Gastroesophageal reflux is a physiological process that occurs during and after meals. However, acid neutralization by saliva and esophageal peristalsis often lead to rapid elimination of physiological reflux. In a minority of people, this reflux, although physiological, causes gastroesophageal symptoms .
Gastroesophageal reflux disease (GERD) occurs when the reflux is frequent or caustic enough to cause the typical symptoms: heartburn, regurgitation and/or dysphagia, with or without mucosal damage.
GERD is made up of 3 phenotypes:
1) Erosive reflux disease (ERE), defined as endoscopic evidence of reflux-related mucosal injury.
2) Barrett’s esophagus
3) Non-erosive reflux disease (NERD), defined as abnormal exposure of the esophagus to acid according to pH tests but without endoscopic injury to the esophageal mucosa.
All of the above-mentioned GERD-related disorders primarily present with heartburn and regurgitation.
Thus, by extension, in clinical practice, heartburn is attributed to GERD, but it is important to recognize that although most patients with GERD have heartburn and/or regurgitation, many who have these symptoms do not have GERD. Most patients with refractory heartburn have a functional disorder of the esophagus.
There are 2 functional esophageal disorders that present mainly with heartburn, without endoscopic expression , with inconclusive manometry tests. They include functional heartburn (FEA) and reflux hypersensitivity (HR; defined as the association of abnormal symptoms during the reflux test, but with normal exposure time to esophageal acid).
Recognition of these functional disorders has improved the understanding of patients with heartburn and normal endoscopy, now classified into the ERNE, AEF or HR group, depending on the evidence.
| Definitions |
> Non-erosive reflux disease
In 2006, the Montreal consensus meeting defined GERD as “a condition that develops when the contents of gastric reflux cause bothersome symptoms and/or complications.” Subsequently, ERGN was defined as ERNE, due to the presence of bothersome symptoms associated with reflux (heartburn and/or regurgitation) in the absence of mucosal lesions on endoscopy.
The Vevey meeting consensus in 2009 best defined ENRE as “bothering reflux-related symptoms, in the absence of erosions and/or ruptures of the esophageal mucosa on conventional endoscopy and without being treated with acid inhibitors.”
” Although the Vevey consensus recognized AEF as a separate entity, unrelated to acid reflux, in the definition of ERNE both consensuses did not include abnormal pH tests, which help separate ENRE from AEF. This led to a redefinition of the ERNE by the Rome committee for functional diseases of the esophagus, distinguishing patients with heartburn and normal endoscopy, on the basis of pHmetry target values.
> Functional heartburn
The term functional heartburn was used about 40 years ago based on the Rome II criteria for functional diseases of the esophagus.
The first definition of the Rome criteria was "burning substernal discomfort or pain, occurring for at least 12 weeks in the preceding 12 months, in the absence of pathological esophageal reflux disease, achalasia, or other motility disorders with recognized pathology." .”
The recognition that heartburn can occur in patients who do not suffer from GERD was a major advance in clinical practice, and provided necessary information on the management of heartburn symptoms in patients who had not responded to treatment with inhibitors. the proton pump (PPI).
The Rome IV criteria define 3 different diseases within the category of patients with heartburn and normal endoscopy. ERNE (abnormal esophageal acid exposure), HR (esophageal acid exposure, normal, but associated with abnormal reflux symptoms), and AEF (esophageal acid exposure, without association with acid symptoms).
On the other hand, the diagnosis of functional esophageal disease requires the presence of symptoms during the last 3 months, with onset at least 6 months before diagnosis and a frequency of at least 6 months before diagnosis, at least 2 times a week, in the absence of structural, inflammatory, motor or metabolic abnormalities.
| Epidemiology |
The combined prevalence of GERD symptoms at least 1 time per week is 1.3% worldwide. Higher prevalence has been observed in South Asia and Southeast Europe (>25%). The lowest prevalence is from Southeast Asia, Canada and France (<10%). On the other hand, the prevalence of GERD varies from 18% to 28% in North America.
Due to the heterogeneity of the standardized definition of ERNE and AEF throughout the literature, the true prevalence of these diseases is difficult to elucidate. However, studies using endoscopy and pH testing indicate that AEF ranges from 10% to 40% of heartburn patients who consult a gastroenterologist.
More than 50% of patients with reflux symptoms presenting to primary care have a negative endoscopy, while some European researchers have shown that the rate of patients with a negative endoscopy could be as high as 75%.
Almost half of patients who have a normal endoscopy also have a normal esophageal acid exposure time during pH testing.
