ESOPHAGUS (MF VELA, SECTION EDITOR)

Functional Heartburn: Definition and Management Strategies

Frank Zerbib & Stanislas Bruley des Varannes &

Mireille Simon & Jean Paul Galmiche

Published online: 27 March 2012# Springer Science+Business Media, LLC 2012

Abstract Functional heartburn (FH) is a functional gastro-intestinal disorder characterized by symptoms of heartburnnot related to gastro-esophageal reflux. The absence ofevidence of reflux-related symptoms relies on absence ofesophagitis at endoscopy (including biopsies to excludeeosinophilic esophagitis), a normal esophageal acid expo-sure during esophageal pH-monitoring together with a neg-ative symptom-reflux association analysis and anunsatisfactory response to proton pump inhibitor therapy.Addition of impedance measurement to pH-monitoring islikely to increase the number of patients with recognizedreflux-related symptoms. The pathophysiology of functionalheartburn remains largely unknown but involves disturbedesophageal perception and psychological factors such asdepression, anxiety and somatization. The treatment of FHremains largely empirical and an individual approach istherefore recommended. The clinician should provide reas-surance and refrain from performing too many invasive testsor therapeutic procedures. The use of pain modulators isrecommended by most experts despite the lack of appropri-ate clinical trials to support it.

Keywords Heartburn . Functional esophageal disorders .

Rome III classification . Esophageal sensitivity . Esophagealimpedance . Esophageal pHmonitoring . Proton pumpinhibitors

Introduction

Heartburn, defined as “a burning sensation behind thebreastbone,” has been reported to occur at least once amonth by 10% to 20% of the general population [1].Although translations and interpretations of the term“heartburn” may vary among countries and languages,typical heartburn is traditionally considered as a specificsymptom for gastro-esophageal reflux disease (GERD),thus allowing diagnosis without the need for any furtherinvasive investigation [2]. This assumption remains validin the majority of patients especially in the primary caresetting. In most patients, heartburn is associated with theoccurrence of acid reflux events. This association can bedemonstrated by esophageal pH-monitoring that allowsnot only a quantitative assessment of gastro-esophagealreflux but also a symptom-reflux association analysis [3].During the last decade, by using esophageal pH-impedance monitoring, it has become evident that notonly acid but also non acid (mainly weakly acidic) refluxevents could elicit heartburn [4, 5]; however, in a subsetof patients, especially those refractory to proton pumpinhibitors (PPI) therapy, heartburn seems to occur inde-pendently of any type of reflux events. Several attemptshave been made in order to better characterize the GERDspectrum according to the presence of esophageal injury(Erosive versus Non erosive reflux disease or NERD)and to reclassify the group(s) of patients with typicalheartburn but without evidence of GERD either at

F. Zerbib :M. SimonGastroenterology and Hepatology Department, Saint André Hospital,Centre Hospitalier Universitaire de Bordeaux;Université Bordeaux Segalen,Bordeaux, France

S. Bruley des Varannes : J. P. GalmicheInstitut des Maladies de l’Appareil Digestif,Centre Hospitalier Universitaire de Nantes,Nantes, France

F. Zerbib (*)Gastroenterology Department, Saint Andre Hospital,1, rue Jean Burguet,33075 Bordeaux, Francee-mail: frank.zerbib@chu-bordeaux.fr

Curr Gastroenterol Rep (2012) 14:181–188DOI 10.1007/s11894-012-0255-7

endoscopy or after pH-monitoring. “Functional heartburn”(FH) is a terminology that has been introduced by theROME group of experts to fully recognize this entity aspart of gastro-intestinal functional disorders and encouragefurther research on it [6, 7].

Considering that not only acid reflux events can elicitheartburn, the pathogenesis of heartburn appears to becurrently much more complex than initially thought andit has to be underlined that the presence of heartburn,even if typical, does not match exactly with an homoge-neous group of patients suffering from the same disease.This heterogeneity is likely contributing to explain why30% to 40% of patients with typical heartburn are com-pletely or partially refractory to acid suppression with aPPI [8]. As a consequence, the management of functionalheartburn remains challenging for physicians.

Definition and Diagnostic Criteria

The definition of FH has evolved between ROME II [6] andROME III [7] systems since the so-called “acid sensitiveesophagus” initially included in the FH group by the ROMEII criteria, has been re-qualified in ROME III classificationas a part of the GERD spectrum (Table 1). Acid sensitiveesophagus is characterized by a positive temporal relation-ship between acid reflux and symptom events despite anormal acid exposure of the esophagus [9, 10] (Fig. 1).The reason to exclude acid sensitive esophagus (hypersen-sitive esophagus) from the FH definition is that this groupresembles other GERD patients in terms of presentation,esophageal motility, impact on quality of life, natural

history, and response to anti-reflux therapy in general, evenif increased acid suppression may be required to reliefheartburn [10–12].

