On August 26, 2006, the National GERD Symposium was held in Sanya, Hainan. In addition to the well-known experts and scholars in the field of gastroenterology in China, there were also scholars from the United States and Japan. They exchanged and discussed on the definition and classification of GERD, diagnosis and treatment, epidemiological research and other related contents, and reached an expert consensus on GERD in China.
Gastroesophageal reflux disease (GERD) is a disease in which gastric contents flow back into the esophagus, causing uncomfortable symptoms and/or complications.
Three types of GERD and their definitions
GERD can be divided into the following three types: non-erosive reflux disease (NERD), erosive esophagitis (EE) and Barrett’s esophagus (BE), which can also be called GERD-related diseases.
NERD refers to the presence of reflux-related discomfort without endoscopic evidence of Barrett’s esophagus and esophageal mucosal breakdown.
EE refers to endoscopic mucosal rupture of the distal esophagus, and the Los Angeles meeting in 1994 proposed a clear grading scale, which was graded from A to D according to the severity of endoscopic esophageal lesions.
BE refers to the replacement of squamous epithelium by columnar epithelium in the distal segment of the esophagus.
Of the three forms of GERD, NERD is the most common; EE can be combined with esophageal strictures, ulcers and gastrointestinal bleeding; BE may progress to esophageal adenocarcinoma. The relationship between these three forms of disease and their progression needs further study.
Reflux symptom cluster
The symptoms associated with reflux are called the reflux symptom cluster. The typical and common symptoms of reflux are heartburn and reflux. Other rare or atypical related symptoms include one or more of the following: epigastric pain, chest pain, belching, abdominal distention, epigastric discomfort, foreign body sensation in the throat, painful swallowing, dysphagia, etc., as well as extraesophageal symptoms such as chronic cough, pharyngitis, asthma, etc.
Heartburn is a burning sensation behind the sternum.
Reflux is a sensation of stomach contents moving toward the pharynx or mouth.
Reflux-related symptoms are called uncomfortable when they have a significant negative impact on the patient’s quality of life. Reflux symptoms that do not have a negative impact on the patient’s quality of life are not considered a diagnosis of GERD. Mild symptoms are considered uncomfortable when they are present for ≥2 days in 1 week or moderate or severe symptoms for ≥1 day in 1 week. In clinical practice, it is up to the patient to decide whether the symptoms are uncomfortable or not.
Prevalence
GERD is common, and the prevalence varies worldwide.
The prevalence of GERD symptoms [heartburn and/or reflux at least once a week] in Western Europe and North America is 10-20%.
Asia is usually lower. Studies in Japan show that the prevalence of GERD symptoms is about 6.6%, in Korea 3.5%, and in Singapore 10.5%. In Guangzhou, China, the prevalence of weekly heartburn symptoms was 6.2%. The prevalence of GERD was 5.77% in both Beijing and Shanghai.
Data from Asian countries showed that the detection rate of GERD by endoscopy ranged from 3.0% to 5.2%. In a retrospective study at Shanghai Changhai Hospital, the endoscopic detection rate of GERD was 2.95%, and in a retrospective study at Beihang Hospital, it was 4.1%. The detection rate of reflux esophagitis is increasing year by year.
Risk factors
The risk factors for GERD include age, gender, smoking, increased body mass index (BMI), excessive alcohol consumption, aspirin, non-steroidal anti-inflammatory drugs and anticholinergic drugs, physical work, social factors, psychosomatic diseases and family history, etc.
Pathogenesis and damage factors
The pathogenesis of GERD is the weakening of defense mechanism and the decrease of acid removal ability of esophagus, the main changes are the decrease of lower esophageal sphincter pressure (LESP) and excessive transient lower esophageal sphincter relaxation (tLESR). The main damage factors are excessive gastric contents, mainly acid reflux into the esophagus, which causes damage to the esophageal mucosa, and bile and digestive enzymes which also damage the esophageal mucosa.
