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ARTICLE IN PRESS Digestive and Liver Disease xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis Marzio Frazzoni a,∗ , Helga Bertani b , Raffaele Manta b , Vincenzo Giorgio Mirante b , Leonardo Frazzoni c , Rita Conigliaro b , Gianluigi Melotti d a
Digestive Pathophysiology Unit, Baggiovara Hospital, Modena, Italy Digestive Endoscopy Unit, Baggiovara Hospital, Modena, Italy c Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy d Department of General Surgery, Baggiovara Hospital, Modena, Italy b
a r t i c l e
i n f o
Article history: Received 4 January 2014 Accepted 11 March 2014 Available online xxx Keywords: Impedance-pH monitoring Oesophageal chemical clearance PPI Refractory GERD Refractory reflux oesophagitis
a b s t r a c t Background: The pathophysiological mechanisms underlying proton pump inhibitor-refractory reflux oesophagitis has been scarcely studied. Aims: To assess impedance-pH parameters relevant to the pathogenesis of refractory reflux oesophagitis. Methods: Cases referred for heartburn/regurgitation refractory to high-dosage proton pump inhibitors between January 2008 and December 2012 were reviewed and subdivided into refractory oesophagitis (29 patients, 72% males, median age 50 years), healed oesophagitis (18 patients, 67% males, median age 54 years), and non-erosive reflux disease (49 patients, 53% males, median age 42 years). On-therapy impedance-pH tracings were blindly re-analysed by one observer to assess gastric and oesophageal acid exposure time and chemical clearance as expressed by the post-reflux swallow-induced peristaltic wave index. Results: The median gastric and oesophageal acid exposure time did not differ among the three groups (35%, 34%, 41% and 1.2%, 0.7%, 0.8%, respectively; P > 0.05 for all comparisons). A normal oesophageal acid exposure time was found in two thirds of patients with refractory oesophagitis. The post-reflux swallowinduced peristaltic wave index was significantly lower in refractory oesophagitis (16%) than in healed oesophagitis (30%) and non-erosive reflux disease (29%) (P = 0.003). Conclusions: Refractory reflux oesophagitis is characterized by impairment of chemical clearance. Adequate acid suppression is found in the majority of patients who would likely not benefit from further proton pump inhibitor dose escalation. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Gastroesophageal reflux disease (GERD) has been defined as a condition that develops when the reflux of gastric contents into the oesophagus leads to troublesome symptoms and/or complications [1,2]. GERD has been further classified according to the presence of reflux symptoms without erosions on endoscopic examination (non-erosive reflux disease) (NERD) or reflux symptoms with reflux oesophagitis (erosive reflux disease) (ERD) [3]. Reflux oesophagitis, defined by the presence of visible mucosal breaks at conventional endoscopic examination of the oesophagus [4], is found in a minority of untreated GERD patients and
∗ Corresponding author at: Fisiopatologia Digestiva, Ospedale Baggiovara, Viale Giardini 1355, 41100 Modena, Italy. Tel.: +39 059 3961201; fax: +39 059 3961201. E-mail address: [email protected] (M. Frazzoni).
