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Keywords:

  • functional heartburn;
  • impedance-pH monitoring;
  • non-acid reflux;
  • non-erosive reflux disease;
  • refractory gastro-esophageal reflux disease;
  • weakly acidic reflux

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Conflict of Interests
  10. References

Background  By analysis of symptom-reflux association, endoscopy-negative refractory heartburn can be related to acid/non-acid refluxes with impedance-pH monitoring. Unfortunately, patients frequently do not report symptoms during the test. We aimed to assess the contribution of quantitative analysis of impedance-pH parameters added to symptom-reflux association in evaluating patients with endoscopy-negative heartburn refractory to high-dose proton pump inhibitor therapy.

Methods  The symptom association probability (SAP), the symptom index (SI), the esophageal acid exposure time and the number of distal and proximal refluxes were assessed at on-therapy impedance-pH monitoring. Relationships with hiatal hernia and manometric findings were also evaluated.

Key Results  Eighty patients were prospectively studied. Refractory heartburn was more frequently related to reflux by a positive SAP/SI and/or abnormal impedance-pH parameters (52/80 cases) (65%) than by a positive SAP/SI only (38/80 cases) (47%) (= 0.038).

In patients with refractory non-erosive reflux disease (NERD) defined by a positive SAP/SI and/or abnormal impedance-pH parameters, the prevalence of hiatal hernia was significantly higher (56%vs 21%, = 0.007) and the mean lower esophageal sphincter tone was significantly lower (18.7 vs 25.8 mmHg, = 0.005) than in those (35%) with reflux-unrelated, i.e., functional heartburn (FH). On the contrary, no significant difference was observed subdividing patients according to a positive SAP/SI only.

Conclusions & Inferences  Quantitative analysis of impedance-pH parameters added to symptom-reflux association allows a subdivision of refractory-heartburn patients into refractory NERD and FH which is substantiated by pathophysiological findings and which restricts the diagnosis of FH to one third of cases.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Conflict of Interests
  10. References

Impedance-pH monitoring is a novel technique that allows detection of all reflux events, distinguishing acid from non-acid (weakly acidic and weakly alkaline) refluxes. Reflux symptoms persisting despite acid suppressive therapy may be associated with either acid or non-acid reflux, or unrelated to reflux episodes. Impedance-pH monitoring is currently emerging as the new gold standard for clarifying the mechanisms of proton pump inhibitor (PPI)-refractory symptoms.1

Heartburn is the cardinal manifestation of gastro-esophageal reflux disease (GERD).2 In uninvestigated patients, symptomatic response to proton pump inhibitor (PPI) therapy may be sufficient to confirm the diagnosis of GERD without further diagnostic testing.2 However, up to one-third of patients with heartburn fail to respond symptomatically, either partially or completely, to a standard dose of PPI, and high dosage schedule may be effective in only one-fourth of them.3 Several patients will then remain symptomatic even with high-dose PPI therapy, and in those who had already undergone upper gastrointestinal endoscopy with negative findings direct reflux testing by impedance-pH monitoring is currently suggested to establish a relationship, if any, of heartburn with reflux.3 By impedance-pH monitoring, patients with endoscopy-negative refractory heartburn can be subdivided into non-erosive reflux disease (NERD) or functional heartburn (FH), the former defined as the presence of typical symptoms of GERD caused by reflux, in the absence of visible esophageal mucosal injury at endoscopy,4 and the latter defined as absence of evidence that reflux is the cause of the symptom.5

By analysis of symptom-reflux association, typical and atypical reflux symptoms persisting on PPI therapy have been more frequently related to non-acid than to acid refluxes by on-therapy impedance-pH monitoring.6–8 Unfortunately, the reliability of methods for symptom-reflux association analysis in separating refractory NERD from FH has not yet been convincingly shown. Moreover, patients frequently do not report symptoms during a 24-h study. Therefore, it has been advocated that impedance-pH monitoring should be analyzed not only for symptom-reflux association but also in a quantitative fashion, similar to traditional pH monitoring, in order to link symptoms to abnormal impedance-pH parameters.3 Whether impedance-pH monitoring should be performed on or off PPI therapy has been a matter of debate.1,3,5,9–12 As a higher than normal number of refluxes in the distal esophagus is a highly reproducible parameter13 not affected by PPI therapy9,14 and predictive of an abnormal EAET at wireless pH-monitoring performed off therapy,10 quantitative analysis of impedance-pH parameters added to symptom-reflux association could improve the efficacy of on-therapy impedance-pH monitoring, allowing a more reliable separation of refractory NERD from FH.