Diagnosis of GERD
Diagnosis according to GERD symptom group
Clinically, if a patient ① has typical heartburn and reflux symptoms without evidence of pyloric obstruction or gastrointestinal obstruction, GERD may be considered clinically. ② If a patient has extraesophageal symptoms and reflux symptoms, GERD may be considered as reflux-related or possibly related extraesophageal symptoms, such as reflux-related cough or reflux-related asthma. However, (3) GERD cannot be diagnosed if there are only extra-esophageal symptoms without typical heartburn and reflux symptoms, and it is advisable to find out more about the time of onset of extra-esophageal symptoms, the relationship with meals and body position, and other triggers. The presence of overlapping symptoms (e.g., GERD and irritable bowel syndrome or functional dyspepsia), anxiety and depression, and sleep disorders should be noted.
Upper gastrointestinal endoscopy
Since China is a country with a high incidence of gastric and esophageal cancer, endoscopy has been widely carried out. Therefore, endoscopy is usually performed first for patients to be diagnosed, especially when the symptoms are frequent and severe, accompanied by alarm signs, or with family history of tumor, or when the patient is eager to have endoscopy.
Endoscopy of the upper gastrointestinal tract can help determine the presence of reflux esophagitis and the presence of comorbidities and complications, such as esophageal hiatal hernia, inflammatory esophageal stricture, and esophageal cancer; it can help in the diagnosis of NERD; and endoscopy first can effectively shorten the diagnosis time than diagnostic treatment first.
Studies have confirmed that GERD patients with reflux symptoms may have intermittent esophageal mucosal rupture, and the severity of reflux esophagitis does not worsen in most patients for 20 years.
Diagnostic treatment
Diagnostic therapy may be used in patients with proposed or suspected extraesophageal symptoms associated with reflux, especially if upper gastrointestinal endoscopy is negative.
Proton pump inhibitor diagnostic therapy (PPI test) has been shown to be effective. A standard dose of PPI is recommended twice a day for 1 to 2 weeks. The PPI test not only helps to diagnose GERD, but also initiates treatment. The essence of the test is that a positive or negative PPI fully emphasizes the relationship between symptoms and acid, and it is a reflux-related test.
There are several possibilities for a negative PPI: (i) inadequate acid suppression; (ii) presence of symptoms induced by factors other than acid; and (iii) not caused by reflux. The advantage of this test is that it is convenient, feasible, non-invasive and sensitive, but the disadvantage is that it has low specificity.
Examination of gastroesophageal reflux evidence
1.X-ray and nuclear examination
The conventional barium esophageal examination combines gastroesophageal imaging and dynamics, and can show the presence of mucosal lesions, strictures and esophageal hiatal hernia, etc., as well as the presence or absence of barium gastroesophageal reflux, thus having a complementary role in diagnosis, but the sensitivity is low; the nuclide gastroesophageal reflux examination can quantitatively show the reflux of nuclide labeled fluid in the stomach, and is more likely to be positive when the barrier at the gastroesophageal junction (EGJ) is low, but the positive rate is However, the positive rate is not high, and it is not commonly used.
2. 24-hour esophageal pH monitoring
The significance of 24-hour esophageal pH monitoring is to confirm the presence or absence of reflux. 24-hour esophageal pH monitoring can show acid reflux, diurnal acid reflux pattern, relationship between acid reflux and symptoms and response to treatment in detail, so that treatment can be individualized. 80% positive rate in EE patients and 50%-75% positive rate in NERD patients. In view of the fact that the use of esophageal pH monitor is still not widespread in China, it is recommended to use it when the presence of reflux is still uncertain after endoscopy and PPI test.
Esophageal manometry
Esophageal manometry does not directly reflect gastroesophageal reflux, but it can reflect the barrier function of EGJ. In the diagnosis of GERD patients, it can be used to predict the efficacy of anti-reflux therapy and the need for long-term maintenance therapy, in addition to assisting in the localization of esophageal pH electrodes, preoperative assessment of esophageal function, and predicting surgery. Thus, esophageal manometry can help to assess esophageal function in patients, especially in patients with treatment difficulties.
Measurement of esophageal bile reflux
Some patients with GERD have a non-acidic reflux factor, especially associated with bile reflux. The presence and extent of bile reflux can be reflected by measuring bilirubin. However, in most cases, reflux of duodenal contents coexists with reflux of gastric contents, and the symptoms are relieved by acid suppression, so the application of bile reflux test has some limitations.
