Dyspepsia (printer-friendly)

http://www.medscape.com/viewarticle/584173_print Authors and Disclosures
Eamonn M.M. Quigley, John Keohane, Alimentary Pharmabiotic Centre, University College Cork, Cork,
Ireland
From Current Opinion in Gastroenterology
Dyspepsia
Eamonn M.M. Quigley; John Keohane
Posted: 12/12/2008; Curr Opin Gastroenterol. 2008;24(6):692-697. 2008 Lippincott Williams & Wilkins Abstract and Introduction
Abstract
Purpose of Review: This review critically evaluates the current status of dyspepsia and, in particular, recent
advances in epidemiology, pathophysiology and management. The very definition of dyspepsia and of functional
dyspepsia, in particular, continues to generate controversy; the Rome III redefinition of functional dyspepsia
remains to be proven to be of clinical value. Overlap with gastroesophageal reflux and irritable bowel syndrome
further complicate clinical definitions.
Recent Findings: Most studies of pathophysiology continue to focus on gastric sensory and motor functions,
though some intriguing early data raise the possibility of an infective or immunological contribution. There have
been few, if any, major breakthroughs in treatment; most recent studies address instead the niceties of
Helicobacter pylori eradication and acid suppressive strategies.
Summary: This continued lack of progress in the area can only lead one to question some very basic concepts
in this disorder, such as does functional dyspepsia, as we have come to know it, really exist as a distinct entity?
Introduction
Although the term 'dyspepsia' is widely used in the medical literature, it has been variably interpreted byclinicians and investigators alike. In the English language, it can be most readily translated as 'indigestion', acommonly used lay term, which encompasses a multitude of upper abdominal and lower retrosternal ills.
Therein lies the dilemma of dyspepsia; its very definition. This imprecision becomes even greater when onefocuses on that subgroup currently defined as functional dyspepsia in which an absence of objectiveendoscopic, radiological or pathological findings leaves the clinician dangling by the slim thread that is asymptom-based criterion. It should come as no surprise that functional dyspepsia has become a territoryravaged by pathophysiological confusion and therapeutic famine.
What is Dyspepsia?
In an era when the incidence of gastric cancer and peptic ulcer disease are decreasing, functionalgastrointestinal disorders such as functional dyspepsia and irritable bowel syndrome (IBS) have achievedincreasing prominence in the medical literature. Indeed, a recent study[1••] supports the high prevalence offunctional dyspepsia and IBS in the community and the stability of their prevalence over time.
Before we rush to accept that functional dyspepsia is a major pestilence that must be recognized anderadicated, we must ask ourselves a fundamental question: what is dyspepsia? If we saw it, would we recognizeit? A critical assessment of the literature suggests, surprisingly, that robust clinical definitions for dyspepsiaremain elusive and that this term and its various qualifiers have been interpreted differently by both physicianand patient alike for years. Dyspepsia is a symptom or constellation of symptoms, not a disease, and is, http://www.medscape.com/viewarticle/584173_print therefore, prey to all of the influences that the expression and interpretation of symptoms are subject to.
Language, culture, age, race,[2] psychological factors,[3] past experiences, to mention but a few, will all influencewhat a patient says and how you, as their clinician, interprets them and translates their words into 'medicalese'.
Other factors influence the prevalence of dyspepsia: alcohol intake,[4] cigarette smoking, intake of nonsteroidalanti-inflammatory drugs and socioeconomic status.[5] Although body weight is associated with bothgastroesophageal reflux disease (GERD) and dyspepsia, modest changes in body weight (up or down) do notappear to lead to additional symptoms.[6] Many of these same factors, as well as the severity and frequency ofsymptoms, will determine the patient's response to these symptoms and whether or not he or she decides toconsult a physician.[7••] Despite attempts by numerous committees and consensus groups to agree on a uniform definition, clinical trialscontinue to use different diagnostic terminology, rendering the interpretation of data challenging. The Rome IIcommittee defined functional dyspepsia as the presence of abdominal pain or discomfort centered in theepigastrium and present for at least 12 weeks over the last 12 months, which cannot be explained by uppergastrointestinal investigation.[8] The more recent Rome III definition[9] requires symptoms to be present for thelast 3 months, with symptom onset at least 6 months before diagnosis. In a major shift in emphasis, it alsoproposed that functional dyspepsia comprises at least two distinct subgroups: the postprandial distresssyndrome, which features postprandial fullness and early satiety; and the epigastric pain syndrome, whichfeatures a more constant and less meal-related pain syndrome.[9] Patients with prominent heartburn areexcluded from both Rome definitions. The Rome committee contends that as heartburn and dyspepsia arisefrom separate organs, the esophagus and the stomach, respectively, these entities should be separated inclinical definitions.[9] Such a clear separation is often impossible on clinical grounds given the overlap that existsbetween these disorders; however, it is clearly evident that dyspeptic patients with predominant heartburn arethose most likely to respond to acid suppression, thereby supporting the value of identifying the predominantsymptom in a given patient.[10] What has led to such a dramatic shift in definition between the Rome II and Rome III criteria? Such variations,within the same essential framework, are reflective of basic difficulties in the clinical categorization of 'dyspeptic'symptoms. Symptoms are poor predictors of cause; Moayyedi et al.,[11] for example, demonstrated that neitherthe clinical impression of a primary care physician or specialist nor patient input into a computer model were ofreal value in distinguishing between organic and functional dyspepsia. Clinical trials conducted in patientpopulations with uninvestigated dyspepsia are likely, therefore, to be heterogeneous and may comprise somewith GERD and peptic ulcers and others with functional dyspepsia. Thus, clarity of definition is mandatory;uninvestigated dyspepsia needs to be clearly differentiated from functional dyspepsia and dyspepsia of organiccausation. Although Rome III offers another opportunity for investigators to link symptom pattern withpathophysiology and treatment response, initial reports suggest that the new classification can lead to theidentification of distinct subgroups in the community;[12] whether this will translate into prediction ofpathophysiology or treatment response, remains to be seen. Functional dyspepsia can be a significant problem;in one tertiary care-based study,[13] the impact on quality of life was more severe than that related to chronicliver disease, with comorbid anxiety and depression contributing considerably.