should be regarded as the most common complication of GERD rather than its principal manifestation [1]. Proton pump inhibitor (PPI) therapy represents the mainstay of medical treatment for GERD, providing the most rapid relief of the typical reflux symptoms, i.e. heartburn/regurgitation, and healing reflux oesophagitis in the highest percentage of patients. However, up to 30% of patients with documented GERD reportedly fail to respond, either partially or completely, to PPI therapy [5,6]. At endoscopic examination, patients with previous reflux oesophagitis who still complain of heartburn/regurgitation despite high-dosage PPI therapy may have refractory reflux oesophagitis (RRE). RRE is characterized by the persistence of at least one oesophageal mucosal break, whereas healed reflux oesophagitis (HRE), is defined by the absence of previously detected mucosal breaks [7]. By impedance-pH monitoring, it has been shown that PPI therapy converts the vast majority of acid refluxes into non-acid refluxes [8], mainly weakly acidic [9], which have been implicated
http://dx.doi.org/10.1016/j.dld.2014.03.005 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Frazzoni M, et al. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis (2014), http://dx.doi.org/10.1016/j.dld.2014.03.005
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in the genesis of PPI-refractory heartburn [3,5,6]. Impedance-pH monitoring allows recording of impedance changes in response to the movement of fluids and gas throughout the oesophagus in retrograde (reflux) as well as in antegrade (swallow) direction and represents a reliable technique to assess bolus transit as induced by peristalsis [10]. Clearance of gastroesophageal reflux is biphasic. During volume clearance, refluxate is cleared from the oesophagus by secondary peristalsis; then, during chemical clearance, the acidified oesophageal mucosa is neutralized by saliva transported by a swallow-induced peristaltic wave [11]. Impedance-pH monitoring allows assessment of chemical clearance independent of volume clearance [12]: a drop in impedance originating in the proximal oesophagus after the end of a reflux episode and reaching the distal oesophagus represents complete transit of saliva elicited by a swallow-induced peristaltic wave. In a recent study, by means of 24-h impedance-pH monitoring we found that oesophageal chemical clearance, as assessed by the post-reflux swallow-induced peristaltic wave (PSPW) index, is significantly impaired in ERD patients compared with NERD patients, evaluated on or off-PPI therapy [13]. The pathophysiological mechanisms underlying RRE have been scarcely studied, but could help for choosing the appropriate management strategy in these difficult-to-treat patients, e.g. further PPI escalation in patients with objective evidence of inadequate acid suppression or anti-reflux surgery in the remainder. As reflux of acidic gastric contents is considered to play a key role in the pathogenesis of oesophageal mucosa breaks in GERD, RRE could be related to inadequate acid suppression despite high-dosage PPI therapy. Additionally, RRE could also be related to impaired chemical clearance prolonging contact time of refluxate with oesophageal mucosa. To further study these relationships, we retrospectively reviewed the 24-h impedance-pH monitoring studies performed in patients with ERD and NERD referred to our centre for PPIrefractory heartburn/regurgitation. Our aim was to assess the role of inadequate acid suppression and of impaired chemical clearance in the pathogenesis of RRE.
2. Materials and methods 2.1. Patients After study approval by our institutional review board, data prospectively collected in our database between January 2008 and December 2012 were reviewed by one investigator (LF) not involved in manometric and impedance-pH testing. In this phase, we selected adult cases referred to our centre for PPI-refractory heartburn/regurgitation, i.e. troublesome heartburn/regurgitation persisting despite 4–8 weeks of high-dosage PPI therapy. Symptoms were routinely assessed by means of a validated [14] questionnaire based on a standard four-grade, Likert-type scale scoring system. Symptom grading was: 0 = none; 1 = mild/occasional, symptom can be ignored; 2 = moderate/frequent, symptom cannot be ignored, but neither daily activities nor sleep are influenced; 3 = severe/constant, symptom influences daily activities and/or sleep. Symptoms assessed were heartburn, regurgitation, dysphagia, chest pain, belching, early satiety, post-prandial fullness, epigastric pain/burn, vomiting, and epigastric bloating. A heartburn/regurgitation score of at least 2 during ongoing 4-week high-dosage PPI therapy (verified by pill count) and a previous endoscopic examination performed after at least 4 weeks of PPI withdrawal (index endoscopy) were required before impedance-pH testing. Patients had to provide written informed consents before undergoing clinical investigations.
