Savarino V, Marabotto E, Zentilin P, Demarzo MG, Pellegatta G, Frazzoni M, De Bortoli N, Tolone S, Giannini EG, Savarino E. Esophageal reflux hypersensitivity: Non-GERD or still GERD? Dig Liver Dis. 2020 Dec, 52(12):1413-1420.

Авторы: Savarino V. / Marabotto E. / Zentilin P. / Demarzo M.G. / Pellegatta G. / Frazzoni M. / de Bortoli N. / Tolone S. / Giannini E.G. / Savarino E.V.

Esophageal reflux hypersensitivity: Non-GERD or still GERD?

Vincenzo Savarino^a, Elisa Marabotto^a, Patrizia Zentilin^a, Maria Giulia Demarzo^a, Gaia Pellegatta^b,
Marzio Frazzoni^c, Nicola De Bortoli^d, Salvatore Tolone^e, Edoardo Giovanni Giannini^a, Edoardo Savarino^f,*

^a Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
^b Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas, Rozzano, Milan, Italy
^c Digestive Pathophysiology Unit, Baggiovara Hospital, Modena, Italy
^d Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy
^e General and Bariatric Surgery Unit, Department of Surgery, Universitàdella Campania Luigi Vanvitelli, Naples, Italy
^f Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy

Краткое изложение на русском языке

ABSTRACT

The most recent iteration of the classifications for functional esophageal disorders, Rome IV, proposed relevant modifications of the previous definitions for Rome III. They specifically considered increased esophageal acid exposure as the marker of gastroesophageal reflux disease (GERD), including the remaining part of non-erosive reflux disease patients with normal acid in the group with functional alterations, considering both reflux hypersensitivity and functional heartburn. However, recent pathophysiological and therapeutic data suggest the need for a return to including reflux hypersensitivity in the GERD spectrum. Indeed, physiologic alterations in esophageal mucosal integrity and chemical clearance, the presence of microscopic esophagitis, and strict symptom-reflux association support the concept that reflux hypersensitivity pertains to GERD. Surgical anti-reflux therapy has resulted in positive outcomes, even in the long term, in patients with reflux hypersensitivity and not in those with functional heartburn. Moreover, clinical trials using neuromodulators have been scarce and provided conflicting results. As a result, the real progress of the Rome IV classifications is in dispute. This article aims to summarize the most recent knowledge of non-erosive reflux disease and reflux hypersensitivity to discuss the utility of Rome IV criteria in the identification and management of functional esophageal disorders.

Keywords: Functional heartburn, Gastro-esophageal reflux disease, Non-erosive reflux disease, Reflux hypersensitivity, Rome IV

©2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

* Correspondence author. E-mail address: edoardo.savarino@ unipd.it (E. Savarino).

Please cite this article as: V. Savarino, E. Marabotto, P. Zentilin et al., Review article – esophageal reflux hypersensitivity: Non-GERD or still GERD? Digestive and Liver Disease, ht tps://doi.org/10.1016/j.dld.2020.10.003


1. Introduction

The most recent iteration of the classifications for functional esophageal disorders, the Rome IV criteria [1], has proposed relevant modifications to the previous Rome III definitions [2]. Although the exclusion of structural, inflammatory, and significant motor abnormalities remains fundamental to attributing typical esophageal symptoms to a functional condition, further exclusionary criteria are based on mechanical obstruction, which nowadays can be reliably identified by high-resolution manometry (HRM) [3], and eosinophilic esophagitis (EoE), which requires specific diagnostic findings from endoscopy and mucosal biopsies [4].