Overlap With Gastroesophageal Reflux Disease and Irritable Bowel Syndrome
We contend that attempts to separate GERD, IBS and dyspepsia are not only clinically challenging but alsounrealistic. Clinical experience, as well as numerous prospective studies, attests to the frequency with whichfunctional dyspepsia and GERD coexist. This topic has been reviewed by us elsewhere recently; suffice it to saythat the overlap between functional dyspepsia and GERD is greatest for those with nonerosive disease andespecially so for those with what is now termed functional heartburn (i.e. those in whom there is no evidentassociation between symptoms and acid exposure).[14] It is thought that the clinical spectrum that extends fromfunctional dyspepsia to nonerosive reflux disease (NERD) may be present in up to 70% of GERD patients in thecommunity. These clinical entities have a considerable socioeconomic impact, with £250 million spent annuallyby UK general practitioners in the treatment of upper gastrointestinal disease, including GERD.[15] It is verydifficult to estimate the true prevalence of the functional dyspepsia-NERD overlap syndrome due to the lack of http://www.medscape.com/viewarticle/584173_print uniformity in the definitions used. El-Serag and Talley[16] found that the prevalence of uninvestigated dyspepsiaranged from 10 to 40% when they used a more inclusive definition of dyspepsia, which incorporated heartburnand regurgitation; when the definition was restricted to upper abdominal pain alone, the prevalence fell to5-12%. This study also demonstrated that dyspepsia is, indeed, a worldwide problem and that the majority ofpatients with uninvestigated dyspepsia actually fall into the functional dyspepsia group.
It is apparent that, irrespective of the definitions used, both functional dyspepsia and NERD are interrelated andcommonly encountered conditions in the community that have an impact on quality of life equivalent tocomplicated GERD, and, therefore, warrant appropriate treatment and investigation. A further reflection ofoverlap with GERD is the observation that functional dyspepsia patients swallow more air and, not surprisingly,are more likely to reflux air.[17] Overlap with IBS is equally prevalent and may prove even more challenging to differentiate. Constipation delaysgastric emptying and is commonly accompanied by upper gut symptoms; similarly, bowel symptoms arecommon in functional dyspepsia. Pain location is commonly used to differentiate between these disordersthough the topography of pain location in IBS would suggest that overlap is very likely. Longitudinal studies ofthe behavior of functional gastrointestinal disorders also attest to overlap between functional dyspepsia and IBS;over 12 years of follow-up, 40% of patients with functional dyspepsia or IBS had switched symptomatology.[1••]Perhaps the time has come to jettison attempts to separate these disorders and instead, given the overlap thatexists in symptoms and purported pathophysiologies, recognize IBS and functional dyspepsia as part of aspectrum.
Functional Dyspepsia: Pathophysiology
For some time, dysmotility has been the prime focus of interest in functional dyspepsia and a variety of motorabnormalities have been described, including delayed gastric emptying, impaired fundic accommodation, antraldistension, unsuppressed postprandial fundic contractility and duodenal dysmotility.[18] Although somecorrelations between individual motor abnormalities and symptom patterns have been borne out,[19] individualsymptoms remain a poor predictor of motor events (and vice versa) and the delineation of a motor deficit hasnot opened the therapeutic avenues once envisaged. This is most clearly illustrated by the disappointment ofprokinetic agents.[20••] Several explanations may be advanced to explain this frustrating lack of progress: theheterogeneity of the patient population, the interrelationships that exist between all manifestations of gastricmotor activity rendering it difficult to isolate one phenomenon and the lack of selectivity of available agents, notto mind the potential influence of stress and other central and neurohumoral factors. In regard to the latter, it hasbeen shown that corticotropin-releasing hormone reduces basal fundic tone[19] and that ghrelin levels are lowerin functional dyspepsia, independent of gastric emptying rate.[21] As an extension of the latter finding, Akamizuet al.,[22] by administering ghrelin, were able to increase hunger and show a trend towards an increase in weightgain among six patients with functional anorexia who fulfilled criteria for functional dyspepsia. Finally, it mustalso be remembered that accelerated, as well as delayed, gastric emptying can cause dyspeptic symptoms.[23] Visceral hypersensitivity plays a major role in all functional disorders and is thought to be present in 30-40% ofpatients with functional dyspepsia based largely on the rather invasive barostat technique. The majority offunctional dyspepsia patients describe their symptoms as being most prominent after food ingestion; the lessinvasive water load test has, therefore, been widely employed as a surrogate to assess the response of thestomach to distension. Using this approach, van den Elzen et al.[24] were able to show that, whereas antraldistension limited water intake in functional dyspepsia, other symptoms such as bloating, pain and fullness weremore closely related to the volume of the proximal stomach. One therapeutic approach that has been utilized infunctional dyspepsia, as in other functional disorders, is the use of low-dose antidepressant therapy. The precisemode of action of these compounds in this setting is unclear. Choung et al.[25] could find no effect of low-dosenortriptyline or mirtazapine on satiation or gastrointestinal symptoms in response to a nutrient load in healthyvolunteers.
