Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis

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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].

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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) (%).

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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 <57% in all 96 patients. 4. Discussion In the 96 patients with PPI-refractory heartburn/regurgitation, GAET, EAET, the number of total, acid and weakly acidic refluxes, bolus exposure and clearance time did not differ among RRE, HRE, and NERD patients. A normal EAET was found in two thirds of patients with RRE. On the other hand, the PSPW index was significantly lower in RRE patients than in either HRE or NERD patients. Currently, PPI resistance is the real challenge in GERD [18]. Our series consisted of 47 ERD cases (29 RRE and 18 HRE) and 49 NERD cases, confirming that the prevalence of PPI-refractoriness is similar in NERD and ERD provided that patients with functional

Table 3 Impedance-pH parameters (on high-dosage proton pump inhibitor) in 96 patients with proton pump inhibitor-refractory heartburn/regurgitation. RRE (n = 29)

HRE (n = 18)

NERD (n = 49)

GAET (%)

35 (28–46) RRE vs. HRE P = 0.710

34 (24–45) RRE vs. NERD P = 0.938

41 (24–52) HRE vs. NERD P = 0.718

EAET (%)

1.2 (0.4–4) RRE vs. HRE P = 0.125

0.7 (0–2) RRE vs. NERD P = 0.437

0.8 (0.3–3) HRE vs. NERD P = 0.269

Total refluxes (n)

67 (45–89) RRE vs. HRE P = 0.246

51 (25–81) RRE vs. NERD P = 0.456

52 (42–71) HRE vs. NERD P = 0.308

Acid refluxes (n)

10 (6–17) RRE vs. HRE P = 0.203

8 (2–18) RRE vs. NERD P = 0.881

12 (5–22) HRE vs. NERD P = 0.165

Weakly acidic refluxes (n)

44 (24–68) RRE vs. HRE P = 0.504

35 (21–67) RRE vs. NERD P = 0.501

41 (25–57) HRE vs. NERD P = 0.671

Weakly alkaline refluxes (n)

0 (0–0) RRE vs. HRE P = 0.672

0 (0–0) RRE vs. NERD P = 0.511

0 (0–0) HRE vs. NERD P = 0.876

Bolus exposure (%)

3.5 (1.5–7.9) RRE vs. HRE P = 0.412

2.5 (0.9–4.7) RRE vs. NERD P = 0.257

2.6 (1.5–3.3) HRE vs. NERD P = 0.994

Bolus clearance time (s)

22 (14–40) RRE vs. HRE P = 0.956

23 (15–34) RRE vs. NERD P = 0.232

18 (14–25) HRE vs. NERD P = 0.229

PSPW index (%)

16 (13–23) RRE vs. HRE P = 0.003

30 (25–36) RRE vs. NERD P = 0.003

29 (25–35) HRE vs. NERD P = 0.989

RRE, refractory reflux oesophagitis; HRE, healed reflux oesophagitis; NERD, nonerosive reflux disease; GAET, gastric acid exposure time; EAET, oesophageal acid exposure time; PSPW, post-reflux swallow-induced peristaltic wave. Data are expressed as median and interquartile range.

