Research advances related to gastroesophageal reflux disease
With the exponential increase in problems caused by obesity, the incidence of gastrointestinal reflux disease and its complications has increased significantly worldwide. Of particular interest is the relationship between central obesity and complications associated with gastrointestinal reflux disease, including esophageal adenocarcinoma.
Due to the improved understanding of the epidemiology and pathophysiology of gastrointestinal reflux disease, it was earlier thought that GERD was due to a major mechanism causing the increased incidence, but it is now increasingly accepted that GERD is a multifactorial disease. Its predisposing factors such as obesity, age, genetic factors, pregnancy, and trauma may also play a role in the damage of the gastroesophageal junction leading to pathological reflux and the corresponding symptoms.
Persistent factors such as obesity, neuromuscular insufficiency, and esophageal fibrosis contribute to the progression of the disease and eventually lead to the formation of a significant esophageal hiatal hernia.
A hiatal hernia is now thought to affect most of the mechanisms that can cause GERD, including reduced sphincter pressure, transient esophageal sphincter relaxation, ability to empty the esophagus, and the location of the acid pouch, making it a major player in the development of GERD, which explains why hiatal hernia is associated with disease severity and mucosal damage.
With the use of proton pump inhibitors, there has been a significant change in the therapeutic management of gastrointestinal reflux disease, with the main therapeutic challenge evolving from promoting mucosal healing to reducing the symptoms of proton pump inhibitor resistance.
At the same time, there is a growing recognition that the symptoms of reflux are equally weak and non-acidic, so it has become necessary to find new complexes or minimally invasive treatments to reduce all types of reflux.
In conclusion, there is a tremendous evolution in our understanding of gastrointestinal reflux disease compared to the past, which will undoubtedly influence the future approach to the treatment of gastrointestinal reflux disease.
Over the past 40 years, reflux disease has evolved from a poorly understood disease to a major clinical problem in gastroenterology. However, the mechanisms by which reflux disease afflicts an increasing number of people are still poorly understood, and indeed our understanding of the pathogenesis, clinical presentation, and epidemiology of GERD is constantly being updated.
Initially, reflux was considered synonymous with esophagitis and esophageal hiatal hernia, then it was thought to be actually a dynamic abnormality, resulting from abnormal esophageal sphincter or esophageal peristalsis, and then it was proposed that reflux is an acid-related digestive dysfunction. Reflux is now considered to be a heterogeneous collection of disorders that includes all of the above involved.
Each period of conceptual advancement in GERD has led to leaps in diagnostic and therapeutic approaches. Barium swallow angiography first identified the presence of a hiatal hernia and visualized reflux for the first time. Manometry and subsequent improvements in testing allowed for the detection of lower esophageal sphincter function, which had previously been difficult to assess. Endoscopy allows for grading of erosive esophagitis. Real-time esophageal pH monitoring can be performed for non-erosive reflux disease.
However, as our understanding of GERD has improved a key advancement has been the widespread clinical use of proton pump inhibitors. However, it is clear that the use of proton pump inhibitors has been overestimated, and it is an opportune time for a new rethinking of the definition, epidemiology, pathologic process, and treatment of GERD.
I. Definition of gastroesophageal reflux disease
The Montreal Conference defined the concept of gastroesophageal reflux disease (GORD) as “a state when reflux of gastric contents causes a series of symptoms and/or complications.” This is the first time that GORD has been defined in terms of what causes it.
The Montreal definition is innovative in that it begins to explore the correlation between celiac and non-celiac disease and between esophageal and extraesophageal manifestations. The definition does not measure the severity of symptoms, i.e. it classifies GERD as long as reflux of gastric contents is present, even if reflux symptoms such as heartburn, for example, are not present.
The definition of refractory GERD was also changed from “persistent mucosal lesions” to “underlying GERD symptoms not improved by treatment with proton pump inhibitors”.
