoms.
Efficiency: the percentage of patients who recovered and improved.
2.12. Statistical methods
The countable parameters (sex, mental state evaluation results, and efficacy evaluation results after 8 weeks of PPI treatment) are described as frequency and percentage; the measurable parameters (age and duration of each group) are presented as mean ± standard deviation. For the sex distribution, psychological evaluation results, and the effective rate after 8 weeks of PPI treatment, the χ2 test was used to compare the differences in the composition ratio of each group. For the comparison of continuous data such as age and course of the disease, analysis of variance (ANOVA) was used to carry out statistical tests, and the Turkey method was used to carry out two-way comparison afterwards. IBM SPSS Statistics for Windows, version 24.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 8.0 (GraphPad Software, Inc., San Diego, CA, USA) were used to analyze and chart the data. Bilateral P < 0.05, which means that the difference is statistically significant.
3. RESULTS
3.1. General statistics of the four groups of patients
There were 21010 patients who met the inclusion criteria, including 6284 patients with RE, 10427 patients with NERD, 2430 patients with RH, and 1870 patients with FH (Table 1, Figure 1). In terms of sex, there were more female patients than male patients in the four groups, and the χ2 test showed that there were statistical differences. Among them, the proportion of females in the FH group was the highest, and the NERD group had the lowest proportion. The average age of onset in the four groups was between 40 and 60 years. The average age of onset of NERD in the four groups was years, which was significantly higher than that in the other three groups (Table 1). The average age of onset of RH in the four groups was years, which was significantly lower than in the other three groups (Table 1). ANOVA analysis showed that there was a significant difference in age among the four groups, and the post hoc analysis showed that there was no statistical difference between the RH and FH groups, but there was a statistical difference in the inter-group comparison. The duration of disease analyses of the four groups showed that the order of average disease duration was as follows: FH>NERD>RH>RE (Table 1, Figure 1). ANOVA analysis showed that there was a significant difference in age among the four groups, and the post hoc analysis showed that there was a statistical difference in the inter-group comparison (Table 1). Most of these patients with heartburn symptoms are NERD patients, and there were more female patients than male in the four groups. And the duration of FH patients was the longest. These distribution characteristics deserve our attention in the clinical work.
Table 1.
General statistics of RE, NERD, RH and FH ($\bar{x}±s$)
| Item | Diseases | χ2/ F value | P value | ||||
|---|---|---|---|---|---|---|---|
| RE | NERD | RH | FH | ||||
| Gender [n (%)] | Male | 2639 (42) | 4693 (45) | 972 (40) | 561 (30) | 152.76 | <0.0001a |
| Female | 3645 (58) | 5734 (55) | 1458 (60) | 1309 (70) | |||
| Age (years) | 45.3±12.1 | 48.1±13.6 | 42.1±12.6 | 42.9±11.5 | 208.7 | <0.0001a | |
| Duration (years) | 0.5±0.3 | 2.5±0.2 | 2.2±0.5 | 3.4±0.5 | 69610.0 | <0.0001a | |
| Total number | 6284 | 10426 | 2430 | 1870 | - | - | |
| Percent (%) | 29.9 | 49.6 | 11.6 | 8.9 | - | - | |
Notes: RE: reflux esophagitis; NERD: non-erosive reflux esophagitis; RH: Reflux hypersensitivity; FH: functional heartburn. The 210 10 patients who met the inclusion criteria were divide into four groups according the inclusion criterias. The data of age, sex, course of disease was collected. The analysis of variance and χ2 test were used to carry out statistical test. aindicates a significant difference among the four groups.
Figure 1. Number and sex distribution of patients in four groups.
The order of the number of cases in each group was as follows: NERD>RE>RH>FH; meanwhile, the proportion of women in each group is higher than that of men. RE: reflux esophagitis; NERD: non-erosive reflux esophagitis; RH: reflux hypersensitivity; FH: functional heartburn.
