Etiology of dyspepsia: Implications for empirical therapydownloads.hindawi.com/journals/cjgh/2002/679683.pdf · 2019-08-01 · Can J Gastroenterol Vol 16 No 9 September 2002 635 REVIEW

Can J Gastroenterol Vol 16 No 9 September 2002 635

REVIEW

Etiology of dyspepsia: Implicationsfor empirical therapy

Richard H Hunt MB FRCP FRCPC FACG1, Carlo Fallone MD FRCPC2,Sander Veldhuyzen van Zanten MD MPH RRCPC3, Phil Sherman MD FRCPC4,

Nigel Flook MD CCFP5, Fiona Smaill MD MB CB FRACP FRCPC1,Alan BR Thomson MD PhD FRCPC6,

on behalf of the Canadian Helicobacter Study Group

1Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario; 2Division of Gastroenterology, Department ofMedicine, McGill University, Montreal, Quebec; 3Division of Gastroenterology, Department of Medicine, Dalhousie University, Halifax,Nova Scotia; 4Division of Gastroenterology and Nutrition, Department of Pediatrics, University of Toronto, Toronto, Ontario; 5Department ofFamily Medicine, and 6Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta

Correspondence: Dr Alan BR Thomson, 519 Newton Research Building, University of Alberta, Edmonton, Alberta T6G 2C2. Telephone 780-407-6490, fax 780-407-7964, e-mail [email protected]

Received for publication February 11, 2002. Accepted July 19, 2002

RH Hunt, C Fallone, S Veldhuyzen van Zanten, et al, onbehalf of the Canadian Helicobacter Study Group. Etiology ofdyspepsia: Implications for empirical therapy. Can JGastroenterol 2002;16(9):635-641.

Dyspepsia describes a symptom complex thought to arise in theupper gastrointestinal tract and includes, in addition to epigastricpain or discomfort, symptoms such as heartburn, acid regurgita-tion, excessive burping or belching, a feeling of slow digestion,early satiety, nausea and bloating. Based on the evidence thatheartburn cannot be reliably distinguished from other dyspepticsymptoms, the Rome definition appears to be too narrow andrestrictive. It is particularly ill suited to the management of unin-vestigated dyspepsia at the level of primary care. In patients pre-senting with uninvestigated dyspepsia, a symptom benefit isassociated with a ‘test and treat’ approach for Helicobacter pyloriinfection. A substantial proportion of those who do not benefitprove to have esophagitis on endoscopy. In those with functionaldyspepsia, the benefits of H pylori eradication, if any, appear to bemodest. Hence, a ‘symptom and treat’ acid-suppression trial withproton pump inhibitors, and a ‘test and treat’ strategy for H pyloriare two acceptable empirical therapies for patients with univesti-gated dyspepsia.

Key Words: Dyspepsia; Empirical therapy; Functional dyspepsia;Uninvestigated dyspepsia

Étiologie de la dyspepsie : Implications pour letraitement empirique

RÉSUMÉ : La dyspepsie désigne un complexe de symptômes dont l’ori-gine se situerait au niveau du tractus digestif supérieur et qui comprend enplus des douleurs, des malaises gastriques, des symptômes tels brûluresd’estomac, régurgitation acide, irritation excessive, sensation de digestionlente, satiété précoce, nausées et ballonnements. Comme la brûlured’estomac ne peut se distinguer de façon fiable d’autres symptômes dys-peptiques, la définition de Rome semble trop étroite et restrictive. Elle estparticulièrement mal adaptée à la prise en charge empirique de la dyspep-sie en médecine de premiers recours. Chez les patients qui se présententpour une dyspepsie n’ayant pas fait l’objet d’épreuves diagnostiques, onconstate un avantage sur le plan des symptômes avec l’approche «tester ettraiter» pour l’infection à Helicobacter pylori. Une proportion substantiellede ceux qui ne se trouvent pas soulagés se révèlent en effet atteints d’œ-sophagite à l’endoscopie. Chez les sujets qui souffrent d’une dyspepsiefonctionnelle, les avantages de l’éradication de H. pylori, le cas échéant,semblent modestes. Ainsi, un essai de suppression acide avec des inhibi-teurs de la pompe à protons et une stratégie «tester et traiter» pourHelicobacter pylori semblent deux traitements empiriques acceptables chezles sujets souffrant de dyspepsie n’ayant pas fait l’objet d’investigation.

