Frazzoni M, Manta R, Mirante VG, et al. Esophageal chemical clearance is impaired in gastro-esophageal reflux disease – A 24 h impedance-pH monitoring assessment // Neurogastroenterol Motil. 2013;25:399-406, e295.

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Авторы: Frazzoni M. / Manta R.  / Mirante V.G. / Conigliaro R. / Frazzoni L. / Melotti G.


Esophageal chemical clearance is impaired in gastro-esophageal reflux disease – a 24-h impedance-pH monitoring assessment

M. Frazzoni,* R. Manta,† V.G. Mirante,† R. Conigliaro,† L. Frazzoni* & G. Melotti‡

*Fisiopatologia Digestiva, Nuovo Ospedale S. Agostino, Modena, Italy
†Endoscopia Digestiva, Nuovo Ospedale S. Agostino, Modena, Italy
‡Chirurgia Generale, Nuovo Ospedale S. Agostino, Modena, Italy

Аннотация на русском языке

Abstract

Background: Impedance-pH monitoring allows assessment of retrograde and antegrade intra-esophageal movement of fluids and gas. Reflux is followed by volume clearance and chemical clearance, elicited by secondary and swallow-induced peristalsis, respectively. We aimed to assess whether chemical clearance is impaired in gastro-esophageal reflux disease (GERD).

Methods: Blinded retrospective review of impedance-pH tracings from patients with erosive reflux disease (ERD) and non-erosive reflux disease (NERD), and from proton pump inhibitor (PPI)-refractory patients before and after laparoscopic fundoplication. The number of refluxes followed within 30 s by swallow-induced peristaltic waves was divided by the number of total refluxes to obtain a parameter representing chemical clearance namely the postreflux swallow-induced peristaltic wave (PSPW) index.

Key Results: The PSPW index was significantly lower in 31 ERD (15%) and in 44 NERD (33%) off-PPI patients than in 30 controls (75%), as well as in 18 ERD (16%) and in 48 NERD (31%) on-PPI patients than in 26 on-PPI functional heartburn (FH) cases (67%) (P < 0.05 for all comparisons). In 29 PPI-refractory patients, the median PSPW index was unaltered by otherwise effective antireflux surgery (20% postoperatively, 21% preoperatively). The overall sensitivity, specificity, positive, and negative predictive values of the PSPW index in identifying GERD patients were 97%, 89%, 96%, and 93%.

Conclusions & Inferences: Impairment of chemical clearance is a primary pathophysiological mechanism specific to GERD: it is unaffected by medical/surgical therapy, is not found in FH, and is more pronounced in ERD than in NERD. Using the PSPW index could improve the diagnostic efficacy of impedance-pH monitoring.

Keywords: esophageal clearance, functional heartburn, impedance-pH monitoring, refractory gastroesophageal reflux disease.

Abbreviations:

BCT – bolus clearance time;
DEA – distal esophageal amplitude;
EAET – esophageal acid exposure time;
ERD – erosive reflux disease;
FH – functional heartburn;
GERD – gastro-esophageal reflux disease;
LES – lower esophageal sphincter;
NERD – non-erosive reflux disease;
PPI – Proton pump inhibitor;
PSPW – postreflux swallow-induced peristaltic wave;
SAP – symptom association probability;
SI – symptom index;

INTRODUCTION

Gastro-esophageal reflux disease (GERD) is currently defined as a condition that develops when the reflux of gastric contents into the esophagus leads to troublesome symptoms and/or complications.[1] In clinical practice, in the uninvestigated patient with troublesome heartburn symptomatic response to proton pump inhibitor (PPI) therapy may be sufficient to confirm the diagnosis of GERD.[1] However, it is estimated that 20–30% of patients with heartburn fail to respond symptomatically, either partially or completely, to a standard dose of PPI, and double-dosage schedules are increasingly used.[2, 3] At upper GI endoscopy, the vast majority of PPI-refractory patients have negative findings. Combined impedance-pH monitoring can establish a relationship, if any of symptoms with acid and non-acid refluxes[4] and is currently suggested[5] to distinguish PPI-refractory non-erosive reflux disease (NERD) from 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[6] and the latter defined as absence of evidence that reflux is the cause of heartburn.[7] The biggest diagnostic gain of impedance-pH monitoring compared with pH-metry alone is in the on-PPI evaluation of patients with refractory heartburn,[8] particularly when quantitative analysis of reflux parameters is added to symptom–reflux association with the aim of distinguishing refractory GERD from FH.[9]