3.2. Analysis of anxiety and depression disorders in the four groups
Repeated heartburn and reflux symptoms will lead to frequent anxiety and depression, which in turn aggravate the symptoms of gastroesophageal reflux disease and form a vicious circle. So in the part we conducted the analysis of anxiety and depression disorders in these patients. There were 1131 RE patients with a mood disorder: 1005 patients had anxiety, 377 patients had depression, and 251 patients had both anxiety and depression. There were 3649 NERD patients with a mood disorder: 3336 patients had anxiety, 1460 patients had depression, and 1147 patients had both anxiety and depression. There were 1531 RH patients with a mood disorder: 1312 patients had anxiety, 608 patients had depression, and 389 patients had bidirectional emotions with anxiety and depression. There were 1590 FH patients with a mood disorder: 1178 patients had anxiety, 823 patients had depression, and 411 patients had bidirectional emotions with anxiety and depression. The number of women with anxiety was significantly higher when compared to men, and the χ2 test showed that there was a statistical difference in the composition ratio among the four groups. The number of men with depression was higher when compared to women, and the χ2 test showed that there was a statistical difference in the composition ratio among the four groups. The χ2 test showed that there was no significant difference in the distribution of anxiety and depression between men and women (Table 2). The prevalence of anxiety and depression disorders in the four groups was as follows: RE, NERD, RH and FH. The χ2 test showed that the difference between the four groups was statistically significant (P < 0.0001).
Table 2.
Statistics of anxiety and depression disorders in RE, NERD, RH and FH patients
| Mood disorder | Disease | χ2 value | P value | |||||
|---|---|---|---|---|---|---|---|---|
| RE | NERD | RH | FH | |||||
| Anxiety | Total number (n) | 1005 | 3336 | 1312 | 1178 | 139.58 | <0.0001a | |
| Gender [n (%)] |
Male | 452 (45) | 1401 (42) | 367 (28) | 342 (29) | |||
| Female | 553 (55) | 1935 (58) | 945 (72) | 836 (71) | ||||
| Depression | Total number (n) | 377 | 1460 | 608 | 823 | 35.53 | <0.0001a | |
| Gender [n (%)] |
Male | 200 (53) | 861 (59) | 383 (63) | 568 (70) | |||
| Female | 177 (47) | 599 (41) | 225 (37) | 255 (30) | ||||
| Anxiety combined with depression | Total number (n) | 251 | 1147 | 389 | 411 | 2.00 | 0.5689a | |
| Gender [n (%)] |
Male | 118 (47) | 585 (51) | 187 (48) | 201 (49) | |||
| Female | 133 (53) | 562 (49) | 202 (52) | 210 (51) | ||||
| Total [n (%)] | 1131 (18) | 3649 (35) | 1531 (63) | 1590 (85) | 3520.24 | <0.000a | ||
Notes: RE: Reflux esophagitis; NERD: non-erosive reflux esophagitis; RH: Reflux hypersensitivity; FH: functional heartburn. HAMA: Hamilton Anxiety Scale; HAMD: Hamilton Depression Scale. The HAMA and HAMD score of patients in four groups was collected. The χ2 test was used. aindicates a significant difference among the four groups.
There were 6831 patients with a mood disorder, accounting for 32.5% of all patients. The proportion of patients with emotional disorders was the highest in the FH group and it’s consistent with the characteristics of FH. The number of women with anxiety was significantly higher than that of men, and the number of men with depression was higher than that of women.
These results had guiding significance for the clinical use of emotion regulating drugs.