According to ROME III definition, “retrosternal burn-ing in the absence of GERD that meets other essentialcriteria for the functional esophageal disorders typifies thediagnosis of FH.” The diagnostic criteria are the following:

“Presence for at least 3 months, with onset at least6 months before diagnosis of:

1. Burning retrosternal discomfort or pain; and2. Absence of evidence that gastro-esophageal acid reflux

is the cause of symptom; and3. Absence of histopathology-based esophageal motility

disorders.”

The minimal frequency of heartburn that is required toconsider the patient’s condition as an illness is not welldefined. However, two or more days weekly of mildheartburn are sufficient in GERD to influence quality oflife and the same threshold can be applied in FH [13].

The most difficult with this definition is to demonstratethe absence of evidence that GERD is the cause of thesymptoms. Indeed absence of evidence does not alwaysmean evidence of absence! Though not sufficient, absenceof mucosal breaks at endoscopy is mandatory, which isobviously very common since most patients are scoped onor shortly after discontinuing PPIs. The role of ambulatoryreflux monitoring is crucial to classify patients as havingFH. The ROME III definition of FH only refers to pHmonitoring but it is important to consider the added valueof impedance to pH monitoring. Indeed, it has been clearlyestablished that when more accurate investigations are usedto detect acid and non acid reflux and to assess the temporalrelationship of reflux events and symptoms, then the pro-portion of patients with a residual diagnosis of FH decreases[5]. As an example, a recent study in patients with refractoryheartburn evaluated by pH-impedance monitoring off ther-apy showed that the proportion of patients with FH washigher when pH alone data were taken into account (39%vs. 29% with impedance data) [14•]. Should investigationsbe performed on or off PPI therapy remains an issue whichhas not been addressed by the ROME experts. Patients withrefractory heartburn and no evidence of temporal relation-ship between symptoms and reflux during 24-h pH-impedance monitoring performed on therapy should proba-bly also be considered as having FH if they meet the otherdiagnostic criteria, although this probably needs furthervalidation. In a study in 80 patients with refractory heart-burn, 53% of the patients had a negative symptom associa-tion analysis on PPI and then were classified as FH [15•]. Inaddition, patients were considered to have NERD instead ofFH if they had an abnormally high number of reflux

Table 1 Diagnostic criteria of functional heartburn (all criteria must bepresent)

- Burning retrosternal discomfort or pain

- Unsatisfactory response to PPIs (twice daily dose)

- Normal upper GI endoscopy (no mucosal breaks)

- Normal esophageal biopsies (no eosinophilic esophagitis)

- Normal esophageal manometry

- Normal ambulatory reflux monitoring off PPI(pH alone or pH-impedance)

▪ Normal esophageal acid exposure

▪ Negative symptom association analysis (SI < 50%; SAP < 95%)

Other potential criteria (to be further validated)

- Normal ambulatory reflux monitoring on PPI (pH-impedance)

▪ Normal bolus exposure

▪ Normal number of reflux episodes

▪ Negative symptom association analysis (SI < 50%; SAP < 95%)

SI Symptom Index; SAP Symptom Association Probability; PPI protonpump inhibitors

182 Curr Gastroenterol Rep (2012) 14:181–188

episodes detected by impedance. As a whole, only 35% ofpatients had FH according to this definition, and were sig-nificantly different from the NERD patients regarding gen-der (more female), lower esophageal sphincter pressure(higher values), and prevalence of hiatus hernia (lower).Whether esophageal bolus exposure and/or high number ofreflux episodes on pH-impedance monitoring should betaken into account in the definition of FH remains to bedetermined.

During ambulatory reflux monitoring, the symptom as-sociation analysis is crucial to demonstrate the temporalrelationship between heartburn and reflux episodes andclassify patients as having NERD with hypersensitiveesophagus or FH (Fig. 1). The clinical accuracy of the twomost popular indices, i.e. symptom index (SI) and symptomassociation probability (SAP), has been confirmed by out-come studies showing that a positive reflux symptom asso-ciation was associated with a better response to anti-refluxtherapy, especially in patients with normal esophageal acidexposure [11, 16, 17]. The agreement between SI and SAPis poor [5, 18]. While SAP is considered by some authors tobe the best method to express the temporal relationshipbetween symptoms and reflux episodes [3], SI is a simple,easy to determine and understand parameter, and describesthe proportion of symptoms that are reflux related. SAPdescribes the probability that the observed relation betweensymptoms and reflux has not occurred by chance. For now,it cannot be stated which test should be used in clinicalpractice, and which should be taken into account if discrep-ancy exists between SI and SAP. Similarly, the adequatetime window before the onset of symptoms to determinetemporal association is still a matter of debate. The 2-mintime window was primarily adopted for symptom analysisas previous works had demonstrated that it was the most

appropriate, at least in patients with chest pain [19], butsome authors use a 5-min time window, which may be moreappropriate for certain symptoms that lack sudden onset[18]. The relevance of these indices has been recently chal-lenged by Slaughter et al. who showed that SI and SAPvalues were largely determined by chance occurrences un-less patients refractory to PPI therapy have high rates ofreflux [20]. Although clinicians should keep in mind theseshortcomings, analysis of symptom–reflux association is ofparamount importance to better identify those patients withsymptoms that are eventually related to GERD.