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heartburn have been excluded [5,18]. However, RRE is exceedingly rare. The vast majority of PPI-refractory GERD patients have negative findings at endoscopic examination [19] despite the increased intercellular space diameter as measured by transmission electron microscopy [20]. Persistent reflux oesophagitis has been detected in only 10% of patients after 8-week standard-dosage PPI, and in only 2% of cases after 4–8 weeks of high-dosage PPI, the latter to be regarded as RRE [7]. Besides healing reflux oesophagitis, PPI therapy is very effective for symptom relief; furthermore, on-PPI symptomatic patients with HRE are even fewer than patients with RRE [7]. Even if there is a direct relationship between PPI-induced acid suppression and healing of reflux oesophagitis [21], a GAET <50% is considered adequate in patients with grades C and D reflux oesophagitis as incremental acid suppression above this threshold does not yield increase in healing rates [22]. In our series, the median GAET did not differ between RRE and HRE patients and was well below 50%; only one fourth of cases with RRE had a GAET >50%. Moreover, RRE was not associated with significantly higher levels of EAET when compared with HRE patients, and only in one third of RRE patients the EAET was higher than normal. Accordingly, RRE is not due to inadequate acid suppression in the majority of cases, and most RRE patients would likely not benefit from further escalation of PPI dosages to heal mucosal lesions. Baclofen could be helpful as add-on therapy with PPIs, but its use is limited by side effects [6]. Current endoscopic treatment modalities cannot be recommended as an alternative to medical or surgical therapy [3], especially in the presence of hiatal hernia, which plays a key role in PPI refractoriness [23], as confirmed by its very high prevalence in our series. Laparoscopic fundoplication is the only GERD treatment modality that repairs hiatal hernia; moreover, it acts by reducing the number of transient LES relaxations accompanied by reflux and the volume of the postprandial acid pocket at the gastroesophageal junction [24]. These effects explain why off-PPI persistent symptom remission and normalization of reflux parameters at the 3-year postoperative evaluation can be achieved by laparoscopic fundoplication in the vast majority of patients with refractory GERD, in conjunction with mucosal healing in RRE cases [24]. GERD is a multifactorial disorder. Many studies exploring the underlying pathophysiology of GERD point towards multiple factors including transient LES relaxations, the presence of an acid pocket, hiatus hernia, reduced LES tone, and impaired clearance [25]. Gastroesophageal refluxate contains a variety of noxious agents, including hydrochloric acid and pepsins. PPIs transform the vast majority of acid refluxes into weakly acidic refluxes [9]. The proteolytic activity of pepsins is maintained up to pH 6 [26] and healing of mucosal breaks occurs through reparative processes that are inhibited at pH 6.5 and abolished at pH 3.0 [27]. Then, weakly acidic refluxes are toxic for the oesophageal mucosa and once refluxate has entered the oesophagus the main defence against development or persistence of mucosal damage is removal of the noxious agents as quickly as possible. Clearance of refluxate is primarily achieved by mechanical (volume) clearance. Volume clearance consists of a secondary peristaltic wave that removes around 90% of the refluxate and is elicited by stretch receptors in the oesophageal lining [11]. However, acid duration is 2-fold greater than bolus exposure [28] and restoration of a neutral pH within the distal oesophageal lumen can be registered by a pH probe only following a swallow-induced peristaltic wave [11]. This, in turn, is elicited by an oesophagosalivary reflex that is mediated through vagal afferents [17] and allows salivary bicarbonate to augment the oesophageal pH (chemical clearance) [29]. Early-occurring swallows reaching the most distal sites of the oesophagus can protect the oesophageal mucosa from the corrosive action of acidic/weakly acidic refluxate by reducing contact time with gastric contents. Impedance can be used to measure the clearance of a swallowed bolus from the oesophagus similar to

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oesophageal transit tests [30], accurately predicting bolus transit [10,31]. A sequential drop in impedance originating in the proximal oesophagus after the end of a reflux episode and reaching the distal oesophagus depicts the efficient transport of saliva from the mouth to the stomach elicited by a swallow-induced peristaltic wave [12] and can represent chemical clearance for acidic as well as for weakly acidic refluxes [13]. The PSPW index is obtained dividing the number of refluxes followed within 30 s by a swallow-induced peristaltic drop in impedance by the number of total refluxes [13]. The PSPW index is not aimed to determine the end of an acidic reflux with restoration of neutral pH, but to assess the occurrence of a peristaltic drop in impedance following a reflux episode in a due time as elicited by an oesophagosalivary reflex, regardless of the acidity of the refluxate. We have shown that the PSPW index is not influenced by the acidity of the reflux episode because similar values have been found in off-PPI and on-PPI ERD patients, as well as in off-PPI and on-PPI NERD patients [13]. Therefore, the PSPW index is suitable for the evaluation of patients off, as well as on, PPI therapy. Off PPI therapy, refluxes are mostly acidic in ERD patients [13,32], whereas on PPI weakly acidic refluxes represent the vast majority of reflux episodes [13]. On-PPI impedance-pH testing has been recommended to clarify the mechanisms of PPI-resistance in patients with typical reflux symptoms [33,34], and a recent study has confirmed that no reflux pattern associated with PPI failure can be demonstrated by impedance-pH monitoring performed off PPI therapy [35]. Given the high sensitivity, specificity, positive and negative predictive values of the PSPW index in identifying GERD patients (97%, 89%, 96%, and 93%, respectively) [13], its use can increase the diagnostic accuracy of on-PPI impedance-pH testing. In the present study, all patients had heartburn/regurgitation refractory to high-dosage PPIs and were studied during ongoing therapy. Oesophageal acid exposure, as expressed by the EAET and by the number of acid refluxes did not differ among RRE, HRE, or NERD patients. Likewise, the number of total and weakly acidic refluxes was not significantly higher in RRE than in either HRE or NERD patients. The mean distal oesophageal amplitude can affect oesophageal clearance and, according to previous studies [36,37], was significantly lower in RRE than in NERD patients, but did not differ between RRE and HRE. Moreover, bolus exposure and clearance time did not differ among the three groups of patients. These results suggest that oesophageal propulsive force and volume clearance do not have a key role in the persistence of mucosal lesions. Conversely, the PSPW index was significantly lower in RRE than in either HRE or NERD patients. Summing up our results, brief reflux episodes have a minor influence on reparative processes in the oesophageal mucosa, whereas impaired chemical clearance, as expressed by a very low PSPW index, can significantly hinder reparative processes by prolonging contact time of the oesophageal mucosa with acidic/weakly acidic refluxes. Thus, impairment of chemical clearance represents a key pathophysiological mechanism in the pathogenesis of RRE, despite other factors, such as defective epithelial and post-epithelial defence cannot be excluded [25]. As we have shown that a low preoperative PSPW index is not corrected in RRE cases by laparoscopic fundoplication, despite persistent symptom remission and normalization of reflux parameters at the 3-year postoperative assessment [13], a low PSPW index should be regarded as a permanent GERD marker reflecting a primary impairment of the oesophagosalivary reflex possibly due to defective oesophageal sensitivity. As laparoscopic fundoplication acts by reducing the number of transient LES relaxations accompanied by reflux and by reducing the volume of the postprandial acid pocket at the gastroesophageal junction [24], we hypothesize that the impairment of the oesophagosalivary reflex remains latent after effective antireflux surgery and is signalled only by a persistently low PSPW index.