For the purpose of this study, patients with achalasia, progressive systemic sclerosis, Sjogren syndrome, previous esophagogastric surgery, as well as patients taking medications causing mouth dryness were excluded. Patients with dyspeptic symptoms or dysphagia, chest pain or extra-oesophageal syndromes dominating the clinical picture were also excluded. 2.2. Endoscopy Patients referred for PPI-refractory heartburn/regurgitation and with previous detection of reflux oesophagitis at off-PPI (4-week wash-out) index endoscopy underwent endoscopic control during ongoing therapy. All the procedures were performed by expert endoscopists (MF, HB, RM, VGM, RC), adopting standardized criteria to evaluate and report oesophageal abnormalities and using high-definition white light endoscopes. Patients routinely received intravenous sedation. The gastroesophageal junction was defined by the most prominent extent of the gastric mucosal folds. Hiatal hernia was defined as a distance between the diaphragmatic hiatus and the gastroesophageal junction >2 cm. Reflux oesophagitis was defined according to the Los Angeles classification [4]. For the purpose of this study, patients with persistent oesophageal mucosal breaks comprised the RRE group, whereas those in whom oesophageal mucosal breaks were no longer detectable comprised the HRE group. 2.3. Impedance-pH monitoring Ambulatory 24-h impedance-pH monitoring was carried out at our centre (MF, VGM) during ongoing high-dosage PPI therapy, verified by pill count in the last 4 weeks, with no concomitant antireflux medication allowed. Impedance-pH monitoring was always preceded by stationary oesophageal manometry to locate the lower oesophageal sphincter (LES) and the position of the pressure inversion point, as well as to assess the basal LES tone and the mean distal oesophageal amplitude. The impedance-pH catheter was passed transnasally and placed to allow 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. The catheter was connected to a portable data logger (Sleuth, Sandhill Scientific; Highland Ranch, CO). Patients were discharged, asked to maintain their normal activities and sleep schedule, and to eat their usual meals at their normal times. Symptoms, meal times, and posture changes were recorded by event markers. Impedance-pH tracings were blindly re-analysed in a random order by one expert observer (MF) who was unaware of the clinical details and of the previous analyses’ results. The Autoscan function of the BioView software (Sandhill Scientific, Highland Ranch, CO) was used in conjunction with a 2-min time window visual analysis, with zooming whenever deemed necessary. Meal times were excluded. The time period with gastric and oesophageal pH < 4, i.e. the percentage gastric acid exposure time (GAET) and the percentage oesophageal acid exposure time (EAET) were computed (EAET upper normal limit at our centre 3.3%) [9]. 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). Data analysis was performed on liquid and mixed (liquid–gas) refluxes. The number of total refluxes (liquid and mixed refluxes detected at least in the two most distal impedance sites) was computed (upper normal limit at our centre 45) [9]. The percentage bolus exposure and the median bolus clearance time were also computed. The symptom association probability (SAP) and the symptom index (SI) were calculated. The SAP and SI were considered positive when they were ≥95% and ≥50%, respectively [15].
Please cite this article in press as: Frazzoni M, et al. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis (2014), http://dx.doi.org/10.1016/j.dld.2014.03.005
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Fig. 1. Impedance-pH tracing showing a weakly acidic reflux episode followed by a drop in impedance from the proximal to the distal oesophagus representing complete transit of swallowed saliva (arrow) elicited by a swallow-induced peristaltic wave.
Patients with PPI-refractory heartburn/regurgitation with normal findings at the off-PPI index endoscopy but abnormal EAET and/or abnormal number of total refluxes and/or a positive SAP/SI comprised the NERD group. Endoscopy-negative PPI-refractory patients with negative impedance-pH results, i.e. normal EAET, normal number of total refluxes, and negative SAP/SI, were considered as functional heartburn [3,5,13] and were excluded. Oesophageal chemical clearance was assessed by means of the PSPW index [13]. A PSPW was defined as an antegrade 50% drop in impedance relative to the pre-swallow baseline originating in the most proximal impedance sites, reaching the most distal impedance sites (complete transit), and followed by at least 50% return to the baseline in the most distal impedance sites (Fig. 1). To limit the overlap with spontaneous swallowing (64 swallows per hour, approximately 1 per minute) [16] and considering the latency period of salivary gland response to oesophageal acidification (10–15 s) [17], only PSPWs occurring within 30 s from the end of the reflux episodes were taken into account. For each impedancepH monitoring tracing, the number of refluxes followed within 30 s
by a PSPW was divided by the number of total refluxes in order to obtain the PSPW index (lower normal limit at our centre 57%) [13]. 2.4. Statistical analysis Taking into account our previous findings in patients on PPI therapy [9,13], we calculated that at least 8 patients were required in each group to demonstrate a significant between-group difference at the 5% significance level, with statistical power of 90%. For categorical variables, the Fisher’s exact test was used. For continuous variables, the Kruskal–Wallis and the Mann–Whitney tests were used with appropriate adjustments for multiple comparisons. A P < 0.05 was considered significant. 3. Results The main demographic characteristics of the 96 PPI-refractory patients (29 RRE, 18 HRE, and 49 NERD) who fulfilled the study inclusion criteria are reported in Table 1. Sixty-eight patients were
Table 1 Demographic characteristics of 96 patients with proton pump inhibitor-refractory heartburn/regurgitation. RRE (n = 29)
HRE (n = 18)
NERD (n = 49)
Male gender
21 (72%) RRE vs. HRE P = 0.749
12 (67%) RRE vs. NERD P = 0.102
26 (53%) HRE vs. NERD P = 0.408
Age (years)
50 (37–57) RRE vs. HRE P = 0.381
54 (43–62) RRE vs. NERD P = 0.277
42 (34–57) HRE vs. NERD P = 0.084
BMI
27 (24–29) RRE vs. HRE P = 0.604
26 (24–31) RRE vs. NERD P = 0.863
28 (25–31) HRE vs. NERD P = 0.179
RRE, refractory reflux oesophagitis; HRE, healed reflux oesophagitis; NERD, nonerosive reflux disease; BMI, body mass index. Data are expressed as median and interquartile range except for male gender (n) (%).
