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Nonulcer Dyspepsia
HELICOBACTER PYLORI, PART I1
0889-8553/00 $15.00
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NONULCER DYSPEPSIA Current Concepts and Management Deirdre A. Mc Namara, MB, MRCPI, Martin Buckley, MD, MRCPI, and Colm A. OMorain, MD, FRCPI
Dyspepsia is a common condition, reported to affect 40% of the adult population in the developed world annually, with an estimated incidence of 8%. Dyspepsia accounts for 2% to 3% of all general practice consultations. It has been estimated that only 10% of sufferers seek medical advice, and 22% of these are referered to a specialist. Older patients are more likely to present, probably because of concern about the possibility of significant underlying pathology. Nonulcer dyspepsia (NUD)is the underlying diagnosis in a considerable proportion of individuals with dyspepsia. The prevalence is highest in young patients (younger than 25 years old), but in patients older than age 60 with dyspepsia, 20% have a normal endoscopy. NUD comprises a symptom complex referable to the upper gastrointestinal tract that persists for longer than 4 weeks, for which neither a biochemical nor structural abnormality can be identified. Diagnostic criteria were established by the Rome Consensus Committee in 199159and were updated in 1998 in Vienna. The cause of NUD appears to be multifactorial, and different mechanisms may result in different subtypes of disease, which have been subgrouped on the basis of the predominant symptom type-ulcerlike, refluxlike, and dysmotilitylike. The management of NUD is varied depending on the cause and individual response to treatment. The role of Helicobacter pylori infection in the pathogenesis and treatment of NUD is an area of ongoing avid research and remains controversial. Patients with NUD are more likely to be infected than asymptomatic individuals, and there is evidence to show benefit, in at least a subset of sufferers, after eradication of H. pylori. Dyspepsia causes considerable morbidity and has substantial socioeconomicimplications, as a result of workdays lost and the expense of medical investigations and treatment. The estimated total cost of dyspepsia to the United States in 1993 was greater than $14 million.
From the Adelaide & Meath Hospital, Trinity College, Dublin, Ireland
GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 29 * NUMBER 4 * DECEMBER 2000
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DEFINITION
NUD or functional dyspepsia is a term used to describe patients with symptoms referable to the upper gastrointestinal tract that persist for more than 3 months and for whch no biochemical or structural abnormality is detected?,59 NUD is a diagnosis of exclusion, necessitating blood tests and imaging to rule out gallbladder disorders and endoscopy to rule out peptic ulcer disease, reflux, or other underlying mucosal pathology. In particular, there is some overlap with the other major functional gastrointestinal disorder, irritable bowel syndrome, which should be excluded on the basis of symptoms according to the Rome criteria. The presence of H. pylori-induced gastritis does not preclude a diagnosis of NUD. Varied symptoms are attributable to NUD, and these have been grouped into subtypes based on the predominant symptom complex-ulcerlike, refluxlike, and dysmotilitylike (Table 1).In general, there is a large overlap between these groups.61Attempts to link underlying cause or response to treatment according to subtype have been controversial. NUD is a heterogeneous condition with marked differences in symptom preponderance and severity among individuals, and this has posed difficulty for researchers in this area. Increasingly the diagnostic criteria proposed by the Rome consensus committee have been adopted. There are pitfalls in assessing the response to treatment in patients with NUD. It is essential that response be assessed by a specific, accepted dyspepsia score, fulfilling the criteria of reproducibility, responsiveness, and ~a1idity.I~. 70 EPIDEMIOLOGY
NUD is a common condition worldwide. The exact incidence is difficult to quantify because most sufferers do not consult a Population-based studies have been performed, screening for dyspepsia using a questionnaire and subsequently investigating positive subjects. In one study involving 2027 individuals, 10.6% to 17.2%were found to have NUD.6 Other investigators have reported an incidence of NUD in dyspeptic patients of 7% to 38%. NUD occurs more frequently in younger patients (38%in patients younger than 25 years old) 35 compared with older patients (3% to 7% in patients older than 60 years Table 1. SYMPTOM SUBGROUPS OF NONULCER DYSPEPSIA
Ulcerlike dyspepsia
Refluxlike dyspepsia
Dysmotilitylike dyspepsia
Nonspecific dyspepsia
Epigastric pain Nighttime pain Pain related to meals Pain relieved by antacids Heartburn Water brash Belching Exacerbation by lying or stooping Nausea Retching or vomiting Bloating Early satiety Postprandial fullness Combinations of the above symptoms
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NUD has been associated with a positive family history of dyspepsia and of peptic ulcer. The incidence is similar among men and women but varies regionally. CAUSE