3.3. Comparison of TCM syndrome distribution
The incidence of heartburn was high, and the condition was easy to repeat. As a comprehensive treatment, TCM has certain advantages in treating the disease through the combination of disease differentiation and syndrome differentiation. In TCM diagnosis and treatment activities, correct syndrome differentiation was the key to correct treatment and obtain the best curative effect. So we collected the TCM syndrome of these patients. There were differences in the distribution of TCM syndromes between NERD, RE, and functional esophagitis (including RH and FH) (P < 0.01). Patients with RE had the highest proportion of heat stagnation in the liver and stomach syndrome, followed by the heat gallbladder invading stomach syndrome. NERD patients had the highest proportion of heat stagnation in liver and stomach syndrome, followed by Qi depression and phlegm obstruction syndrome. The proportion of Qi depression and phlegm obstruction syndrome in patients with functional esophagitis was the highest, followed by heat stagnation in liver and stomach syndrome. The proportion of heat gallbladder invading stomach syndrome and blood stasis obstructing collateral syndrome in patients with RE was higher than that in patients with NERD and functional esophageal disease. The proportion of spleen deficiency and dampness-heat syndrome in patients with functional esophageal disease was significantly higher than that in the NERD and RE groups (Table 3). There was no significant difference in the distribution of TCM syndromes between patients with RH and FH (Table 4). The proportion of Heat Stagnation in Liver and Stomach Syndrome in patients with RE and NERD was the highest and the results was consistent with the syndrome type of GERD patients. The high proportion of Qi Depression and Phlegm Obstruction Syndrome in patients with functional esophagitis is relative with the mood disorder.
Table 3.
Distribution statistics of TCM syndromes in 21010 patients with reflux / heartburn symptoms [n (%)]
| Classification | Number | Heat stagnation in liver and stomach syndrome | Heat gallbladder invading stomach syndrome | Qi depression and phlegm obstruction syndrome | Blood stasis obstructing collaterals syndrome | Deficiency of Qi and inversion syndrome | Spleen deficiency and dampness-heat syndrome |
|---|---|---|---|---|---|---|---|
| RE | 6284 | 2450 (38.99) | 1307 (20.80) | 969 (15.42) | 818 (13.02) | 401 (6.38) | 339 (5.39) |
| NERD | 10426 | 3534 (33.90) | 1428 (13.70) | 2464 (23.63) | 286 (2.74) | 1301 (12.48) | 1413 (13.55) |
| Functional esophageal disease | 4300 | 1100 (25.58) | 557 (12.95) | 1555 (36.16) | 173 (4.02) | 262 (6.09) | 653 (15.19) |
Notes: TCM syndrome of the patients was collected. TCM: Traditional Chinese Medicine; RE: reflux esophagitis; NERD: non-erosive reflux esophagitis. The TCM syndrome symptom of RE and NERD patients was collected. The χ2 test was used.
Table 4.
Distribution of TCM syndromes in 4300 patients with functional esophageal disease [n (%)]
| Classification | Number | Heat stagnation in liver and stomach syndrome | Heat gallbladder invading stomach syndrome | Qi depression and phlegm obstruction syndrome | Blood Stasis obstructing collaterals syndrome | Deficiency of Qi and inversion syndrome | Spleen deficiency and dampness-heat syndrome | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| RH | 2430 | 635 (26.13) | 323 (13.29) | 832 (34.24) | 101 (4.16) | 158 (6.50) | 381 (15.68) | ||||||||
| FH | 1870 | 465 (24.87) | 234 (12.51) | 723 (38.66) | 72 (3.85) | 104 (5.56) | 272 (14.55) | ||||||||
Notes: TCM: Traditional Chinese Medicine; RE: reflux esophagitis; NERD: non-erosive reflux esophagitis; RH: reflux hypersensitivity; FH: functional heartburn. The TCM syndrome symptom of RH and FH patients was collected. The χ2 test was used.