Gastro-esophageal reflux disease is a multifactorial disorder. Many studies exploring the underlying pathophysiology of GERD point toward multiple factors including transient lower esophageal sphincter (LES) relaxations, hiatus hernia, reduced LES tone, a postprandial acid pocket just distal to the squamo-columnar junction, impaired esophageal clearance, visceral hypersensitivity, and delayed gastric emptying.[10] Once reflux occurs, the bulk of refluxed gastric material is quickly expelled from the esophageal lumen by a secondary peristaltic wave around the bolus that forces it back into the stomach (volume clearance)[11]; secondary peristalsis is a local reflex response elicited by stretch receptors in the esophageal lining. Volume clearance is not sufficient to rapidly clear the gastric acid and effective clearance (chemical clearance) depends on swallow-induced peristaltic waves elicited by an esophagosalivary reflex mediated through vagal afferents.[12] Accordingly, chronic xerostomia increases esophageal acid exposure and is associated with reflux esophagitis despite normal esophageal motility.[13] Higher levels of esophageal acid exposure time (EAET) distinguish patients with ERD from those with NERD and both from FH and healthy subjects[14]: provided that volume clearance is not defective, increased EAET could depend on defective chemical clearance.

Impedance-pH monitoring allows 24-h recording of impedance changes in response to movement of fluids and gas throughout the esophagus not only in retrograde (reflux) but also in antegrade (swallow) direction.[15, 16] Accordingly, impedance-pH monitoring can be used to evaluate chemical clearance by assessing swallow-induced peristaltic waves following reflux episodes: in a small series of infants with GERD, a decline in the efficiency of chemical clearance has been reported using 24-h impedance-pH monitoring.[17] To the best of our knowledge, chemical clearance as assessed by postreflux swallow-induced peristaltic waves (PSPW) has not yet been extensively evaluated using 24-h impedance-pH monitoring in adults with GERD, off- or on-PPI therapy. We hypothesized an impairment of chemical clearance in GERD patients, inducing prolonged contact time of the esophageal mucosa with acid and weakly acidic reflux, the latter having a key role in the pathogenesis of PPI-refractory reflux esophagitis.[18] We then decided to retrospectively review 24-h impedance-pH monitoring studies performed in patients referred to our center for possible antireflux surgery because of PPI-dependent or PPI-refractory heartburn, with/without reflux esophagitis, and evaluated off- or on-PPI therapy. Our aim was to establish whether esophageal chemical clearance is impaired in GERD.

MATERIALS AND METHODS

Patients

Files registered in our database between January 2008 and December 2011 were reviewed by one of us (RM) not involved in manometric and impedance-pH testing, who selected adult cases referred to our center by their caring physicians for the following reasons: (i) presurgical evaluation for troublesome heartburn with/without regurgitation well controlled by PPI therapy but recurring and persisting for more than 4 weeks after PPI withdrawal (PPI-dependent patients); (ii) presurgical evaluation for troublesome heartburn with/without regurgitation persisting despite at least 4-week double-dosage PPI therapy (PPI-refractory patients). Symptoms had been assessed by means of a validated questionnaire[19] directly administered by the patient and based on a standard four-grade, Likert-type scale scoring system, with reference to the last month. Symptom grading was: 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 assessed 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 this study. Patients with dysphagia, chest pain or extra-esophageal syndromes dominating the clinical picture were excluded as well as those with achalasia, diffuse esophageal spasm, progressive systemic sclerosis, Sjogren syndrome, and previous antireflux surgery. Patients taking medications known to alter salivary function (tricyclic antidepressants, opiates, neuroleptics, antihistamines, anticholinergics, diuretics, beta-blockers) were also excluded. All patients had provided written informed consents before undergoing clinical investigations.

