Importance of esophageal pH monitoring and manometry in indicating surgical treatment of gastroesophageal reflux disease.

OBJECTIVE
To demonstrate the need of performing esophageal pH monitoring and manometry in patients with clinical suspicion of Gastroesophageal reflux disease, as more accurate and practical complementary exams in the indication of surgical treatment.


METHODS
A systematic review was carried out in the PubMed/Medline database, based on the recommendations of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) protocol, selecting studies in humans, published in Portuguese, Spanish, and English, from January 1, 2009 to August 5, 2020. The following descriptors were used: "reflux gastroesophageal" AND "surgery" AND "surgical treatment" AND "esophageal manometry" OR "pH monitoring". After that, retrospective or prospective observational studies with a sample of less than 100 individuals, or with limited access, reports or case series, review articles, letters, comments, or book chapters were excluded. To facilitate the application of the exclusion criteria, the Rayyan management base was used.


RESULTS
Out of the 676 studies found, 19 valid and eligible studies were selected to make inferences.


CONCLUSIONS
Based on the best evidence, currently, considering national particularities, performing a 24-hour esophageal pH monitoring and esophageal manometry for all patients undergoing anti-reflux surgery.


INTRODUCTION
Gastroesophageal reflux refers to the retrograde passage of stomach contents into the esophagus. In the presence of associated symptoms and/or lesions on the esophageal mucosa (esophagitis), it becomes a pathologic condition called gastroesophageal reflux disease (GERD) 1,2 . The most important protective mechanisms from gastric reflux include: (1) the functional integrity of the esophageal body and lower esophageal sphincter, (2) constant swallowing of saliva and (3) gravity 1 .
Being one of the most common diseases in practice, GERD is a highly prevalent disease in all age groups and in both sexes, affecting up to 20% of the entire western world population 3,4 .
The first therapeutic approach to GERD is the use of proton pump inhibitors (PPI) and anti-reflux behavioral measures.
In refractory (i.e., those with persistent symptoms for more than once a week after at least two months of full-dose PPI therapy) 5 or complicated cases (i.e., those with recurrent esophagitis, stenosis, or Barrett's esophagus >3 cm), or patient refusal to prolonged PPI therapy, anti-reflux surgery, such as fundoplication with or without hiatoplasty, may be indicated 6 .
Establishing a correct early diagnosis and identifying the conditions that may prevent a good response to medical management in GERD patients is essential. Currently, the diagnosis of GERD may be provided with endoscopy and 24-hour pH monitoring (pH-24h). Endoscopic findings suggestive of GERD include severe esophagitis (Los Angeles C or D), Barrett's esophagus (confirmed by histological findings), and peptic stenosis. In addition, pH-24h results showing an acid exposure time (AET) greater than 6% is consistent with pathologic reflux 3 . AET refers to the percentage of time that the esophageal mucosa is exposed to acid reflux at pH<4 3 . At AETs between 4 to 6%, however, the Lyon Consensus recommends that other adjuvant parameters should be considered to establish the diagnosis of pathologic reflux, such as the DeMeester Index or the identification of more than 80 refluxes in 24 hours 3 .
For cases in which anti-reflux surgery is indicated, esophageal manometry is warranted to evaluate the presence of esophageal motility disorders before surgery, weigh the risks for complications (e.g., dysphagia, meteorism, recurrence of symptoms, etc.) and prognosticate on the expected results 4,7 .
Although pH-24h and esophageal manometry should ideally be part of the pre-operative evaluation of all GERD patients, this is not the case in the daily medical practice in Brasil. This review aimed to demonstrate and justify, based on the best available evidence, the importance of requesting both pH-24h and esophageal manometry for all GERD patients, especially for those eligible for surgical treatment.

METHODS
Based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 8  To facilitate the use of the exclusion criteria above and help eliminate duplicate or triplicate studies, the Rayyan management database was used (Qatar Computing Research Foundation Institute, Doha, Qatar), available at https://rayyan.qcri.org 9 .

RESULTS
Of the 676 studies found through the aforementioned search engine, 19 valid and eligible studies were selected based on pre-established inclusion and exclusion criteria to foster future inferences. The flowchart describes the entire search and selection process ( Figure 1).
Although there are intrinsic methodological limitations in most of the 19 eligible studies, these did not hinder the analysis of the inferences drawn in this review (Table 1).