Overall, among those with normal endoscopy and normal pH testing, 40% have HR (positive correlation between symptoms and reflux events) and 60% have AEF. Therefore, it is estimated that AEF represents 21% of all untreated patients presenting with heartburn.
| natural evolution |
The literature on the natural history of patients with GERD and AEF is limited. Most studies are retrospective, limiting inferences about how these disease states may affect clinical outcomes. A systematic review showed that annual progression rates from NERD to ERE ranged from 0% to 30%, while nearly 1% to 13% of patients with GERD develop Barrett’s esophagus (BE).
A multicenter prospective study evaluated progression vs. regression of GERD phenotypes over 2 years in a cohort of 4,000 patients and found that among patients with GERD, the disease progressed to GERD in only a minority.
The incidence of BE was 0.5% in patients with GERD, the majority of whom did not progress over time and only a small minority progressed from GERD phenotype to another, mainly to low-grade erosive esophagitis (classification A/ B d Los Angeles).
On the other hand, the natural history of patients with AEF is not known. One study suggests that AEF is a chronic disease in the majority of patients, with a significant impact on quality of life.
| Pathophysiology |
The mechanism involved in the symptoms of patients with NERD is related to the transient increase in relaxation of the lower esophageal sphincter, which causes the reflux of harmful agents (acid and/or bile) into the distal esophagus.
This leads to an increase in the dilation of the intercellular spaces (EIC) and the permeability of the esophageal epithelial lining, favoring reflux. This allows noxious agents to activate nociceptive receptors, such as vanilloid transient receptor potential 1.
On the other hand, alterations in esophageal clearance time, the presence of gas mixed with the reflux liquid, and the proximal extension of reflux have also been implicated in the perception of symptoms in NERD. When the pathophysiological characteristics of patients with ERNE are compared with those of patients with AEF, the former have a higher prevalence of hiatal hernia, decreased lower esophageal sphincter tone, and a greater number of abnormal esophageal acid exposure.
Multiple studies of n patients with AEF, who underwent esophageal distension with a balloon or electrical stimulation, have shown lower pain perception thresholds compared to patients with ERNE. This increased sensitivity of the esophagus to pain in AEF patients is associated with increased afferent sensitivity because the normal latency of evoked potential responses could be due to reduced afferent input.
One study found that patients with ERNE had lower pain perception thresholds (induced by acid) than those with ERE, while patients with AEF had greater sensitivity to acid as well as saline infusion. In general, patients with AEF have been shown to be more sensitive to both mechanical and chemical stimuli.
| Clinical presentation |
In general, the clinical presentation of AEF does not differ from the presentation of NERD or any other GERD phenotype. Heartburn as a symptom has poor reliability and correlates with abnormal pH tests in 54% to 72% of patients.
Although both disorders mainly affect young and middle-aged women, the severity of symptoms of patients with AEF has also been shown to be inversely related to age, while the opposite is true for patients with ERNE.
Patients with AEF have a longer history of heartburn and a significantly higher somatization score compared to patients with ERNE.
More importantly, concomitant functional disorders such as functional dyspepsia and irritable bowel syndrome (77%) are more common in patients with AE. These patients are also more likely to have other dyspeptic symptoms such as bloating, early satiety, nausea, and postprandial fullness, compared to patients with ERNE.
| Diagnosis |
> Endoscopy
Endoscopy is the most sensitive test to identify abnormalities of the esophageal mucosa, such as erosive esophagitis and BE. Biopsy samples obtained during upper endoscopy can rule out other disorders that have been associated with heartburn, such as eosinophilic esophagitis and lymphocytic esophagitis.
However, the role of histology in the diagnosis of ERNE and differentiation from AEF has been very limited. Most histological markers related to GERD have shown little diagnostic value.
An international consensus developed a histological severity score for ERNE using the following parameters: basal cell hyperplasia, papillary elongation, DEI, and the presence and number of intraepithelial eosinophils, neutrophils, and mononuclear cells. The evaluation of this score in patients with ERNE and AEF according to pHmetry has shown a sensitivity of 74% and a specificity of 86% in differentiating the two disorders.
Another study in patients with GERD refractory to PPIs showed that the application of this histological score was able to differentiate patients with NERD and AEF, with a sensitivity of 85%, a specificity of 64%, a positive predictive value of 71%. and a negative predictive value of 80%.
However, its application in clinical practice is very limited because the distribution of microscopic findings varies significantly depending on the distance to the squamocolumnar junction. On the other hand, the interpretation of the findings could have great variability among pathologists.