Epidemiology of GERD
The incidence of GERD is increasing worldwide. And the incidence and mortality of esophageal adenocarcinoma has also increased. Complications associated with GERD, reflux symptoms, Barrett’s esophagus, and esophageal adenocarcinoma vary by gender, geographic location, and race
Increased incidence of obesity and decreased prevalence of H. pylori infection have been associated with increased early onset GERD. This directly contributes to the long-term chronic GERD in large populations, which subsequently causes an increased incidence of Barrett’s esophagus and esophageal adenocarcinoma. Abdominal obesity is also an independent risk factor for increased incidence of Barrett’s esophagus and esophageal adenocarcinoma.
Central obesity leads to increased abdominal pressure, which promotes the formation of GERD and esophageal hiatal hernia. Moreover, obesity induces Barrett’s esophagus and esophageal adenocarcinoma by other mechanisms other than those causing gastroesophageal reflux, such as inducing an inflammatory response, releasing various metabolites, cytokines, chemokines, etc., leading to the development of atypical hyperplasia.
There is also an increased incidence of GERD in children, which directly leads to an increased incidence of chronic GERD. The prolonged duration of GERD symptoms has led to an increased incidence of Barrett’s esophagus and esophageal adenocarcinoma. In the United States, the incidence of GERD in infants and children increased threefold between 2000 and 2005, and 40-50% of these asymptomatic patients began to require pharmacologic treatment 10 years after diagnosis.
Although there is no consistent correlation between the presence or treatment of H. pylori and GERD symptoms, a comprehensive data suggests that H. pylori may be a preventive factor for erosive esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma. A meta-analysis showed that H. pylori, especially the cag-A strain, is a protective factor for Barrett’s esophagus.
This may be due to reduced acid production due to gastritis or atrophy of the gastric epithelium caused by H. pylori, which decreases the risk of esophageal exposure to a low pH environment, and thus reduces the risk of Barrett’s esophagus and esophageal adenocarcinoma.
H. pylori infection may also partially explain the epidemiological features of GERD, as H. pylori infection is common in areas with a low incidence of Barrett’s esophagus and esophageal adenocarcinoma, but there is no evidence that the incidence of H. pylori or its associated gastritis differs between men and women.
III. Theoretical theories related to the pathogenesis of gastroesophageal reflux disease
Initially, GERD was understood to be equivalent to a hiatal hernia, then the influence of lower esophageal sphincter function was discovered, then the theory of transient lower esophageal sphincter relaxation was proposed, and now it is gradually recognized that GERD is actually a multifactorial disease in which all of the above factors can be involved and interact with each other.
The major developments in the understanding of the pathogenesis of GERD in recent years include the following.
(1) The recognition that the gastroesophageal junction is an important component of the lower esophageal sphincter complex and that the pedicle of the diaphragm is the main structure preventing the occurrence of tension-induced reflux.
(2) Transient lower esophageal sphincter relaxation rather than lower esophageal sphincter relaxation is the main mechanism leading to the occurrence of GERD.
(3) Prolonged acid clearance in the esophagus rather than frequent acid reflux events are the main cause of esophageal inflammation and associated sequelae.
(4) Decreased compliance at the esophagogastric junction leads to increased volume of gastric contents entering the esophagus per reflux occurrence, decreased ability to limit gas reflux, and increased odds of symptomatic GERD.
(5) Again, it was found that the peak postprandial acid secretion secreted little gastric acid mixed with chyme in the proximal stomach.
(6) Recognized that longitudinal muscles in the lamina propria of the esophagus are essential for controlling the opening of the lower esophageal sphincter and for inducing reflux symptoms.
(7) Confirmation that esophageal hiatal hernia can affect or exacerbate all of the factors addressed above.
IV. Management options for symptomatic GERD
Initially, GERD was equated with esophagitis, when the goal of treatment was to promote healing of the damaged esophageal mucosa. As the understanding of GERD has improved, there has been increasing interest in how to treat persistent reflux symptoms or reflux symptoms when no esophagitis is present.
Proton pump inhibitors have been effective in reducing the progression of esophagitis and the development of heartburn, regurgitation, chest pain, cough, laryngitis and asthma. However, it is now necessary to develop alternative treatment options that can both effectively suppress reflux and simultaneously treat the associated factors affecting disease development, because acid-free or weakly acidic reflux can also cause reflux symptoms, and such patients may respond poorly to proton pump inhibitor regimens.