The last criterion that is required to document the absenceof evidence that gastro-esophageal acid reflux is the cause ofsymptom is an unsatisfactory response to a PPI trial.Although a favorable response to a brief therapeutic trialusing high doses of a PPI is not specific for GERD [21], oneshould remember the pitfalls and unsolved issues regardingthe diagnostic yield of ambulatory pH or pH-impedancemonitoring. Finally, clinical experience suggests that thelack of response probably has certainly a high negativepredictive value for the diagnosis of GERD.

In this chapter we have adopted the ROME III definitionof FH but it should be acknowledged that a large part of thereference literature is not based on similar definitions of FH,making comparisons between works sometimes hazardous.

Epidemiology and Clinical Presentation

Epidemiological studies using stringent definitions of FHare scarce. Studies using both endoscopy and ambulatorypH monitoring to objectively establish evidence ofGERD indicate that functional heartburn is likely torepresent less than 10% of heartburn patients presenting

Fig. 1 Classification ofpatients with heartburn andno evidence of esophagitisat endoscopy using pHmonitoring and response toPPIs; the group classified asfunctional heartburn (FH)corresponds to theROME III definition.Patients with hypersensitiveesophagus belong to thenon erosive reflux disease(NERD) group. Adapted fromGalmiche et al. [7]

Curr Gastroenterol Rep (2012) 14:181–188 183

to gastroenterologists [22]. The proportion may varybetween primary care settings and tertiary centers wherepH-impedance monitoring is performed with symptomassociation analysis for acid and non acid reflux epi-sodes. In a population of 100 patients referred to tertiarycenters for reflux testing with pH-impedance monitoringoff therapy, the reported prevalence of FH was 21% inpatients refractory to PPIs [23•].

Similar to other gastro-intestinal functional disorders, afemale predominance in patients with FH as compared to theNERD group has been reported [15•]. Interestingly, and irre-spective of the clinical setting (i.e. primary care or specialtypractice), FH frequently occurs in association with symptomsusually considered components of the dyspeptic syndromesuch as post-prandial fullness, bloating, nausea and earlysatiety [24•]. Irritable bowel syndrome symptoms also, seemmore prevalent in FH than in GERD patients [25–27].

Pathogenesis of Heartburn in FH

FH is part of digestive functional disorders and thereforeshares many common factors with irritable bowel syndromeand functional dyspepsia. Not surprisingly, the prevailingview regarding FH is to consider disturbed visceral percep-tion as a major factor involved in its pathogenesis [28].Hypersensitivity includes allodynia (defined by the percep-tion of stimuli normally not perceived, for example slightchanges in intraluminal esophageal pH) and hyperalgesia(pain greater than normally expected for a given stimulus).Both phenomenon may be involved in FH. Moreover,“esophageal hypersensitivity” can include peripheral, cen-tral, and eventually psychological factors which may actindependently or more likely interact between. The mainissue with the concept of hypersensitivity in FH is to deter-mine the stimulus that elicits symptoms, since it is stated inthe definition that symptoms cannot be associated withany type of reflux events. As an example, physiologicalstudies have demonstrated that mechanical stimuli suchas esophageal balloon distension can also elicit heartburnperception [29].

Irrespectively of the esophageal stimulus considered, theconventional theory of heartburn pathogenesis implies thepenetration of the noxious component either through muco-sal beaks (in reflux esophagitis) or because of an increasedpermeability of the epithelial esophageal barrier. Thesealterations of the esophageal barrier may be themselves theconsequence of the chronic exposure of the mucosa to anoxious agent (usually acid in GERD) refluxing from thestomach. During the last decades, the consistent observationby several authors of an increase intercellular space betweenepithelial cells in both erosive esophagitis and NERD haslent support to this penetration theory. Indeed, this

morphological change (called dilated intercellular space orDIS) is supposed to allow the noxious esophageal stimuli toactivate more easily nociceptive receptors such as theTRPV1 (vanilloid) receptor or the transient receptor poten-tial acid-sensing ion channel (ASIC). Activation of thesereceptors generates signals that are transmitted to the CNSvia either vagal or spinal nerves [30]. However, the role ofDIS in FH has been recently challenged by a study showingno significant difference between FH patients and controlsregarding intercellular distance [31•]. Only 9% of thepatients with FH had an intercellular distance superior tothe normal range (compared to 60% of those with GERD).These results, although deserving further confirmation onlarger samples of patients, are the first to suggest the use of amorphological marker capable of distinguishing FH fromGERD. They also showed that heartburn perception mayarise despite the fact that the integrity of the mucosa ismaintained. Conversely, it has also been shown that DISalone was not sufficient to elicit symptoms, at least inhealthy subjects in whom esophageal perfusions of acidand or bile were performed [32].