The cause of NUD is multifactorial (Table 2). Abnormalities of visceral perception, motor dysfunction, gastric acid secretion, psychologic stress, and environmental factors all have been implicated.61There is abundant research in this area, but as yet the exact underlying pathophysiological mechanisms have not been identified. Gastric emptying has been examined by various means in patients with NUD; there appears to be a delay in gastric emptying after ingestion of a meal in 45% of ~ufferers.'~, 37, 43, 71 Treatment with cisapride, a prokinetic agent, results in significant symptom improvement in some of these patient^.^ Attempts to link this mechanism with a distinct subgroup of patients have been unsuccessful. Some patients with NUD show altered visceral perception as assessed by inflation of an intragastric balloon when compared with nondyspeptic matched controls.42Perception also is altered in the proximal small intestine in these patients. Subsequent work found that in a proportion of sufferers there is a defect in efferent vagal function as shown by the production of pancreatic polypeptide in response to hypoglycemia.28The role of altered visceral perception remains to be clarified. Alteration in gastric acid secretion has been shown in patients with NUD who are infected with H. pylori. El-Omar et all9 showed that patients infected with H. pylori regardless of the underlying diagnosis had higher stimulated gastric acid output than controls. Patients with duodenal ulceration show a sixfold increase, whereas patients with NUD and H. pylori infection show a significant increase but to a lesser extent. Gastrin-stimulated acid secretion levels for duodenal ulcer, NUD, and H. pylori-positive controls were 39.1, 29.6, and 19.0. These findings suggest that approximately 50% of subjects with NUD have a disturbance in gastric acid secretion similar to duodenal ulcer patients. The role of psychologic stress and personality traits in the pathophysiology of functional gastrointestinal disorders is controversial. Alterations in autonomic activity and motility, linked to these disorders, have been associated with stress, 31 An association with alterations in central serotonin conflicts, and aggression.29, function and seretoninergic sensitivity has been postulated. Using a buspirone challenge, Chua et all7showed that patients with NUD were overly sensitive to serotonin, and this has been linked to delayed gastric emptying. There is conflicting evidence, however, using DL-fedUramine challenge.64 Environmental factors have been implicated, including smoking and other dietary factors and socioeconomic statusa A major environmental contributory factor is H. pylori infection, which is considered separately.
Table 2. CAUSES OF NONULCER DYSPEPSIA
Gastric physiology Nociception Motor dysfunction Central nervous system dysfunction Psychologic Environmental
t Gastric acid secretion t Visceral perception of distention
.1 Gastric emptying T' ' Serotonin sensitivity t Stress, conflicts, aggression 7 H. pylori, smoking
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No clear association between any of these causative factors and NUD subgroup or response to treatment has been shown. A combination of factors probably is responsible in variable proportions in any individual. As such, which treatment would be effective also varies among patients. HELICOBACTER PYLORI INFECTION
H. pylori infection has been linked causally with peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Association of H. pylori with NUD is controversial. There is strong epidemiologic evidence to support a role for H. pylori in the cause of NUD, and appropriate pathophysiological mechanisms have been explored. There is evidence to show that in at least a subset of patients, eradication of H. pylori results in symptom improvement in the long-term. The evidence is not equivocal, however. Epidemiology
Studies have shown that almost 50% of patients who present with NUD are
H.pylori positive. In Western countries, studies have reported prevalence rates of 39% to 87%.’”30, 51, 58 The prevalence of H. pylori infection is accepted to be higher in patients with NUD than in asymptomatic controls. A meta-analysis reported that subjects with NUD are twice as likely to be H. pylori positive compared with controls? Whether this association is related to symptom development is debated. Symptoms
There is evidence to show that H. pylori infection precedes the onset of symptoms in dyspeptic patients. Parsonnet et a147showed in a cohort of epidemiologists that H. pylori infection was present before the development of symptoms and that subjects who seroconverted were 4 times more likely to develop dyspepsia. A more recent study involving 3589 subjects reported that those who were positive for H. pylori were more likely to complain of heartburn (odds ratio, 1.26), abdominal pain (odds ratio, 1.33), and nocturnal pain (odds ratio, 1.62). Individuals who were IgG positive for H. pylori but asymptomatic at study entry were at a significantly increased risk of developing symptoms during the study follow-up (odds ratio, 1.71)22Recurrence of H. pylori infection after successful treatment is uncommon; a report from Taiwan revealed that during a follow-up of 1 year, 3% of patients who were treated for duodenal ulceration became reinfected and that reinfection was associated with a recurrence of symptorns,l6 supporting a role for H. pylori infection in the development of dyspeptic symptoms. Attempts to associate H. pylori infection with a subgroup of symptoms have been disappointing. Several have not found a significant difference in the presence or absence of dyspeptic symptoms based on H. pylori ~tatus.2~, 56, The issue remains to be clarified. Pathophysiology H. pylori infection is associated with an active chronic gastritis, which is characterized by a neutrophilic infiltrate and the production of inflammatory