In the present study, we prospectively evaluated the added value of analyzing impedance-pH monitoring tracings not only for symptom-reflux association but also in a quantitative fashion in patients on high-dose PPI therapy, in order to detect any possible relationship of endoscopy-negative refractory heartburn with reflux and to ascertain if such a relationship is substantiated by pathophysiological findings peculiar to GERD.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Conflict of Interests
  10. References

Patients

We prospectively studied adult patients referred to our center because of troublesome endoscopy-negative heartburn persisting despite at least 4-week high-dose PPI therapy. All patients were on double-dose of their particular PPI at enrolment and continued the PPI at the dosage that they were on at the time of entering the study. Troublesome heartburn was defined by means of a validated questionnaire (score 2 or greater, see below). Previous antireflux surgical or endoscopic interventions, progressive systemic sclerosis, and pregnancy were reasons for exclusion. Patients with regurgitation, dysphagia, chest pain or extra-esophageal symptoms dominating the clinical picture were excluded.

Patients with reflux esophagitis (at least one mucosal break in the distal esophageal epithelium)15 at previous off-therapy (4-week PPI wash-out) upper endoscopy were excluded. All patients had undergone endoscopic examination at our center, where standardized criteria are adopted to evaluate and report esophageal abnormalities. Particular attention is routinely paid to identify the gastroesophageal junction, determining the most prominent extent of the gastric mucosal folds during withdrawal of the endoscope with minimal air insufflations. Hiatal hernia was considered to be present when the distance between the gastroesophageal junction and the diaphragmatic impression was >2 cm on withdrawing the endoscope. Biopsy-proven Barrett’s esophagus constituted additional exclusion criteria. Esophageal biopsies were not routinely performed in the absence of visual abnormalities suggestive of eosinophilic esophagitis, as dysphagia was not a presenting symptom.5

The severity of symptoms was rated by means of a validated questionnaire16 based on a standard four-grade, Likert-type scale scoring system. Patients were asked to refer to the last month. Symptoms were graded as follows: 0 = none; 1 = mild/occasional, symptom could be ignored; 2 = moderate/frequent, symptom could not be ignored, but neither daily activities nor sleep were influenced; 3 = severe/constant, symptom influenced daily activities and/or sleep. Symptoms included in the questionnaire were heartburn, regurgitation, dysphagia, chest pain, belching, early satiety, postprandial fullness, epigastric pain/burn, vomiting, and epigastric bloating. A heartburn score of at least 2 was required for entering the study.

Patients were asked to participate in the study after receiving comprehensible and detailed explanations. The study protocol was approved by our Institutional Review Board. A written informed consent was obtained by all patients.

Esophageal manometry

Standard esophageal manometry was performed before impedance-pH monitoring in all patients (MF, VGM). The station pull-through method was used to locate the lower esophageal sphincter (LES). An 8-channel, water perfused manometry catheter was used: the four distal ports were located at the same level with a radial orientation of 90°; the four proximal ports were 5 cm apart and also radially oriented. The catheter was placed nasally into the stomach and slowly withdrawn. The position of the pressure inversion point and of the LES were identified, and then, at each 0.5 cm station the resting pressure of the LES was measured at the end of expiration and the relaxation was assessed with wet swallows. LES hypotension was defined by a basal LES pressure <10 mm Hg, according to standard criteria.17 Esophageal body peristalsis was assessed and pressures measured with at least 10 wet swallows. The upper esophageal sphincter was finally identified and the catheter removed. All manometric data were processed using the Polygram Net module (Medtronic Functional Diagnostics A/S, Tonsbakken, Denmark) to obtain the mean LES tone and the mean distal esophageal amplitude (DEA). Achalasia and diffuse esophageal spasm constituted exclusion criteria5 as well as inadequate LES relaxation and nutcracker esophagus, all defined according to standard criteria.17