Please cite this article in press as: Frazzoni M, et al. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis (2014), http://dx.doi.org/10.1016/j.dld.2014.03.005
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Table 2 Endoscopic and manometric characteristics of 96 patients with proton pump inhibitor-refractory heartburn/regurgitation. Index endoscopy was performed after at least 4-week wash-out from PPI therapy. Repeat endoscopy was performed after 4–8 weeks of high-dosage PPIs during ongoing therapy. RRE (n = 29)
HRE (n = 18)
NERD (n = 49)
Hiatal hernia
25 (86%) RRE vs. HRE P = 0.990
15 (83%) RRE vs. NERD P = 0.064
32 (65%) HRE vs. NERD P = 0.230
Grade C/D oesophagitis at index endoscopy
14 (48%)
11 (61%) RRE vs. HRE P = 0.549
–
Grade B oesophagitis at index endoscopy
9 (31%)
3 (17%) RRE vs. HRE P = 0.324
–
Grade A oesophagitis at index endoscopy
6 (21%)
4 (22%) RRE vs. HRE P = 0.999
–
Grade C/D oesophagitis at repeat endoscopy Grade B oesophagitis at repeat endoscopy Grade A oesophagitis at repeat endoscopy
3 (10%) 13 (45%) 13 (45%)
0 0 0
– – –
LES tone (mmHg)
15 (11–19) RRE vs. HRE P = 0.411
18 (13–19) RRE vs. NERD P = 0.110
18 (12–25) HRE vs. NERD P = 0.400
MDEA (mmHg)
59 (45–73) RRE vs. HRE P = 0.255
66 (52–103) RRE vs. NERD P = 0.003
87 (62–108) HRE vs. NERD P = 0.174
RRE, refractory reflux oesophagitis; HRE, healed reflux oesophagitis; NERD, nonerosive reflux disease; LES, lower oesophageal sphincter; MDEA, mean distal oesophageal amplitude. PPI, proton pump inhibitor. Data are expressed as number (n) and percentage (%) except for LES tone and MDEA (median and interquartile range).