Reflux esophagitis was defined according to the Los Angeles classification.[20] A 4-week washout from any antisecretory treatment was required before endoscopic examination, except for those PPI-refractory patients with a previous diagnosis of reflux esophagitis who underwent repeat endoscopic examination while on ongoing double-dosage PPI treatment.

PPI-refractory patients with persistent reflux esophagitis on double-dosage PPI therapy constituted the PPI-refractory erosive reflux disease (ERD) group. Proton pump inhibitor-dependent patients with previous detection of reflux esophagitis constituted the PPI-dependent ERD group. Proton pump inhibitor-dependent and double-dosage PPI-refractory patients with normal off-PPI endoscopic findings but with abnormal impedance-pH monitoring results constituted the PPI-dependent and the PPI-refractory NERD group, respectively. Double-dosage PPI-refractory patients with normal off-PPI endoscopic findings and with normal on-PPI impedance-pH monitoring results constituted the FH group. Data from ERD and NERD patients evaluated off-PPI therapy were compared with those from 30 healthy subjects previously evaluated at our center who served as age/sex-unmatched controls. We also evaluated postoperative data from patients with PPI-refractory GERD who had undergone robot-assisted laparoscopic fundoplication at our center and had completed the scheduled 3-year follow-up assessment within December 2011 with persistent postoperative heartburn/regurgitation remission and normal impedance-pH findings.

Impedance-pH monitoring

Combined 24-h impedance-pH monitoring was performed after a PPI washout (antacids allowed) of at least 4 weeks in PPI-dependent patients or on at least 4-week double-dosage PPI therapy in PPI-refractory patients (MF, VGM). An ambulatory, multichannel, intraluminal 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). Standard esophageal manometry was routinely carried out before impedance-pH monitoring to locate the LES by the station pull-through method, and to obtain the mean LES tone and the mean distal esophageal amplitude (DEA) (MF, VGM). Ineffective esophageal motility (at least 50% pressure waves < 30 mm Hg in the distal esophagus)[21, 22] constituted additional exclusion criteria. After esophageal manometry was completed, 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 encouraged to maintain normal activities, sleep schedule, and eat their usual meals at their normal times. 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. Impedance and pH information was analyzed using a dedicated software program (BioView Analysis, Sandhill Scientific, Inc; Highland Ranch, CO, USA) in conjunction with a 2-min time window visual analysis, with zooming when deemed necessary. Meal times were excluded from analysis. 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 esophageal pH < 4, i.e., the %EAET was computed (upper normal limit at our center 3.3%).[23] The time period with gastric pH < 4, i.e., the percentage gastric acid exposure time was also computed. 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.[24] Data analysis was performed on liquid and mixed reflux episodes for acid, weakly acidic and weakly alkaline refluxes. The number of total refluxes was computed, the upper normal limit at our center being 45 total refluxes/24 h.[23] The median bolus clearance time (BCT) was also calculated as well as the symptom association probability (SAP) and the symptom index (SI) by means of the BioView Analysis software. A positive SAP was defined by 95% or more of symptoms associated with reflux, and a positive SI was defined by 50% or more of symptoms associated with reflux.[25]

For the purpose of this study, all tracings were blindly reanalyzed in a random order by one of us (MF) who was rendered unaware of patient's identity and clinical details, and of previous analysis results. A PSPW was defined as an antegrade 50% drop in impedance relative to the preswallow baseline originating in the most proximal impedance site, reaching all the distal impedance sites, and followed by at least 50% return to the baseline in all the distal impedance sites (bolus exit) (Fig. 1).[26] Postreflux swallows not reaching the distal impedance sites and/or not followed by return to the baseline were excluded. To limit overlap with spontaneous swallowing (64 swallows h−1, approximately 1 min−1)[27] and considering the latency period of salivary gland response to esophageal acidification (10–15 s),[12] only PSPWs occurring within 30 s from the end of reflux episodes were taken into account (Fig. 1). For each impedance-pH monitoring tracing, the number of refluxes followed within 30 s by a PSPW was divided by the number of total refluxes to obtain a parameter representing the efficacy of chemical clearance namely the PSPW index.