(A) Improvement of lifestyle habits and weight control
Since obesity, especially abdominal obesity, is an important pathogenesis of GERD, a proper diet/avoidance of foods that cause or aggravate reflux is effective in reducing the occurrence of GERD. Studies have shown that even in women with normal BMI, the risk of GERD is reduced by 40% when BMI is reduced by 3.5 kg/m2.
However, if weight control is to be achieved through bariatric surgery, it is important to note that different surgical procedures have different effects on GERD. Gastric banding and gastric sleeve resection can lead to an increased incidence of GERD and esophagitis, while only R-en-Y gastric bypass surgery has the effect of reducing the occurrence of reflux and controlling reflux symptoms.
(ii) Reduction of acidity in the stomach
Although there is no significant difference in the amount of gastric acid secretion in patients with GERD compared with asymptomatic controls, the most widely used treatment option for symptomatic GERD is still to reduce gastric acid secretion. General antacids are used to treat mildly symptomatic GERD and are characterized by a rapid onset of action but a short duration of effectiveness.
H2 receptor antagonists can be used to treat symptomatic episodes on an as-needed basis.
Proton pump inhibitors are the first-line treatment for the control of patients with moderate to severe GERD. The efficacy of the different proton pump inhibitor drugs now commonly available on the market is generally consistent. However, if treatment with one conventional dose of a proton pump inhibitor is not effective, switching to another may be effective. Alternatively, patients may benefit from increasing the dose of the drug.
(iii) Reflux symptoms that do not respond to acid control therapy
The effect of acid control therapy to reduce gastric acid secretion on underlying GERD symptoms is not consistent. This may be because excessive acid secretion is not the main pathogenesis of GERD and a large proportion of reflux symptoms are not caused by acid reflux. Therefore, this group of patients is likely to be those for whom proton pump inhibitor therapy is ineffective.
In patients who are not treated with proton pump inhibitors, it is necessary to perform dynamic esophageal pH monitoring. It is only reasonable to discontinue proton pump inhibitors if the dynamic pH is always within the normal range, and only the pH measured by an intraluminal pH resistance monitor is accurate.
Patients who respond poorly to proton pump inhibitor therapy can be classified into 4 categories based on monitored pH values (Figure 3). Each category has unique treatment considerations. Of these, category 4 is the best treated. Patients in this category have physiologic reflux and a diagnosis of GERD can be ruled out. Any anti-reflux therapy is ineffective in this category and a new alternative treatment should be sought.
More complex is type 3, a patient with high reflux volume but no clear temporal correlation between the onset of reflux and the appearance of symptoms. Academically, these patients suffer from GERD. Patients with pulmonary and ear, nose, and throat symptoms are typical of this group, and their treatment is particularly challenging because of the lack of high-quality evidence that any anti-reflux treatment regimen is effective.
Treatment of type 2 patients is also challenging. Patients in this group have a physiologic basis for the presence of GERD, but are relatively complicated by the presence of esophageal hypersensitivity, which may reduce the effectiveness of traditional anti-reflux treatment regimens. Again, there is a lack of high-quality evidence that any anti-reflux treatment regimen is effective for this type of treatment. Anecdotal data suggest that the use of sensory modulators may be effective.
Patients with type 1 have physiological evidence of the presence of reflux and clinical manifestations of the presence of massive reflux, with a clear correlation between reflux and symptoms. Patients with this type may benefit from alternative therapies such as medication changes, increased doses of proton pump inhibitors, or surgical treatment.
Patients with reflux who have failed to respond to proton pump inhibitor therapy are classified according to dynamic esophageal pH monitoring.
(iv) Treatment options other than acid-control drugs
Prokinetic drugs that accelerate gastric emptying, increase lower esophageal sphincter tone, and accelerate the clearance of esophageal reflux may appear to benefit patients with GERD. However, treatment with gastrofacial, domperidone, and cisapride has not yielded the desired reduction in reflux symptoms.