Aberrant cerebral processing of visceral stimuli and visceral events has been well documented in functional http://www.medscape.com/viewarticle/584173_print disorders of the esophagus and intestine but, until recently, was scarcely explored in functional dyspepsia. Now,Vandenberghe et al.[26••] have shown that, although functional dyspepsia patients and control participants bothactivate the lateral pain system in response to gastric distension, the medial pain system is not activated infunctional dyspepsia. Furthermore, activation of components of the lateral pain system occurs at lowerdistending pressures among those functional dyspepsia patients who demonstrate evidence of visceralhypersensitivity.
In recent years, other avenues of pathophysiology have been explored in IBS, including genetics and thepotential roles of infection and inflammation; some interest is now being shown in these areas in functionaldyspepsia. Although evidence to date does not suggest a significant genetic contribution to functionaldyspepsia,[27] some evidences have emerged to suggest an interaction between polymorphisms of genesresponsible for components of the immune response and Helicobacter pylori infection among some patientswith functional dyspepsia.[28] Others have shown differences in the phenotype of intraepithelial lymphocytes inH. pylori-negative functional dyspepsia patients[29] and others still prominent eosinophils in the first and secondparts of the duodenum.[30••] The precise significance of these findings remain unclear; they do not appear torepresent, at least in the case of eosinophilia, part of a generalized eosinophilic disorder;[30••] whether theyreflect the mucosal response to some luminal factor remains to be defined. These findings not only raise newpossibilities in the pathogenesis of functional dyspepsia but also reinforce the importance of the duodenum inthis disorder.
Dyspepsia: Management Strategies
What of the management of dyspepsia? In the patient with uninvestigated dyspepsia, the clinician may choosefrom a number of management approaches: test for H. pylori and treat accordingly (the so called 'test and treat'approach), proceed forthwith to endoscopy, or treat empirically with a proton pump inhibitor. In the latestupdates of the Cochrane Collaboration Reviews on the pharmacological treatment for and the impact of H.
pylori on dyspepsia, Moayyedi et al.[31,32] consider the relative merits of each of these approaches inconsiderable detail and conclude, first, that proton pump inhibitors (PPIs) are effective in the treatment ofdyspepsia and, second, that although early endoscopy and H. pylori testing may benefit some patients, thisapproach is not cost effective. In a head-to-head comparison of the two approaches, Ford et al.[33] found that'test-and-treat' was more cost effective than prompt endoscopy, though the latter was marginally more likely toresult in a cure. Clearly, several factors will influence the choice of approach in a given patient, including, ageand gender, as well as the background prevalences of H. pylori positivity, peptic ulceration and gastric cancer.
The impact of the prevalence of H. pylori was nicely demonstrated by Barton et al.[34] who found that empiricPPI therapy was the most cost-effective approach among younger patients in whom infection was less likely,although a 'test-and-treat' strategy was more effective among 60 year olds. Endoscopy was the leastcost-effective strategy across all age groups. In relation to endoscopy, it is also important to note that, whenformally tested, the 'reassurance value' of a negative endoscopy could not be demonstrated in patients withfunctional dyspepsia.[35] In contrast, others found that a patient's knowledge of their H. pylori status led to lessrecourse to healthcare services in the following year.[36] Traditionally, the clinician has also relied on the identification of 'alarm' symptoms to guide the initialmanagement of the dyspeptic patient; the recent meta-analysis by Vakil et al.[37] makes for sobering reading inthis regard. These authors found 'alarm' features poorly predictive of malignancy, with their sensitivity varyingfrom zero to 83% and specificity from 40 to 98%. Although the clinical diagnosis of the clinician was very specific(97-98%), it was poorly sensitive (11-53%). These findings further reinforce the vague nature of the concept ofdyspepsia.
What of the management of the patient who is deemed to have functional dyspepsia? Here, the options narrowfurther. Again we have the conclusions of an updated Cochrane Review to guide us. Of the various therapiesevaluated, only prokinetics [relative risk reduction (RRR) 33%, 95% confidence interval (CI) 18-45%] and PPIs(RRR 13%, 95% CI 4-20%) were judged to have a significant benefit.[31] The benefits for all agents were,however, small. It is important to note that they expressed a concern that the prokinetic result could have been http://www.medscape.com/viewarticle/584173_print favorably influenced by publication bias. Furthermore, some of these prokinetic agents have been withdrawnand others have never been approved for use in the United States. Hiyama et al.[20••] came to a similarconclusion and also pointed out that benefit for prokinetics had, for the most part, been shown in short-termstudies only.