Figure 1. Impedance-pH tracing illustrating a weakly acidic reflux episode followed by a swallow-induced peristaltic wave (arrow).


Statistics

For all the continuous variables, a Kruskal–Wallis one-way analysis of variance by ranks was performed to analyze the differences between the groups. Specific differences were identified using a Dunn's post-test. Pre- and postsurgical data were analyzed by the Wilcoxon rank sum test. For all the categorical variables, the Chi-squared or the Fisher's exact test was used. A P < 0.05 was considered significant. Taking into account our previous data in patients with ERD, NERD, and FH,[14] we calculated that 13 patients were required in each group to demonstrate a significant between-group difference at the 5% significance level, with statistical power of 90%. Sensitivity, specificity, and positive and negative predictive values of the PSPW index were defined on the basis of a GERD diagnosis provided by abnormal endoscopic and/or impedance-pH findings as detailed above.

RESULTS

Files from 180 patients with PPI-dependent or PPI-refractory heartburn were initially selected: six cases (3%) were excluded because ineffective esophageal motility had been found at esophageal manometry and seven cases were excluded because they were taking medications causing mouth dryness. All impedance-pH tracings from the resultant 167 patients were blindly reanalyzed by one of us (MF) between April and June 2012, as well as those from 30 controls. The main pathophysiological findings in the 197 subjects included in the study are reported in Tables 1 and 2. No significant differences were found concerning age and gender between the various groups. The prevalence of hiatal hernia did not differ between PPI-dependent (48/75, 64%) and PPI-refractory (44/66, 67%) patients (P = 0.877).

Table 1. Pathophysiological findings (off PPI therapy) in PPI-dependent ERD and NERD and in controls

 

ERD (n = 31)

(21 males, median age 54 years)

NERD (n = 44)

(22 males, median age 48 years)

Controls (n = 30)

(13 males, median age 48 years)

LES tone (mm Hg)

12.4 (9.3–22.2)

ERD vs NERD

P  <   0.05

20.6 (15.6–31.5)

NERD vs controls

P > 0.05

20 (14.6–25.1)

ERD vs controls

P  <   0.05

DEA (mm Hg)

66.2 (45.2–83.9)

ERD vs NERD

P  <   0.05

87.6 (61.8–107.6)

NERD vs controls

P > 0.05

70.7 (56.9–91.7)

ERD vs controls

P > 0.05

EAET (%)

9.5 (5.7–12.4)

ERD vs NERD

P  <   0.05

4.8 (3.6–7.2)

NERD vs controls

P  <   0.05

0.7 (0.2–1.5)

ERD vs controls

P  <   0.05

Total refluxes (n)

56 (50–76)

ERD vs NERD

P > 0.05

50 (41–70)

NERD vs controls

P  <   0.05

17 (10–23)

ERD vs controls

P  <   0.05

Acid refluxes (n)

49 (39–70)

ERD vs NERD

P > 0.05

39 (32–55)

NERD vs controls

P  <   0.05

13 (5–18)

ERD vs controls

P  <   0.05

Weakly acidic refluxes (n)

9 (7–21)

ERD vs NERD

P > 0.05

11 (7–18)

NERD vs controls

P  <   0.05

5 (2–9)

ERD vs controls

P  <   0.05

Weakly alkaline refluxes (n)

0 (0–0)

ERD vs NERD

P > 0.05

0 (0–0)

NERD vs controls

P > 0.05

0 (0–0)

ERD vs controls

P > 0.05

BCT (s)

15 (11–19)

ERD vs NERD

P > 0.05

15 (11–20)

NERD vs controls

P > 0.05

12 (8–17)

ERD vs controls

P > 0.05

PSPW index (%)

15 (10–24)

ERD vs NERD

P < 0.05

33 (24–41)

NERD vs controls

P < 0.05

75 (66–86)

ERD vs controls

P < 0.05

All values are expressed as median and interquartile range. P < 0.05 bold typed.