Another alternative treatment strategy is to target transient lower esophageal sphincter relaxation. For example, the GABA-B receptor antagonist baclofen partially inhibits reflux, but this drug is not suitable for GERD treatment because of its significant neurological side effects. Baclofen analogs and other one-pass antagonists of lower esophageal sphincter relaxation are also available, but their use is limited by significant side effects.
Targeted therapy for esophageal hypersensitivity is another optional alternative treatment modality. For example, TRPV1 antagonists, but studies have not been successful. There are data suggesting that tricyclic antidepressants and selective 5-hydroxytryptamine reuptake inhibitors are effective in reducing esophageal hypersensitivity, but data from controlled studies are lacking.
A relatively new concept recently proposed for the pathogenesis of reflux esophagitis is the formation of acid pockets. It is the selective development of a hyperacidic state in the proximal stomach after a meal under certain circumstances. Recent research evidence suggests that acid pouch formation is the primary mechanism of postprandial reflux and symptomatic reflux formation, and suggests this as a target for treatment. One of the therapeutic approaches is the development of drug combinations of alginates and antacids. Alginates are polysaccharides derived from seaweed that, when combined with water, form a mucoadhesive gel that is suspended in the proximal stomach. Gagapin is a combination of alginates and gastric mucosa-protective drugs.
Studies have shown that Gagapin can significantly increase the distance between the formed acid pouch and the gastroesophageal junction, and can even cause the acid pouch to disappear. A placebo-controlled study noted that in 110 patients with symptomatic GERD, the use of Gagapine was effective in reducing reflux symptoms compared to the placebo group.
(v) Non-pharmacologic treatment options
Laparoscopic fundoplication has been shown to be effective in reducing all acidic, weakly acidic, or non-acidic reflux symptoms. However, the results of a 5-year randomized controlled study showed no significant advantage of this procedure for symptom relief compared with the use of esomeprazole. In terms of residual symptoms, patients in the proton pump inhibitor group had more persistent regurgitation, and those who underwent fundoplication had more persistent symptoms of dysphagia, bloating, and belching.
In recent years, scholars have conducted numerous studies on the possibility of endoscopic treatment simulating laparoscopic surgery. However, the results have been unsatisfactory. Studies have shown no difference in symptom improvement in patients with gastroesophageal reflux treated using endoscopic suturing techniques and endoscopic radiofrequency ablation compared with those treated with sham surgery. Therefore, endoscopic anti-reflux treatment is not recommended for clinical use.
The results of a 2-year uncontrolled study suggest that a transoral folding device, EsophyX, may promote relief of GERD symptoms and reduce the use of proton pump inhibitors in patients without esophageal hiatal hernia.
Another alternative laparoscopic anti-reflux technique is the placement of a movable band of magnetic beads at the gastroesophageal junction, which has been shown to be effective in reducing acid exposure in the esophagus (from 10.9% to 3.3%), improving symptoms and reducing the use of proton pump inhibitors. However, the study lacked a sham-operated control group and had only 1 year of follow-up.
The third technique is electrical stimulation of the lower esophageal sphincter using laparoscopically implanted electrodes to increase sphincter tone, decrease reflux, and reduce symptoms by stimulating contraction of the lower esophageal sphincter, again lacking a sham-operated control group for comparison.
Summary
The incidence of gastroesophageal reflux disease and its complications (erosive esophagitis, Barrett’s esophagus and esophageal adenocarcinoma) has increased significantly worldwide. Recent findings of a correlation between central obesity and GERD explain why Caucasian male patients are more likely to develop complications.
It is also becoming recognized that GERD is not caused by a single mechanism but is a multifactorial disease. The use of proton pump inhibitors has led to a significant improvement in GERD symptoms. The difficulty of treatment has changed from “promoting mucosal healing” to “reducing proton pump inhibitor resistance”.
At the same time, it was further recognized that both weak acid and acid-free exposures could cause reflux, which led to the need to find new complexes targeting non-acidic reflux-generating mechanisms to alleviate all types of reflux symptoms (including those that respond poorly to proton pump inhibitor therapy). This is a new challenge for the treatment of GERD.