The overlap between GERD and functional dyspepsia undoubtedly influences the response to PPIs given thatthe 'overlap patient' most likely to respond to PPI therapy is the functional dyspepsia patient with heartburn.
Similarly, a failure to exclude (or, perhaps the impossibility of excluding) all GERD patients from some functionaldyspepsia studies may explain the response to PPIs in functional dyspepsia. Similarly, in a recentmeta-analysis,[38] the benefits of PPI therapy in functional dyspepsia accrued only to those who were classifiedas 'reflux-like' or 'ulcer-like' and not to those who were 'motility-like'. Just as the presence of GERD symptomsmay predict PPI responsiveness, the prominence of IBS-type symptoms augurs failure.[39] Overall, PPIs dowork in dyspepsia, albeit in a minority of patients. For example, in a large population with heartburn, epigastricpain, or both symptoms, PPI therapy or a 'test-and-treat' strategy were equally effective at 1 year in terms ofsymptom resolution, impact on quality of life and cost effectiveness.[40] Unfortunately, an early response (i.e. 1week) to PPI is not very predictive of long-term outcome.[41,42] Given the relative ineffectiveness of PPI therapy in functional dyspepsia, as well as the reported prevalence ofmotor dysfunction in many of these patients, efforts have continued to find a prokinetic or motility-modulatingagent that offers therapeutic benefit. Hopes were raised by a positive phase II study in functional dyspepsia witha new generation prokinetic agent, itopride,[43] only to be dashed by two subsequent and, as yet, unpublishednegative phase III studies. Efforts continue to find a fundic relaxing agent that not only relieves symptoms butalso has a favorable adverse event profile.[44] The benefits of identifying those functional dyspepsia patients who are H. pylori positive and proceeding toeradication have also been assessed in several studies and meta-analyses with conflicting results. Theconfusing literature on this topic may be best summarized as demonstrating, at best, a small long-term (i.e. at12 months) increase in cure rate among the eradicated but at the cost of testing and prescribing triple therapyfor a very large number of functional dyspepsia patients who do not derive benefit.[45] Other factors such as adesire to prevent gastric cancer may dictate strategies.
What options are left to the frustrated and disappointed patient and physician? Talley[46] suggests turning to acentral approach at this stage. In this regard, one is basing one's decisions more on clinical experience andextrapolation from IBS rather than on substantive evidence. Many, based on their experience in IBS and on thefrequent overlap between IBS and functional dyspepsia (especially among those who are not responders toPPIs), as well as some data, will try either an antidepressant or an anxiolytic. Again reflecting experience in IBS,melatonin has also been shown to relieve symptoms in functional dyspepsia.[47] A recent meta-analysis[48] aswell as yet another Cochrane review[49] evaluated the impact of psychological interventions in functionaldyspepsia and concluded that there was insufficient evidence to confirm their efficacy, despite reports of benefitsfor both psychotherapy and hypnotherapy in individual studies.
It should come as no surprise in this climate of therapeutic nihilism that functional dyspepsia patients commonlyresort to alternative remedies.[50,51] These are not to be dismissed as some, such the herbal extract, STW 5 oriberogast, have been shown to have modest efficacy in well conducted trials.[52] Conclusion
In summary, precise definitions are needed for dyspepsia and functional dyspepsia, and future trials shouldinclude strict criteria to avoid unnecessary confusion. As we come to understand the pathophysiology of thesecomplex disorders, novel agents (e.g. visceral analgesics) may offer therapeutic hope.
References
http://www.medscape.com/viewarticle/584173_print Papers of particular interest, published within the annual period of review, have been highlighted as:• of special interest•• of outstanding interest 1. Halder SL, Locke GR 3rd, Schleck CD, et al. Natural history of functional gastrointestinal disorders: a 12-year longitudinal population-based study. Gastroenterology 2007; 133:799-807.
•• This study describes in detail the natural history of functional gastrointestinal disorders (FGIDs) and ofIBS and functional dyspepsia, in particular, and demonstrates that, although the point prevalence of bothIBS and functional dyspepsia remained stable over the 12-year study period, there was substantialmovement from one diagnosis to the other over time.
2. Minocha A, Wigington WC, Johnson WD. Detailed characterization of epidemiology of uninvestigated dyspepsia and its impact on quality of life among African-Americans as compared to Caucasians. Am JGastroenterol 2006; 101:336-342.
3. Geeraerts B, Vandenberghe J, Van Oudenhove L, et al. Influence of experimentally induced anxiety on gastric sensorimotor function in humans. Gastroenterology 2005; 129:1437-1444.
4. Halder SL, Locke GR, Schleck CD, et al. Influence of alcohol consumption on IBS and dyspepsia.
Neurogastroenterol Motil 2006; 18:1001-1008.
5. Wildner-Christensen M, Hansen JM, De Muckadell OB. Risk factors for dyspepsia in a general population: nonsteroidal anti-inflammatory drugs, cigarette smoking and unemployment are moreimportant than Helicobacter pylori infection. Scand J Gastroenterol 2006; 41:149-154.
6. Cremonini F, Locke GR, Schleck CD, et al. Relationship between upper gastrointestinal symptoms and changes in body weight in a population-based cohort. Neurogastroenterol Motil 2006; 18:987-994.
7. Ford AC, Forman D, Bailey AG, et al. Who consults with dyspepsia? Results from a longitudinal 10-yr follow-up study. Am J Gastroenterol 2007; 102:957-965.