The greatest difference between the Rome III and Rome IV criteria relies on the more restrictive definition of GERD, as shown in Fig. 1. The Rome III diagnosis of GERD included patients complaining of heartburn with negative endoscopy and abnormal esophageal acid exposure time (AET), or a positive correlation between symptoms and acid reflux events. A positive response to proton pump inhibitors (PPIs) was added as an additional empiric criterion. Negative endoscopy, normal AET, no symptom-acid reflux association, and lack of response to PPIs identified patients with functional heartburn (FH) and accordingly, FH was excluded from the GERD realm [2]. The relationship between symptoms and weakly acidic reflux (WAR) was not considered because the clinical use of 24-hour impedance-pH (MII-pH) was minimal at that time [5]. Subsequent studies using this novel technique allowed a subgroup of patients with an esophagus hypersensitive to WAR to be identified. In those patients, symptoms were associated with physiologic reflux between pH 4.0 and 7.0 [6, 7] and, therefore, did not pertain to the FH group. In other words, the temporal relationship between patients’ symptoms and reflux episodes on impedance-pH tracings represents the sine qua non condition for referring them to RH or FH populations.

Fig. 1. Differences in NERD definition according to Rome III and Rome IV criteria.
PPI = proton pump inhibitor; AET = acid exposure time.

The Committee of Rome IV criteria sustained the need for this relevant change because visceral hypersensitivity is predominant in patients with reflux hypersensitivity (RH), who have physiologic AET and for whom the response to PPI therapy is an unreliable criterion. Furthermore, the criteria state that the classification of non-erosive reflux disease (NERD) based on MII-pH findings is questionable, because this technique is not perfect for GERD diagnosis and can be affected by falsely negative results and day-to-day variability [8, 9]. As a fact, Penagini et al. [10], using the wireless BRAVO system for 48 h, found that one-third of patients classified as functional heartburn (FH) at 24-hour MII-pH can be re-classified as NERD after a more prolonged pH recording period. An additional limitation of catheter-based impedance-pH testing may be a reduced sensitivity because patients with a catheter in place may not eat, drink, or perform activities as usual. Also, the role of WAR in triggering typical esophageal symptoms is questioned because there are no consistent data on the outcome of this relationship.

However, the displacement of the subgroups of patients with an esophagus hypersensitive to acid or WAR or both, from GERD to the world of functional disorders, dramatically reduces the number of patients with NERD. To date, NERD patients represent the majority of the GERD population (∼70%−80%) [11]. Indeed, if only patients with abnormal AET are identified as affected by GERD, about 40% of the current NERD population is excluded from this disease. These findings are depicted in several studies performed off- and on-therapy [5-7] and, according to Rome IV criteria (Fig. 2), out of our 3390 patients studied with MII-pH off-PPI therapy from 2006 to 2019, 60% pertained to the population of functional esophageal disorders. In particular, 36% of patients with RH were subtracted from the NERD group and, therefore, from the entire GERD population. The remaining patients had erosive esophagitis (EE) (13%) and pH-positive NERD (40%) (unpublished data).

Fig. 2. Proportions of erosive (ERD) and non-erosive reflux disease (NERD) phenotypes in our population studied off-PPIs by means of 24-hour impedance-pH monitoring.

Based on these findings, this article aimed to assess whether Rome IV criteria for functional esophageal disorders are acceptable in daily clinical practice. Computerized (Medline, Embase) and manual literature searches were conducted using the following terms: functional heartburn, hypersensitive esophagus, reflux hypersensitivity, gastro-esophageal reflux disease, erosive esophagitis, non-erosive reflux disease (NERD), esophageal pH-metry, and esophageal impedance-pH monitoring. The terms above were used alone or in combination with the following ones: pathophysiology, treatment, management, PPIs, proton pump inhibitors, H₂ receptor antagonists, laparoscopic fundoplication, anti-reflux surgery, tricyclic anti-depressants, serotonin-norepinephrine reuptake inhibitors, and selective serotonin reuptake inhibitors. We reviewed all full-text papers and relevant abstracts published in English. Moreover, the reference lists of the various contributors were examined to identify any additional studies that have been missed during the process.

2. Is esophageal reflux hypersensitivity still attributable to functional esophageal disorders?

In contrast to the above definitions and the findings advanced in support of the Rome IV criteria, a consistent body of new pathophysiological, diagnostic, and therapeutic studies appear to sustain the need to maintain the umbrella concept of different subpopulations of NERD and, therefore, GERD.