Other
Ultrastructural studies of the esophageal mucosa can provide an understanding of the pathophysiological basis for the presence of reflux; wireless esophageal pH measurements can provide longer-term detection of acid reflux; the application of intraluminal impedance techniques can monitor all reflux events and clarify the nature of the reflux (gas, liquid, or gas-liquid mixture), and the combination with esophageal pH monitoring can clarify whether the reflux is acidic or non-acidic and clarify the relationship between reflux and reflux symptoms. The relationship between reflux and reflux symptoms can be clarified.
Non-Celiac Reflux Disease
There is insufficient clinical follow-up data to elucidate the natural course of NERD, but the limited data available suggest that most NERD does not progress to EE during its evolution.
The diagnosis of NERD relies primarily on symptomatology, with heartburn and reflux being the typical symptoms. The diagnosis of NERD can be made when the patient complains of heartburn symptoms, if other diseases that may cause heartburn symptoms can be excluded, and if no esophageal mucosal rupture is seen on endoscopy.
The diagnostic value of endoscopy for NERD is to exclude EE or BE, as well as other upper gastrointestinal diseases such as ulcer or gastric cancer.
Portable 24-hour esophageal pH monitoring can determine the presence of pathologic acid reflux, but only about 50%-75% of NERD patients meet the positive criteria. The symptom index is the ratio of the number of heartburn episodes associated with acid reflux (pH <4) to the total number of heartburn episodes, and is positive if it exceeds 50%.
PPI test is the most practical method for clinical diagnosis of NERD, and the disappearance or significant relief of typical reflux symptoms such as heartburn after PPI treatment indicates that the symptoms are related to acid reflux, and if there is no evidence of esophageal mucosal damage on endoscopy, the clinical diagnosis of NERD can be made.
Patients with atypical symptoms of NERD, such as epigastric pain, abdominal distension, non-cardiac chest pain, chronic cough, asthma or chronic sore throat, should be examined for evidence related to reflux to clarify the relationship between symptoms and GERD.
NERD should be differentiated from functional heartburn. According to Rome III criteria, the diagnostic criteria for functional heartburn are: the patient has symptoms of heartburn, but there is no evidence of reflux causing the symptoms, such as ① no esophageal mucosal damage on endoscopy; ② negative 24-hour pH test for esophageal acid reflux; or ③ negative symptom index (50% PI test treatment) indicates that the symptoms of heartburn are not closely related to acid reflux and are not GERD, but a positive result cannot exclude functional heartburn. However, a positive result does not exclude functional heartburn, as its specificity is not high.
Barrett’s esophagus
Clinical manifestations
Barrett’s esophagus (BE) itself is usually asymptomatic, and the clinical manifestations are mainly symptoms of gastroesophageal reflux disease (GRED), such as heartburn, reflux, retrosternal pain and dysphagia. However, about 25% of patients do not have GRED symptoms, so screening for BE cases should not be limited to those with reflux-related symptoms, and the presence of BE should also be noted in patients without reflux symptoms during routine gastroscopy.
Diagnosis of BE
The diagnosis of BE is mainly based on endoscopy and esophageal mucosal biopsy findings. BE can be diagnosed when endoscopy reveals obvious columnar epithelial hyperplasia in the distal esophagus and confirmed by pathological examination.
1. Endoscopic findings:
Endoscopic manifestations are important to clearly distinguish between squamous and columnar epithelial junction (SCJ) and gastroesophageal junction (EGJ) for identifying BE.
(1) SCJ endoscopic sign: it is a dentate Z-line formed at the junction of squamous and columnar epithelium of esophagus.
(2) EGJ endoscopic landmark: it is the junction between the tubular esophagus and the capsular stomach, and its endoscopic localization is marked by the proximal edge of the gastric mucosal folds in the minimally inflated state and/or the end of the longitudinal fenestrated vessels at the lower esophagus.
The typical endoscopic appearance of BE is an orange colored columnar epithelium proximal to the EGJ, i.e., the separation of the SCJ from the EGJ. the length of BE should be measured from the EGJ up to the SCJ. endoscopic melan staining is useful for localization of focal intestinal metaplasia and can guide biopsy.
2. Pathological diagnosis:
(1) Biopsy sampling: four-quadrant biopsy method is recommended, that is, biopsies should be taken in four quadrants at 2 cm intervals from the EGJ; biopsies should be taken in four quadrants at 1 cm intervals upward for suspected BE carcinoma; biopsies should be taken for pathological examination for ulcers, erosions, plaques, small nodular stenoses and other intraluminal abnormalities.