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In a very recent study, the PSPW index has been compared with baseline impedance in PPI-responsive and PPIunresponsive endoscopy-negative patients, all with normal traditional impedance-pH parameters [38]. Lower baseline impedance and lower PSPW index have been found in PPI-responsive patients in comparison with PPI-refractory patients, with a direct significant relationship between the two parameters, suggesting that impairment of oesophageal mucosa integrity as expressed by a low baseline impedance is strictly related to impairment of chemical clearance [38]. These results confirm that a low PSPW index is relevant to the pathogenesis of mucosal damage in GERD and suggest that these new parameters may contribute to distinguish hypersensitive oesophagus from functional heartburn. A retrospective analysis can introduce selection bias. In our study, data were prospectively collected with a standardized protocol and we adhered to strict inclusion and exclusion criteria. To ensure an objective evaluation, all impedance-pH tracings were blindly re-analysed in a random order by one expert observer. Our normative values for the EAET and for the number of total refluxes [9] are lower than those reported by others [28,39], but were defined in non-overweight healthy subjects eating their usual meals in a Mediterranean region, being very close to those detected in our country when a standardized diet was adopted [32,40]. In conclusion, in patients with PPI-refractory heartburn/regurgitation, RRE is associated with a more severe impairment of chemical clearance but similar levels of acid exposure when compared with HRE. Adequate acid suppression is found in the majority of RRE patients who would likely not benefit from further PPI escalation. Until more efficient medical or endoscopic treatment modalities become available, laparoscopic fundoplication should be regarded as an appropriate therapeutic choice in the majority of patients with RRE, provided that an adequate level of acid suppression at on-PPI impedance-pH monitoring has been shown. By prolonging contact time of oesophageal mucosa with acidic/weakly acidic refluxate, impairment of chemical clearance plays a relevant role in the pathogenesis of RRE. Funding The study was conducted without any financial support. Conflict of interest None declared. References [1] Vakil N, van Zanten S, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. American Journal of Gastroenterology 2006;101:1900–20. [2] Kahrilas P, Shaheen N, Vaezi M. American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:1383–91. [3] Katz P, Gerson L, Vela M. Guidelines for the diagnosis and management of gastroesophageal reflux disease. American Journal of Gastroenterology 2013;108:308–28. [4] Lundell L, Dent J, Bennett J, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999;45:172–80. [5] Scarpignato C. Poor effectiveness of proton pump inhibitors in non-erosive reflux disease: the truth in the end! Neurogastroenterology and Motility 2012;24:697–704. [6] Sifrim D, Zerbib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut 2012;61:1340–54. [7] Kinoshita Y, Hongo M, the Japan TWICE Study Group. Efficacy of twice-daily rabeprazole for reflux oesophagitis patients refractory to standard once-daily administration of PPI: the Japan-based TWICE study. American Journal of Gastroenterology 2012;107:522–30. [8] Vela M, Camacho-Lobato L, Srinivasan R, et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology 2001;120:1599–606.

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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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[38] Martinucci I, De Bortoli N, Savarino E, et al. Oesophageal baseline impedance levels in patients with pathophysiological characteristics of functional heartburn. Neurogastroenterology and Motility 2014;26:546–55. [39] Zerbib F, Bruley Des Varannes S, Roman S, et al. Normal values and day-today variability of 24-h ambulatory oesophageal impedance-pH monitoring in

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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