3.4. Efficacy of 8 weeks of PPI treatment in the four groups
PPI treatment is the most commonly used for patients with heartburn symptom. Patients in different groups have different effect after PPI treatment. So in the part we analysis the efficacy of 8 weeks of PPI treatment. In the RE, NERD, RH, and FH groups, the cure rates after PPI treatment for 8 weeks were 2639 (42%), 2189 (21%), 559 (23%), and 0 (0%), respectively, and the effective rates were 89%, 72%, 54%, and 0%, respectively. Eight weeks of PPI treatment in the patients with FH were ineffective. The ranking of the proportion of patients who recovered was RE>RH>NERD, and the proportion of patients who improved was NERD>RE>RH, and the proportion of patients for whom the treatment was ineffective was RH>NERD>RE. The effective rate of patients was RE>NERD>RH, and the statistical results showed significant differences (P < 0.0001). In the four groups, the cure rates and effective rates of RE group were the highest, and the FH were the lowest. This was in line with the basic law of these diseases.
3.5. General situation of patients with RE regarding emotional disorders and the efficacy of PPI treatment for 8 weeks
We will pay more attention to RE patients because of the damage of lower esophageal mucosa. In the part we analysis the situation of RE patients. A total of 6284 patients with RE met the inclusion criteria. According to the Los Angeles classification, the number of patients with esophagitis A, B, C, and D was 5272 (83.9%), 855 (13.6%), 138 (2.2%), and 19 (0.3%), respectively. Regarding the sex distribution of RE patients at all levels, there were more female patients than male patients in grade A (P < 0.0001). There were more male patients than female patients in grades B, C, and D (P < 0.0001). The average age of patients with RE at the A, B, C, and D levels was (42.9 ± 11.5), (43.7 ±11.9), (46.8 ±12.6), and (48.2 ±13.8) years, respectively. ANOVA analysis showed that the comparison of average age was statistically significant (F = 7.2, P < 0.001). The post hoc analysis of comparisons between groups A and C, and groups B and C were significantly different (P = 0.0006, P = 0.0187) (Table 5). The duration of disease analyses of the four groups showed that the order of average disease duration was as follows: D [(0.6 ±0.4) years]>C [(0.6 ± 0.2) years]>B [(0.5 ± 0.2) years]>A [(0.3 ± 0.1) years] (Table 5). The ANOVA analysis showed that the comparison of the duration of each grade was statistically significant (F = 896.00, P < 0.0001) (Table 5). The post hoc analysis results of the two groups showed that the differences between any two groups except group C and group D were statistically significant (Table 5). The number of patients with anxiety, depression, and anxiety combined with depression was 848 (16%), 306 (6%), and 205 (4%) in grade A; 138 (16%), 59 (7%), and 39 (5%) in grade B; and 18 (13%), 10 (7%), and 6 (4%) in grade C; 1 (5%), 2 (11%), and 1 (5%), respectively. The χ2 test showed that there was no significant difference in the proportion of patients with mood disorders among the four groups (P = 0.6480). The effective rates of 8 weeks of PPI treatment were 91%, 81%, 69%, and 63% in RE patients at the A, B, C, and D levels, respectively, and the results were statistically significant (P < 0.0001) (Table 5). The proportion of men was higher in patients with severe esophagus mucosal injury. It should be noted that grade A and B RE patients have the highest proportion of emotional disorders. The recovered rate of grade A patients with RE was the highest that was consistent with the degree of esophageal mucosal injury.
Table 5.