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mediators. The relationship between H. pylori infection and the possible causative processes in NUD has been examined (Table 3). Gastric Acid Secretion
Acid secretion is enhanced in patients who are infected with H. pylori compared with controls. As previously stated, patients who are H. pylori positive have a higher gastrin-stimulated gastric acid secretory response compared with H. pylori-negative subjects with NUD. Gastric Motor Dysfunction
Delayed gastric emptying has been documented in NUD. The effect of H. pylori infection on gastric emptying is confusing. Most studies have reported no association between H. pylori and altered gastric motility.25,68 There are reports with conflicting results to suggest an accelerated and a decreased gastric emptying in response to meals.'" 42 A Japanese group has shown that in patients with delayed gastric emptying, cure of infection resulted in a return to normal transit times with resultant symptom impr0vement.4~ Nociception
The effect of H. pylori on visceral perception is diverse. Chronic inflammation could result in an alteration of enteric neuromuscular function or afferent or efferent signaling in response to normal stimuli.= Current data fail to show that NUD patients with H. pylori infection have more sensitive mucosa to acid or bile installati~n.~~ Treatment Studies
Evidence to show an improvement in symptoms in patients after eradication of H. pylori infection strongly supports a causal link between H . pylori and NUD (Table 4). The evidence is not clear-cut, however. Many studies assessing the possible therapeutic benefits of H. pylori eradication in patients with NUD have been flawed. Clinical trials in NUD do not have an objective endpoint. Symptom improvement is the main outcome measure, which is subjective, and it is essential that a validated method of quantifying dyspepsia symptoms is employed. The duration of follow-up also is important because there is a considerable placebo response to treatment in the short-term (30% to 60%).46Many studies have had an insufficient follow-up to determine the true effect of eradication therapy versus placebo.
Table 3. POSSIBLE HELlCOBACTER PYLORFINDUCED PATHOPHYSIOLOGICAL MECHANISMS IN NONULCER DYSPEPSIA Smooth muscle dysfunction Gastric peptides Nociception Central nervous dysfunction
Altered gastric emptying T Acid secretion T Substance P J. Somatostatin f Prostanoids Gut-brain-gut axis
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Table 4. HELlCOBACTER PYLORl TREATMENT STUDIES IN NONULCER DYSPEPSIA Study
No. Subjects
FoIIow-UP (mo)
Symptom Improvement
TrespP7 Veldhuyzen van Zanten69 Fertolaniso FrazzonP McCarthp EltaZo Sheus Gilvarry" Blum (OCAY)* Talley (ORCHID)" McCol14'
20 49 48 20 75 26 41 49 328 237 308
6 6 8 10 12 34 12 12 12 12 12
Yes No Yes No Yes No Yes Yes No No Yes
Previously, several studies were reported and examined in a meta-analysis by Laheij et a133in which 10 adequately structured studies were identified. Overall, 73% of patients who became H. pylori negative and 45% who remained H. pylori positive after treatment had significant symptom improvement. Symptom improvement was observed in the short term in patients with persistent irifection, consistent with a placebo effect. Large multicenter placebo-controlled trials have since been published2Of22 40, 50, 53, 67, 69 The OCAY (Omeprazole plus Clarithromycin and Amoxicillin: Effect one year after treatment) study involved 328 patients, and the treatment group received proton-pump inhibitor-based triple therapy. Patients were followed for 1 year. There was no significant difference in symptom improvement between the two groups (27.4% versus 20.7%). In the treatment group, there was no difference in outcome between those who were treated successfully and those who remained H. pylori positive.* Similar results were reported by the ORCHID group. Complete symptom resolution occurred in 24% who received treatment and in 22% of the placebo group. Further analysis based on symptom subgroup revealed no benefit from active treatment. The ORCHID study did report a sigruficant symptom improvement for patients with no or mild gastritis at the end of 1 year (32% and 17%; R0.008). Forty-one patients had mild or no gastritis; as expected, most were in the active treatment group.6oConflicting evidence is provided by another welldesigned single-center study from Glasgow. McColl et a141reported a sigruficant difference in symptom resolution between treatment and placebo groups (21% and 7%). Patients with a symptom duration before study entry of less than 5 years were more likely to respond to treatment? Work performed in the authors' institution involving a 1-year follow-up found results similar to the Glasgow group with regard to complete symptom res0lution.2~ The role of H. pylori in NUD is not as definite as for other diseases, such as peptic ulcer, and treatment cannot guarantee improvement. The evidence suggests that using eradication therapy results in a sigruficant resolution of symptoms, compared with placebo, for a proportion of patients, possibly as a result of healing associated gastritis. As yet, it is not possible based on symptom subtype or by any other means to identify patients who would benefit. MANAGEMENT