•• This study identifies factors which lead an individual with dyspepsia to seek medical care.
8. Talley NJ, Stanghellini V, Heading RC, et al. Functional gastroduodenal disorders. Gut 1999; 45(Suppl 9. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology 2006; 10. Veldhuyzen van Zanten SJO, Flook N, Chiba N, et al, and for the Canadian Dyspepsia Working Group.
An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacterpylori. CMAJ 2000; 162:3-23.
11. Moayyedi P, Talley NJ, Fennerty MB, Vakil N. Can the clinical history distinguish between organic and functional dyspepsia? JAMA 2006; 295:1566-1576.
12. Choung RS, Locke GR, Schleck CD, et al. Do distinct dyspepsia subgroups exist in the community? A population-based study. Am J Gastroenterol 2007; 102:1983-1989.
13. Haag S, Senf W, Häuser W, et al. Impairment of health-related quality of life in functional dyspepsia and chronic liver disease: the influence of depression and anxiety. Aliment Pharmacol Ther 2008;27:561-571.
14. Keohane J, Quigley EMM. Functional dyspepsia and non-erosive reflux disease: clinical interactions and their implications. Med Gen Med 2007; 9:31-36.
15. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101:1900-1920.
16. El-Serag HB, Talley NJ. Systematic review: the prevalence and clinical course of functional dyspepsia.
Aliment Pharmacol Ther 2004; 19:643-654.
17. Conchillo JM, Selimah M, Bredenoord AJ, et al. Air swallowing, belching, acid and nonacid reflux in patients with functional dyspepsia. Aliment Pharmacol Ther 2007; 25:965-971.
18. Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of functional dyspepsia.
Gastroenterology 2004; 127:1239-1255.
19. van den Elzen BD, van den Wijngaard RM, Tytgat GN, Boeckxstaens GE. Influence of corticotropin- releasing hormone on gastric sensitivity and motor function in healthy volunteers. Eur J GastroenterolHepatol 2007; 19:401-407.
http://www.medscape.com/viewarticle/584173_print 20. Hiyama T, Yoshihara M, Matsuo K, et al. Meta-analysis of the effects of prokinetic agents in patients with functional dyspepsia. J Gastroenterol Hepatol 2007; 22:304-310.
•• This study nicely summarizes the frustrations of prokinetic studies in functional dyspepsia; overall thereis no benefit for prokinetics; some individual drugs show some modest benefits.
21. Takamori K, Mizuta Y, Takeshima F, et al. Relation among plasma ghrelin level, gastric emptying, and psychologic condition in patients with functional dyspepsia. J Clin Gastroenterol 2007; 41:477-483.
22. Akamizu T, Iwakura H, Ariyasu H, et al, FD Clinical Study Team. Repeated administration of ghrelin to patients with functional dyspepsia: its effects on food intake and appetite. Eur J Endocrinol 2008;158:491-498.
23. Lawal A, Barboi A, Krasnow A, et al. Rapid gastric emptying is more common than gastroparesis in patients with autonomic dysfunction. Am J Gastroenterol 2007; 102:618-623.
24. van den Elzen BD, Bennink RJ, Holman R, et al. Impaired drinking capacity in patients with functional dyspepsia: intragastric distribution and distal stomach volume. Neurogastroenterol Motil 2007;19:968-976.
25. Choung RS, Cremonini F, Thapa P, et al. The effect of short-term, low-dose tricyclic and tetracyclic antidepressant treatment on satiation, postnutrient load gastrointestinal symptoms and gastric emptying:a double-blind, randomized, placebo-controlled trial. Neurogastroenterol Motil 2008; 20:220-227.
26. Vandenberghe J, Dupont P, Van Oudenhove L, et al. Regional cerebral blood flow during gastric balloon distension in functional dyspepsia. Gastroenterology 2007; 132:1684-1693.
•• This study extends observations made with advanced imaging techniques in IBS to functionaldyspepsia.
27. Lembo A, Zaman M, Jones M, Talley NJ. Influence of genetics on irritable bowel syndrome, gastro- oesophageal reflux and dyspepsia: a twin study. Aliment Pharmacol Ther 2007; 25:1343-1350.
28. Arisawa T, Tahara T, Shibata T, et al. Genetic polymorphisms of molecules associated with inflammation and immune response in Japanese subjects with functional dyspepsia. Int J Mol Med 2007; 20:717-723.
29. Gargala G, Lecleire S, François A, et al. Duodenal intraepithelial T lymphocytes in patients with functional dyspepsia. World J Gastroenterol 2007; 13:2333-2338.
30. Talley NJ, Walker MM, Aro P, et al. Nonulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case-control study. Clin Gastroenterol Hepatol 2007; 5:1175-1183.
•• From data generated in a population study in Sweden, the authors report a significant associationbetween duodenal mucosal eosinophilia and dyspepsia.
31. Moayyedi P, Soo S, Deeks J, et al. Pharmacological interventions for nonulcer dyspepsia. Cochrane 32. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for nonulcer dyspepsia. Cochrane 33. Ford AC, Qume M, Moayyedi P, et al. Helicobacter pylori 'test and treat' or endoscopy for managing dyspepsia: an individual patient data meta-analysis. Gastroenterology 2005; 128:1838-1844.