In Canada, approximately two-thirds of adult patientswith upper gastrointestinal symptoms have an identifi-

able lesion on upper gastrointestinal endoscopy (esopha-gogastroduodenoscopy [EGD]), most commonly erosive

esophagitis (1). In patients with dyspepsia and a normalEGD, evidence suggests that a number of abnormalities,including disordered neuromuscular function or nocicep-tion, may drive symptom expression. Slow or incomplete

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resolution of such abnormalities may explain persistentsymptoms after suspected triggers of injury, such asHelicobacter pylori infection, have been eliminated. Theseconcepts have developed concurrently with a substantialchange in the prevalence of known causes of upper gas-trointestinal symptoms, particularly a declining incidenceof peptic ulcers and an increasing incidence of gastro-esophageal reflux disease (GERD). Both have implicationsfor the rational selection of empirical therapies and the useof diagnostic procedures.

The Canadian Helicobacter Study Group met in Ottawa,June 22 to 24, 2001. The names of the participants arelisted in Appendix 1. This document reflects the consensusof the discussions and is approved by the attendees. Equalat-arms’-length financial support was received with appreci-ation from Abbott Laboratories Limited, AstraZenecaCanada Inc, Axcan Pharma Inc, Glaxo Wellcome andSolvay Pharma/BYK Inc.

DEFINITIONS AND PREVALENCE OFDYSPEPSIA

Dyspepsia, a disorder in which epigastric pain or discomfortis the major symptom, encompasses a broad range of uppergastrointestinal symptoms of varying intensity, descriptionand location. The underlying cause of these symptoms isusually benign, but serious disease, such as gastric cancer,rarely may be present. The prevalence of dyspepsia in thegeneral adult population is estimated to range between 20%and 45% (2-4). In a population-based study in Canada,29% of those surveyed reported persistent or recurrentsymptoms within the preceding three months, whereas only34% of this sample population had never experienced sig-nificant dyspepsia (5).

Despite evidence that only a small proportion of thesepatients seeks medical attention (6), dyspepsia is the fourthmost common complaint in patients seen in primary care(7). The presentation of dyspepsia may include a variety ofsymptoms such as retrosternal or epigastric burning, belch-ing, burping, nausea, bloating or a feeling of slow digestion.By definition, dyspepsia involves epigastric symptoms, butit may be difficult to isolate epigastric symptoms from het-erogeneous complaints referable to other areas of the body.There has been particular controversy about the diagnosticreliability with which heartburn, defined as a burning ret-rosternal pain radiating upwards toward the mouth, can bedistinguished from epigastric pain. Dyspepsia criteria rele-vant to primary care practice that exclude heartburn andother symptoms of GERD are too restrictive due to symp-tom overlap or ambiguous complaints. Moreover, studies ofboth primary care physicians and specialists demonstratepoor discrimination of GERD and peptic ulcer disease onthe basis of clinical symptoms alone (8).

Dyspepsia is not a diagnosis, but rather a symptom orsymptom complex suggestive of an upper gastrointestinaltract source. Efforts to treat the dominant symptom, as rec-ommended in the Rome criteria (9), or symptom clusters, asrecommended in a subsequent modification of the original

Rome criteria (10), are hampered by the fact that a highproportion of patients have multiple, overlapping symp-toms, or symptoms that fit poorly into a single category. Inaddition to heartburn and regurgitation, which are charac-terized as reflux-like dyspepsia, other symptom subgroupsare ulcer-like, signifying focal epigastric pain that is oftenrelieved by meals, or dysmotility-like dyspepsia, with bloat-ing, fullness and/or early satiety. The Rome classificationsare intended to guide treatment rather than to diagnose anetiology.