The treatment of NUD is difficult and involves instigating changes in lifestyle and symptomatic treatment with antacids, prokinetics, or antiserotonin-
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ergic agents, the initial choice depending on the predominant symptom group. Patients with NUD present with dyspepsia. With the increasing availability of noninvasiv H. pylori tests and the economic benefits of empiric treatment of dyspepsia, the management of NUD is related integrally to how one treats dyspepsia. Several management strategies have been explored. The underlying diagnosis reported in young patients (<45 years old) who have undergone endoscopy is gastroesophageal reflux (32%),peptic ulcer (18%), NUD (43%),and gastric cancer (0.05%). The prevalence of serious underlying pathology, such as gastric cancer, increases with age and is infrequent in young patient^.^, 12,26, 38, 57 H. pylori infection is associated with peptic ulcer and NUD. The management of dyspepsia should include strategies to diagnose and treat H. pylori infection. Empiric Therapy
Previously the standard management of dyspepsia on first presentation depended on addressing lifestyle issues and a therapeutic trial of acid-lowering agents. Although the rationale for this approach is not evidence based, there is evidence to indicate that greater acid suppression is beneficial to some patients.49 Early Endoscopy
Some reports show that prompt endoscopy is beneficial to patients and is more effective than empiric treatment. In one report, patients who underwent early endoscopic investigation benefited from positive reassurance, which resulted in less time lost from work, a reduced need for medications, and an overall improvement in symptoms.59This study was performed without reference to H. pylori status. The availability and cost of endoscopy services promotes the use of empiric therapy initially. Test and Treat or Test and Scope
The availability of effective and affordable noninvasive tests for H. pylori, including I3C-ureabreath testing, laboratory or office-based serologic tests, and stool antigen assays, has led to the development of new approaches to dyspepsia management (Fig. 1).66 Strategies that have been proposed include a test and scope policy. This policy involves noninvasive H. pylori testing followed by empiric treatment for H. pylori-negative patients and endoscopy for H. pyloripositive patients to document significant underlying pathologyll. 48 One report of a test and scope policy revealed that endoscopy workload was reduced by one third, while being safe and effective. Subsequently a test and treat strategy has been advocated and examined based on the premise that a large proportion of young patients with dyspepsia who are H. pylori positive have peptic ulcer disease or NUD and would benefit from empiric eradication therapy; endoscopy is reserved for patients who are negative for H. pylori infection. A similar reduction in endoscopy workload has been reported for test and treat and test and scope regimens (37%).3,9, 72 Cost-Effectiveness
The aforementioned management strategies have been shown to result in significant cost savings.18 Silverstein et a154showed that noninvasive H. pylori
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7 r--
symptomatic therapy
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c Treat ABx
Figure 1. Test and treat management strategy. Hp = He/icobacterpy/ori,ABx = antibiotics; UBT = urea breath test.
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testing and subsequent treatment of H. pylori-positive patients is less costly when compared with endoscopy for all but more expensive than global empiric treatment of dyspepsia. There was little difference in the overall long-term cost between endoscopy or empiric therapy for all subjects. An additional report by S ~ n n e n b e r gconcluded ~~ that if only 10% of patients with NUD responded to H. pylori eradication, noninvasive testing and treatment would be cost-effective, as a result of symptom improvement and the prevention of peptic ulcer development. Consensus Three consensus meetings have reported findings on how a patient with dyspepsia should be managed: Maastricht/ European, Canadian, and American. The Maastricht group examined the best currently available data and were in favor of a test and treat strategy for younger patients without alarm symptoms.65 The Canadian and American groups were less definite.lS3O In their view, the evidence for a significant benefit being obtained by H. pylori treatment in NUD was equivocal, and the risk of side effects from treatment and the development of resistant strains was considerable. The suggestion was that possible benefits and problems should be considered on a case-by-case basis. The success of any particular approach depends on the incidence of H. pylori in the community, the availability of endoscopy and noninvasive H. pylori tests, and referral practices. There is evidence to support a selective (based on H. pylori status) empiric treatment regimen. SUMMARY