> Reflux test
Because endoscopy alone is insufficient to distinguish ERNE from AEF, an integral component in the evaluation of patients with heartburn who are not receiving PPIs or who have heartburn refractory to treatment is ambulatory pH monitoring. This can be done by transnasal pH monitoring for 24 hours or by extending the recording time to 48 or 96 hours, using the wireless pH monitoring system, to increase the diagnostic possibility.
The specificity and sensitivity of the transnasal pH monitoring test for the diagnosis of GERD has been reported to be 92% and 77%, respectively, with little prognostic value. This was primarily due to the variability of acid reflux events and the ability to capture abnormal intraluminal reflux during the follow-up period.
The wireless pH monitoring system may be particularly useful if the 24-hour pH study was negative despite high suspicion of GERD, or if the patient cannot tolerate the transnasal catheter.
The main outcome of ambulatory reflux monitoring is the time of exposure to acid, therefore, the test performed with this technology should always be done without the patient being under the effect of gastric acid inhibitors because the pHmetry results will be normal. The Lyon consensus proposed that acid exposure time <4% should be considered definitely normal , while if it is >6%, it is definitely abnormal .
Intermediate values between these limits are not conclusive. Thus, patients with acidity, normal endoscopy and a TEA >6% correspond to the diagnosis of ERNE, while patients with an acid exposure time <4% and negative symptom rates should be classified as AEF, once ruled out. other structural and motility disorders.
The symptom index and probability of symptom association (PAS) are the most commonly used common symptom indices in clinical practice. The percentage of symptom events preceded by reflux episodes and SBP are statistical calculations to express the probability that symptom events and reflux episodes are actually associated.
Heartburn symptom index >50% and SBP >95% are considered positive. However, it is important to keep in mind that the reliability of these metrics can be highly variable, particularly for the Common Extraesophageal Symptoms indices.
Few studies have evaluated the additional utility of pH impedance parameters in distinguishing patients with NERD from patients with AEF, due to the unclear clinical implications of non-acid reflux. However, in patients with acid exposure time between 4% and 6%, the additional information given by the impedance test and the evaluation of the number of reflux episodes in 24 hours may be useful.
Patients with more than 80 reflux episodes (acidic, weakly acidic, or weakly alkaline) in 24 hours are definitely abnormal, while a number <40 is physiological. Two new parameters, detected by impedance, have been investigated within GERD phenotypes, which could increase the diagnostic value of pH monitoring by impedance, and distinguish patients with NERD from those with AEF.
However, the application of these metrics in clinical practice has been limited due to the lack of automated analyzes and the need for cumbersome manual calculations. Furthermore, there is no consensus on the diagnostic criteria for pH impedance testing in patients with AEF.
> Post-reflux swallowing peristaltic wave
In healthy individuals, reflux episodes trigger peristalsis to eliminate the reflux, and primary peristalsis to neutralize the acidified esophageal mucosa with saliva.
This physiological reflex, which becomes evident with the anterograde progression of impedance within 30 seconds of a reflux episode, is called the post-reflux peristaltic swallowing wave (OPDP).
The proportion of reflux episodes followed by an OPDP (over the total number of refluxes) is called the OPDP index . Studies have shown that this index can differentiate ERE and ERNE from AEF and controls, with a sensitivity of 99% to 100% and a specificity of 92%. However, currently, this evaluation is done manually and is therefore time-consuming and the inter-rater variability is unknown.
> Average nocturnal basal impedance
The nocturnal basal impedance can be a surrogate marker of the integrity of the esophageal mucosa because low values have been found in ERE and NERD. They were also found to correlate with IED and reflux symptoms. However, assessment of baseline impedance is limited by frequent swallowing and reflux events, which may affect the measurement, while the catheter may not make direct contact with the mucosa during the course of the study.
To avoid these tricks and obtain a more reliable basal impedance, it is best to correlate it with the pH impedance traces recorded during sleep, which is called mean nocturnal basal impedance (NMBI), since 3 periods of 10 minutes are averaged, with 1 hour intervals. It has been shown that IBNM is low in patients with NERD compared to those with AEF and healthy controls.
A cutoff value <2,100 ohms has a sensitivity of 78% and a specificity of 71% to differentiate patients with NERD from patients with AEF. Another study found that IBNM of 2,292 ohms was an independent predictor of treatment response. Antireflux agents are accompanied by better predictions.
> Esophageal manometry
In general, esophageal manometry is indicated in patients with heartburn and normal endoscopy or to rule out major esophageal motility diseases (esophagogastric junction [EGJ] outflow obstruction, achalasia, jackhammer esophagus, absence of contractility). or distal esophageal spasm).