(2) Histotyping: ① Cardia gland type, similar to cardia epithelium, with gastric hollows and mucus glands, but without principal cells and mural cells. (2) Fundic gland type, similar to the fundic epithelium, with principal cells and mural cells, but the BE epithelium is more obviously atrophied, and the glands are fewer and shorter. This type is mostly located in the distal part of BE near the cardia. (3) Special intestinal metaplasia type, in which cup-shaped cells can be seen in the metaplasia of columnar epithelium is its characteristic change.
3. Heterotypic hyperplasia of BE:
(1) Low degree heterogeneous hyperplasia (LGD): it consists of more small and round glandular ducts, elongated glandular epithelial cells, densely stained nuclear chromatin, pseudostratified nuclei, little or no mucus secretion, and the hyperplastic cells can extend to the mucosal surface.
(2) High heterogeneous hyperplasia (HGD): the ducts are irregular, branching or folded, and some areas lose polarity. Compared with low-grade heterogeneous hyperplasia, the nuclei are larger, irregularly shaped and arranged in clusters, with thickened nuclear membranes and distinctly biphasic nuclei. There is no interstitial infiltration.
BE typing
1. Classification according to the length of the metaplastic columnar epithelium: ① Long segment BE (LSBE) refers to the metaplastic columnar epithelium involving the whole circumference of the esophagus and the length is ≥3 cm; ② Short segment BE (SSBE) refers to the metaplastic columnar epithelium not involving the whole circumference of the esophagus, or although the whole circumference is involved, the length is <3 cm.
2. Classification according to endoscopic morphology: it can be divided into circumferential type (serrated), lingual type and insular type.
3, Recorded according to the Bragg C&M classification: C represents the length of the circumferential type of septic mucosa; M represents the maximum length of septic mucosa. For example, C3-M5 indicates that the columnar epithelium of the circumferential segment of the esophagus is 3 cm, and the non-circular segment or lingual extension is 5 cm above the union; C0-M3 indicates that there is no full circumferential segment of septic mucosa, and the lingual extension is 3 cm above the EGJ.
Contents of BE diagnosis records
1. morphological classification (circumferential, lingual and insular)
2. Length
3. histological type
4. Heterotypic hyperplasia and degree
5. complications (erosion, ulceration, stenosis, bleeding).
Today, there are two international opinions on the diagnosis of BE: it can be diagnosed as long as the squamous epithelium of the distal esophagus is replaced by columnar epithelium and it can be diagnosed only when there is intestinal epithelial hyperplasia in the columnar epithelium of the distal esophagus. In view of the lack of in-depth research on BE in China, the presence of columnar epithelial metaplasia in the distal esophagus is a more appropriate diagnostic criterion, but the histological type and the presence of intestinal epithelial metaplasia must be specified. In addition to endoscopic diagnosis, histological diagnosis must also be available, and the combination of endoscopic and pathological diagnosis will help to further improve the clinical diagnosis of BE in the future.
Monitoring and follow-up
Since BE has the risk of developing into esophageal adenocarcinoma, patients with BE should be followed up regularly with the aim of early detection of heterogeneous hyperplasia and carcinoma.
Follow-up period: The interval of endoscopy should depend on the degree of heterogeneous growths. For BE patients without heterogeneous hyperplasia, endoscopy should be repeated every 2 years. If no heterogeneous hyperplasia or carcinoma is detected in both reviews, the follow-up interval can be relaxed as appropriate; for patients with mild heterogeneous hyperplasia, endoscopy should be repeated every 6 months in the first year, and if the heterogeneous hyperplasia does not progress, it can be repeated once a year; for BE patients with severe heterogeneous hyperplasia, endoscopic mucosal resection or surgery should be recommended, and follow-up should be closely monitored.
Treatment
The goals of treatment are to cure esophagitis, relieve symptoms, improve quality of life, and prevent complications, and to treat GERD in the following ways:
Lifestyle changes
Lifestyle changes such as elevating the head of the bed, not eating 3 hours before bedtime, avoiding high-fat foods, quitting smoking and alcohol, and losing weight may benefit some patients with GERD, but these changes are not sufficient to control symptoms for most patients. Furthermore, there are no controlled studies on lifestyle changes and GERD treatment. There are no studies on the potential negative impact of lifestyle changes on patients’ quality of life.