2.1. Diagnostic features

There is no doubt that the criterion of response to PPI therapy to distinguish GERD from non-GERD patients is devoid of strong scientific evidence. Patients with abnormal AET or severe EE may not respond to PPIs, even given at double dosage [12, 13] and, on the contrary, the response of some FH patients to PPIs is likely the result of a placebo effect [14, 15]. Also, patients with RH to acid can respond to high-dose PPIs [16]. Overall, the meta-analysis by Numans et al. [17] highlights the low specificity of PPI trials and it is well known that NERD patients respond to PPIs less than EE ones by a factor of about 20%, due to the overlap with FH [18].

We have already mentioned the limitations of 24-hour MII-pH for GERD diagnosis, but this technique has represented a real progress in defining the various phenotypes included in the umbrella term of NERD. These definitions are emphasized in recent guidelines and systematic reviews that consider MII-pH to be fundamental in the diagnostic algorithm of patients with symptoms suggestive of GERD [19-24]. Moreover, MII-pH has made it possible to segregate patients with GERD from those with other conditions, such as rumination or belching syndromes [25, 26]. A recent retrospective study showed that almost half of patients with a diagnosis of RH have behavior disorders, including excessive supragastric belching (SGB) or rumination, associated with typical reflux symptoms [27]. These findings appear to confirm that also the subgroup of patients with RH is not a homogenous population and that different mechanisms may explain their symptoms. Therefore, the lack of a perfect tool to diagnose with certainty the various phenotypes of patients with typical GERD symptoms renders difficult to attribute them to one or the other subset of functional esophageal disorders and weakens also the Rome IV assumption that they are only caused by visceral hypersensitivity. This point is clinically relevant because the therapeutic approach might differ in relation to the various pathophysiological characteristics.

As to the temporal association between reflux episodes and symptoms, it is well known that the traditional symptom index (SI) and symptom association probability (SAP) index have significant pitfalls [28]. However, published data are suggesting their value in predicting symptom outcomes [16, 29, 30]. Further, two new impedance metrics, mean nocturnal baseline impedance (MNBI) and the post-reflux swallow-induced peristaltic wave (PSPW) in dex, have been shown to overcome the limitations of symptom association analysis (i.e., poor reproducibility and difficulties of reporting symptoms by patients), and to improve the diagnosis of GERD [31, 32]. MNBI is an expression of esophageal mucosal integrity, and PSPW index reflects the impairment of esophageal peristalsis and chemical clearance [33]. MNBI shows that patients with pathophysiological characteristics of FH who, however, respond to PPIs have baseline impedance (BI) values lower than those of PPI-refractory FH, and similar to patients with RH. Although we found that MNBI has a moderate sensitivity (56%) in diagnosing RH patients [36] , this value remains better than that of the traditional indexes (SI and SAP), even when they are concordant (46%). Moreover, in the same study we have emphasized that MNBI should be analyzed together with PSPW, because only their combined assessment allowed to obtain an effective separation of RH from FH on ROC analysis, affording an excellent AUC ( > 0.90), which was significantly greater than that achieved by the two parameters calculated separately. Moreover, MNBI and PSPW were abnormal in the vast majority of RH patients with negative or discordant SI and SAP, who represented more than half of patients in our series. These findings confirm that FH and RH are different populations [34-36]. Moreover, patients with FH who responded to PPI therapy had impedance pH features, such as higher AET and greater number of reflux events, similar to those of patients with RH. Although there is a group of RH patients who do not respond to PPI therapy, many of them share the same pathophysiological findings of FH patients responding to PPIs and this is the background leading to the success of antisecretory drugs or surgical interventions in them, as reported in the following therapeutic chapter. On the other hand, the existence of a different response to PPIs by the global RH population is further confirmation that it is heterogeneous and not characterized by univocal physiologic alterations. Anyway, these data support that RH patients pertain to GERD and not to functional esophageal disorders. Finally, a lack of improvement in impaired chemical clearance characterizes patients with PPI-refractory GERD as well as those with PPI-refractory EoE [37, 38]. To note, although these two impedance metrics are calculated from the tracings of MII-pH which suffer of day-to-day variability of acid exposure and symptoms reporting, their reliability and reproducibility, in particular that of MNBI, have been proved by several authors with the same methodology of calculation, and their values do not strictly depend from acid exposure or symptoms occurrence during the testing day [30, 32, 37].