When symptom clusters are used to describe subgroups ofpatients with dyspepsia, they are characterized as reflux-likein approximately 20% of cases, ulcer-like in 11% and dys-motility-like in 7%. Approximately 20% of patients cannotbe placed into any of these groups because of symptom over-lap, and an additional 40% cannot be categorized becausetheir symptoms are so nonspecific (11). When dominantsymptoms, rather than symptom clusters, were used to char-acterize subgroup patients in a Canadian population-basedstudy, the presentation was characterized as dysmotility-likein 55%, reflux-like in 43% and ulcer-like in only approxi-mately 12% (5).

About two-thirds of patients with dyspepsia, whendefined to include heartburn, have endoscopic evidence ofreflux esophagitis (1). Peptic ulcer disease is observed in lessthan 10%. In North America, malignancy is exceedinglyrare in subjects with dyspepsia, particularly in those under50 years of age and who have no alarm features such asweight loss, dysphagia, bleeding or anemia. The remainingpatients have a normal EGD and are classified as havingfunctional dyspepsia.

Except for complicated ulcer disease and malignancy,both of which are uncommon in an otherwise healthy pop-ulation, dyspepsia is usually a relatively benign condition.However, dyspepsia does cause a significant impairment inthe quality of life of the sufferer. In a Canadian population-based study, work absenteeism among people with dyspepsiawas nine times more frequent than in those without dys-pepsia (5). Nonprescription drugs were taken by 51% ofthose with dyspepsia, versus only 6% of those withoutsymptoms. Patients with dyspepsia also had impairment inobjective measures of psychosocial function relative tohealthy controls.

ETIOLOGY: CURRENT CONCEPTSAcid secretion is an important contributor to identifiablecauses of dyspepsia, such as duodenal ulcer or GERD.Impaired gastrointestinal motility is also implicated in thepathogenesis of dyspepsia, but its role as an independentfactor is much less clear. In patients with functional dyspep-sia who are poorly responsive to therapies targeted at eitherof these factors, there is mounting evidence for a complexrelationship between stress, gastrointestinal dysfunction,mucosal injury and symptomatology (12). Current studiesare focused on the possibility that functional dyspepsia is aconsequence of changes in visceral hypersensitivity, as wellas neuromuscular dysfunction, potentiated by activation of

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the immune system. Although specific stimuli, includinginfection with H pylori, may play a critical role in initiatingdyspepsia, the condition may be slowly resolving or evenself-perpetuating once it has been triggered.

An emerging concept regarding the pathogenesis offunctional dyspepsia is an interrelationship between theimmune system, the afferent nervous system and neuromus-cular function (13). Although there may be considerableinterpatient differences in the specific sequence of events,altered neuromuscular function and visceral hypersensitiv-ity are likely to occur as a result of the activation ofcytokines and neuropeptides secondary to associatedinflammation, local tissue injury and stress, or a combina-tion of these.

There is increasing evidence to support the importanceof the gut-brain-gut axis in both normal gastrointestinalfunction and disease. For example, experiments first pub-lished a decade ago demonstrated an association betweengastrointestinal inflammation and an alteration in centralnervous system activity and behaviour (14). Subsequentstudies correlating stress with an increased susceptibility formucosal inflammation indicate that communicationbetween the brain and the gut is bidirectional (15). Thepresence of inflammation also increases the sensitivity ofthe intestinal tract to subsequent stress (16). The mecha-nisms by which persistent changes might be expected toaffect neuromuscular function or to sensitize perception tonormal gastrointestinal events include altered levels of sub-stance P (a peptide associated with decreased muscle con-traction) and activation of afferent nerve pathways.

Functional dyspepsia defines a population of individualswith symptoms but without evidence of macroscopic lesionsin the gastrointestinal tract. This does not eliminate thepossible release of inflammatory cytokines (either as a pre-cipitating event or as a subclinical process causing dyspep-sia), but it does suggest that the relationship is complex.One theory is that the activation of immune factors duringan initial episode of inflammation triggers a process thatpersists after the inflammation has resolved. Cytokines suchas interleukin-6 and tumour necrosis factor-alpha inhibitmuscle contraction and alter neural activity, and pathwaysmay be activated even after resolution of obvious mucosalinflammation (17). Moreover, these cytokines may potenti-ate pathogenic processes by stimulating the release of neu-ropeptides or other endogenous factors, which in turn altergastrointestinal function.