on esomeprazole, 14 on lansoprazole, 6 on rabeprazole, 6 on pantoprazole, and 2 patients were on omeprazole, all taken at double dosages. The endoscopic and manometric characteristics are reported in Table 2. The mean distal oesophageal amplitude was significantly lower in RRE than in NERD patients. Impedance-pH parameters are reported in Table 3. The PSPW index was the only parameter distinguishing RRE from HRE and NERD patients (median 16%, 30%, and 29%, respectively) (P = 0.003). The GAET was >50% in 7/29 (24%) RRE patients, in 3/18 (17%) HRE patients, and in 13/49 (27%) NERD patients (P > 0.05 for all comparisons). The EAET was >3.3% in 9/29 (31%) RRE patients, in 3/18 (17%) HRE patients, and in 11/49 (22%) NERD patients (P > 0.05 for all comparisons). The number of total refluxes was >45 in 21/29 (72%) RRE patients, in 10/18 (56%) HRE patients, and in 35/49 (71%)
NERD patients (P > 0.05 for all comparisons). The PSPW index was
ARTICLE IN PRESS Digestive and Liver Disease xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis Marzio Frazzoni a,∗ , Helga Bertani b , Raffaele Manta b , Vincenzo Giorgio Mirante b , Leonardo Frazzoni c , Rita Conigliaro b , Gianluigi Melotti d a
Digestive Pathophysiology Unit, Baggiovara Hospital, Modena, Italy Digestive Endoscopy Unit, Baggiovara Hospital, Modena, Italy c Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy d Department of General Surgery, Baggiovara Hospital, Modena, Italy b
a r t i c l e
i n f o
Article history: Received 4 January 2014 Accepted 11 March 2014 Available online xxx Keywords: Impedance-pH monitoring Oesophageal chemical clearance PPI Refractory GERD Refractory reflux oesophagitis
a b s t r a c t Background: The pathophysiological mechanisms underlying proton pump inhibitor-refractory reflux oesophagitis has been scarcely studied. Aims: To assess impedance-pH parameters relevant to the pathogenesis of refractory reflux oesophagitis. Methods: Cases referred for heartburn/regurgitation refractory to high-dosage proton pump inhibitors between January 2008 and December 2012 were reviewed and subdivided into refractory oesophagitis (29 patients, 72% males, median age 50 years), healed oesophagitis (18 patients, 67% males, median age 54 years), and non-erosive reflux disease (49 patients, 53% males, median age 42 years). On-therapy impedance-pH tracings were blindly re-analysed by one observer to assess gastric and oesophageal acid exposure time and chemical clearance as expressed by the post-reflux swallow-induced peristaltic wave index. Results: The median gastric and oesophageal acid exposure time did not differ among the three groups (35%, 34%, 41% and 1.2%, 0.7%, 0.8%, respectively; P > 0.05 for all comparisons). A normal oesophageal acid exposure time was found in two thirds of patients with refractory oesophagitis. The post-reflux swallowinduced peristaltic wave index was significantly lower in refractory oesophagitis (16%) than in healed oesophagitis (30%) and non-erosive reflux disease (29%) (P = 0.003). Conclusions: Refractory reflux oesophagitis is characterized by impairment of chemical clearance. Adequate acid suppression is found in the majority of patients who would likely not benefit from further proton pump inhibitor dose escalation. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Gastroesophageal reflux disease (GERD) has been defined as a condition that develops when the reflux of gastric contents into the oesophagus leads to troublesome symptoms and/or complications [1,2]. GERD has been further classified according to the presence of reflux symptoms without erosions on endoscopic examination (non-erosive reflux disease) (NERD) or reflux symptoms with reflux oesophagitis (erosive reflux disease) (ERD) [3]. Reflux oesophagitis, defined by the presence of visible mucosal breaks at conventional endoscopic examination of the oesophagus [4], is found in a minority of untreated GERD patients and
∗ Corresponding author at: Fisiopatologia Digestiva, Ospedale Baggiovara, Viale Giardini 1355, 41100 Modena, Italy. Tel.: +39 059 3961201; fax: +39 059 3961201. E-mail address: [email protected] (M. Frazzoni).