Drug treatment
1. Inhibition of gastric acid secretion
Gastric acid suppression therapy is the basic treatment for GERD. The drugs that inhibit gastric acid include H2 receptor antagonists and proton pump inhibitors (PPI), etc.
(1) Initial treatment
Trials of cimetidine, ranitidine, famotidine and nizatidine in the treatment of GERD suggest that the efficacy of H2 receptor antagonists in relieving mild to moderate GERD symptoms is better than that of placebo, with an efficacy of 60% to 70%. However, most patients showed drug resistance after 4-6 weeks, and the long-term efficacy was not good. Therefore, H2 receptor antagonists are only suitable for the initial treatment of mild to moderate GERD and short-term relief of symptoms.
The efficacy of PPI in the treatment of GERD has been recognized worldwide. Short-term use of PPI in patients with erosive esophagitis (EE) has shown that PPI cures esophagitis and completely relieves heartburn symptoms more rapidly than H2 receptor antagonists. The efficacy of standard doses of various PPIs in the treatment of EE was essentially the same, and PPIs were also effective in patients with H2 receptor antagonist-resistant EE. endoscopic healing rates of PPIs for EE at 4 and 8 weeks were about 80% and 90%, respectively.
Based on the advantages of PPI in terms of efficacy and speed of symptom relief, the standard dose of PPI should be preferred for the treatment of EE, and the dose can be increased in some patients with unsatisfactory symptom control.
Several trials have demonstrated that PPIs are less effective than EE patients in relieving heartburn symptoms in patients with non-erosive reflux disease (NERD), but PPIs are more effective than H2 receptor antagonists and prokinetic agents in improving symptoms. The time frame for PPI treatment in NERD patients is not clear, but the available studies suggest that it should be longer than 4 weeks.
PPI therapy for GERD extraesophageal symptoms such as reflux pharyngitis is effective in most patients.
(2) Maintenance therapy
Since GERD is a chronic disease, from the perspective of symptom control and prevention of complications, GERD requires maintenance therapy. With the standard dose of PPI maintenance therapy, more than 80% of patients can still maintain normal after six months of follow-up.
On-demand treatment is a form of intermittent treatment, which means that the drug is administered only when symptoms appear and continues to be used until the symptoms resolve.
There are no multicenter, randomized, double-blind controlled studies of PPI maintenance therapy in patients with NERD. The available literature suggests that on-demand treatment is also effective in patients with NERD.
2. Prokinetic drug therapy
In the treatment of GERD, prokinetic drugs can be used as an adjunct to acid-suppressive drug therapy.
Surgical treatment
Anti-reflux surgery is as effective as drug therapy in relieving symptoms and healing esophagitis. However, surgical complications and mortality are closely related to the surgeon’s experience and skill level. Common postoperative complications include abdominal distention (12%) and dysphagia (6%), and a significant proportion of patients (11%-60%) still require regular medication after surgery. Studies have shown that anti-reflux surgery does not reduce the risk of esophageal adenocarcinoma. Therefore, the decision of whether to perform anti-reflux surgery should be made after taking into account the patient’s personal wishes and the opinion of the surgical specialist.
However, in principle, surgery should be performed for BE patients with proven cancer.
Endoscopic treatment
Short-term preliminary studies suggest that endoscopic treatment can improve GERD symptom scores, improve patient satisfaction and quality of life, and reduce PPI dosage. However, there are no data directly comparing endoscopic treatment with pharmacological treatment. In addition, some rare but serious complications of endoscopic treatment (including perforation, death, etc.) have been observed. Because many questions remain unanswered regarding the long-term efficacy, patient acceptability and safety, and effectiveness in relieving atypical symptoms of GERD, trained endoscopists are advised to proceed with caution.
In patients with BE with heterogeneous hyperplasia and intramucosal carcinoma, endoscopic resection can be considered after exclusion of lymph node metastasis by ultrasound endoscopy.
In conclusion, the symptoms and esophageal mucosal damage of most GERD patients can be controlled by pharmacological treatment. When the patient fails to respond to medication, the diagnosis should be reconsidered as to whether it is correct. Timely adjustment of medication and dosage is one of the important measures to improve the efficacy of GERD treatment. Surgical treatment and endoscopic treatment should be considered together before making a careful decision.