PPI, proton pump inhibitor; ERD, erosive reflux disease; NERD, non-erosive reflux disease; LES, lower esophageal sphincter; DEA, distal esophageal amplitude; EAET, esophageal acid exposure time; BCT, bolus clearance time; PSPW, postreflux swallow-induced peristaltic wave.


Table 2. Pathophysiological findings (on PPI therapy) in PPI-refractory ERD and NERD and in FH

 

ERD (n = 18)

(12 males, median age 50 years)

NERD (n = 48)

(25 males, median age 42 years)

FH (n = 26)

(11 males, median age 45 years)

LES tone (mm Hg)

12.9 (10.3–18.9)

ERD vs NERD

P > 0.05

17.9 (11.8–25.0)

NERD vs FH

P  <   0.05

21.1 (18.8–28.5)

ERD vs FH

P  <   0.05

DEA (mm Hg)

63.3 (47.7–89)

ERD vs NERD

P > 0.05

88.1 (63.4–108.8)

NERD vs FH

P > 0.05

74.8 (56.0–109.3)

ERD vs FH

P > 0.05

EAET (%)

1.3 (0.3–4.0)

ERD vs NERD

P > 0.05

0.7 (0.3–2.3)

NERD vs FH

P  <   0.05

0 (0.0–0.1)

ERD vs FH

P  <   0.05

Total refluxes (n)

77 (50–98)

ERD vs NERD

P > 0.05

54 (44–72)

NERD vs FH

P  <   0.05

15 (5–22)

ERD vs FH

P  <   0.05

Acid refluxes (n)

10 (6–17)

ERD vs NERD

P > 0.05

12 (4–21)

NERD vs FH

P  <   0.05

1 (0–3)

ERD vs FH

P  <   0.05

Weakly acidic refluxes (n)

64 (40–88)

ERD vs NERD

P > 0.05

42 (27–58)

NERD vs FH

P  <   0.05

13 (2–21)

ERD vs FH

P  <   0.05

Weakly alkaline refluxes (n)

0 (0–0)

ERD vs NERD

P > 0.05

0 (0–0)

NERD vs FH

P > 0.05

0 (0–0)

ERD vs FH

P > 0.05

BCT (s)

20 (12–43) 

ERD vs NERD

P > 0.05

17 (14–24)

NERD vs FH

P > 0.05

13 (11–17)

ERD vs FH

P > 0.05

PSPW index (%)

16 (13–25)

ERD vs NERD

P < 0.05

31 (24–39)

NERD vs FH

P < 0.05

67 (60–85)

ERD vs FH

P < 0.05

All values are expressed as median and interquartile range. P < 0.05 bold typed.

PPI, proton pump inhibitor; ERD, erosive reflux disease; NERD, non-erosive reflux disease; FH, functional heartburn; LES, lower esophageal sphincter; DEA, distal esophageal amplitude; EAET, esophageal acid exposure time; BCT, bolus clearance time; PSPW, postreflux swallow-induced peristaltic wave.

 

In PPI-dependent patients, all evaluated off-PPI therapy, the %EAET was significantly higher in ERD than in NERD and in both groups when compared with controls. The number of total, acid and weakly acidic refluxes was significantly higher in ERD and NERD patients than in controls but did not differ significantly between ERD and NERD. The median BCT did not differ between the various groups whereas the PSPW index was significantly lower in ERD than in NERD, and in both groups when compared with controls (Fig. 2).

 


Figure 2. Postreflux swallow-induced peristaltic wave (PSPW) index (%, median values). The PSPW index was significantly lower in untreated erosive reflux disease (ERD) than in untreated non-erosive reflux disease (NERD), and in both groups when compared with controls (P < 0.05). The PSPW index was significantly lower in treated ERD than in treated NERD, and in both groups when compared with functional heartburn (FH) (P < 0.05). No significant difference was found between untreated and treated ERD, untreated and treated NERD, controls and FH.