In general, dyspepsia associated with peptic ulcer diseaseand erosive esophagitis resolves with healing of the under-lying pathology. The same processes leading to tissue injuryand impaired gastrointestinal function in these conditionsmay have parallels in persons with functional dyspepsia.The presence of injurious agents exacerbated by stress maytrigger a cascade of events that include immune activation,increased production of prostanoids and increased produc-tion of neuropeptides involved in acid secretion. Whileinflammation progresses to mucosal damage in only aminority of patients, hypersensitivity of the gut in persons

with functional dyspepsia may persist until the triggers ofsensory abnormalities resolve.

In animal models of H pylori infection, altered levels ofneurotransmitters, such as acetylcholine, and an increase insubstance P, calcitonin gene-related peptide and vasoactiveintestinal peptide-circulating nerves, indicate the potentialfor this bacterium to alter neural circuitry in the gastroin-testinal tract (13). Experimental data suggest that thesechanges are not related to the bacterium itself, but rather tothe level of the chronic inflammatory response induced bythe H pylori infection. Many of the changes observed withthis infection resolve after the successful eradication ofH pylori. However, some of the functional and structuralchanges, such as those induced by an increase in macrophageinfiltration and recruitment of mononuclear cells, may per-sist. This provides a basis for the speculation that eradica-tion may not be sufficient to restore function to normal.

The pathogenicity of the specific H pylori strain alsocould be a factor in the risk of sustained damage. Forinstance, increased gastric epithelial permeability second-ary to H pylori infection has been linked to the presence ofthe vacuolating cytotoxin vacA gene (18). By openingintercellular tight junctions in the gastric mucosa, the toxincould increase the risk of an immune response leading todyspeptic symptoms through the exposure of nerve endingsto acid. The opening of tight junctions in the esophagealmucosa by processes unrelated to H pylori infection is also aprominent focus of studies attempting to explain symptomsof gastroesophageal reflux in the absence of erosiveesophagitis (19).

Changes in mucosal permeability and neuromuscularfunction leading to functional dyspepsia are not yet fullysupported by clinically relevant studies. However, theseconcepts provide an important direction for understandingthe roles of both H pylori infection and other pro-inflam-matory factors that may initiate similar dysfunction. Forexample, evidence for comparable events in patients withthe irritable bowel syndrome, a functional gastrointestinaldisorder not related to H pylori infection, support the con-cept of a disturbance of the gut-brain-gut axis in immunefunction and neuromuscular activity (20,21). Thesehypotheses, which also incorporate psychogenic stress as afactor in determining symptom expression, provide a physi-ological basis for identifying potential new targets for med-ical therapy.

PRACTICAL MANAGEMENT: CURRENT CONCEPTS

In considering the management of patients with dyspepsia,it is important to differentiate between uninvestigated andinvestigated (functional) dyspepsia. There may be confu-sion if these two distinct clinical groups are consideredtogether. When a patient presents for the first time to a pri-mary care physician with dyspeptic symptoms, he or she hasnot been investigated (uninvestigated), and the cause oftheir dyspepsia is unknown. The most common diagnosesare GERD, functional dyspepsia, ulcer disease and, rarely,

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malignancy. Before embarking on empirical therapy foruninvestigated dyspepsia, a history should be taken to ruleout other pathologies, particularly those involving the car-diovascular and hepatobiliary systems. Somatoform disor-ders may also mimic dyspepsia. Iatrogenic causes ofdyspepsia, particularly due to acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAIDs), should also beexcluded. About 30% of patients on chronic NSAID ther-apy develop dyspepsia (22), although the risk may bereduced but not eliminated with the use of cyclooxygenase-2-selective inhibitors (23). In patients with mild or intermit-tent symptoms, lifestyle modifications such as a change inthe diet, may be appropriate before embarking on drug ther-apy, although a benefit from such modification has not beenproven (24,25).