The purpose of esophageal manometry is the precise placement of pH measurement or impedance pH catheters.
Distal esophageal spasm is particularly important in patients with refractory heartburn. A recent international consensus described the pathophysiological classification of motor findings in GERD, with a focus on measurements of EGJ incompetence as a potential physiological marker. The Lyon consensus proposed adopting 2 metrics, one that expresses the anatomical morphology and the other, which summarizes the contractile vigor of the EGJ.
The anatomical morphology of the EGJ is classified into 3 high-resolution manometry (HRM) subtypes, based on the relative location of the lower esophageal sphincter (LES) and crural diaphragm pressure figures:
- Type 1: LES with superimpedance and crural diaphragm.
- Type 2: axial separation <3cm
- Type 3: separation ≥3.
The morphology of EGJ type 3 has been associated with reduced LES pressure and could be correlated with the severity of reflux (number of reflux episodes, longer mean acid exposure time, and association with a higher positive symptom).
The second MAR metric quantifies the inferior contractility integral of the EGJ using a similar methodology to the distal contractility integral (DIC). This metric has been shown to have good diagnostic accuracy with high specificity in distinguishing GERD and functional heartburn, but has been limited in clinical practice due to a lack of normative values, with a wide range of normal ranges in the literature.
Another MAR metric that may be useful in the evaluation of patients with GERD is the CDI, which quantifies the strength of esophageal peristalsis. Esophageal peristalsis is usually weak in GERD, with an ICD <450 mm Hg/cm/s, resulting in ineffective esophageal motility. This peristaltic dysfunction is increasingly accentuated in NERD, GERD and BE, with a parallel increase in severity. However, it is very rarely seen in patients with AEF.
The Chicago Classification defines ineffective esophageal motility as ≥50% of the swallow test with an ICD <450 mm Hg-cm-s. Commonly, in NERD, motility is normal. However, the use of MAR metrics to evaluate EGJ morphology (hypotensive, with or without hiatal hernia) and esophageal peristalsis (normal, weak, absent) may add valuable information in the management of patients with GERD and, specifically, , in those with ERNE.
> Mucosal integrity tests
In vivo testing using a multichannel intraluminal impedance catheter (esophageal multichannel intraluminal impedance test) has shown that patients with ERNE have a lower baseline esophageal impedance than patients with AEF and controls. Since 2015, there has been a new device that measures mucosal impedance (MI), which allows the integrity of the esophageal epithelium to be directly measured.
It has been shown to correlate inversely with the degree of DEI and to normalize with therapy. The pattern of MI along the esophageal axis is significantly different in patients with GERD (ERE or NERD) or eosinophilic esophagitis, compared to patients with AEF and controls.
Patients with ERNE tend to have lower IM (ohms) in the area closest to the squamocolumnar junction, which increases with the distance from the squamocolumnar junction (GERD pattern), while patients with eosinophilic esophagitis (EoE) have a low MR throughout the esophagus (EoE pattern).
Patients with AEF are similar to controls, with higher MR (ohms) throughout the esophagus. To identify patients with erosive esophagitis, the MI pattern has shown greater specificity (95%) and positive predictive value (96%) than wireless pH monitoring (64% and 40%, respectively).
More recently, a balloon IM device has been developed, which reduces interoperator variability arising from lack of adequate contact of the catheter with the esophageal mucosa due to movement driven by intraluminal gas and fluid. This device is capable of quickly distinguishing GERD (ERE and ERNE) and EoE.
On the other hand, patients with NERD have a different mucosal perimeter impedance compared to patients with AEF and HR. To apply this technique in clinical practice, studies are still needed to obtain more data.
| Treatment |
> Non-erosive reflux disease
In ERNE, the therapeutic objective is to relieve symptoms, prevent relapses and improve quality of life.
Due to the broad definition of ERNE, which does not exclude AEF or HR, therapeutic trials did not exclude these two functional disorders. functional. PPIs have been shown to be superior to histamine-2 receptor antagonists in patients with NERD.
A systematic review of 7 trials evaluating resolution of heartburn with PPIs in patients with NERD compared to patients with SRE showed that the therapeutic gain over placebo ranged from 25% to 35%.
Response rates after 4 weeks were significantly higher in patients with SRE (56%) than in patients with ERNE (37%). This lower response rate in NERD patients is mainly attributed to the heterogeneity of this group in the aforementioned studies.