 

In PPI-refractory patients, all evaluated on double-dosage PPI therapy, the %EAET and the number of total, acid and weakly acidic refluxes were significantly higher in ERD and in NERD than in FH, but no significant difference was found between ERD and NERD. Vice versa, the PSPW index was significantly lower in ERD than in NERD, and in both groups when compared with FH (Fig. 2). The median BCT did not differ between the various groups. The %EAET was higher than normal in 6/18 (33%) ERD and in 9/48 (19%) NERD cases, respectively (P = 0.322). The number of total refluxes was higher than normal in 17/18 (94%) ERD and in 36/48 (75%) NERD cases, respectively (P = 0.094).

The PSPW index did not significantly differ either between the PPI-dependent and the PPI-refractory ERD patients or between the PPI-dependent and the PPI-refractory NERD patients; similarly, values found in controls did not differ significantly from those found in non-GERD (FH) patients (Fig. 2). We defined the lower normal limit for the PSPW index as the 5th percentile of values found in healthy controls (57%). Overall, the PSPW index was lower than normal in 49/49 (100%) ERD cases, in 88/92 (96%) NERD cases, in 1/30 (3%) healthy controls, and in 5/26 (19%) FH cases. The overall sensitivity, specificity, positive, and negative predictive values of the PSPW index to predict the status of GERD were 97%, 89%, 96%, and 93%, respectively.

In PPI-dependent GERD patients, a positive SAP/SI was found in 24/31 (77%) ERD cases, in 20/24 (83%) for acid refluxes only, and in 30/44 (68%) NERD cases, in 24/30 (80%) for acid refluxes only; SAP/SI positivity did not differ between NERD and ERD patients (P = 0.441). In PPI-refractory GERD patients, a positive SAP/SI was found in 3/18 (17%) ERD cases, in 2/3 (67%) for weakly acidic refluxes only, and in 34/48 (71%) NERD cases, in 18/34 (53%) for weakly acidic refluxes only; SAP/SI positivity was significantly lower in ERD than in NERD patients (P = 0.001).

In 29 PPI-refractory GERD patients (17 males, median age 37 years) with persistent postoperative heartburn/regurgitation remission and normal impedance-pH monitoring findings at 3-year follow-up, the postoperative PSPW index values (median 20%, interquartile range 13–33%) did not differ from those found preoperatively (median 21%, interquartile range 15–30%) (P = 0.669) (Fig. 3).



Figure 3. Postreflux swallow-induced peristaltic wave (PSPW) index (%,) before and 3 years after laparoscopic fundoplication in 29 proton pump inhibitor-refractory GERD patients with persistent postoperative heartburn/regurgitation remission and normal esophageal acid exposure time.

 

DISCUSSION

In this study, we found that esophageal chemical clearance, as represented by the PSPW index, is impaired in GERD. In off-therapy PPI-dependent patients, the median PSPW index was significantly lower in ERD than in NERD and in both groups when compared with healthy controls. Likewise, in on-therapy PPI-refractory patients, the median PSPW index was significantly lower in ERD than in NERD and in both groups when compared with FH. While the PSPW index was significantly lower and the %EAET was significantly higher in off-PPI ERD patients in comparison with off-PPI NERD patients, a significantly lower PSPW index was the only pathophysiological characteristic distinguishing on-PPI ERD from on-PPI NERD patients. The PSPW index was not altered by medical therapy as it did not differ between treated and untreated ERD patients nor between treated and untreated NERD patients. Moreover, the PSPW index was not modified by surgical therapy as there was no difference between preoperative and 3-year postoperative values in patients who had undergone otherwise effective robot-assisted laparoscopic fundoplication.