General situation of RE patients, combined with emotional disorders, 8-week PPI efficacy statistics
| Item | Classification of RE | χ2/F value | P value | ||||
|---|---|---|---|---|---|---|---|
| A | B | C | D | ||||
| Total [n (%)] | 5272 (83.9) | 855 (13.6) | 138 (2.2) | 19 (0.3) | - | ||
| Gender (n) | Male | 2054 | 489 | 84 | 12 | 124.68 | <0.0001 |
| female | 3218 | 366 | 54 | 7 | |||
| Age (years) | 42.9±11.5 | 43.7±11.9 | 46.8±12.6 | 48.2±13.8 | 7.20 | <0.0001 | |
| Duration (years) | 0.3±0.1 | 0.5±0.2 | 0.6±0.2 | 0.6±0.4 | 896.00 | <0.0001 | |
| Mood disorder [n (%)] | Anxiety | 848 (16) | 138 (16) | 18 (13) | 1 (5) | 1.65 | 0.6480 |
| Depression | 306 (6) | 59 (7) | 10 (7) | 2 (11) | |||
| Anxiety combined with depression | 205(4) | 39 (5) | 6 (4) | 1 (5) | |||
| Teatment of PPI for 8 weeks [n (%)] | Recovery | 2272 (43) | 320 (38) | 43 (31) | 4 (21) | - | - |
| Improved | 2521 (48) | 372 (43) | 52 (38) | 8 (42) | |||
| Ineffective | 479 (9) | 163 (19) | 43 (31) | 7 (37) | |||
| Effective rate (%) | 91 | 81 | 69 | 63 | 146.63 | <0.0001 | |
Notes: RE: reflux esophagitis; NERD: non-erosive reflux esophagitis; RH: reflux hypersensitivity; FH: functional heartburn; PPI: proton pump inhibitor. The 8-week PPI treatment results of RE patients was recorded. The analysis of variance and χ2 test were used to carry out statistical test.
4. DISCUSSION
Reflux and heartburn are common symptoms of the digestive system. Studies have found that in the general population, approximately 10%-30% of people have heartburn and/or reflux symptoms at least once a week in Western countries, while the proportion in East Asia is slightly lower. Nearly 10% of people still have heartburn and/or reflux symptoms at least once a week, and the incidence of reflux symptoms is increasing.12 The epidemiological characteristics of patients with reflux/ heartburn symptoms are important for guiding clinical diagnosis and treatment. However, few reports have focused on the symptoms of reflux/heartburn.
According to the Montreal Consensus Guidelines and Rome IV, the common diseases causing reflux/heartburn symptoms are RE, NERD, RH, and FH.4,5 Our study found that in 21010 patients with reflux/heartburn symptoms, the incidence of RE with positive endoscopy results was 29.9%, which was consistent with the results of Fass et al.13 According to the Los Angeles classification of RE, the vast majority of patients (83.9%) were grade A, while patients with grades B, C, and D accounted for only 16.1% of patients with RE. Patients with NERD accounted for 50% of the total number of patients with negative endoscopy results, followed by patients with RH and FH, accounting for 12% and 9%, respectively. Another study reported that approximately 35% of untreated heartburn patients had NERD, 14% had RH, and 21% had FH.1,14 A retrospective study of 233 patients with heartburn symptoms found that the incidence of GERD was less than 40%, while the incidence of FH was close to 34% and that of RH was close to 15%. The results of this study showed that the prevalence of NERD was higher, while the prevalence of FH was lower, which may be related to the different study populations. This study focused on patients with reflux and/or heartburn, while the other two studies focused on patients with heartburn, which is the main clinical symptom of FH. However, based on our results, the prevalence of functional esophageal diseases is greater than 20%, which is worthy of clinical attention.