24-h impedance-pH monitoring

Combined 24-h impedance-pH monitoring was performed on double-dose PPI therapy by two experienced investigators (MF, VGM) who had trained together to minimize inter-observer variation in the interpretation of impedance-pH tracings. An ambulatory, multi-channel, intra-luminal impedance system was used, consisting of a portable data logger and a combined impedance-pH catheter (Sleuth ambulatory system, Sandhill Scientific, Inc., Highland Ranch, CO, USA). The combined impedance-pH catheter was passed transnasally and was placed in reference to the manometrically located proximal border of the LES. The configuration of the catheter adopted allowed monitoring changes in intraluminal impedance at 3, 5, 7, 9, 15, and 17 cm above the LES. In addition, pH was monitored at 5 cm above and 10 cm below the upper border of the LES. Subjects were discharged and were encouraged to maintain normal activities, sleep schedule, and eat their usual meals at their normal times. They were asked to remain upright during the day, and lie down only during their usual nocturnal bedtime. Event markers on the data-logger recorded symptoms, meal times, and posture changes. Impedance, pH, and symptom signals were collected at a resolution of a 50-Hz sampling rate on a 256-MB compact flash card. All studies were performed for 24 h, after which patients returned to the lab for catheter removal and data review. Impedance and pH information was analyzed using a dedicated software program (BioView Analysis; Sandhill Scientific, Inc.) coupled with a 2-min time windows visual analysis and zooming when deemed necessary. Analysis included identification, enumeration and characterization of individual reflux events and their relationship with symptoms. Meal times were excluded. Liquid-only reflux was defined as a retrograde 50% fall in impedance from baseline in the two distal impedance sites. Gas reflux was defined as a rapid increase in impedance >3000 ohms, occurring simultaneously at least in two esophageal measuring segments. Liquid–gas (mixed) reflux was defined as gas reflux occurring immediately before or during a liquid reflux. Gas reflux events without liquid (belches) were considered separately and not included in the analysis. The time period with gastric pH <4, i.e., the percentage gastric acid exposure time was computed for the total study period as well as the time period with esophageal pH <4, i.e., the percentage esophageal acid exposure time (EAET). Using the pH tracings, reflux events were classified as (i) acid (nadir pH <4), (ii) weakly acidic (nadir pH between 4 and 7) or (iii) weakly alkaline (nadir pH not below 7) refluxes.18 Data analysis was performed on liquid and mixed reflux episodes for acid, weakly acidic and weakly alkaline refluxes; the number of total reflux events (distal refluxes) and the number of proximal reflux events (reaching the 15 cm impedance site) (proximal refluxes) were evaluated. The 95th percentile of values obtained in 20 healthy controls who had previously underwent impedance-pH monitoring off PPI therapy at our center14 served as the upper normal limit.

Symptom-reflux association analysis was carried out to investigate the relationship between the occurrence of reflux episodes and heartburn. The symptom association probability (SAP) and the symptom index (SI) were calculated using the BioView Analysis software (Sandhill Scientific, Inc.). According to the setting of this software, heartburn was considered related to reflux if it occurred within a 2-min (SAP) or 5-min (SI) time window after the onset of the reflux episode.7 A positive SAP was defined by 95% or more of symptoms associated with reflux.7 A positive SI was defined by 50% or more of symptoms associated with reflux.7 A negative SAP was defined by less than 95% of symptoms associated with reflux. A negative SI was defined by less than 50% of symptoms associated with reflux. Positive symptom-reflux association was defined by a positive SAP and/or a positive SI (positive SAP/SI). Negative symptom-reflux association was defined by a negative SAP and a negative SI (negative SAP/SI).