Based on the findings above, it appears that the subset of patients whose symptoms are associated with reflux events or generated by behavior disorders, although with normal AET, must be maintained separate from FH, where any kind of reflux, SGB, or rumination cannot be documented [39] . Nowadays, we know that stimuli other than acid can be responsible for reflux symptoms, that is WAR and weakly alkaline refluxes. Indeed, also bile reflux plays an important role in the origin of GERD symptoms, as recently shown by De Bortoli et al. [40], who have demonstrated that the presence of bile in the refluxate of NERD patients is associated with more severe heartburn and lower values of MNBI and chemical clearance. It is likely that only the future availability of more accurate diagnostic techniques will permit to understand better the complexity of the universe of Rome IV functional esophageal disorders and to refine the diagnosis of both RH and FH in further pathophysiological subsets.

2.2. Pathophysiological and psychological features

The ROME IV proposal to unify two different conditions (RH and FH) into a group of functional esophageal disorders was based on the assumption that they are due to a common pathogenetic mechanism of visceral hypersensitivity. However, previous studies do not permit to know exactly which stimulation is implicated in symptom generation and which function is altered in each of them. Ignoring the answers to these questions may lead to the wrong therapeutic decisions.

At present, subgrouping this complex population from a pathophysiological point of view can only be achieved with reflux monitoring and, more accurately, with MII-pH, which should be performed off-PPI therapy [19-24, 41]. On-PPI tests should be reserved for those clinical conditions, for which the reasons for nonresponse to PPIs are sought [42, 43]. However, it must be borne in mind that MII-pH performed on PPIs necessarily measures an increase in WAR. This happens because these drugs reduce the acid content in favor of the weakly acidic one, but maintains the same reflux burden before and after treatment [44]. Therefore, most of these patients recognize WAR as responsible for their refractoriness, although the result is contaminated by acidsuppressive therapy. A recent study by Abdallah et al. [45] confirms that a large part of the reflux events registered in patients with heartburn refractory to once-daily PPIs and studied by on-PPI MII-pH are weakly acidic. These authors did not find any statistical difference in impedance-pH parameters between GERD patients who responded and those who failed PPI therapy. They concluded that there is an overlap of well documented GERD and functional esophageal disorders, specifically 62.5% with FH and 12% with RH. However, their study has important limitations, mainly the fact that the sample size was small (13 patients in the PPI success group and 16 in the PPI failure group). Further, there was no difference between the two groups in terms of mucosal integrity expressed by MNBI, which has been shown to be significantly lower in patients with proven GERD than in those with FH [23, 35, 46]. Moreover, their patients did not undergo an attempt to double the dose of PPIs, which improves the response to symptoms from 37% to 60% [16, 47, 48]. Finally, patients were not evaluated with HRM to exclude major esophageal motor disorders [49, 50], which can share the heartburn symptoms. The same Rome IV criteria [1] state that only after negative esophageal manometry can the diagnosis of FH be established. Despite these relevant limitations, Abdallah et al. sustained the Rome IV proposal that patients starting with proven GERD and diagnosed with increased AET or EE and Barrett’s esophagus, when studied on-PPIs, can eventually be affected by RH or even FH. This overlap is confusing for both specialists and primary care physicians and does not favor the correct management of these heterogeneous subgroups of patients. Moreover, this is a strong confirmation that it is really difficult to segregate not only the different esophageal functional disorders from each other, but also structural from functional abnormalities.