Due to the traditional association between dyspepsia andpeptic ulcers, first-line empirical therapies for persistentepigastric discomfort have been targeted in ulcer disease.When H pylori infection was first recognized as the mostimportant etiological factor for peptic ulcer, a ‘test andtreat’ eradication strategy was widely advocated (26). A‘test and treat’ strategy is preferable over antisecretory drugsfor possible peptic ulcer, because it can lead to a cure of theunderlying disease.

H pylori is a pathogen that causes chronic active gastritis.It is reasonable to consider that this gastritis contributes toupper gastrointestinal symptoms (ie, be one of the causes ofdyspepsia) and that eradication of the infection can lead tosymptom resolution. Indeed, many consensus conferenceshave advocated the ‘test and treat’ approach in the initialmanagement of patients with dyspepsia, despite a lack ofconvincing evidence from randomized, controlled trials.The Canadian Adult Dyspepsia Empirical Treat – H pyloriStudy (CADET-Hp) provides the first level 1 evidence thatH pylori eradication improves dyspeptic symptoms inpatients with uninvestigated dyspepsia seen at the primarycare level (27). The number needed to treat to achievesymptom resolution is one patient in seven. Thus, good evi-dence now supports such a ‘test and treat’ strategy for patientsseen in primary care with uninvestigated dyspepsia.

However, the prevalence of peptic ulcer disease has beendiminishing and, in Canada, endoscopic studies suggestthat peptic ulcers, once considered the cause of dyspepsia inup to 25% of patients, are now found in fewer than 10%(1). One explanation for the diminishing incidence of pep-tic ulcer is the decline in the prevalence of H pylori infec-tion. Except in aboriginals and some groups of recentimmigrants, the prevalence of H pylori infection has fallento less than 30% in most parts of Canada. In addition, it isnow recognized that a smaller proportion of peptic ulcerscan be attributed to H pylori infection than was previouslyappreciated. For example, in one study conducted inMontreal, H pylori was identified in 95% of patients withpeptic ulcers in 1993, but in only 62% in 1998 (28).

These data predict that there will be limited benefitsfrom a test and treat strategy in patients with uninvesti-gated dyspepsia, based on the cure of an underlying peptic

ulcer. However, theoretical benefits from eradication of aninfection that leads to chronic gastritis have also supportedthis test and treat approach. Yet, the objective evidence ofbenefit from H pylori eradication in functional dyspepsia,including two recent meta-analyses (29,30), has been con-flicting. In one analysis of data from seven trials, the oddsratio for a response one month after anti-Helicobacter ther-apy was 29% greater in those receiving eradication treat-ment versus controls, but it needs to be stressed that thisdifference was not statistically significant (29). In the othermeta-analysis of nine trials, the response rate was 36% inthose treated with an eradication regimen compared with28% among controls (P<0.002) (30). It was estimated that15 subjects would require therapy to eradicate H pyloriinfection for one patient to benefit.

This relatively low proportion of H pylori-positivepatients with functional dyspepsia who benefit from cure ofthe infection is likely due to the complexity of symptomexpression, rather than to the absence of a significant rela-tionship of the pathogenesis of dyspepsia with thispathogen. Eradication of H pylori infection may well beimportant but is insufficient for immediate or completesymptom relief. Importantly, the relationship betweenH pylori infection and abnormalities of gastric function pro-vide a context in which to identify mechanisms of neuro-muscular dysfunction or altered nociception that areindependent of the infection. The details of the endoge-nous responses to changes in gastrointestinal function areessential for the development of new targets of therapy.

Evidence suggests that the benefit from H pylori eradica-tion in patients with uninvestigated dyspepsia is limited toa relatively small subgroup (only about 14% of patientswith uninvestigated dyspepsia). Taken together with thedeclining risk of peptic ulcer disease, these data also ques-tion the strategy of test and treat as a first-line empiricalmanagement approach, if it is assumed that only patientswith peptic ulcer disease benefit. Although previous studieshave shown that a test and treat approach is cost effectivein an uninvestigated population due to fewer referrals fordiagnostic endoscopy (26), indiscriminant eradication ofH pylori infection in an otherwise tolerant host is beingincreasingly challenged because of a potential, but unde-fined, risk to benefit ratio of eliminating what some con-sider to be normal biota (31). Conversely, a recent study hasshown that H pylori infection is a significant risk factor forgastric cancer, particularly in patients with dyspepsia (32).