should be regarded as the most common complication of GERD rather than its principal manifestation [1]. Proton pump inhibitor (PPI) therapy represents the mainstay of medical treatment for GERD, providing the most rapid relief of the typical reflux symptoms, i.e. heartburn/regurgitation, and healing reflux oesophagitis in the highest percentage of patients. However, up to 30% of patients with documented GERD reportedly fail to respond, either partially or completely, to PPI therapy [5,6]. At endoscopic examination, patients with previous reflux oesophagitis who still complain of heartburn/regurgitation despite high-dosage PPI therapy may have refractory reflux oesophagitis (RRE). RRE is characterized by the persistence of at least one oesophageal mucosal break, whereas healed reflux oesophagitis (HRE), is defined by the absence of previously detected mucosal breaks [7]. By impedance-pH monitoring, it has been shown that PPI therapy converts the vast majority of acid refluxes into non-acid refluxes [8], mainly weakly acidic [9], which have been implicated
http://dx.doi.org/10.1016/j.dld.2014.03.005 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Frazzoni M, et al. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis (2014), http://dx.doi.org/10.1016/j.dld.2014.03.005
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in the genesis of PPI-refractory heartburn [3,5,6]. Impedance-pH monitoring allows recording of impedance changes in response to the movement of fluids and gas throughout the oesophagus in retrograde (reflux) as well as in antegrade (swallow) direction and represents a reliable technique to assess bolus transit as induced by peristalsis [10]. Clearance of gastroesophageal reflux is biphasic. During volume clearance, refluxate is cleared from the oesophagus by secondary peristalsis; then, during chemical clearance, the acidified oesophageal mucosa is neutralized by saliva transported by a swallow-induced peristaltic wave [11]. Impedance-pH monitoring allows assessment of chemical clearance independent of volume clearance [12]: a drop in impedance originating in the proximal oesophagus after the end of a reflux episode and reaching the distal oesophagus represents complete transit of saliva elicited by a swallow-induced peristaltic wave. In a recent study, by means of 24-h impedance-pH monitoring we found that oesophageal chemical clearance, as assessed by the post-reflux swallow-induced peristaltic wave (PSPW) index, is significantly impaired in ERD patients compared with NERD patients, evaluated on or off-PPI therapy [13]. The pathophysiological mechanisms underlying RRE have been scarcely studied, but could help for choosing the appropriate management strategy in these difficult-to-treat patients, e.g. further PPI escalation in patients with objective evidence of inadequate acid suppression or anti-reflux surgery in the remainder. As reflux of acidic gastric contents is considered to play a key role in the pathogenesis of oesophageal mucosa breaks in GERD, RRE could be related to inadequate acid suppression despite high-dosage PPI therapy. Additionally, RRE could also be related to impaired chemical clearance prolonging contact time of refluxate with oesophageal mucosa. To further study these relationships, we retrospectively reviewed the 24-h impedance-pH monitoring studies performed in patients with ERD and NERD referred to our centre for PPIrefractory heartburn/regurgitation. Our aim was to assess the role of inadequate acid suppression and of impaired chemical clearance in the pathogenesis of RRE.
2. Materials and methods 2.1. Patients After study approval by our institutional review board, data prospectively collected in our database between January 2008 and December 2012 were reviewed by one investigator (LF) not involved in manometric and impedance-pH testing. In this phase, we selected adult cases referred to our centre for PPI-refractory heartburn/regurgitation, i.e. troublesome heartburn/regurgitation persisting despite 4–8 weeks of high-dosage PPI therapy. Symptoms were routinely assessed by means of a validated [14] questionnaire based on a standard four-grade, Likert-type scale scoring system. Symptom grading was: 0 = none; 1 = mild/occasional, symptom can be ignored; 2 = moderate/frequent, symptom cannot be ignored, but neither daily activities nor sleep are influenced; 3 = severe/constant, symptom influences daily activities and/or sleep. Symptoms assessed were heartburn, regurgitation, dysphagia, chest pain, belching, early satiety, post-prandial fullness, epigastric pain/burn, vomiting, and epigastric bloating. A heartburn/regurgitation score of at least 2 during ongoing 4-week high-dosage PPI therapy (verified by pill count) and a previous endoscopic examination performed after at least 4 weeks of PPI withdrawal (index endoscopy) were required before impedance-pH testing. Patients had to provide written informed consents before undergoing clinical investigations.