As to the poorly-documented role of WAR in originating symptoms and microscopic esophageal lesions, Vela et al. [44] were the first to show that this kind of reflux can induce the same typical symptoms of the acid refluxate. Subsequently, many other pathophysiological and clinical studies demonstrated the relationship between WAR and both typical and extra-esophageal symptoms [5-7, 14, 15, 51-53]. More importantly, several studies have clearly shown that the success of both medical and surgical anti-reflux therapy relies on the control of not only acid but also of WAR [54-58]. Furthermore, WAR has been shown to induce microscopic esophageal damage in several in vitro and in vivo studies. For instance, Farrèet al. assessed the effects of different solutions, including one at pH 5.0, on rabbit esophageal mucosa, and found an increased permeability and dilated intercellular spaces at electron microscopy [59]. Another study showed the development of esophageal damage by perfusing the human mucosal cells with solutions at pH 5.5 [60].

Furthermore, Savarino et al. observed that microscopic esophagitis developed much more frequently in patients with hypersensitive esophagus (HE) than in those with FH. The former population also comprised cases with RH to WAR [61]. In addition, it has been demonstrated that MNBI is highly correlated with the severity of microscopic mucosal damage. Its value is significantly lower in patients with RH than in those with FH, who instead have levels of baseline impedance similar to those of healthy volunteers [35, 36, 46]. Unfortunately, there are no studies assessing the regression of microscopic esophagitis due to WAR after surgical therapy. Anti-reflux surgery (i.e. fundoplication) is the only way to control every kind of reflux, if the use of the neurotoxic drug baclofen is ruled out. It is also noteworthy that many studies have confirmed that patients with FH do not present any histopathological alterations on either electron or light microscopy of esophageal biopsies [62-64]. Also, their impedance-pH findings are similar to those of healthy subjects [5, 7].

It is in contrast with other features the concept that esophageal hypersensitivity is the exclusive mechanism sustaining the generation of typical symptoms in the broad category of NERD with normal acid, including both RH and FH. First of all, patients with FH overlap with functional dyspepsia (FD) [65, 66] and irritable bowel syndrome (IBS) [67] significantly more often than those with RH and pH-positive NERD. This overlap is predictive of PPI failure [68]. However, Ribolsi et al. [69] have recently shown that also RH patients not responding to PPI therapy have a significantly higher proportion of IBS and dyspeptic symptoms compared to PPI-responder patients. Nevertheless, these results are related to the response or not to PPIs and do not reflect clinical findings observed in untreated subjects. Overall, the above observations confirm that FH, FD, and IBS share the same pathophysiological derangement at the level of the enteric nervous system and are associated with psychological disturbances such as anxiety and somatization [64, 70]. This association strongly suggests the inclusion of only FH in the GI tract’s functional disorders. As further confirmation of the relationship between RH and GERD, Kessing et al. [71] performed a prospective study of patients with symptoms suggestive of GERD who underwent ambulatory MII-pH off-PPI and the measurement of anxiety and depression levels using a validated scale. They diagnosed GERD in 147 and RH in 36 patients (78 patients had FH) and found that increased levels of anxiety were associated with the increased severity of retrosternal pain, heartburn, and reduced quality of life. Moreover, patients with RH had similar levels of anxiety, depression, and quality of life scores as other patients with GERD. In contrast, patients with FH had higher levels of anxiety than patients with GERD.

In summary, the above findings appear to confirm that RH to both acid and WAR events share common pathophysiological and psychological features with NERD and, by extension, with GERD. The attempt to unify them with FH creates confusion from a pathophysiological point of view. Even though an exaggerated visceral and central sensitivity can be hypothesized in both populations [64], the fact that symptoms are triggered by physiologic reflux in the former and not in the latter seems to justify the separation of the two forms. These differences should stimulate the continuous search for drugs able to control both microscopic mucosal lesions and consequent symptoms in RH [72, 73], whereas therapy should be exclusively focused on symptoms relief in FH patients, whose esophageal mucosal integrity is preserved. Interestingly, the use of a more direct and rapid measurement of mucosal integrity through the application of the endoscopy-guided mucosal impedance (MI) technique could be helpful soon to conduct larger and simpler studies in patients with symptoms suggestive of GERD. Moreover, the use of this procedure could improve our understanding of mucosal integrity in patients with RH and FH [74, 75].