Meal ingestion is the most frequent trigger for heartburngeneration suggesting that some components of food, espe-cially fat, may induce or exacerbate symptoms. Fat ingestionhas been shown to exacerbate upper GI sensation throughthe postprandial release of cholecystokinin [33]. A similareffect could exist for heartburn perception since it has beenshown that fat infusion into the duodenum of reflux patientsreduced the latency of heartburn occurrence in response toesophageal acid infusion and increased the symptom sever-ity [34]. The interpretation of this phenomenon remainslargely speculative, but beside the role of cholecystokinin,other neurotransmitters such as the calcitonine gene relativepeptide or the substance P may influence esophageal per-ception by acting either peripherally (on vagal afferences) orcentrally.

The role of cortico-cerebral processing of esophagealsignals has been investigated more recently in few studiesusing recording of cortical potentials evoked by esophagealballoon distension or acid perfusion [35] and by new imag-ing technologies such as positron emission tomography(PET) and Functional Magnetic Resonance Imaging [36,37]. All these studies strongly suggest that the central pro-cessing of esophageal signals either after noxious or phys-iological (normally non painful) stimuli may be differentbetween healthy subjects, and patients with GERD or FH.FH patients (Rome III definition) seem to be more sensitiveto mechanical or chemical stimuli than NERD patients.Moreover a phenomenon of sensitization of acid che-moreceptors may significantly influence the response ofpressure-sensitive receptors suggesting cooperative in-teraction between them in the process of esophagealhyperalgesia [38].

184 Curr Gastroenterol Rep (2012) 14:181–188

To summarize, although heartburn cannot be reliablyassociated with reflux occurrence in FH patients and nospecific stimulus can be clearly identified, there are accu-mulating data that demonstrate the presence of esophagealhypersensitivity in these patients.

Role of Psychological Factors

Psychological factors probably play a major role in FH.Several models of acute experimental stress e.g. auditorystress [39] or sleep deprivation [40] have shown that stressenhances perception of esophageal acid in GERD patients.The effect of life stress on symptoms of heartburn has beenstudied in a cohort of patients followed prospectively for4 months [41]. The presence of severe sustained life stressduring the previous 6 months significantly predicted in-creased heartburn symptoms during the following 4 months.Anxiety was strongly associated with impaired quality oflife and depression to heartburn medication use. In anotherstudy, whereas, psychological profiles did not differentiatesubjects with normal esophageal acid exposure and noesophagitis from those having elevated acid exposure times,patients with FH demonstrated greater anxiety and somati-zation scores as well as poor social support than those withreflux-provoked symptoms [42]. Shapiro et al. conducted astudy comparing physiological and clinical characteristics oftwo groups of NERD and FH patients [43]. There was nostatistical difference in demographic, frequency of hiatushernia and Helicobacter pylori infection rate between thetwo groups. In contrast FH patients demonstrated increasedreports of chest pain, somatization and alteration of auto-nomic function (assessed by heart rate variability and skinconductance).

Clinical Evaluation

Like the other gastro-intestinal functional disorders, FH is achallenging clinical situation for clinicians. As a first step,clarification of the actual nature of the symptom is crucial[6]. Heartburn is characterized by pain or discomfort ofburning quality that originates high in the epigastrium withintermittent cephalad restrosternal radiation. In clinical prac-tice, many patients are referred for refractory heartburnwhich appears to be, after a careful interview, either epigas-tric burning or sore throat. There are no evidence-based datato determine the specific symptom features of FH, includingdiurnal characteristics, exacerbating factors, and ameliorat-ing maneuvers. The benefit of structured questionnaires tobetter identify and categorize patients suffering from heart-burn in a primary care setting remains controversial. Func-tional heartburn usually occurs during the day and, like the

heartburn of GERD, may be elicited or exacerbated bycertain foods and by lying down or bending over. However,it is difficult to extrapolate from data representing the whole“heartburn spectrum” to that of FH.

In clinical practice, patients in whom FH is suspected areusually referred to a tertiary center after a long history oftroublesome heartburn that have been partially or complete-ly unresponsive to a PPI trial, usually consisting in a doubledose regimen administered for several months. By defini-tion, the diagnosis of FH requires specific investigations.Upper gastro-intestinal endoscopy must be performed, ide-ally after discontinuation of PPIs for at least 2 weeks. Theabsence of esophageal mucosal breaks is part of the FHdefinition. It is very important to perform at least 5 esoph-ageal biopsies during the endoscopic evaluation, regardlessof the gross appearance of the esophageal mucosa, to avoidthe diagnostic of eosinophilic esophagitis which can presentas refractory GERD in up to 35% of adult cases [44]. Sincethe prevalence of heartburn has been reported to be as highas 35% in achalasia [45], esophageal manometry is recom-mended to avoid any primary esophageal motility disorder.

As outlined above, ambulatory reflux monitoring(whatever the technique used) should carefully analysisthe temporal relationships between the occurrence ofsymptoms and reflux events (both acid and non acid)and results should be expressed using SAP or SI values.It should be emphasized that the prolongation (from 24to 48 h) of reflux recordings with a wireless pH capsulealso increases the likelihood of establishing a positivesymptom–reflux association, with an overall increaseddiagnostic yield as high as 31% [46]. There is somecontroversy on whether pH (or pH impedance) monitoringshould be performed “on” or “off” PPI therapy in patientswith GERD refractory to PPI; in these challenging situations,most patients do not have any evidence of documented GERDand it may be useful to perform studies off therapy. Moreover,although not clearly stated in the ROME III definition, thediagnosis of FH requires in theory to discontinue PPI therapyfor at least 7 days before performing the procedure; however,patients with negative symptom association analysis duringpH-impedance monitoring performed on PPIs should proba-bly also be considered to have FH.