The alternatives to a test and treat strategy for the first-line management of dyspepsia include the use of empiricaltherapies or early use of endoscopy, which is a reliable butexpensive diagnostic tool. While endoscopy should be usedearly in patients older than age 50 years with new onsetdyspepsia, or any individual with alarm symptoms (such asunexplained weight loss, unexplained vomiting, upper gas-trointestinal bleeding, anemia, abdominal mass or dyspha-gia), universal screening is impractical and expensive.Furthermore, virtually all the lesions found in a recentstudy of 1040 dyspeptic Canadians having a prompt endo-

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scopy were amenable to treatment with acid suppressiontherapy, H pylori eradication therapy or elimination ofNSAIDs (1).

Of the empirical therapies studied in uninvestigated dys-pepsia, proton pump inhibitors (PPIs) are the most likely toprovide symptom relief. In clinical trials, significant symp-tom improvement is observed in almost one-half of patientswith ulcer-like symptoms and two-thirds of those withreflux-like symptoms (33). Although PPIs are not superiorto placebo in the relief of dysmotility-like symptoms, aresponse to empirically administered PPI therapy is consid-ered diagnostic for GERD (34). Response rates are high inboth those with and those without esophageal lesions atendoscopy. In an empirical antisecretory treatment strategy,PPIs are preferred over H2-receptor antagonists, because itis expected that the superior acid control will increase sen-sitivity for both the detection and the treatment of an acid-related disorder.

One risk of initiating empirical acid suppression ratherthan a test and treat strategy for dyspepsia is the potentialdelay in establishing a diagnosis of peptic ulcer disease.Although the population at risk of ulcer disease is dimin-ishing, this important concern should be weighed againstthe patient’s clinical presentation and the risk of complica-tions. In otherwise healthy individuals under the age of 50years, refractory or frequently recurring symptoms after dis-continuation of acid suppression therapy and a positivefamily history of peptic ulcer disease should increase theindex of suspicion for a duodenal or gastric ulcer, or forGERD, warranting either an empirical test and treat strat-egy or endoscopy. In most individuals, however, the rela-tively low risk of peptic ulcer disease, and the even lowerrisk of complications from a delayed diagnosis, suggest thata more appropriate first step is to determine whether thedyspeptic symptoms are acid related.

Many patients who are anxious about the possibility of aserious disease, particularly malignancy, often derive reas-surance from negative findings at endoscopy. Endoscopy isassociated with significant improvements in patient satis-faction (35,36). Although endoscopy is not an appropriatescreening tool for dyspepsia, it is a valuable procedure inpatients with persistent complaints who are unresponsive toempirical therapies.

Some physicians have the clinical impression that theremay be a psychogenic component to functional dyspepsia.However, controlled trials of antidepressants and other psy-chotropic agents have not consistently demonstrated signif-icant benefit (37). The potential for benefit frompsychotherapy in selected patients, particularly any inter-vention aimed at reducing stress, cannot be completely dis-counted. The evidence for the importance of gut-brain-gutinteractions in functional gastrointestinal diseases shouldbe misinterpreted as a foundation for suspecting hypochon-driasis. Anxiolytics should not be considered as primarytherapy of dyspepsia, whether uninvestigated or functional,unless there is underlying anxiety for which there is a clearindication to try anxiolytics.

Flexibility is an essential component of treatment algo-rithms developed for the management of patients withuninvestigated dyspepsia. Clinical impressions are unavoid-able, but unaided clinical diagnosis is generally unreliable.In an endoscopically controlled study that compared gen-eral practitioners with experienced gastroenterologists, thesensitivity for either group in diagnosing peptic ulcer wasonly 60% (8). Importantly, nearly one-half of the patientswith ulcer or esophagitis were misclassified. There wasagreement between the general practitioners and the gas-troenterologists in only 45% of cases, and the likelihood ofa correct diagnosis correlated poorly with the physicians’degree of conviction of the diagnosis.