2.3. Therapeutic features

PPIs remain the mainstay of medical treatment for EE, both in the short- and long-term, because of their well-documented efficacy in relieving heartburn, healing lesions, and maintaining the disease in remission [76, 77]. In patients with NERD, the success of PPIs is less predictable and necessarily linked to their pathophysiological heterogeneity [20, 57]. If we can easily anticipate that NERD patients with increased AET can respond to PPIs in the same way as EE [18, 78], the therapeutic approach to the other subpopulations of NERD with normal AET is more complex and difficult to address. However, several trials have shown that PPIs, primarily at high doses, can be successful in NERD patients with hypersensitivity to acid [16, 76, 79]. Furthermore, a recent analysis of prospectively-collected data in patients studied off-PPI by Patel et al. [57] evaluated the role of the impedance-measured MNBI metric, a surrogate marker of impaired mucosal integrity. The study showed that this parameter represents an independent predictor of GERD response to both medical and surgical treatment. Subsequently, these authors found that a low distal esophageal MNBI was also independently predictive of symptomatic improvement after prolonged (on average, more than three years) anti-reflux therapy and RH patients were also included [80]. The impairment of mucosal integrity, which is similar in RH and GERD patients and is absent in FH patients [35, 36, 46], has been advocated to explain the positive response of RH to both medical (PPI) and surgical treatment.

The results of clinical trials using neuromodulators to reduce visceral hypersensitivity in these patients have provided conflicting results, as displayed in Table 1. Some studies have shown the efficacy of pain modulators, such as selective serotonin reuptake inhibitors, in patients with RH to acid [81] and in those with heartburn and normal endoscopy who failed once-daily PPIs [82]. On the contrary, other studies using tricyclic antidepressants showed no beneficial effect of these drugs in patients with refractory heartburn and normal endoscopy. A recent randomized, placebo-controlled trial showed that imipramine was similarly ineffective in both RH and FH [83]. A randomized crossover study by Forcelini et al. [84] comparing nortriptyline and placebo, found that the decrease in heartburn was similar between the two treatments.

Table 1.
Controlled studies evaluating the efficacy of neuromodulators in patients with heartburn and without erosive esophagitis. TCA = tricyclic anti-depressant; SSRI: selective serotonin reuptake inhibitor; H₂RA = Histamine 2 receptor antagonist; NA = not available

Authors and reference	Class of drug	Medication	Dose	Disorder	Response rate
Limsrivilai et al83	TCA	Imipramine	50 mg/day	RH, FH	37.2%
Forcelini et al84	TCA	Nortriptyline	10 mg/7d + 25 mg/14d	RH, FH∗	No difference with placebo
Hershcovici et al85 (abstract only)	TCA	Nortriptyline	50 mg/day	PPI-refractory GORD	23.1%
Viazis et al81	SSRI	Citalopram	20 mg/day	RH	61.5%
Ostovaneh et al82	SSRI	Fluoxetine	20 mg/day	PPI-refractory GORD	37%

^∗ Patients were identified based on heartburn during oesophageal acid perfusion and negative endoscopy, without categorization according to reflux testing.


Furthermore, Hershcovici et al. [85] reported the effect of three treatment strategies in 140 patients with refractory GERD. Both the rate of complete heartburn resolution and the number of heartburn-free days were similar among PPI combined with nortriptyline, a single-dose PPI with placebo, and a double-dose PPI. It must also be emphasized that, despite the large number of patients commonly diagnosed with functional esophageal disorders under the Rome IV criteria, the number of clinical trials using pain modulators was unexpectedly scarce, particularly when compared with those performed in IBS patients. A systematic review of the effects of antidepressants in patients with functional esophageal disorders concluded that there is limited evidence that antidepressants benefit this group of patients [86]. This review suggested, however, that more controlled trials are needed to assess their actual therapeutic role.