Finally, other esophageal (e.g. primary motility disorders)and non-esophageal sources (e.g. coronary artery disease)should be considered and appropriately evaluated whenatypical or unusual symptom characteristics (e.g., exerciseexacerbations) are associated with heartburn. Similarly it isimportant to carefully consider the associated burden relatedto other symptoms such as dyspepsia or IBS, because thesefunctional manifestations may contribute to the impairmentof quality of life. Understanding the main expectations ofthe patient, taking into consideration his/her socioeconomicstatus are also important parts of a good clinical evaluation.

Curr Gastroenterol Rep (2012) 14:181–188 185

Treatment

The role of diet is frequently advocated by patients withfunctional gastrointestinal gastro-intestinal disorders butthere is no clear evidence for a benefit of excluding specificfoods (e.g. acidic or spicy foods). On the contrary there aresome arguments suggesting that chronic ingestion of chiliwhich contains capsaicin may improve functional dyspepsiaand reflux symptoms by desensitization of the TRPV 1receptors [47]. Similarly, as fat can increase esophagealsensitivity to acid, heavy meals are usually avoidedspontaneously by the patients themselves. In fact, inclinical practice it is important to reassure the patientconcerning the harmless effects of many foods and toconvince him/her to avoid too restrictive dietary regimens.The role of obesity in FH has not been really investigated butit is common sense to attempt reducing overweight.

Randomized clinical trials in FH are scarce. By defini-tion, the diagnosis of FH is considered when a patient withheartburn fails to improve on PPI therapy. Although thedefinition stipulates that symptoms are not related to reflux,it may be useful to check for compliance, dosing time(before meals), and to try an increased dose of PPI. Theaddition of a prokinetic to PPI therapy is not supported byevidence. Because the pathophysiology mainly involvesheightened visceral sensation, use of pain modulators likelow dose tricyclic antidepressants and possibly selectiveserotonin reuptake inhibitors is reasonable. Indeed, no dataare yet available in FH but several controlled studies haveshown that these compounds were effective in patients withnon cardiac chest pain, esophageal motility disorders relatedpain 48] and hypersensitive esophagus [49]. Similarly, psy-chological approaches such as behavioral modification orrelaxation therapy [50] may be beneficial. However, to dateno published controlled trials demonstrate efficacy of any ofthese interventions in FH patients.

Several compounds may potentially exert an influence onvisceral perception which may be exploited in functionalesophageal disorders in general and in FH in particular. Forexample, the effect of tegaserod, a 5-HT4 agonist, has beentested in a placebo-controlled cross-over trial conducted inpatients with overlapping symptoms of FH and FunctionalDyspepsia (ROME II definition). The severity of heartburn,regurgitation, early fullness and bloating was significantlylower following tegaserod compared to placebo [51]. In thesame study mechanical sensitivity was assessed using thebarostat technique and tegaserod was shown to increase thepressure threshold for gastric pain. However the study con-clusions are limited by the small sample of patients and thecross-over design of the trial. Moreover, tegaserod is notwidely available making applications very limited. Amongother molecules, antagonists of the TRPV1 receptor(AZD1386) have been recently developed and proof-of-

concept studies have been published [52]. In healthyhumans, AZD 1386 increased esophageal and skin heat painthresholds and was well tolerated. Therefore this new classof drug may have a potential in NERD and FH as well but itis too early to extrapolate from pharmacodynamic effects tothe clinic.

Although anti-reflux surgery in patients with FH has notbeen fully evaluated, surgical management should beavoided in these patients who do not have any evidence ofGERD. Several studies report worse post-surgical outcomein patients with normal pre-operative pH test [53, 54].Although symptom association indices are far from beingperfect, a positive SI or SAP may be associated with morefavorable outcome in patients with refractory GERD symp-toms tested with pH-impedance monitoring on PPIs [55]. Astudy recently challenged this assumption, showing thatpostoperative outcomes were similar in patients with posi-tive or negative SAP, but it is of note that all patients hadabnormal esophageal acid exposure and therefore were notconsidered to have FH[56]. Some patients with recurrentheartburn after surgery have negative esophageal pHmonitoring but psychiatric co-morbidities thus suggestingthat FH rather than GERD may be responsible for persistingheartburn [57]. The same prudent limitation should be appliedto endoscopic anti-reflux procedures, although some of themsuch as a radiofrequency energy delivery (Stretta procedure)may affect esophageal sensitivity [58].