After a reflux episode, esophageal clearance depends on volume and chemical clearance. Volume clearance consists of a secondary peristaltic wave, a local reflex response elicited by stretch receptors in the esophageal lining, which signals the end of a reflux episode as assessed by impedance electrodes located in the esophagus. However, according to acid perfusion studies in the laboratory setting, chemical clearance, as assessed by evidence of restoration of a neutral pH within the distal esophageal lumen, is registered by the pH probe only after a swallow-induced peristaltic wave, in turn elicited by an esophagosalivary reflex mediated through vagal afferents.[11, 12] Intraluminal impedance recording can accurately predict bolus transit[28, 29] whereas high resolution esophageal manometry is reportedly unfit for such a purpose.[30] Therefore, the efficiency of esophageal chemical clearance mechanisms can be assessed in the clinical setting by impedance monitoring which allows to assess swallow-induced peristaltic waves following reflux episodes throughout a 24-h period.[17] We then decided to investigate chemical clearance in GERD by reanalyzing impedance-pH tracings in patients previously evaluated at our center. We elected to divide the number of refluxes followed within 30 s by swallow-induced peristaltic waves by the number of total refluxes to obtain a parameter representing the efficiency of chemical clearance namely the PSPW index. Patients with ineffective motility as currently defined at esophageal manometry[21, 22] were excluded because unambiguous evaluation of the end of reflux episodes and of the antegrade progression of swallow-induced peristaltic waves can be hampered by defective peristalsis. Taking into account that a mean number of 64 swallows h−1 (approximately 1 min−1) has been reported in healthy volunteers[27] and that the latency period of salivary gland response to esophageal acidification varies between 10 and 15 s,[12] we chose to assess a 30-s postreflux interval to limit overlap of reflux-elicited swallows with spontaneous swallows. It is conceivable that early occurrence of a PSPW can prevent esophageal mucosal damage due to gastroesophageal refluxate by reducing the contact time of the latter with esophageal mucosa: the more pronounced impairment of the PSPW index in ERD than in NERD patients is in keeping with this view and support the soundness of the PSPW index as a parameter expressing the efficiency of chemical clearance in GERD.

We showed that acid refluxes, which constitute the vast majority of refluxes in untreated GERD patients, elicit swallow-induced peristaltic waves significantly less frequently in off-PPI ERD and off-PPI NERD patients than in controls. Given that we excluded patients with ineffective esophageal motility and that secondary peristalsis, as assessed by the median BCT, did not differ between ERD, NERD, and controls, impaired esophageal chemical clearance could represent the primary factor in determining increased EAET in untreated ERD and NERD patients. Moreover, as the %EAET was significantly higher and the PSPW index was significantly lower in untreated ERD than in untreated NERD patients, chemical clearance should be regarded as a major protective mechanism against the development of esophageal mucosal damage in GERD. These hypotheses appear confirmed by our findings in PPI-refractory GERD patients. As expected,[23] on-PPI therapy the vast majority of reflux episodes were weakly acidic and the %EAET did not differ between ERD and NERD whereas the PSPW index was significantly lower in ERD than in NERD, and in both groups when compared with FH. As the median BCT did not differ between ERD, NERD, and FH, the PSPW index was the only pathophysiological characteristic distinguishing PPI-treated ERD from PPI-treated NERD patients. This confirms that increased %EAET in untreated ERD and NERD is merely a consequence of impaired chemical clearance. It could be argued that weakly acidic refluxes cannot elicit swallow-induced peristaltic waves but this argument is contradicted by the high PSPW index values found in PPI-treated FH patients, quite similar to those detected in untreated controls and showing that chemical clearance can be elicited by weakly acidic refluxes too. We found that PSPW index values were quite similar in off-PPI and on-PPI ERD patients, as well as in off-PPI and on-PPI NERD patients. These findings show that impairment of chemical clearance is a primary factor in the pathogenesis of GERD: it induces prolonged contact time of the esophageal mucosa with gastric contents in off-PPI as well as in on-PPI patients, up to the development of erosive esophagitis in untreated ERD patients and to the on-PPI persistence of esophageal mucosal breaks in PPI-refractory ERD patients. In addition, impairment of chemical clearance appears as a permanent marker of GERD: we found that it was not corrected in patients with persistent symptom remission and normalization of %EAET 3 years after robot-assisted laparoscopic fundoplication, in accordance with previous studies showing that esophageal motility remains unchanged after fundoplication.[31] Impairment of esophageal chemical clearance should therefore be regarded as a primary pathophysiological mechanism specific to GERD as it is unaffected by medical or surgical therapy and is not found in FH. Moreover, it appears to have a major role in the development and persistence of esophageal mucosal damage in GERD.