NUD is a common heterogeneous condition with a multifactorial cause. NUD is a cause of considerable morbidity with an annual incidence of 8% and similar incidence of spontaneous resolution.& Its economic effects are considerable. The estimated annual cost to the community of NLJD is $431 per patient for the initial 6 months after diagnosis. The annual Health Maintenance Organization (HMO) expenditure on acid-related disorders in one Northern California HMO was estimated to be $59.4 million, of whch NUD represented a significant proportion.34The association of H. pylori infection with NUD is controversial. There are strong epidemiologic evidence and supportive pathophysiological mechanisms to implicate H. pylori causally in a subset of cases. Treatment studies are likewise conflicting. Evidence suggests that treatment cannot guarantee improvement in all cases of H. pylori-related NUD but that a subset would benefit with complete symptom resolution in the long term. It is not possible currently to predict which patients would or would not respond to eradication therapy. The strength of evidence is such that empiric eradication therapy, based on noninvasive H. pylori testing, can be advocated in young patients with dyspepsia safely and effectively with resultant financial savings. References 1. American Gastroenterological Association: American Gastroenterological Association medical position statement Evaluation of dyspepsia. Gastroenterology 114:579, 1998 2. Armstrong D: Helicobacter pylori infection and dyspepsia. Scand J Gastroenterol 3l(suppl215):38, 1996
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3. Asante MA, Mendall M, Pate1 P, et al: A randomised trial of endoscopy versus no endoscopy in the treatment of seronegative Helicobacter pylori dyspepsia. Eur J Gastroenterol Hepatol 10:983, 1998 4. Ayoola EA, al-Rashed RS, al-Mofleh IA, et al: Diagnostic yield of upper gastrointestinal endoscopy in relation to age and gender: A study of 10,112 Saudi patients. Hepatogastroenterology 43:405, 1996 5. Barbara L, Camilleri M, Corinalesi R, et al: Definition and investigation of dyspepsia: Consensus of an international adhoc working party. Dig Dis Sci 34:1272, 1989 6. Bemeasen 8, Johnsen R, Straume B: Non-ulcer dyspepsia and peptic ulcer: Their distribution in a population and their relation to risk factors. Gut 38:822, 1996 7. Besherdus K, Leahy A, Mason I, et al: The effect of cisapride on dyspepsia symptoms and the electrogastrogram in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther 12:755, 1998 8. Blum AL, Talley NJ, OMorain C, et al: Lack of effect of treating Helicobacter pylori infection in patients with non-ulcer dyspepsia: Omeprazole plus Clarithromycin and Amoxicillin: Effect one year after treatment (OCAY) study group. N Engl J Med 3391875, 1998 9. Breslin NP, Lee J, Buckley M, et ak Rapid serological tests in the assessment of young dyspeptic patients. Gut 39(suppl2):A117, 1996 10. Buckley M, OMorain C A Prevalence of Helicobacter pylori in non-ulcer dyspepsia. Aliment Pharmacol Ther 9(suppl2):53, 1995 11. Buckley MJ, Scanlon C, McGurgan P, et al: A validated dyspepsia symptom score. Ital J Gastroenterol29495, 1997 12. Bytzer P, Hansen JM, Schaffalizky de Muckadell OB: Empirical H2 blocker therapy or prompt endoscopy in management of dyspepsia. Lancet 343:811, 1994 13. Bytzer P, Schaffalizky de Muckadell 08: Prediction of major pathological conditions in dyspeptic patients referred for endoscopy: A prospective validation study of a scoring system. Scand J Gastroenterol27987, 1992 14. Camilleri M Gastric and autonomic response to stress and functional dyspepsia. Dig Dis Sci 31:1169, 1986 15. Caldwell RH, Malenalla G, Marshall BJ, et al: Helicobacter pylori infection and gastric emptying of series in humans. J Gastrointest Motil4111, 1992 16. Chen TS, Chang FY, Lee SO, et al: Recurrence of H. pylori infection and dyspeptic symptoms after successful eradication in patients cured of duodenal ulcer disease. Hepatogastroenterology 46:252, 1999 17. Chua A, Kealing NJ, Hamilton D, et al: Central serotonin receptors and delayed gastric emptying in non-ulcer dyspepsia. BMJ 305:280, 1992 18. Ebell MH, Warbasse L, Brenner C: Evaluation of the dyspeptic patient: A cost utility study. J Fam Pract 44:545, 1997 19. El-Omar E, Penman J, Ardill JE, et al: A substantial proportion of non-ulcer dyspepsia patients have the same abnormality of acid secretion as duodenal ulcer patients. Gut 36:534, 1995 20. Elta CH, Scheiman JM, Barrett JL, et al: Long term follow up of Helicobacter pylori eradication in non-ulcer dyspepsia patients. Am J Gastroenterol90:1089, 1995 21. Fobat FM, Gribble RJ, Baron J H Gastrointestinal endoscopy in the young. BMJ 295:365, 1987 22. Frazzoni M, Lonardo A, Grisendi A, et al: Are routine duodenal and antral biopsies useful in the management of functional dyspepsia? A diagnostic and therapeutic study. J Clin Gastroenterol 17101, 1993 23. George AA, Iahghtuosa M, Dooley CP: Sensitivity of the gastric mucosa to acid and duodenal contents in patients with non-ulcer dyspepsia. Gastroenterology 101:3, 1991 24. Gilvarry J, Buckley MJM, Beattie S, et al: Eradication of Helicobacter pylori affects symptoms in NUD. Scand J Gastroenterol32:535, 1997 25. Goh KL, Paramsothy M, Azian M, et al: Does Helicobacter pylori infection affect gastric emptying in patients with functional dyspepsia? J Gastroenterol Hepatol 12:790, 1997 26. Heikkinen M, Pikkarainen P, Takula J, et al: Etiology of dyspepsia in four hundred unselected consecutive patients in general practice. Scand J Gastroenterol30:519, 1995 27. Holtmann G, Goebell H, Holtmann H, et al: Dyspepsia in healthy blood donors: Patterns of symptoms and associations with Helicobacter pylori. Dig Dis S a 39:1090,1994