34. Barton PM, Moayyedi P, Talley NJ, et al. A second-order simulation model of the cost-effectiveness of managing dyspepsia in the United States. Med Decis Making 2008; 28:44-55.
35. van Kerkhoven LA, van Rossum LG, van Oijen MG, et al. Upper gastrointestinal endoscopy does not reassure patients with functional dyspepsia. Endoscopy 2006; 38:879-885.
36. Ford AC, Forman D, Nathan J, et al. Clinical trial: knowledge of negative Helicobacter pylori status reduces subsequent dyspepsia-related resource use. Aliment Pharmacol Ther 2007; 26:1267-1275.
37. Vakil N, Moayyedi P, Fennerty MB, Talley NJ. Limited value of alarm features in the diagnosis of upper gastrointestinal malignancy: systematic review and meta-analysis. Gastroenterology 2006; 131:390-401.
38. Wang WH, Huang JQ, Zheng GF, et al. Effects of proton-pump inhibitors on functional dyspepsia: a meta-analysis of randomized placebo-controlled trials. Clin Gastroenterol Hepatol 2007; 5:178-185.
39. Gwee KA, Hwang JE, Ho KY, et al. In-practice predictors of response to proton pump inhibitor therapy in primary care patients with dyspepsia in an Asian population. J Clin Gastroenterol 2008; 42:134-138.
40. Delaney BC, Qume M, Moayyedi P, et al. Helicobacter pylori test and treat versus proton pump inhibitor in initial management of dyspepsia in primary care: multicentre randomised controlled trial (MRC-CUBEtrial). BMJ 2008; 336:651-654.
http://www.medscape.com/viewarticle/584173_print 41. Talley NJ, Vakil N, Lauritsen K, et al, STARS I Study Group. Randomized-controlled trial of esomeprazole in functional dyspepsia patients with epigastric pain or burning: does a 1-week trial of acid suppressionpredict symptom response? Aliment Pharmacol Ther 2007; 26:673-682.
42. van Zanten SV, Flook N, Talley NJ, et al, STARS II Study Group. One-week acid suppression trial in uninvestigated dyspepsia patients with epigastric pain or burning to predict response to 8 weeks'treatment with esomeprazole: a randomized, placebo-controlled study. Aliment Pharmacol Ther 2007;26:665-672.
43. Holtmann G, Talley NJ, Liebregts T, et al. A placebo-controlled trial of itopride in functional dyspepsia. N 44. Boeckxstaens GE, Tytgat GN, Wajs E, et al. The influence of the novel 5-HT1A agonist R137696 on the proximal stomach function in healthy volunteers. Neurogastroenterol Motil 2006; 18:919-926.
45. Jin X, Li YM. Systematic review and meta-analysis from Chinese literature: the association between Helicobacter pylori eradication and improvement of functional dyspepsia. Helicobacter 2007; 12:541-546.
46. Talley NJ. How to manage the difficult-to-treat dyspeptic patient. Nat Clin Pract Gastroenterol Hepatol 47. Klupin'ska G, Poplawski T, Drzewoski J, et al. Therapeutic effect of melatonin in patients with functional dyspepsia. J Clin Gastroenterol 2007; 41:270-274.
48. Hojo M, Miwa H, Yokoyama T, et al. Treatment of functional dyspepsia with antianxiety or antidepressive agents: systematic review. J Gastroenterol 2005; 40:1036-1042.
49. Soo S, Moayyedi P, Deeks J, et al. Psychological interventions for nonulcer dyspepsia. Cochrane 50. von Arnim U, Peitz U, Vinson B, et al. STW 5, a phytopharmacon for patients with functional dyspepsia: results of a multicenter, placebo-controlled double-blind study. Am J Gastroenterol 2007; 102:1268-1275.
51. Melzer J, Rösch W, Reichling J, et al. Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast). Aliment Pharmacol Ther 2004; 20:1279-1287.
52. Pilichiewicz AN, Horowitz M, Russo A, et al. Effects of Iberogast on proximal gastric volume, antropyloroduodenal motility and gastric emptying in healthy men. Am J Gastroenterol 2007;102:1276-1283.
References
1. Halder SL, Locke GR 3rd, Schleck CD, et al. Natural history of functional gastrointestinal disorders: a 12-year longitudinal population-based study. Gastroenterology 2007; 133:799-807.
•• This study describes in detail the natural history of functional gastrointestinal disorders (FGIDs) and ofIBS and functional dyspepsia, in particular, and demonstrates that, although the point prevalence of bothIBS and functional dyspepsia remained stable over the 12-year study period, there was substantialmovement from one diagnosis to the other over time.
2. Minocha A, Wigington WC, Johnson WD. Detailed characterization of epidemiology of uninvestigated dyspepsia and its impact on quality of life among African-Americans as compared to Caucasians. Am JGastroenterol 2006; 101:336-342.
3. Geeraerts B, Vandenberghe J, Van Oudenhove L, et al. Influence of experimentally induced anxiety on gastric sensorimotor function in humans. Gastroenterology 2005; 129:1437-1444.
4. Halder SL, Locke GR, Schleck CD, et al. Influence of alcohol consumption on IBS and dyspepsia.
Neurogastroenterol Motil 2006; 18:1001-1008.