For the purpose of this study, patients with achalasia, progressive systemic sclerosis, Sjogren syndrome, previous esophagogastric surgery, as well as patients taking medications causing mouth dryness were excluded. Patients with dyspeptic symptoms or dysphagia, chest pain or extra-oesophageal syndromes dominating the clinical picture were also excluded. 2.2. Endoscopy Patients referred for PPI-refractory heartburn/regurgitation and with previous detection of reflux oesophagitis at off-PPI (4-week wash-out) index endoscopy underwent endoscopic control during ongoing therapy. All the procedures were performed by expert endoscopists (MF, HB, RM, VGM, RC), adopting standardized criteria to evaluate and report oesophageal abnormalities and using high-definition white light endoscopes. Patients routinely received intravenous sedation. The gastroesophageal junction was defined by the most prominent extent of the gastric mucosal folds. Hiatal hernia was defined as a distance between the diaphragmatic hiatus and the gastroesophageal junction >2 cm. Reflux oesophagitis was defined according to the Los Angeles classification [4]. For the purpose of this study, patients with persistent oesophageal mucosal breaks comprised the RRE group, whereas those in whom oesophageal mucosal breaks were no longer detectable comprised the HRE group. 2.3. Impedance-pH monitoring Ambulatory 24-h impedance-pH monitoring was carried out at our centre (MF, VGM) during ongoing high-dosage PPI therapy, verified by pill count in the last 4 weeks, with no concomitant antireflux medication allowed. Impedance-pH monitoring was always preceded by stationary oesophageal manometry to locate the lower oesophageal sphincter (LES) and the position of the pressure inversion point, as well as to assess the basal LES tone and the mean distal oesophageal amplitude. The impedance-pH catheter was passed transnasally and placed to allow 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. The catheter was connected to a portable data logger (Sleuth, Sandhill Scientific; Highland Ranch, CO). Patients were discharged, asked to maintain their normal activities and sleep schedule, and to eat their usual meals at their normal times. Symptoms, meal times, and posture changes were recorded by event markers. Impedance-pH tracings were blindly re-analysed in a random order by one expert observer (MF) who was unaware of the clinical details and of the previous analyses’ results. The Autoscan function of the BioView software (Sandhill Scientific, Highland Ranch, CO) was used in conjunction with a 2-min time window visual analysis, with zooming whenever deemed necessary. Meal times were excluded. The time period with gastric and oesophageal pH < 4, i.e. the percentage gastric acid exposure time (GAET) and the percentage oesophageal acid exposure time (EAET) were computed (EAET upper normal limit at our centre 3.3%) [9]. 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). Data analysis was performed on liquid and mixed (liquid–gas) refluxes. The number of total refluxes (liquid and mixed refluxes detected at least in the two most distal impedance sites) was computed (upper normal limit at our centre 45) [9]. The percentage bolus exposure and the median bolus clearance time were also computed. The symptom association probability (SAP) and the symptom index (SI) were calculated. The SAP and SI were considered positive when they were ≥95% and ≥50%, respectively [15].
Please cite this article in press as: Frazzoni M, et al. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis (2014), http://dx.doi.org/10.1016/j.dld.2014.03.005
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Fig. 1. Impedance-pH tracing showing a weakly acidic reflux episode followed by a drop in impedance from the proximal to the distal oesophagus representing complete transit of swallowed saliva (arrow) elicited by a swallow-induced peristaltic wave.
Patients with PPI-refractory heartburn/regurgitation with normal findings at the off-PPI index endoscopy but abnormal EAET and/or abnormal number of total refluxes and/or a positive SAP/SI comprised the NERD group. Endoscopy-negative PPI-refractory patients with negative impedance-pH results, i.e. normal EAET, normal number of total refluxes, and negative SAP/SI, were considered as functional heartburn [3,5,13] and were excluded. Oesophageal chemical clearance was assessed by means of the PSPW index [13]. A PSPW was defined as an antegrade 50% drop in impedance relative to the pre-swallow baseline originating in the most proximal impedance sites, reaching the most distal impedance sites (complete transit), and followed by at least 50% return to the baseline in the most distal impedance sites (Fig. 1). To limit the overlap with spontaneous swallowing (64 swallows per hour, approximately 1 per minute) [16] and considering the latency period of salivary gland response to oesophageal acidification (10–15 s) [17], only PSPWs occurring within 30 s from the end of the reflux episodes were taken into account. For each impedancepH monitoring tracing, the number of refluxes followed within 30 s
by a PSPW was divided by the number of total refluxes in order to obtain the PSPW index (lower normal limit at our centre 57%) [13]. 2.4. Statistical analysis Taking into account our previous findings in patients on PPI therapy [9,13], we calculated that at least 8 patients were required in each group to demonstrate a significant between-group difference at the 5% significance level, with statistical power of 90%. For categorical variables, the Fisher’s exact test was used. For continuous variables, the Kruskal–Wallis and the Mann–Whitney tests were used with appropriate adjustments for multiple comparisons. A P < 0.05 was considered significant. 3. Results The main demographic characteristics of the 96 PPI-refractory patients (29 RRE, 18 HRE, and 49 NERD) who fulfilled the study inclusion criteria are reported in Table 1. Sixty-eight patients were
Table 1 Demographic characteristics of 96 patients with proton pump inhibitor-refractory heartburn/regurgitation. RRE (n = 29)
HRE (n = 18)
NERD (n = 49)
Male gender
21 (72%) RRE vs. HRE P = 0.749
12 (67%) RRE vs. NERD P = 0.102
26 (53%) HRE vs. NERD P = 0.408
Age (years)
50 (37–57) RRE vs. HRE P = 0.381
54 (43–62) RRE vs. NERD P = 0.277
42 (34–57) HRE vs. NERD P = 0.084
BMI
27 (24–29) RRE vs. HRE P = 0.604
26 (24–31) RRE vs. NERD P = 0.863
28 (25–31) HRE vs. NERD P = 0.179
RRE, refractory reflux oesophagitis; HRE, healed reflux oesophagitis; NERD, nonerosive reflux disease; BMI, body mass index. Data are expressed as median and interquartile range except for male gender (n) (%).