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without testing for Helicobacter pylori for dyspepsia: A decision analysis. Gastroenterology 110:72, 1996 55. Sonnenberg A: Cost benefit analysis of testing for Helicobacter pylori in dyspeptic subjects. Am J Gastroenterol 91:1773, 1996 56. Stone MA, Bamett DB, Mayberry JF: Lack of correlation between self-reported symptoms of dyspepsia and infection with Helicobacter pylori in a general population sample. Eur J Gastroenterol Hepatol 10:301, 1998 57. Stranghellini V, Tosetti C, Pateric OA, et al: Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology 110:1036, 1996 58. Strauss RM, Wang TC, Kelsey PB, et al: Association of Helicobacter pylori infection with dyspeptic symptoms in patients undergoing gastroduodenoscopy. Am J Med 89:464, 1990 59. Talley NJ, Collin-Jones D, Nyreno KM, et al: Functional dyspepsia a classification and guidelines for diagnosis and management. Gastroenterology 4:45, 1991 60. Talley NJ, Janssens J, Lauritsen K, et al: Eradication of Helicobacter pylori in functional dyspepsia: Randomised double blind placebo controlled trial with 12 month follow up. BMJ 318:833, 1999 61. Talley NJ, Phillips SF: Non-ulcer dyspepsia: Potential causes and pathophysiology. Ann Intern Med 108:865, 1988 62. Talley NJ, Weaver AL, Tesmer DL, et al: A lack of discriminant value of dyspepsia subgroups in patients referred for upper endoscopy. Gastroenterology 105:1378, 1993 63. Talley NJ, Weaver AL, Zinsmester AR Smoking, alcohol and non-steroidal anti-inflammatory drugs in outpatients with non-ulcer dyspepsia and among dyspepsia subgroups. Am J Gastroenterol89:524, 1994 64.Tanum L, Bratveit-Johansen K, Multu F, et al: Fenfluramine and idiopathic pain in non-psychiatric patients with functional gastrointestinal disorders. Scand J Gastroenterol 33:684, 1998 65. The European Helicobacter pylori Study Group: Current concepts in the management of Helicobacter pylori infection: The Maastricht consensus report. Gut 4193, 1997 66. Thomas JE, Gibson JR, Darbae MK. Isolation of Helicobacter pylori from human faeces. Lancet 340:1194, 1992 67. Trespi E, Broglia F, Vilaani L, et al: Distinct profile of gastritis in dyspepsia subgroups and their different clinical responses to gastritis healing after Helicobacter pylori eradication. Scand J Gastroenterol29:884, 1994 68. Tucci A, Corinaldesi R, Stranghellini V, et al: H. pylori infection and gastric function in patients with chronic idiopathic dyspepsia. Gastroenterology 103:768, 1992 69. Veldhuyzen van Zanten SJO, Malatjalian D, Tanton R, et al: The effect of eradication of Helicobacter pylori (Hp) on symptoms of NUD (NUD): A randomised double blind placebo controlled trial. Gastroenterology 108:A252, 1995 70. Veldhuyzen van Zanten SJO, Tytgat GMAJ, Pollok PT,et al: Can severity of symptoms be used as an outcome measure in trials of non-ulcer dyspepsia and Helicobacter pylori gastritis. I Clin Euidemiol46273, 1993 71. k a n g S, Cheng B, Wu H, et al: A scintigraphic study of gastric emptying in patients with non-ulcer dyspepsia. J Tongji Med Univ 1641, 1996 72. Werdmuller BF, van der Patten AB, Loffeld RJ: Symptom clusters cannot be used in distinguishing Helicobacter pylori positive or negative patients with dyspepsia. Neth J Med 53:164, 1998 73. Werdmuller BF, van der Patten AB, Veenendaal RA, et al: Can screening for IgG antibodies against Helicobacter pylori be used in clinical practice? Omit endoscopy in seropositive or seronegative patients? Dig Dis S a 43:2296-2300, 1998
Address reprint requests to Deirdre A. Mc Namara, MB, MRCPI Adelaide and Meath Hospitals Trinity College Tallaght Dublin 24 Ireland
0889-8553/00 $15.00
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NONULCER DYSPEPSIA Current Concepts and Management Deirdre A. Mc Namara, MB, MRCPI, Martin Buckley, MD, MRCPI, and Colm A. OMorain, MD, FRCPI
Dyspepsia is a common condition, reported to affect 40% of the adult population in the developed world annually, with an estimated incidence of 8%. Dyspepsia accounts for 2% to 3% of all general practice consultations. It has been estimated that only 10% of sufferers seek medical advice, and 22% of these are referered to a specialist. Older patients are more likely to present, probably because of concern about the possibility of significant underlying pathology. Nonulcer dyspepsia (NUD)is the underlying diagnosis in a considerable proportion of individuals with dyspepsia. The prevalence is highest in young patients (younger than 25 years old), but in patients older than age 60 with dyspepsia, 20% have a normal endoscopy. NUD comprises a symptom complex referable to the upper gastrointestinal tract that persists for longer than 4 weeks, for which neither a biochemical nor structural abnormality can be identified. Diagnostic criteria were established by the Rome Consensus Committee in 199159and were updated in 1998 in Vienna. The cause of NUD appears to be multifactorial, and different mechanisms may result in different subtypes of disease, which have been subgrouped on the basis of the predominant symptom type-ulcerlike, refluxlike, and dysmotilitylike. The management of NUD is varied depending on the cause and individual response to treatment. The role of Helicobacter pylori infection in the pathogenesis and treatment of NUD is an area of ongoing avid research and remains controversial. Patients with NUD are more likely to be infected than asymptomatic individuals, and there is evidence to show benefit, in at least a subset of sufferers, after eradication of H. pylori. Dyspepsia causes considerable morbidity and has substantial socioeconomicimplications, as a result of workdays lost and the expense of medical investigations and treatment. The estimated total cost of dyspepsia to the United States in 1993 was greater than $14 million.