In summary, the treatment of FH remains largely empir-ical and an individual approach is therefore recommended.The clinician should provide reassurance and refrain fromperforming too many invasive tests or therapeutic proce-dures. Regarding the underlying pathophysiology, the useof pain modulators is recommended by most experts despitethe lack of appropriate clinical trials to support it. Althoughthe long-term natural history of FH is poorly known, somestudies as well as clinical experience suggest considerable“turn-over” of functional gastrointestinal disorders withappearance and disappearance of different categories offunctional disorders in the same patient. Such findingsmay have important implications in favor of a veryconservative and non invasive approach in FH patients.

Conclusions

Functional heartburn is a functional gastro-intestinal disor-der characterized by symptoms of heartburn not related togastro-esophageal reflux. It is now well established thataddition of impedance measurement to pH-monitoring islikely to increase the number of patients with recognizedreflux-related symptoms. The pathophysiology of functionalheartburn remains largely unknown but involves disturbedesophageal perception and psychological factors. As a

186 Curr Gastroenterol Rep (2012) 14:181–188

consequence, the treatment of FH remains largely empiricalbut the use of pain modulators is recommended by mostexperts despite the lack of appropriate clinical trials tosupport it. In the future, cognitive therapy or nociceptorblockers currently in development may have a role in themanagement of FH and should be further evaluated.

Disclosure Dr. S. Bruley des Varannes has been a board member forJanssen Cilag, IPRAD Laboratories, Cephalon Laboratories, MayoliSpindler Laboratories, a consultant for Given Imaging, Novartis, andDanone, and has received payment for lectures from Astra Zeneca,Takeda, and Nycomed; Dr. J. P. Galmiche has been a board memberand consultant for Astra Zeneca, and a consultant for Norgine andXenoport. He has received payment for development of educationalpresentations from Shire Movetis, travel and accommodation reimburse-ment fromGiven Imaging, and support from Mauna Kea Technology;Dr. F. Zerbib has been a board member for Shire Movetis and aconsultant for Given Imaging, Shire Movetis, Norgine, Xenoport,and Addex Pharma. He has received payment for lectures fromJanssen Cilag, Abbott France, and AstraZeneca, and payment fordevelopment of educational presentations from Cephalon, Pfizer,and Nycomed; Dr. M. Simon reported no potential conflicts ofinterest relevant to this article.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance

1. Locke 3rd GR, Talley NJ, Fett SL, et al. Prevalence and clinicalspectrum of gastroesophageal reflux: a population-based studyin Olmsted County, Minnesota. Gastroenterology. 1997;112:1448–56.

2. Carlsson R, Dent J, Bolling-Sternevald E, et al. The usefulness of astructured questionnaire in the assessment of symptomatic gastro-esophageal reflux disease. Scand J Gastroenterol. 1998;33:1023–9.

3. Bredenoord AJ, Weusten BL, Smout AJ. Symptom associationanalysis in ambulatory gastro-oesophageal reflux monitoring.Gut. 2005;54:1810–7.

4. Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal refluxmonitoring: review and consensus report on detection and defini-tions of acid, non-acid, and gas reflux. Gut. 2004;53:1024–31.

5. Zerbib F, Roman S, Ropert A, et al. Esophageal pH-impedancemonitoring and symptom analysis in GERD: a study in patients offand on therapy. Am J Gastroenterol. 2006;101:1956–63.

6. Clouse RE, Richter J, Heading RC. Functional esophageal disor-ders. In: Corazziari E, Talley NJ, Thompson WG, Whitehead WE,editors. Rome II—the functional gastrointestinal disorders. 2nd ed.MacLean: Degnon Associates; 2000. p. 247–98.

7. Galmiche JP, Clouse RE, Balint A, et al. Functional esophagealdisorders. Gastroenterology. 2006;130:1459–65.

8. Fass R, Sifrim D. Management of heartburn not responding toproton pump inhibitors. Gut. 2009;58:295–309.

9. Shi G, Bruley des Varannes S, Scarpignato C, et al. Reflux relatedsymptoms in patients with normal oesophageal exposure to acid.Gut. 1995;37:457–64.

10. Trimble KC, Douglas S, Pryde A, et al. Clinical characteristics andnatural history of symptomatic but not excess gastroesophagealreflux. Dig Dis Sci. 1995;40:1098–104.

11. Watson RG, Tham TC, Johnston BT, et al. Double blind cross-overplacebo controlled study of omeprazole in the treatment of patientswith reflux symptoms and physiological levels of acid reflux—the“sensitive oesophagus”. Gut. 1997;40:587–90.

12. Sacher-Huvelin S, Gournay J, Amouretti M, et al. Acid-sensitiveesophagus: natural history and effect on the quality of life.Comparison with gastroesophageal reflux. Gastroenterol ClinBiol. 2000;24:911–6.

13. Dent J, Armstrong D, Delaney B, et al. Symptom evaluation inreflux disease: workshop background, processes, terminology,recommendations, and discussion outputs. Gut. 2004;53 Suppl4:iv1–iv24.

14. • Savarino E, Marabotto E, Zentilin P, et al. The added value ofimpedance-pH monitoring to Rome III criteria in distinguishingfunctional heartburn from non-erosive reflux disease. Dig LiverDis. 2011;43:542–7. This study demonstrates that pH-impedancemonitoring decreases the proportion of patients with functionalheartburn since it allows identification of more patients withpositive symptom association analysis (compared to pH alonemonitoring).