Statistics

For the continuous variables, the student’s t test was adopted to analyze the differences between the groups. For the categorical variables, the chi-square test was used to analyse the differences between the groups. A < 0.05 was considered significant. Agreement between SAP and SI was evaluated using the kappa statistics (kappa values >0 indicate agreement that is significantly greater than chance).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Conflict of Interests
  10. References

Between May 2007 and March 2011, 80 patients (35 males, mean age 47 years) met the inclusion criteria and entered the study consecutively. Thirty-five patients (44%) had a hiatal hernia. The mean gastric acid exposure time was 35% (95% confidence interval 30–40%). The mean values of the main manometric and impedance-pH parameters are reported in Table 1. Symptom-reflux association and abnormal impedance-pH parameters are reported in Table 2. Fifty-four (68%) patients reported heartburn during the study. A positive SAP and/or SI was found in 38/80 (48%) patients; SAP and SI were both positive in 28 cases, whereas in three cases the SAP was positive and the SI was negative and in 7 cases the SI was positive and the SAP was negative. A negative SAP and a negative SI were found in 16/80 (20%) patients (all with normal impedance-pH parameters) whereas 12/80 (15%) and 14/80 (18%) patients with normal and abnormal, respectively impedance-pH parameters did not report heartburn during the study. Overall, SAP and SI were either positive or both negative in 44 (82%) of the 54 patients who reported heartburn during the study (kappa = 0.38). The majority of heartburn episodes registered during the impedance-pH monitoring test were associated with weakly acidic refluxes; no heartburn episode was associated with weakly alkaline refluxes. The EAET was above the normal range in 7/80 (9%) patients, two with no heartburn episode during the 24-h study but with an abnormal number of distal refluxes, four with a positive SAP/SI and an abnormal number of distal refluxes, and one with a positive SAP/SI but distal refluxes in the normal range. A higher than normal number of distal and proximal refluxes was found in 45/80 (56%) and in 33/80 (41%) cases, respectively. Fourteen of the 26 patients reporting no symptom during the test had abnormal impedance-pH parameters: a higher than normal number of distal and proximal refluxes was found in 14/14 (100%) and in 9/14 (64%) cases, respectively, whereas an abnormal EAET was found in 2/14 (14%) cases only. Patients with a hiatal hernia and patients with LES hypotension had a higher number of distal and proximal refluxes than patients without (Table 3).

Table 1.   Manometric and impedance-pH parameters in 80 patients (35 males, mean age 47 years) with refractory heartburn
 Mean (95% CI)Normal values
  1. LES, lower esophageal sphincter; DEA, distal esophageal amplitude; EAET, esophageal acid exposure time; CI, confidence interval.

LES tone (mmHg)21 (18.6–23.4)17–37
DEA (mmHg)88 (80.1–95.9)62–136
EAET (%) 1.6 (1–2.2)<3.3
Acid refluxes (n)13 (10–16)<23
Weakly acidic refluxes (n)63 (54–72)<27
Weakly alkaline refluxes (n)1 (0–2)<2
Distal refluxes (n) 77 (66–88)<45
Proximal refluxes (n)48 (40–56)<32
Table 2.   Symptom-reflux association and rates of abnormal impedance-pH parameters in 80 patients with refractory heartburn
 Patients (n) (%)
  1. SAP, symptom association probability; SI, symptom index; EAET, esophageal acid exposure time.

Patients reporting heartburn during the 24-h impedance-pH study54/80 (68%)
SAP+ and SI+28/54 (52%)
SAP+ and SI-3/54 (5%)
SAP- and SI+7/54 (13%)
SAP- and SI-16/54 (30%)
SAP+ and/or SI+ for acid refluxes only7/38 (18%)
SAP+ and/or SI+ for acid and weakly acidic refluxes9/38 (24%)
SAP+ and/or SI+ for weakly acidic refluxes only22/38 (58%)
Abnormal EAET7/80 (9%)
Abnormal number of distal refluxes45/80 (56%)
Abnormal number of proximal refluxes33/80 (41%)
Table 3.   Distal and proximal refluxes in patients with/without hiatal hernia and with/without LES hypotension
 Distal refluxes (n)Proximal refluxes (n)
  1. LES, lower esophageal sphincter; Values expressed as mean (95% confidence interval).