The role of antireflux surgery in patients with NERD has also been poorly studied. Compared with patients with SRE, after antireflux surgery patients with SRE have a lower rate of symptom improvement, a higher level of dissatisfaction, and more reports of postoperative dysphagia.
The greatest predictor of successful outcome after antireflux surgery tends to be a response to pH. Therefore, the predictability of success after laparoscopic fundoplication is directly proportional to the degree of certainty that the underlying cause of symptoms is GER.
Endoscopic antireflux therapy is also an option in patients with NERD, including full-thickness plication, radiofrequency energy delivery to the LES, and incisionless transoral fundoplication. Many studies have demonstrated short-term efficacy and safety of these procedures in selected NERD patients with mild to moderate acid exposure time and a hiatal hernia <3 cm. However, data on long-term efficacy and safety are lacking. Trials with laparoscopic fundoplication are limited.
> Functional heartburn
PPIs or any other antireflux modality have no role in the management of patients with AEF. In fact, these patients often have an underlying cause that makes the disease refractory to PPI treatment. Instead, treatment should be aimed at reducing esophageal hypersensitivity and coexisting psychological features, such as depression, anxiety, somatization, emotional lability, and poor social support.
A study using the Rome II definition of AEF (which includes patients with RH) found that almost 50% of patients responded to a standard dose of PPI. Rome III removed the HR group from the definition of AEF.
Using this criterion, the PPI response rate could have been ≤25%. It is difficult to differentiate placebo response due to short follow-up periods, but overlapping antacid therapy could have an indirect effect on esophageal sensitivity.
A controlled study of patients with AEF treated with oral ranitidine 150 mg twice/day or placebo for 7 days found that ranitidine significantly decreased esophageal sensitivity to acid. As a result, researchers suggested that histamine-2 receptor antagonists may serve as visceral analgesics, modulating the pain perception threshold, and may therefore provide benefits to patients with AEF.
Antireflux surgery has no role in the treatment of patients with AEF since the subjective results are significantly worse.
In patients with GERD refractory to PPI treatment, the most common underlying cause is particularly overlap with AEF but also with RH. In this clinical scenario, PPI treatment can be maintained to control GER while a neuromodulator could be added to treat an overlapping esophageal functional disorder.
Despite being a common disorder, there are few studies for the pharmacological treatment of AEF because it is often excluded from GERD drug treatment trials.
Currently, the therapeutic pillar for AEF are pain modulators, based on their effectiveness in other functional disorders of the esophagus, such as non-cardiac chest pain. Therefore, tricyclic antidepressants and selective serotonin and norepinephrine reuptake inhibitors are indicated.
Inhibitors are an option for patients with AEF. Other studies have attempted to target modulation of novel esophageal pain receptors, such as vanilloid transient potential receptor 1, with variable results. The decision about which neuromodulator to use depends on comorbidities and medical history.
Typically, in their daily practice, the authors begin treatment with 10 mg/day of amitriptyline, with gradual increases until reaching 25 mg/day, according to tolerance. Due to the possible side effects of sedation, they recommend taking this medication at night, before sleeping. Since these medications work as neuromodulators, it may take 8 to 12 weeks for symptom improvement to be noted.
Recently, the action of hypnotherapy directed at the esophagus has been studied for the treatment of AEF, with which one study showed a significant decrease in visceral anxiety, improvement in emotional quality of life and decrease in the severity of symptoms. However, the possibility of being applied in clinical practice is limited due to the lack of routine access to a psychologist trained in this type of hypnotherapy.
Another study evaluated the role of acupuncture for 4 weeks in patients with heartburn refractory to treatment with daily omeprazole. And acupuncture was found to significantly improve heartburn symptoms compared to doubling the PPI dose. In general, since patients with AEF have a benign clinical course, reassurance is key.
Since by definition there is no pathological reflux, it is important to inform the patient that complications due to acid reflux are unlikely to develop.
The authors state that it is essential to recognize that there is a significant impact of symptoms on quality of life, and that the majority of patients with AEF continue to have heartburn beyond one year of follow-up. Therefore, therapy should focus on improving esophageal hypersensitivity, firming, and treating any coexisting and functional psychological disorders.
| Conclusions |
Heartburn is a symptom commonly encountered in clinical practice, and although most patients with GERD have heartburn and/or regurgitation, many patients with these symptoms do not have GERD.
Up to 70% of these patients have a normal endoscopy and should undergo outpatient reflux monitoring and esophageal manometry to rule out an alternative etiology and better categorize this subgroup of patients: ERNE or HR.