15. • Frazzoni M, Conigliaro R, Mirante VG, et al. The added value ofquantitative analysis of on-therapy impedance-pH parameters in dis-tinguishing refractory non-erosive reflux disease from functional heart-burn. Neurogastroenterol Motil. 2011. doi:10.1039/C1AY05569K.This study suggests that pH-impedance on PPIs can help identifyingpatients with functional heartburn whose characteristics are differentfrom NERD patients.

16. Aanen MC, Weusten BL, Numans ME, et al. Effect of proton-pump inhibitor treatment on symptoms and quality of life inGERD patients depends on the symptom-reflux association. J ClinGastroenterol. 2008;42:441–7.

17. Taghavi SA, Ghasedi M, Saberi-Firoozi M, et al. Symptomassociation probability and symptom sensitivity index: preferablebut still suboptimal predictors of response to high dose omeprazole.Gut. 2005;54:1067–71.

18. Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux inpatients with persistent symptoms despite acid suppressive thera-py: a multicentre study using combined ambulatory impedance-pHmonitoring. Gut. 2006;55:1398–402.

19. Lam HG, Breumelhof R, van Berge Henegouwen GP, et al.Temporal relationships between episodes of non-cardiac chestpain and abnormal oesophageal function. Gut. 1994;35:733–6.

20. Slaughter JC, Goutte M, Rymer JA, et al. Caution about overin-terpretation of symptom indexes in reflux monitoring for refractorygastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2012;[Epub ahead of print].

21. Numans ME, Lau J, de Wit NJ, et al. Short-term treatment withproton-pump inhibitors as a test for gastroesophageal refluxdisease: a meta-analysis of diagnostic test characteristics. AnnIntern Med. 2004;140:518–27.

22. Martinez SD, Malagon IB, Garewal HS, et al. Non-erosive refluxdisease (NERD)–acid reflux and symptom patterns. AlimentPharmacol Ther. 2003;17:537–45.

23. • Zerbib F, Belhocine K, Simon M, et al. Clinical, but not oesopha-geal pH-impedance, profiles predict response to proton pump inhib-itors in gastro-oesophageal reflux disease. Gut. 2012;61:501–6.This study shows that, when multivariate analysis is performed,only clinical features (i.e. no esophagitis, functional disordersand normal or low BMI) are associated with PPI failure. NopH-impedance parameter could predict the response to PPIs.

24. • Savarino E, Pohl D, Zentilin P, et al. Functional heartburn hasmore in common with functional dyspepsia than with non-erosivereflux disease. Gut. 2009;58:1185–91. This study show a high

Curr Gastroenterol Rep (2012) 14:181–188 187

prevalence of functional dyspepsia symptoms in patients withfunctional heartburn.

25. Lee SY, Lee KJ, Kim SJ, et al. Prevalence and risk factors foroverlaps between gastroesophageal reflux disease, dyspepsia, andirritable bowel syndrome: a population-based study. Digestion.2009;79:196–201.

26. Nojkov B, Rubenstein JH, Adlis SA, et al. The influence ofco-morbid IBS and psychological distress on outcomes andquality of life following PPI therapy in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther.2008;27:473–82.

27. Jung HK, Halder S, McNally M, et al. Overlap of gastro-oesophageal reflux disease and irritable bowel syndrome: preva-lence and risk factors in the general population. Aliment Pharma-col Ther. 2007;26:453–61.

28. Fass R, Tougas G. Functional heartburn: the stimulus, the pain, andthe brain. Gut. 2002;51:885–92.

29. Fass R, Naliboff B, Higa L, et al. Differential effect of long-termesophageal acid exposure on mechanosensitivity and chemosensi-tivity in humans. Gastroenterology. 1998;115:1363–73.

30. Knowles CH, Aziz Q. Visceral hypersensitivity in non-erosivereflux disease. Gut. 2008;57:674–83.

31. • Vela MF, Craft BM, Sharma N, et al. Refractory heartburn:comparison of intercellular space diameter in documented GERDvs. functional heartburn. Am J Gastroenterol. 2011;106:844–50. Thisstudy shows that DIS is associated with NERD but not functionalheartburn and may be a marker of GERD.

32. Farre R, Fornari F, Blondeau K, et al. Acid and weakly acidicsolutions impair mucosal integrity of distal exposed and proximalnon-exposed human oesophagus. Gut. 2010;59:164–9.

33. Fried M, Feinle C. The role of fat and cholecystokinin in functionaldyspepsia. Gut. 2002;51 Suppl 1:i54–7.

34. Meyer JH, Lembo A, Elashoff JD, et al. Duodenal fat intensifiesthe perception of heartburn. Gut. 2001;49:624–8.

35. Yang M, Li ZS, Xu XR, et al. Characterization of cortical poten-tials evoked by oesophageal balloon distention and acid perfusionin patients with functional heartburn. Neurogastroenterol Motil.2006;18:292–9.