With hiatal hernia (35 patients)80 (60–100)51 (35–67)
Without hiatal hernia (45 patients)49 (40–58)29 (23–35)
 = 0.004= 0.007
With LES hypotension (10 patients)125 (80–170)93 (55–131)
Without LES hypotension (70 patients)53 (45–61)31 (26–36)
 = 0.001= 0.001

By a positive SAP/SI and/or abnormal impedance-pH parameters, refractory heartburn could be related to reflux in 52/80 (65%) patients, a significantly higher proportion than by a positive SAP/SI only (38/80) (47%) (= 0.038). When patients were subdivided according to a positive SAP/SI only, no significant difference was found in pathophysiological characteristics, i.e., hiatal hernia prevalence, mean LES tone and mean DEA (Table 4). On the other hand, subdividing patients according to a positive SAP/SI and/or abnormal impedance-pH parameters, the prevalence of hiatal hernia was significantly higher (56%vs 21%, = 0.007) and the mean LES tone was significantly lower (18.7 vs 25.8 mmHg, = 0.005) in patients defined as refractory NERD than in those defined as FH (Table 5).

Table 4.   Pathophysiological characteristics in 80 patients with refractory heartburn, subdivided into refractory NERD and FH according to a positive SAP/SI only
 Refractory NERDFHP
  1. NERD, non-erosive reflux disease; FH, functional heartburn; SAP, symptom association probability; SI, symptom index; LES, lower esophageal sphincter; DEA, distal esophageal amplitude; CI, confidence interval; ns, not significant.

Hiatal hernia (n) (%)21/38 (55%)14/42 (33%)ns
LES tone (mmHg) (mean) (95% CI)19.5 (16.8–22.2)22.6 (18.8–26.4)ns
DEA (mmHg) (mean) (95% CI)92.5 (80.4–104.6)83.4 (72.8–94)ns
Table 5.   Pathophysiological characteristics in 80 patients with refractory heartburn, subdivided into refractory NERD and FH according to a positive SAP/SI and/or abnormal impedance-pH parameters
 Refractory NERDFHP
  1. NERD, non-erosive reflux disease; FH, functional heartburn; SAP, symptom association probability; SI, symptom index; LES, lower esophageal sphincter; DEA, distal esophageal amplitude; CI, confidence interval; ns, not significant.

Hiatal hernia29/52 (56%)6/28 (21%)0.007
LES tone (mmHg) (mean) (95% CI)18.7 (16.1–21.3)25.8 (21.4–30.2)0.005
DEA (mmHg) (mean) (95% CI)85.9 (75.9–95.9)91.2 (77.8–104.6)ns

Twenty-one patients took part in a study aimed to assess impedance-pH parameters and symptoms 3 months after laparoscopic fundoplication in patients with refractory GERD19: in 15/21 (71%) cases a positive SAP/SI was found whereas six patients (29%) reported no symptom during the preoperative impedance-pH monitoring study but had a higher than normal number of distal refluxes. Three months after intervention, in the absence of any acid suppressive therapy from at least 2 months normal values of EAET and of distal refluxes were detected in 21/21 (100%) and 17/21 (81%) cases, respectively while total symptom remission (heartburn score = 0) was reported by 21/21 (100%) patients.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Conflict of Interests
  10. References

In the present study, we evaluated a selected series of 80 consecutive patients with endoscopy-negative heartburn persisting despite high-dose PPI therapy. By a positive SAP/SI and/or abnormal impedance-pH parameters, a diagnosis of refractory NERD was achieved in 65% of our patients, significantly more often than by a positive SAP/SI only (47%), diagnosis of FH resulting then restricted to one third of cases The distinction of refractory NERD from FH obtained with quantitative analysis of impedance-pH parameters added to symptom-reflux association was substantiated by pathophysiological findings peculiar to GERD: we found a prevalence of hiatal hernia significantly higher and a LES tone significantly lower in patients defined as refractory NERD than in those defined as FH.

The prevalence of hiatal hernia is significantly higher and the LES tone is significantly lower in patients with NERD as compared with patients with FH.20,21 Hiatal hernia and LES weakness are well-recognized factors favouring gastroesophageal reflux. In the present series, both hiatal hernia and LES hypotension were associated with significantly higher number of distal as well as of proximal refluxes. Interestingly, defining patients with refractory NERD by means of a positive SAP/SI and/or abnormal impedance-pH parameters we found that the prevalence of hiatal hernia was significantly higher and the mean LES tone was significantly lower than in patients defined as FH. On the contrary, no significant pathophysiological difference was observed when patients with refractory heartburn were subdivided on the basis of a positive SAP/SI only. Therefore, a diagnosis of refractory NERD based on a positive SAP/SI and/or abnormal impedance-pH parameters appears substantiated by pathophysiological findings peculiar to GERD, whereas a diagnosis of refractory NERD based on a positive SAP/SI only appears as pathophysiologically unsound.