Please cite this article in press as: Frazzoni M, et al. Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis. Dig Liver Dis (2014), http://dx.doi.org/10.1016/j.dld.2014.03.005
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Table 2 Endoscopic and manometric characteristics of 96 patients with proton pump inhibitor-refractory heartburn/regurgitation. Index endoscopy was performed after at least 4-week wash-out from PPI therapy. Repeat endoscopy was performed after 4–8 weeks of high-dosage PPIs during ongoing therapy. RRE (n = 29)
HRE (n = 18)
NERD (n = 49)
Hiatal hernia
25 (86%) RRE vs. HRE P = 0.990
15 (83%) RRE vs. NERD P = 0.064
32 (65%) HRE vs. NERD P = 0.230
Grade C/D oesophagitis at index endoscopy
14 (48%)
11 (61%) RRE vs. HRE P = 0.549
–
Grade B oesophagitis at index endoscopy
9 (31%)
3 (17%) RRE vs. HRE P = 0.324
–
Grade A oesophagitis at index endoscopy
6 (21%)
4 (22%) RRE vs. HRE P = 0.999
–
Grade C/D oesophagitis at repeat endoscopy Grade B oesophagitis at repeat endoscopy Grade A oesophagitis at repeat endoscopy
3 (10%) 13 (45%) 13 (45%)
0 0 0
– – –
LES tone (mmHg)
15 (11–19) RRE vs. HRE P = 0.411
18 (13–19) RRE vs. NERD P = 0.110
18 (12–25) HRE vs. NERD P = 0.400
MDEA (mmHg)
59 (45–73) RRE vs. HRE P = 0.255
66 (52–103) RRE vs. NERD P = 0.003
87 (62–108) HRE vs. NERD P = 0.174
RRE, refractory reflux oesophagitis; HRE, healed reflux oesophagitis; NERD, nonerosive reflux disease; LES, lower oesophageal sphincter; MDEA, mean distal oesophageal amplitude. PPI, proton pump inhibitor. Data are expressed as number (n) and percentage (%) except for LES tone and MDEA (median and interquartile range).
on esomeprazole, 14 on lansoprazole, 6 on rabeprazole, 6 on pantoprazole, and 2 patients were on omeprazole, all taken at double dosages. The endoscopic and manometric characteristics are reported in Table 2. The mean distal oesophageal amplitude was significantly lower in RRE than in NERD patients. Impedance-pH parameters are reported in Table 3. The PSPW index was the only parameter distinguishing RRE from HRE and NERD patients (median 16%, 30%, and 29%, respectively) (P = 0.003). The GAET was >50% in 7/29 (24%) RRE patients, in 3/18 (17%) HRE patients, and in 13/49 (27%) NERD patients (P > 0.05 for all comparisons). The EAET was >3.3% in 9/29 (31%) RRE patients, in 3/18 (17%) HRE patients, and in 11/49 (22%) NERD patients (P > 0.05 for all comparisons). The number of total refluxes was >45 in 21/29 (72%) RRE patients, in 10/18 (56%) HRE patients, and in 35/49 (71%)
NERD patients (P > 0.05 for all comparisons). The PSPW index was