The study also found that the incidence of reflux and/or heartburn was higher in women than in men,15 and reflux symptoms have a greater impact on women with GERD, and that women with GERD have a worse quality of life than men with GERD, suggesting that women seem to be more sensitive to heartburn and pain symptoms than men and are more likely to be affected in daily life. It is interesting to note that more patients with RE were female than male and that more males than females were in stages B-D, suggesting that males tend to be more vulnerable to esophageal mucosal damage than females. Studies have shown that alcohol consumption, smoking, and obesity are closely related to RE. Compared to women, men have a higher prevalence of unhealthy lifestyle habits (such as alcoholism, smoking, overeating, etc.) that are likely to cause or aggravate esophageal mucosal damage.16 In addition, some studies have found that estrogen enhances the barrier of the esophageal mucosa and consequently has a protective effect on GERD-related esophageal mucosal damage.17
In addition, our study showed that patients with functional esophageal diseases had higher rates of anxiety and depression. The proportions of FH, RH, NERD, and RE patients with anxiety and depression disorders were as high as 85%, 63%, 35%, and 18%, respectively. This finding also shows that the pathogenesis of the four diseases is different, and the visceral hypersensitivity associated with FH and RH is more prominent conducted a psychological analysis on patients with persistent reflux symptoms.1,18 The results showed that the anxiety score of FH patients was significantly higher than that of the patients in the RH and RE groups (P < 0.05) and that the depression score was significantly higher than that of the RH group (P < 0.05), which was similar to that of the NERD group. Compared with RE and NERD patients, psychological factors have a more significant impact on patients with functional esophageal disease. At present, it is not clear what mechanisms or psychological factors affect or aggravate reflux/heartburn symptoms. Depression and anxiety are believed to cause neurotransmitter disorders, leading to abnormal brain-intestinal axis function, which causes gastrointestinal motility disorders and increases esophageal sensitivity, thereby affecting or aggravating reflux/heartburn symptoms.11,19 In addition, psychological factors such as anxiety and depression may influence the central perception of visceral stimuli through excessive attention and increased psychological processes so that patients overreact to weak stimuli in the esophagus.20
Traditional Chinese Medicine has obvious advantages in the treatment of refractory GERD and functional esophageal diseases.21 Accurate judgment of TCM syndrome is the basic premise for the effective diagnosis and treatment of diseases. The study on the standardization of TCM syndromes of GERD and functional esophageal diseases is of great significance to improve the accuracy and consistency of clinical syndrome differentiation and improve the clinical curative effect. This study found that the clinical symptoms of RE, NERD, and functional esophageal diseases (including RH and FH) were similar, but there were significant differences in the distribution of TCM syndromes, suggesting that there was heterogeneity in the pathophysiology between them. We found that the proportion of heat stagnation in liver and stomach syndrome in patients with RE and NERD was significantly higher, which was in line with the characteristics of its pathogenesis. Modern studies have found that mental and psychological factors (such as anxiety and depression) have obvious correlation with the occurrence and development of GERD, and NERD is more significant than RE. TCM studies shown that liver dominated emotion, anxiety and depression are responsible for liver depression and Qi stagnation in TCM syndrome differentiation. Therefore, the proportion of Qi Depression and Phlegm Obstruction Syndrome in NERD is higher than RE. The incidence of blood stasis obstructing collateral syndrome in patients with RE is significantly higher than that in patients with NERD and functional esophageal disease, which may be related to different degrees of mucosal damage, severe damage, and collateral damage.22 Our previous study also found that the esophageal mucosal blood flow of RE model rats was significantly lower than that of normal rats, which can also indirectly explain the high proportion of RE blood stasis obstructing collateral syndrome.23 The proportion of Qi depression and phlegm obstruction syndrome in patients with functional esophageal disease was the highest, followed by NERD patients. Studies have shown that, NERD patients have a prolonged and difficult condition compared with RE patients.24 The prolonged disease duartion indicated spleen deficiency, and Spleen Deficiency and Dampness-heat Syndrome was more common in NERD patients. The study also found that patients with functional esophageal disease had the highest rate of mental and psychological problems such as anxiety and depression, followed by NERD patients. The above results were consistent with the TCM concept that the liver affects emotion. There was no significant difference in the distribution of TCM syndromes between RH and FH, suggesting that there may be a high similarity in the pathophysiology of the two diseases.
In summary, middle-aged women are more likely to suffer from reflux/heartburn symptoms; NERD is the most common cause of symptoms, followed by RE, RH, and FH. Gastroscopy, 24-h pH-impedance detection, esophageal manometry, and experimental PPI treatment are helpful for the differential diagnosis of these diseases. Patients with reflux/heartburn symptoms have a high prevalence of anxiety and depression disorders, and these disorders are most prominent in patients with functional esophageal diseases. The clinical manifestations of RE, NERD, RH, and FH are similar, but the distribution of TCM syndromes is significantly different. This may explain why PPI has different therapeutic effects on these diseases. Therefore, paying attention to the research on TCM syndrome is of great significance to improve the treatment of these diseases.
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