DISCUSSION
Currently, the pH-24h is considered the gold standard for the diagnosis of GERD 2,4,10 . Although the identification of histologic changes (i.e., dilatation of the intercellular spaces of the esophageal epithelium and expression of TRPV1 receptors) may confirm the diagnosis of GERD 11 , its use has been questionable in clinical practice due to limited data on literature. This reinforces the value of pH-24h in medical practice ( Figure 2A).
Although the pH-24h may be improved with impedance reflux monitoring by increasing the understanding of the pathophysiology and etiology of GERD to establish differential diagnoses 12 , the use of both tests may not be feasible considering the costs and accessibility of the examinations in most Brazilian territory. The use of pH-24h alone should be considered a mandatory examination for the precise diagnosis of GERD and in the preparation of patients for surgical treatment, for reasons described as follows: The use of pH-24h may avoid the issues concerning the use of PPIs in both diagnostics and treatment. High diagnostic errors (error rates: 30 to 51% of cases) related to the use of a low specificity therapeutic trial of PPI for 14 days implies that it may not be reliable to prove a pathologic acid reflux in the esophagus 10,12,13 . Furthermore, the prolonged and inappropriate use of PPIs in cases of misdiagnosis may cause adverse effects (e.g., osteoporosis) and unnecessary expenses to patients 5,10,[13][14][15] . This may be apparent in cases of functional pyrosis, in which placebo effects related to the use of drugs, especially PPI, have been reported. In addition, this may also be evident in patients with non-specific laryngeal changes in videolaryngoscopy, or in those with chronic cough (eight weeks more) 2,11,14 . Although some changes in the laryngeal mucosa (e.g., erythema and edema of the posterior larynx) can occur in GERD, these changes are not diagnostic 2 .
Moreover, the pH-24h with two sensors can establish an accurate diagnosis of laryngeal or superior reflux through the superior sensor 15 . This may further classify the type of gastroesophageal reflux (a) based on the affected region: (1) isolated proximal, (2) isolated distal, (3) proximal and distal reflux; and (b) based on patient position: (1) predominantly supine, (2) orthostatic or (3) mixed reflux, for better treatment planning 1 .
In addition, the pH-24h may predict the most severe forms of esophagitis, as evidenced by the higher frequency of reflux episodes >5 min, higher AET, and higher DeMeester score 10 .
Consequently, the high negative correlation between clinical presentation and presence of pathologic acid reflux, especially in patients with anxiety disorders, may be further evaluated 2,23 .