Management of FH is challenging: surgery must be avoided because it can have deleterious effects, whereas the efficacy of visceral pain modulators has not yet been convincingly shown. On the other hand, laparoscopic fundoplication may represent an effective therapeutic option in patients with refractory typical GERD symptoms, i.e., heartburn and/or regurgitation)22: therefore, efforts to relate refractory heartburn to reflux appear justified as management can be altered. Impedance-pH monitoring can have a major role in selecting patients for antireflux surgery,23,24 particularly in those with refractory heartburn as heartburn can have a number of nonreflux related causes.2 Impedance-pH monitoring is currently considered the best method to relate refractory symptoms to reflux but whether it should be performed on or off PPI therapy is still debated1,3,5,9–12,24,25: to solve the problem, treatment outcome studies have been advocated.11,23,25 By combining quantitative analysis of impedance-pH parameters with symptom-reflux association at on-therapy impedance-pH monitoring, we restricted the diagnosis of FH to one third of our patients, a result quite similar to that found in a recent series of patients evaluated with off-therapy impedance-pH monitoring.26 Recently, we have shown that laparoscopic fundoplication significantly improves impedance-pH parameters as well as heartburn/regurgitation when compared with high-dose PPI therapy in patients with refractory reflux esophagitis and refractory NERD, the latter defined by a positive SAP/SI and/or abnormal impedance-pH parameters at preoperative on-therapy impedance-pH monitoring.19 Twenty-one patients in the present series participated in that study and favourable postsurgical outcomes were found even in those who did not record heartburn during the preoperative impedance-pH study but had a higher than normal number of distal refluxes. These results indicate that quantitative analysis of on-therapy impedance-pH parameters improves the diagnostic yield of impedance-pH monitoring in refractory-heartburn patients, contributing to correctly identify those with refractory NERD.

The total number of refluxes in the distal esophagus is a reproducible parameter13 that does not vary appreciably off and on PPI therapy9,14 and is predictive of an abnormal EAET at off-therapy wireless pH-monitoring.10 In the present study, we found a higher than normal number of distal refluxes in all patients who did not report heartburn during the test but who had at least one abnormal impedance-pH parameter. Our data then confirm that the number of distal refluxes is the most useful parameter in the quantitative analysis of impedance-pH monitoring tracings.10 Our upper normal limits have been defined by the 95th percentile of values obtained off-therapy in 20 healthy controls at our center14 and are at variance with those reported by previous series.13,27 This can be explained by different dietary habits. Our data were obtained in healthy non-overweight subjects eating their usual meals in a Mediterranean region and are very close to those found in our country when a standardized Mediterranean diet was adopted.28,29

It has been shown that a significant proportion of symptoms associated with non-acid reflux may be missed with just the use of a 2-min time window30 and that the reproducibility of SAP and SI does not differ when a 5-min time window is adopted.31 Both parameters have been used on and off PPI therapy6–9 and both have merits and shortcomings.32 As in previous on-therapy impedance-pH monitoring studies the majority of heartburn episodes were related to non-acid refluxes,6–9 we decided to evaluate the symptom–reflux association by means of both the SAP and the SI. The concordance between SAP and SI was only moderate, confirming that both indices should be used in the evaluation of patients with refractory heartburn.

We conclude that quantitative analysis of impedance-pH parameters added to symptom-reflux association improves the efficacy of on-therapy impedance-pH monitoring in patients with refractory heartburn. It allows a subdivision of patients into refractory NERD and FH which is substantiated by pathophysiological findings and which restricts the diagnosis of FH to one third of cases.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Conflict of Interests
  10. References

MF designed the study, performed esophageal manometry and impedance-pH metry, collected and analyzed data and wrote the manuscript; VGM performed esophageal manometry and impedance-pH metry, collected and analyzed data, approved the final version of the manuscript; RC and GM designed the study, approved the final version of the manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Conflict of Interests
  10. References
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