From the Adelaide & Meath Hospital, Trinity College, Dublin, Ireland
GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 29 * NUMBER 4 * DECEMBER 2000
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DEFINITION
NUD or functional dyspepsia is a term used to describe patients with symptoms referable to the upper gastrointestinal tract that persist for more than 3 months and for whch no biochemical or structural abnormality is detected?,59 NUD is a diagnosis of exclusion, necessitating blood tests and imaging to rule out gallbladder disorders and endoscopy to rule out peptic ulcer disease, reflux, or other underlying mucosal pathology. In particular, there is some overlap with the other major functional gastrointestinal disorder, irritable bowel syndrome, which should be excluded on the basis of symptoms according to the Rome criteria. The presence of H. pylori-induced gastritis does not preclude a diagnosis of NUD. Varied symptoms are attributable to NUD, and these have been grouped into subtypes based on the predominant symptom complex-ulcerlike, refluxlike, and dysmotilitylike (Table 1).In general, there is a large overlap between these groups.61Attempts to link underlying cause or response to treatment according to subtype have been controversial. NUD is a heterogeneous condition with marked differences in symptom preponderance and severity among individuals, and this has posed difficulty for researchers in this area. Increasingly the diagnostic criteria proposed by the Rome consensus committee have been adopted. There are pitfalls in assessing the response to treatment in patients with NUD. It is essential that response be assessed by a specific, accepted dyspepsia score, fulfilling the criteria of reproducibility, responsiveness, and ~a1idity.I~. 70 EPIDEMIOLOGY
NUD is a common condition worldwide. The exact incidence is difficult to quantify because most sufferers do not consult a Population-based studies have been performed, screening for dyspepsia using a questionnaire and subsequently investigating positive subjects. In one study involving 2027 individuals, 10.6% to 17.2%were found to have NUD.6 Other investigators have reported an incidence of NUD in dyspeptic patients of 7% to 38%. NUD occurs more frequently in younger patients (38%in patients younger than 25 years old) 35 compared with older patients (3% to 7% in patients older than 60 years Table 1. SYMPTOM SUBGROUPS OF NONULCER DYSPEPSIA
Ulcerlike dyspepsia
Refluxlike dyspepsia
Dysmotilitylike dyspepsia
Nonspecific dyspepsia
Epigastric pain Nighttime pain Pain related to meals Pain relieved by antacids Heartburn Water brash Belching Exacerbation by lying or stooping Nausea Retching or vomiting Bloating Early satiety Postprandial fullness Combinations of the above symptoms
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NUD has been associated with a positive family history of dyspepsia and of peptic ulcer. The incidence is similar among men and women but varies regionally. CAUSE
The cause of NUD is multifactorial (Table 2). Abnormalities of visceral perception, motor dysfunction, gastric acid secretion, psychologic stress, and environmental factors all have been implicated.61There is abundant research in this area, but as yet the exact underlying pathophysiological mechanisms have not been identified. Gastric emptying has been examined by various means in patients with NUD; there appears to be a delay in gastric emptying after ingestion of a meal in 45% of ~ufferers.'~, 37, 43, 71 Treatment with cisapride, a prokinetic agent, results in significant symptom improvement in some of these patient^.^ Attempts to link this mechanism with a distinct subgroup of patients have been unsuccessful. Some patients with NUD show altered visceral perception as assessed by inflation of an intragastric balloon when compared with nondyspeptic matched controls.42Perception also is altered in the proximal small intestine in these patients. Subsequent work found that in a proportion of sufferers there is a defect in efferent vagal function as shown by the production of pancreatic polypeptide in response to hypoglycemia.28The role of altered visceral perception remains to be clarified. Alteration in gastric acid secretion has been shown in patients with NUD who are infected with H. pylori. El-Omar et all9 showed that patients infected with H. pylori regardless of the underlying diagnosis had higher stimulated gastric acid output than controls. Patients with duodenal ulceration show a sixfold increase, whereas patients with NUD and H. pylori infection show a significant increase but to a lesser extent. Gastrin-stimulated acid secretion levels for duodenal ulcer, NUD, and H. pylori-positive controls were 39.1, 29.6, and 19.0. These findings suggest that approximately 50% of subjects with NUD have a disturbance in gastric acid secretion similar to duodenal ulcer patients. The role of psychologic stress and personality traits in the pathophysiology of functional gastrointestinal disorders is controversial. Alterations in autonomic activity and motility, linked to these disorders, have been associated with stress, 31 An association with alterations in central serotonin conflicts, and aggression.29, function and seretoninergic sensitivity has been postulated. Using a buspirone challenge, Chua et all7showed that patients with NUD were overly sensitive to serotonin, and this has been linked to delayed gastric emptying. There is conflicting evidence, however, using DL-fedUramine challenge.64 Environmental factors have been implicated, including smoking and other dietary factors and socioeconomic statusa A major environmental contributory factor is H. pylori infection, which is considered separately.