In the practical management of dyspepsia, both clini-cians and patients must be prepared for some degree ofuncertainty. It is the level of acceptable uncertainty thatwill prompt intervention. Based on current risk factors inCanadians with dyspepsia, empirical antisecretory treat-ment with a PPI is an appropriate first step in youngerpatients with symptoms consistent with an acid-related dis-order, such as heartburn, acid regurgitation or epigastricpain relieved by food or antacid, particularly when there areno alarm features. Prokinetic agents also might be consid-ered for use in a trial of empirical therapy, but the therapeu-tic options are limited with the withdrawal of cisapridefrom the Canadian market. Although current data suggestthat only a small proportion of patients obtain symptomrelief with H pylori eradication, a major benefit of thisapproach is that one in seven patients is cured of their dys-pepsia (27). If a noninvasive H pylori test is negative, onecan be reasonably certain that an H pylori infection is notpresent and the patient can be reassured that seriouspathology is unlikely. If dyspepsia persists, an endoscopycan be performed to provide reassurance. Indeed, the abilityto rule out serious organic disease may be the most impor-tant contribution of endoscopy in the management of thepatient with dyspepsia.

There are few similarities between adults and children inthe approach to the diagnosis and treatment of dyspepsia.Upper gastrointestinal symptoms are common in children(up to 10% of the school age population), but these symp-toms are less commonly associated with gastrointestinalpathology such as peptic ulcers or esophagitis (38).Whereas treating for H pylori infection in adults with dys-pepsia will benefit the small proportion who have pepticulcer disease that would respond to a test and treat strategy,there is little current justification for screening childrenwith dyspepsia for H pylori infection (39).

CONTROVERSIAL MANAGEMENT ISSUESAND FUTURE DIRECTIONS

The discovery that H pylori infection is a major cause ofpeptic ulcers has been the impetus to question manyassumptions about upper gastrointestinal physiology andpathophysiology. Over the course of the past two decades,the pendulum of scientific opinion has swung back andforth in regard to the nature and role of H pylori infection,



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and its threat to the human host. Although H pylori is adocumented pathogen, the majority of those infected toler-ate life-long infection with no discernible symptoms. Whileuniform eradication is a widely cited goal of the efforts todevelop a vaccine, most management guidelines now cau-tion against the indiscriminate screening for and eradica-tion of H pylori infection.

A further debate, generated by the results of an uncon-trolled trial, was the purported risk of gastric atrophy andintestinal metaplasia from the use of long term PPI therapyin patients with H pylori infection (40). However, aprospective observational trial comparing long term PPIwith fundoplication surgery as a control group, did not showthat long term PPI therapy in H pylori-infected patientsresulted in progression of gastric atrophy (41). A placebocontrolled trial of H pylori eradication in patients on longterm PPI of sufficient duration, however, is still lacking.Thus, at present, good evidence is not available to advocatea strategy of tests for and eradicating H pylori in patients onchronic PPI. Furthermore, data to show that this approachis harmful are also lacking.

Less well understood is whether H pylori increases therisk of NSAID-induced gastropathy. It is logical to predictthat two independent factors for damage to the gastricmucosa would have additive effects on tissue integrity, butstudies to date have been contradictory (42). Although itmay be prudent to test and treat for H pylori in patients whohave developed peptic ulcers while undergoing NSAIDtherapy, the benefits with regard to a diminished risk ofulcer complications caused by NSAIDs have not been doc-umented. Alternative approaches in patients who are unableto discontinue NSAIDs include adding a PPI, changing to amore selective cyclooxygenase-2 inhibitor or adding amucosal protective agent such as misoprostol.

New agents already entering investigation for the con-trol of dyspepsia include kappa opioid agonists, substance Pantagonists, and 5-hydroxytryptamine3 antagonists. Someof these have already reached clinical testing in other func-

tional gastrointestinal disorders, such as the irritable bowelsyndrome. What role these drugs will have in the therapy ofdyspepsia is not yet known. However, evidence of efficacyin randomized, controlled trials will dramatically alter ourunderstanding of the causes of dyspepsia, and advance ther-apies specific to the underlying etiology.