On the other hand, attempts to control both acid and WAR using surgical therapy have provided promising results, and the prolonged follow-up of patients in some studies has confirmed the positive outcomes of this treatment over time. These outcomes are summarized in Table 2 [32, 42, 56, 87-93]. For instance, Frazzoni et al. showed that WAR plays an important role in inducing symptoms in PPI-refractory NERD patients, and laparoscopic fundoplication was able to obtain an almost total remission of typical symptoms three months after surgery [88]. Furthermore, these authors demonstrated that normal reflux parameters associated with persistent symptom remission were maintained in the majority of patients, at three-year follow-up [56]. Also, Broeders et al. [89] confirmed that patients with acid hypersensitivity benefitted from laparoscopic fundoplication as much as those with abnormal AET, in that functional reflux parameters were normalized in almost all patients three months after surgery. Further, the number of patients with resolved or improved symptoms at five-year follow-up was similar between the two groups. Another study [42] in PPI-refractory patients demonstrated the usefulness of laparoscopic fundoplication in controlling almost completely their symptoms over a mean follow-up period of 41.3 months. Finally, Spechler et al. recently published a randomized, controlled study [93] showing that impedance-pH stratification of PPI-refractory GERD patients into the various subgroups of NERD, RH, and FH resulted in their better management. Further, these authors demonstrated that patients with both abnormal acid exposure and positive SAP and those with positive SAP only responded to surgery more than to active medical treatment (high-dose omeprazole, baclofen, or desipramine) or controlled medical treatment (omeprazole plus placebo). These findings provided a significant confirmation of the success of anti-reflux surgery, even in patients with RH.

Table 2.
Studies evaluating the efficacy of surgical therapies in patients with refractory GORD stratified according to MII-pH monitoring. MII-pH = multichannel intraluminal impedance with pH; AET = acid exposure time; SAP = symptom association probability; SI = symptom index; LF = laparoscopic fundoplication; NRE = number of reflux episodes. ^& = including also patients with abnormal AET. NA = not available.

Authors and reference	Study design	No. patients	Reflux monitoring prior to surgery on- or off- therapy	pH/MII-pH metrics used for GORD diagnosis	Mean follow-up duration (months)	Surgery vs. alternative therapy	Adequate relief
Rengarajan A, et al. 201932	Retrospective cohort	63	MII-pH off-therapy	SAP positive (n=23), abnormal AET (n=40)	37	NA	80%
Desjardin M, et al. 201642	Retrospective cohort	33	MII-pH on-therapy	Increased reflux episodes and/or abnormal AET and/or SAP positive (n=31)$	41.3	NA	76%
Frazzoni M, et al. 201187	Prospective uncontrolled	40	MII-pH on-therapy	SAP positive (n=23), abnormal AET/NRE (n=17)	3	NA	100%
Frazzoni M, et al. 201188	Retrospective cohort	20	MII-pH on-therapy	SAP positive (n=14), abnormal AET/NRE (n=6)	3	LF (n=10) vs Esophyx (n=10)	100% vs 30%
Frazzoni M, et al. 201356	Prospective uncontrolled	40	MII-pH on-therapy	SAP positive (n=23), abnormal AET/NRE (n=17)	36	NA	91%
Broeders JA, et al. 200989	Retrospective cohort	154	pH-metry off-therapy	SAP/SI positive with acid only (n=28) vs abnormal AET (n=126)	60	NA	85% vs 88%
Mainie I, et al. 200690	Prospective uncontrolled	19	MII-pH on-therapy	SI positive	14	NA	94%
Patel A, et al. 201591	Retrospective cohort	59	MII-pH on- (n=24) and off-therapy (n=35)	SAP positive (n=40)& abnormal AET (n=36)	39.9	NA	77.8%
Del Genio G, et al. 200892	Prospective uncontrolled	62	MII-pH off-therapy	Abnormal AET (n=33), abnormal NRE and SI positive (n=17), SI positive (n=12)	12	NA	98.3%
Spechler SJ, et al. 201993	Prospective, randomised	78	MII-pH on-therapy	SAP positive (n=38), abnormal AET (n=15), SAP positive and abnormal AET (n=25)	12	LF (n=27) vs Omeprazole plus Baclofen, Despiramine (n=25) vs Omeprazole plus Placebo (n=26)	66.7% vs 28% vs 11.5%