5. Wildner-Christensen M, Hansen JM, De Muckadell OB. Risk factors for dyspepsia in a general population: nonsteroidal anti-inflammatory drugs, cigarette smoking and unemployment are moreimportant than Helicobacter pylori infection. Scand J Gastroenterol 2006; 41:149-154.
6. Cremonini F, Locke GR, Schleck CD, et al. Relationship between upper gastrointestinal symptoms and changes in body weight in a population-based cohort. Neurogastroenterol Motil 2006; 18:987-994.
7. Ford AC, Forman D, Bailey AG, et al. Who consults with dyspepsia? Results from a longitudinal 10-yr follow-up study. Am J Gastroenterol 2007; 102:957-965.
•• This study identifies factors which lead an individual with dyspepsia to seek medical care.
8. Talley NJ, Stanghellini V, Heading RC, et al. Functional gastroduodenal disorders. Gut 1999; 45(Suppl http://www.medscape.com/viewarticle/584173_print 9. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology 2006; 10. Veldhuyzen van Zanten SJO, Flook N, Chiba N, et al, and for the Canadian Dyspepsia Working Group.
An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacterpylori. CMAJ 2000; 162:3-23.
11. Moayyedi P, Talley NJ, Fennerty MB, Vakil N. Can the clinical history distinguish between organic and functional dyspepsia? JAMA 2006; 295:1566-1576.
12. Choung RS, Locke GR, Schleck CD, et al. Do distinct dyspepsia subgroups exist in the community? A population-based study. Am J Gastroenterol 2007; 102:1983-1989.
13. Haag S, Senf W, Häuser W, et al. Impairment of health-related quality of life in functional dyspepsia and chronic liver disease: the influence of depression and anxiety. Aliment Pharmacol Ther 2008;27:561-571.
14. Keohane J, Quigley EMM. Functional dyspepsia and non-erosive reflux disease: clinical interactions and their implications. Med Gen Med 2007; 9:31-36.
15. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101:1900-1920.
16. El-Serag HB, Talley NJ. Systematic review: the prevalence and clinical course of functional dyspepsia.
Aliment Pharmacol Ther 2004; 19:643-654.
17. Conchillo JM, Selimah M, Bredenoord AJ, et al. Air swallowing, belching, acid and nonacid reflux in patients with functional dyspepsia. Aliment Pharmacol Ther 2007; 25:965-971.
18. Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of functional dyspepsia.
Gastroenterology 2004; 127:1239-1255.
19. van den Elzen BD, van den Wijngaard RM, Tytgat GN, Boeckxstaens GE. Influence of corticotropin- releasing hormone on gastric sensitivity and motor function in healthy volunteers. Eur J GastroenterolHepatol 2007; 19:401-407.
20. Hiyama T, Yoshihara M, Matsuo K, et al. Meta-analysis of the effects of prokinetic agents in patients with functional dyspepsia. J Gastroenterol Hepatol 2007; 22:304-310.
•• This study nicely summarizes the frustrations of prokinetic studies in functional dyspepsia; overall thereis no benefit for prokinetics; some individual drugs show some modest benefits.
21. Takamori K, Mizuta Y, Takeshima F, et al. Relation among plasma ghrelin level, gastric emptying, and psychologic condition in patients with functional dyspepsia. J Clin Gastroenterol 2007; 41:477-483.
22. Akamizu T, Iwakura H, Ariyasu H, et al, FD Clinical Study Team. Repeated administration of ghrelin to patients with functional dyspepsia: its effects on food intake and appetite. Eur J Endocrinol 2008;158:491-498.
23. Lawal A, Barboi A, Krasnow A, et al. Rapid gastric emptying is more common than gastroparesis in patients with autonomic dysfunction. Am J Gastroenterol 2007; 102:618-623.
24. van den Elzen BD, Bennink RJ, Holman R, et al. Impaired drinking capacity in patients with functional dyspepsia: intragastric distribution and distal stomach volume. Neurogastroenterol Motil 2007;19:968-976.
25. Choung RS, Cremonini F, Thapa P, et al. The effect of short-term, low-dose tricyclic and tetracyclic antidepressant treatment on satiation, postnutrient load gastrointestinal symptoms and gastric emptying:a double-blind, randomized, placebo-controlled trial. Neurogastroenterol Motil 2008; 20:220-227.
26. Vandenberghe J, Dupont P, Van Oudenhove L, et al. Regional cerebral blood flow during gastric balloon distension in functional dyspepsia. Gastroenterology 2007; 132:1684-1693.
•• This study extends observations made with advanced imaging techniques in IBS to functionaldyspepsia.
27. Lembo A, Zaman M, Jones M, Talley NJ. Influence of genetics on irritable bowel syndrome, gastro- oesophageal reflux and dyspepsia: a twin study. Aliment Pharmacol Ther 2007; 25:1343-1350.
28. Arisawa T, Tahara T, Shibata T, et al. Genetic polymorphisms of molecules associated with inflammation and immune response in Japanese subjects with functional dyspepsia. Int J Mol Med 2007; 20:717-723.
29. Gargala G, Lecleire S, François A, et al. Duodenal intraepithelial T lymphocytes in patients with http://www.medscape.com/viewarticle/584173_print functional dyspepsia. World J Gastroenterol 2007; 13:2333-2338.