CONCLUSIONSThe diversity of symptoms in patients with dyspepsiaappears to be matched by the complexity of underlyingpathological factors. H pylori eradication is of symptomaticbenefit in a small proportion of patients with uninvesti-gated dyspepsia, and acid suppression with a PPI is effectivein many patients, particularly those with heartburn orulcer-predominant dyspepsia. The optimal approach forsome nonresponders is reassurance regarding the absence ofa serious underlying disorder, including performing anendoscopy to provide that reassurance. Although eradica-tion of H pylori infection in uninvestigated dyspepsiaimproves symptoms, the symptomatic benefit of H pylorieradication in patients with functional dyspepsia is small.The effects of this bacterium on gastrointestinal functionpromise new clues about the interrelationship between theimmune responses and the gut-brain-gut axis in functionalgastrointestinal disorders. Details about this interrelation-ship likely will prove to be relevant to symptom expressionfor pathogenic triggers in addition to H pylori infection.Hence, a ‘symptom and treat’ acid-suppression trial withPPIs, and a ‘test and treat’ strategy for H pylori infection aretwo acceptable empirical approaches for patients with unin-vestigated dyspepsia.

ACKNOWLEDGEMENTS: The authors and participants thankMr Ted Bosworth for his assistance in drafting this manuscript.Equal at-arms’-length financial support was received with appreci-ation from Abbott Laboratories Limited, AstraZeneca CanadaInc, Axcan Pharma Inc, Glaxo Wellcome and Solvay Pharma/BYK Inc.

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Dr David ArmstrongHamilton, Ontario

Dr Allen AusfordEdmonton, Alberta

Dr Bill BartleToronto, Ontario

Dr Premysl BercikHamilton, Ontario

Dr Linda BestHamilton, Ontario

Mr Ted BosworthNew York, New York

Dr Raymond BourdagesLevis, Quebec

Dr Marc BradetteQuebec, Quebec

Dr Malcolm Champion Ottawa, Ontario

Dr Hugh ChaunVancouver, British Columbia

Dr Naoki ChibaGuelph, Ontario

Dr Alan CockeramSt John’s, Newfoundland

Dr Brian CraigSt John, New Brunswick

Dr Carlo FalloneMontreal, Quebec

Dr Nigel FlookEdmonton, Alberta

Dr Richard HuntHamilton, Ontario

Dr Liisa JaakkimainenToronto, Ontario

Dr Kevan JacobsonVancouver, British Columbia

Dr Nicola JonesToronto, Ontario

Dr Alan KaplanToronto, Ontario

Dr Frank LinToronto, Ontario

Dr Keith MacCannellCalgary, Alberta

Dr Bernard MarlowToronto, Ontario

Dr Serge MayrandMontreal, Quebec

Dr Jon MeddingsCalgary, Alberta

Dr Garth NoadHamilton, Ontario

Dr Tony OtleyHalifax, Nova Scotia

Dr Pierre PareSainte-Foy, Quebec

Dr Phil ShermanToronto, Ontario

Dr Lesley SmithEdmonton, Alberta

Dr Connie SwitzerEdmonton, Alberta

Dr Diane TaylorEdmonton, Alberta

Dr Alan ThomsonEdmonton, AlbertaDr Scott Whittaker

Vancouver, British ColumbiaDr Gary Wild

Montreal, QuebecDr Robert Woodland

St John’s, NewfoundlandMs Gloria Zaror-Behrens

Ottawa, OntarioMr Remi Corbeil (Abbott)Mr Joe Manning (Abbott)Ms Wendy Smith (Astra)

Mr Rob Chouinard (Astra)Ms Krista Nevin (Astra)

Ms Yves Levasseur (Axcan)Mr Neil Mellor (Solvay)

APPENDIX 1Participants in the Canadian Helicobacter Study Group meeting, Ottawa, Ontario, June 22 to 24, 2001

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Etiology of dyspepsia: Implications for empirical therapydownloads.hindawi.com/journals/cjgh/2002/679683.pdf · 2019-08-01 · Can J Gastroenterol Vol 16 No 9 September 2002 635 REVIEW