Overall, the uncontrolled studies reviewed above and the last randomized controlled trial by Spechler et al. assessing the benefits of both medical and surgical therapy in different impedance-detected GERD phenotypes seem to support the concept that reflux events play a significant role in eliciting symptoms of RH patients and, therefore, corroborate the need to include them in the GERD realm. The diagnostic role of MII-pH in distinguishing RH from FH is invaluable. Moreover, it is important to stress that the outcome of surgery is poor in patients with FH [94-96]. The success of surgical therapy is an additional factor supporting the need for accurately identifying patients with RH and distinguishing them from FH using MII-pH before intervention. Finally, the above-mentioned surgical results were considered to be so relevant that two recent international consensuses recommended laparoscopic fundoplication as the treatment of choice in PPI-refractory GERD when the pre-operative work-up clearly identifies RH [97, 98]. However, it must be mentioned that in general surgeons are reluctant to operate patients with normal endoscopy and normal AET, even though a recent study reporting the ICARUS guidelines for antireflux surgery suggests that the majority of patients with RH are possibly good candidates for surgery, provided that a rigorous preoperative diagnostic work-up is necessarily performed [99]. A definite role for surgical therapy can be obviously derived only from further prospective and randomized studies performed ad hoc in well defined RH patients.

3. Conclusions

The new Rome IV classification of functional esophageal disorders contains important findings on the epidemiological features of both RH and FH. Because the population with GERD is reduced by about 40%, all studies on the prevalence and incidence of GERD must be revisited and the statistical variables must be changed significantly. However, there are many new pathophysiological, diagnostic, and therapeutic reasons that induce to re-consider RH within the GERD spectrum. The use of both traditional symptom reflux association indexes and the novel impedance metrics have confirmed relevant functional differences between RH and FH.

Furthermore, patients with RH appear to present the same prevalence of non-esophageal functional gastrointestinal disorders (i.e., FD and IBS) as well as levels of anxiety and depression similar to those reported in GERD patients and different from the FH ones. In addition, both medical and surgical therapies have obtained positive outcomes in patients with RH, but not in those with FH. On the contrary, clinical trials using neuromodulators have been scarce, despite the large number of patients complaining of heartburn with normal endoscopy and normal acid, and have even provided conflicting results.

Despite the need of maintaining RH and FH patients as separate entities and the support of pathophysiological findings and therapeutic trials in re-considering the majority of RH patients as part of the GERD spectrum, we are aware that both disorders do not contain homogeneous populations and their razor-sharp delineation is not possible. New diagnostic tools are necessary for subdividing each of them in further subsets, but the classification of Rome IV seems to be questionable because most of RH patients seem to be more associated to GER than to simple visceral hypersensitivity and this aspect is important to avoid the wrong therapeutic decisions.

Conflict of interest

ES has received lecture or consultancy fees from Medtronic, Reckitt Benckiser, Takeda, Merck & Co, Bristol-Myers Squibb, Abbvie, Amgen, Novartis, Fresenius Kabi, Sandoz, Sofar, Malesci, Janssen, Grifols, Aurora Pharma, Innovamedica, Johnson&Johnson, SILA, Unifarco, Alfasigma, Shire, EG Stada Group. VS, EM, PZ, MGD, GP, MF, NDB, ST, EGG have no conflicts of interest to declare.

Financial support

None.

Acknowledgements

(i) Guarantor of the article: Vincenzo Savarino

(ii) Specific author contributions: VS: study concept, data analysis, critical review of manuscript, drafting and finalization of manuscript; EM, PZ, MGD, GP, MF, NdB, ST, EGG: data analysis, and critical review of manuscript; ES: data analysis, critical review of manuscript, drafting and finalization of manuscript

(iii) All authors approved the final version of the manuscript.

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