We found a significantly lower %EAET in off-therapy NERD than ERD patients, and a significantly higher SAP/SI positivity, mainly for weakly acidic refluxes in on-therapy NERD than ERD patients. These results are consistent with the current view that NERD patients have less severe acid reflux but greater esophageal sensitivity than ERD patients, and will therefore perceive also less intense stimuli such as weakly acidic reflux.[32] Conversely, in ERD patients lower esophageal sensitivity could represent the mechanism leading to impairment of esophageal chemical clearance, the latter in turn increasing %EAET and determining esophageal mucosal damage.

In PPI-refractory heartburn patients, impedance-pH monitoring represents the test of choice to show a causal link, if any between persisting symptoms and reflux,[8] to avoid needless surgery in FH[33]; as no reflux pattern associated with PPI failure has been demonstrated off-PPI therapy,[34] evaluation of patients on-PPI therapy still represents the best approach to demonstrate whether persistent symptoms are related to reflux.[8] Recently, the reliability of SAP/SI positivity has been disputed.[35] To distinguish refractory GERD from FH during ongoing PPI therapy, we rely not only on SAP/SI positivity but also on quantitative analysis of reflux parameters based on evaluation of the %EAET and the number of total refluxes, the latter representing a parameter not affected by PPI therapy[23] and predictive of an abnormal %EAET at off-therapy pH-only monitoring.[36] Such an approach allowed us to obtain a subdivision of patients into refractory GERD and FH which was predictive of successful short-term postsurgical subjective and objective outcome.[37, 38] The PSPW index represents then a novel parameter potentially useful for the quantitative assessment of impedance-pH tracings in clinical practice: it is easy to calculate and not time consuming at the usual 2-min time window visual analysis. Given the very high sensitivity, specificity, positive, and negative predictive values of the PSPW index, its assessment could further improve the efficiency of on-therapy impedance-pH monitoring in distinguishing refractory GERD from FH; however, outcome studies are warranted to address this issue.

A few limitations of our study should be acknowledged. Even if data had been collected prospectively, they were retrospectively analyzed; however, to ensure objective evaluation all tracings were blindly reanalyzed in a random order by one expert observer. We excluded patients with ineffective esophageal motility; however, they constituted a small minority (3%) of the patients with PPI-dependent or PPI-refractory heartburn referred to our center, and we believe that our sample is representative of the vast majority of the GERD population.

In conclusion, we have shown an impairment of esophageal chemical clearance in GERD, significantly more pronounced in ERD than in NERD, off- and on-PPI therapy, and persistent after otherwise effective surgical treatment. Impairment of chemical clearance represents a primary pathophysiological mechanism specific to GERD as it is unaffected by medical or surgical therapy and is not found in FH. Moreover, it appears to have a major role in the development and persistence of esophageal mucosal damage in GERD. Evaluation of chemical clearance by the PSPW index could improve the efficiency of on-therapy impedance-pH monitoring in distinguishing refractory GERD from FH; however, this issue should be addressed by future outcome studies.

Acknowledgments: Guarantor of the article: Marzio Frazzoni, MD.

Funding: The study was conducted without any financial support.

Disclosures: The authors have no competing interests.

Author Contributions

MF study concept and design; acquisition, analysis, and interpretation of data; statistical analysis; drafting of the manuscript; RM, VGM acquisition, analysis, and interpretation of data; critical revision of the manuscript. RC, LF, GM study concept; critical revision of the manuscript.

 

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Address for Correspondence: Dr. Marzio Frazzoni, Fisiopatologia Digestiva, Nuovo Ospedale S. Agostino, Viale Giardini 1355, 41100 Modena, Italy. Tel/fax: 0039 (0)59 3961201; e-mail: marziofrazzoni @ gmail.com



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