36. Kern MK, Birn RM, Jaradeh S, et al. Identification and character-ization of cerebral cortical response to esophageal mucosal acidexposure and distention. Gastroenterology. 1998;115:1353–62.

37. Kern M, Hofmann C, Hyde J, et al. Characterization of the cerebralcortical representation of heartburn in GERD patients. Am J Phys-iol Gastrointest Liver Physiol. 2004;286:G174–81.

38. Yang M, Li ZS, Chen DF, et al. Quantitative assessment andcharacterization of visceral hyperalgesia evoked by esophagealballoon distention and acid perfusion in patients with functionalheartburn, nonerosive reflux disease, and erosive esophagitis. ClinJ Pain. 2010;26:326–31.

39. Fass R, Naliboff BD, Fass SS, et al. The effect of auditory stress onperception of intraesophageal acid in patients with gastroesopha-geal reflux disease. Gastroenterology. 2008;134:696–705.

40. Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation ishyperalgesic in patients with gastroesophageal reflux disease. Gas-troenterology. 2007;133:1787–95.

41. Naliboff BD, Mayer M, Fass R, et al. The effect of life stress onsymptoms of heartburn. Psychosom Med. 2004;66:426–34.

42. Johnston BT, Lewis SA, Collins JS, et al. Acid perception ingastro-oesophageal reflux disease is dependent on psychosocialfactors. Scand J Gastroenterol. 1995;30:1–5.

43. Shapiro M, Green C, Bautista JM, et al. Functional heartburnpatients demonstrate traits of functional bowel disorder but lack auniform increase of chemoreceptor sensitivity to acid. Am J Gas-troenterol. 2006;101:1084–91.

44. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esoph-agitis in children and adults: a systematic review and consensusrecommendations for diagnosis and treatment. Gastroenterology.2007;133:1342–63.

45. Ponce J, Ortiz V, Maroto N, et al. High prevalence of heartburn andlow acid sensitivity in patients with idiopathic achalasia. Dig Dis Sci.2011;56:773–6.

46. Prakash C, Clouse RE. Value of extended recording time withwireless pH monitoring in evaluating gastroesophageal refluxdisease. Clin Gastroenterol Hepatol. 2005;3:329–34.

47. Gonlachanvit S. Are rice and spicy diet good for functional gas-trointestinal disorders? J Neurogastroenterol Motil;16:131–8.

48. Viazis N, Karamanolis G, Vienna E, et al. Selective-serotoninreuptake inhibitors for the treatment of hypersensitive esophagus.Therap Adv Gastroenterol. 2011;4:295–300.

49. Viazis N, Keyoglou A, Kanellopoulos AK, et al. Selective seroto-nin reuptake inhibitors for the treatment of hypersensitive esoph-agus: a randomized, double-blind, placebo-controlled study. Am JGastroenterol. 2011;Epub ahead of print.

50. McDonald-Haile J, Bradley LA, Bailey MA, et al. Relaxation train-ing reduces symptom reports and acid exposure in patients withgastroesophageal reflux disease. Gastroenterology. 1994;107:61–9.

51. Miner Jr PB, Rodriguez-Stanley S, Proskin HM, et al. Tegaserod inpatients with mechanical sensitivity and overlapping symptoms offunctional heartburn and functional dyspepsia. Curr Med ResOpin. 2008;24:2159–72.

52. Krarup AL, Ny L, Astrand M, et al. Randomised clinical trial: theefficacy of a transient receptor potential vanilloid 1 antagonistAZD1386 in human oesophageal pain. Aliment Pharmacol Ther.2011;33:1113–22.

53. Khajanchee YS, Hong D, Hansen PD, et al. Outcomes of antirefluxsurgery in patients with normal preoperative 24-hour pH testresults. Am J Surg. 2004;187:599–603.

54. Campos GM, Peters JH, DeMeester TR, et al. Multivariate analysisof factors predicting outcome after laparoscopic Nissen fundopli-cation. J Gastrointest Surg. 1999;3:292–300.

55. Mainie I, Tutuian R, Agrawal A, et al. Combined multichannelintraluminal impedance-pH monitoring to select patients withpersistent gastro-oesophageal reflux for laparoscopic Nissenfundoplication. Br J Surg. 2006;93:1483–7.

56. Broeders JA, Draaisma WA, Bredenoord AJ, et al. Impact ofsymptom-reflux association analysis on long-term outcome afterNissen fundoplication. Br J Surg. 2011;98:247–54.

57. Thompson SK, Cai W, Jamieson GG, et al. Recurrent symptomsafter fundoplication with a negative pH study–recurrent reflux orfunctional heartburn? J Gastrointest Surg. 2009;13:54–60.

58. Arts J, Sifrim D, Rutgeerts P, et al. Influence of radiofrequency energydelivery at the gastroesophageal junction (the Stretta procedure) onsymptoms, acid exposure, and esophageal sensitivity to acid perfusionin gastroesophagal reflux disease. Dig Dis Sci. 2007;52:2170–7.

188 Curr Gastroenterol Rep (2012) 14:181–188