30. Talley NJ, Walker MM, Aro P, et al. Nonulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case-control study. Clin Gastroenterol Hepatol 2007; 5:1175-1183.
•• From data generated in a population study in Sweden, the authors report a significant associationbetween duodenal mucosal eosinophilia and dyspepsia.
31. Moayyedi P, Soo S, Deeks J, et al. Pharmacological interventions for nonulcer dyspepsia. Cochrane 32. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for nonulcer dyspepsia. Cochrane 33. Ford AC, Qume M, Moayyedi P, et al. Helicobacter pylori 'test and treat' or endoscopy for managing dyspepsia: an individual patient data meta-analysis. Gastroenterology 2005; 128:1838-1844.
34. Barton PM, Moayyedi P, Talley NJ, et al. A second-order simulation model of the cost-effectiveness of managing dyspepsia in the United States. Med Decis Making 2008; 28:44-55.
35. van Kerkhoven LA, van Rossum LG, van Oijen MG, et al. Upper gastrointestinal endoscopy does not reassure patients with functional dyspepsia. Endoscopy 2006; 38:879-885.
36. Ford AC, Forman D, Nathan J, et al. Clinical trial: knowledge of negative Helicobacter pylori status reduces subsequent dyspepsia-related resource use. Aliment Pharmacol Ther 2007; 26:1267-1275.
37. Vakil N, Moayyedi P, Fennerty MB, Talley NJ. Limited value of alarm features in the diagnosis of upper gastrointestinal malignancy: systematic review and meta-analysis. Gastroenterology 2006; 131:390-401.
38. Wang WH, Huang JQ, Zheng GF, et al. Effects of proton-pump inhibitors on functional dyspepsia: a meta-analysis of randomized placebo-controlled trials. Clin Gastroenterol Hepatol 2007; 5:178-185.
39. Gwee KA, Hwang JE, Ho KY, et al. In-practice predictors of response to proton pump inhibitor therapy in primary care patients with dyspepsia in an Asian population. J Clin Gastroenterol 2008; 42:134-138.
40. Delaney BC, Qume M, Moayyedi P, et al. Helicobacter pylori test and treat versus proton pump inhibitor in initial management of dyspepsia in primary care: multicentre randomised controlled trial (MRC-CUBEtrial). BMJ 2008; 336:651-654.
41. Talley NJ, Vakil N, Lauritsen K, et al, STARS I Study Group. Randomized-controlled trial of esomeprazole in functional dyspepsia patients with epigastric pain or burning: does a 1-week trial of acid suppressionpredict symptom response? Aliment Pharmacol Ther 2007; 26:673-682.
42. van Zanten SV, Flook N, Talley NJ, et al, STARS II Study Group. One-week acid suppression trial in uninvestigated dyspepsia patients with epigastric pain or burning to predict response to 8 weeks'treatment with esomeprazole: a randomized, placebo-controlled study. Aliment Pharmacol Ther 2007;26:665-672.
43. Holtmann G, Talley NJ, Liebregts T, et al. A placebo-controlled trial of itopride in functional dyspepsia. N 44. Boeckxstaens GE, Tytgat GN, Wajs E, et al. The influence of the novel 5-HT1A agonist R137696 on the proximal stomach function in healthy volunteers. Neurogastroenterol Motil 2006; 18:919-926.
45. Jin X, Li YM. Systematic review and meta-analysis from Chinese literature: the association between Helicobacter pylori eradication and improvement of functional dyspepsia. Helicobacter 2007; 12:541-546.
46. Talley NJ. How to manage the difficult-to-treat dyspeptic patient. Nat Clin Pract Gastroenterol Hepatol 47. Klupin'ska G, Poplawski T, Drzewoski J, et al. Therapeutic effect of melatonin in patients with functional dyspepsia. J Clin Gastroenterol 2007; 41:270-274.
48. Hojo M, Miwa H, Yokoyama T, et al. Treatment of functional dyspepsia with antianxiety or antidepressive agents: systematic review. J Gastroenterol 2005; 40:1036-1042.
49. Soo S, Moayyedi P, Deeks J, et al. Psychological interventions for nonulcer dyspepsia. Cochrane 50. von Arnim U, Peitz U, Vinson B, et al. STW 5, a phytopharmacon for patients with functional dyspepsia: results of a multicenter, placebo-controlled double-blind study. Am J Gastroenterol 2007; 102:1268-1275.
51. Melzer J, Rösch W, Reichling J, et al. Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast). Aliment Pharmacol Ther 2004; 20:1279-1287.
52. Pilichiewicz AN, Horowitz M, Russo A, et al. Effects of Iberogast on proximal gastric volume, http://www.medscape.com/viewarticle/584173_print antropyloroduodenal motility and gastric emptying in healthy men. Am J Gastroenterol 2007;102:1276-1283.
Reprint Address
Eamonn M.M. Quigley, MD, FRCP, FACP, FACG, FRCPI, Department of Medicine, Clinical Sciences Building, Cork University
Hospital, Cork, Ireland Tel: +353 21 490 1228; E-mail: e.quigley@ucc.ie
Curr Opin Gastroenterol. 2008;24(6):692-697. 2008 Lippincott Williams & Wilkins

Source: http://www.medicinreferenser.se/iberogast/eamon_08.pdf