Author
Year of publication All patients were referred by their respective physicians for pH-24h and manometry. This may result in selection bias that could overrepresent the severe cases of GERD and atypical GERD symptoms without GERD pathology. In addition, a single clinical questionnaire was used to evaluate GERD. There is a possibility that some GERD patients were incorrectly classified due to: (1) limited 24h evaluation period with impedance pH monitoring; (2)   The questionnaire used was not specific for digestive disease and did not include analysis of depression. Furthermore, the availability of endoscopic data was limited.
Markedly, it may also eliminate a false GERD diagnosis from endoscopy. According to the Lyon Consensus 3 , mild esophagitis seen on upper gastrointestinal endoscopy cannot be considered a diagnostic criterion for GERD due to the possibility of error in the subjective visual impression of the endoscopist (e.g., might be confused with drug-induced esophagitis caused by the use of tetracycline or other medications) 13 .
Furthermore, the pH-24h has a role in diagnosing cases that do not require surgical treatment, such as functional pyrosis (i.e., absence of esophagitis in upper GI endoscopy associated with normal AET and negative symptoms for reflux), hypersensitive esophagus (i.e., absence of esophagitis in upper GI endoscopy associated with normal AET and positive symptoms for reflux), and irritable bowel syndrome 11,13,14 . It is worth noting that cases of hypersensitive esophagus may have clinical presentations even with normal AET values 11 .
More importantly, it may identify patients who may require higher PPI doses or those who may benefit more from surgery. The comparison between anti-reflux surgery and PPI treatment (esomeprazole 20 or 40 mg/day) have shown that although both treatments significantly reduced the total 24h AET in the distal esophagus, acid exposure is lower in patients undergoing anti-reflux surgery (almost eliminating reflux) 16 . However, patients with supine-type pathologic reflux warrants higher PPI doses (esomeprazole 40 mg/day) divided into two daily doses to improve control of nighttime reflux and effectively reduce AET 16 .
Finally, even in post-surgical GERD patients with recurrence of symptoms, there is an advantage in using pH-24h to confirm that the symptoms are related to the pathologic acid reflux 4,10 . Nevertheless, evidence of acid reflux in pH-24h after fundoplication should not be considered an exclusive indication for revision surgery, since patients have a reduced ability to perceive reflux after fundoplication 4 .
Esophageal manometry plays a key role in the study of esophageal motility to confirm other differential diagnoses of GERD, especially achalasia (which can present with pyrosis in 40% of cases) and diffuse esophageal spasm 1,13,17 . Furthermore, this can also establish the optimal surgical technique for GERD and determine the most accurate position for the pH-24h catheter sensor 13 . A study by Belo et al. 13 have shown that up to 3% of patients initially diagnosed with GERD and referred for surgery were identified to have achalasia in esophageal manometry, illustrating that this test is essential to avoid iatrogenic effects.
Esophageal manometry has an undeniable importance to detect esophageal dysmotility in GERD patients. Roughly 25 to 48% of these patients may present with esophageal motility disorder, and the prevalence of dysmotility increases according to the severity of esophagitis due to the pathologic reflux 18 . Ineffective esophageal motility (defined by an esophageal body contraction amplitude <30 mmHg and/or non-transmission of 30% or more wet swallowing to the distal esophagus) is the most common esophageal dysmotility in GERD patients (20 to 50% of cases), followed by nutcracker esophagus and diffuse esophageal spasm 1,18 . The presence of esophageal dysmotility can impair the esophageal clearance of gastric content, thereby increasing the occurrence of superior reflux 18 . Esophageal body hypomotility, characterized by a decreased mean range of contractions (less than or equal to 30 mmHg) in the esophageal segment, is also a frequent finding in patients with severe esophagitis due to GERD 1 .
In addition, esophageal manometry provides a detailed evaluation of the esophagogastric junction, helps discover etiologic factors, and estimates GERD severity.
Moreover, it can also identify and adequately classify esophageal hiatus hernias, which are often misdiagnosed due to the incorrect interpretation of subjective endoscopic findings and failure in considering the physiologic movement of the esophagogastric junction 17,19 . The evaluation of esophageal junction morphology and contractility could identify patients with decreased lower esophageal sphincter pressure (more common in patients with isolated distal esophageal reflux) who may potentially respond better to surgery 1,17 . This may also estimate the esophageal length within the abdominal cavity, as a decreased length favors greater acid exposure 17 .
Moreover, aging, elevated body-mass index (BMI), and central obesity are risk factors for the development of esophagogastric junction disorders (i.e., diseases between the diaphragmatic crura and the lower esophageal sphincter), decreased resting pressure, and shorter length of the abdominal esophagus 19 . Furthermore, patients with type II and III esophagogastric junction (hiatal hernia) had higher acid exposure 19 . Despite this, the study by Fornari et al. 20 have shown that obese patients (BMI= or >30 kg/m 2 ) had stronger esophageal peristalsis, lower esophageal sphincter pressure, and higher AET, regardless of the presence of GERD.
When accessible, the possibility of performing high-resolution esophageal manometry (>8 sensors) could improve the evaluation of the esophagogastric junction by determining the esophagogastric junction contractility index ( Figure 2B). At values below 13 mmHg.cm, there is a higher occurrence of reflux episodes and higher AET in the esophagus, which could be crucial to plan the degree of fundoplication valve continence 21 . At values, higher than 47 mmHg.cm, reflux episodes are rare 21 .
Furthermore, esophageal manometry plays an important role in understanding the pathophysiology of clinical manifestations related to GERD. For example, it has been shown that acid regurgitation is associated with pathologic gastroesophageal acid reflux with no significant effect on esophageal motility, suggesting that esophageal contraction should generally not occur during regurgitation 18 . However, chronic cough, voice hoarseness, and dysphagia have been associated with esophageal motility disorders in patients with abnormal exposure to acid in the esophagus 18 .
Although it is not the focus of this review, the use of contrast-enhanced esophagoduodenal radiography in the pre-operative evaluation of GERD patients is worth mentioning. Radiography may provide crucial esophageal anatomy to evaluate the esophageal hiatus hernias and identify Schatzki's ring and peptic stenosis. However, it has a low sensitivity (40%) and specificity (85%) for the diagnosis of GERD, since it rarely shows the presence of gastric content reflux into the esophagus. Moreover, the presence of reflux is not necessarily associated with the GERD as identified at pH-24h 13 . Therefore, a contrast-enhanced esophagoduodenal X-ray should not be used to diagnose GERD and should not replace pre-operative pH-24h and esophageal manometry 13 .
Clearly, the surgical treatment for GERD aims to provide an anti-reflux barrier by increasing the length of a new pressure zone at the level of the esophagogastric junction. However, it is necessary to pay attention to some aspects when evaluating the results and post-operative follow-up of patients 6 . To predict the outcome of anti-reflux surgery in GERD patients, patients with inadequate pre-operative esophageal peristalsis and excessive esophageal exposure to acid, especially in the supine position, must be closely monitored 22 . Patients who had both variables before surgery had a ten-fold increase in the incidence of surgical treatment failure regarding the definitive control of pathologic acid exposure compared to patients without the two pre-operative factors 22 . These variables are better predictors of post-operative outcomes than other factors such as demographic data, clinical manifestations (pyrosis and regurgitation), age, sex, body mass index, hiatal hernia size, presence of esophagitis, and lower esophageal sphincter pressure 22 .
Finally, although anti-reflux surgery is associated with a percentage of epithelial regression in patients with Barrett's esophagus (mostly of the short type), 7% of cases progressed with the onset of dysplasia or adenocarcinoma. This reinforces the need for regular endoscopic follow-up even after the anti-reflux surgery, especially in those with anaplastic risk factors (e.g., Barrett's esophagus with minimal progression for ten years, with length >3 cm, or when associated with esophagitis) 6 .

CONCLUSIONS
Based on the current best evidence and national particularities, all patients indicated for anti-reflux surgery are recommended to undergo both 24-hour pH monitoring and esophageal manometry to avoid diagnostic errors and improve surgical treatment planning.