Table 2. CAUSES OF NONULCER DYSPEPSIA
Gastric physiology Nociception Motor dysfunction Central nervous system dysfunction Psychologic Environmental
t Gastric acid secretion t Visceral perception of distention
.1 Gastric emptying T' ' Serotonin sensitivity t Stress, conflicts, aggression 7 H. pylori, smoking
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No clear association between any of these causative factors and NUD subgroup or response to treatment has been shown. A combination of factors probably is responsible in variable proportions in any individual. As such, which treatment would be effective also varies among patients. HELICOBACTER PYLORI INFECTION
H. pylori infection has been linked causally with peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Association of H. pylori with NUD is controversial. There is strong epidemiologic evidence to support a role for H. pylori in the cause of NUD, and appropriate pathophysiological mechanisms have been explored. There is evidence to show that in at least a subset of patients, eradication of H. pylori results in symptom improvement in the long-term. The evidence is not equivocal, however. Epidemiology
Studies have shown that almost 50% of patients who present with NUD are
H.pylori positive. In Western countries, studies have reported prevalence rates of 39% to 87%.’”30, 51, 58 The prevalence of H. pylori infection is accepted to be higher in patients with NUD than in asymptomatic controls. A meta-analysis reported that subjects with NUD are twice as likely to be H. pylori positive compared with controls? Whether this association is related to symptom development is debated. Symptoms
There is evidence to show that H. pylori infection precedes the onset of symptoms in dyspeptic patients. Parsonnet et a147showed in a cohort of epidemiologists that H. pylori infection was present before the development of symptoms and that subjects who seroconverted were 4 times more likely to develop dyspepsia. A more recent study involving 3589 subjects reported that those who were positive for H. pylori were more likely to complain of heartburn (odds ratio, 1.26), abdominal pain (odds ratio, 1.33), and nocturnal pain (odds ratio, 1.62). Individuals who were IgG positive for H. pylori but asymptomatic at study entry were at a significantly increased risk of developing symptoms during the study follow-up (odds ratio, 1.71)22Recurrence of H. pylori infection after successful treatment is uncommon; a report from Taiwan revealed that during a follow-up of 1 year, 3% of patients who were treated for duodenal ulceration became reinfected and that reinfection was associated with a recurrence of symptorns,l6 supporting a role for H. pylori infection in the development of dyspeptic symptoms. Attempts to associate H. pylori infection with a subgroup of symptoms have been disappointing. Several have not found a significant difference in the presence or absence of dyspeptic symptoms based on H. pylori ~tatus.2~, 56, The issue remains to be clarified. Pathophysiology H. pylori infection is associated with an active chronic gastritis, which is characterized by a neutrophilic infiltrate and the production of inflammatory
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mediators. The relationship between H. pylori infection and the possible causative processes in NUD has been examined (Table 3). Gastric Acid Secretion
Acid secretion is enhanced in patients who are infected with H. pylori compared with controls. As previously stated, patients who are H. pylori positive have a higher gastrin-stimulated gastric acid secretory response compared with H. pylori-negative subjects with NUD. Gastric Motor Dysfunction
Delayed gastric emptying has been documented in NUD. The effect of H. pylori infection on gastric emptying is confusing. Most studies have reported no association between H. pylori and altered gastric motility.25,68 There are reports with conflicting results to suggest an accelerated and a decreased gastric emptying in response to meals.'" 42 A Japanese group has shown that in patients with delayed gastric emptying, cure of infection resulted in a return to normal transit times with resultant symptom impr0vement.4~ Nociception
The effect of H. pylori on visceral perception is diverse. Chronic inflammation could result in an alteration of enteric neuromuscular function or afferent or efferent signaling in response to normal stimuli.= Current data fail to show that NUD patients with H. pylori infection have more sensitive mucosa to acid or bile installati~n.~~ Treatment Studies
Evidence to show an improvement in symptoms in patients after eradication of H. pylori infection strongly supports a causal link between H . pylori and NUD (Table 4). The evidence is not clear-cut, however. Many studies assessing the possible therapeutic benefits of H. pylori eradication in patients with NUD have been flawed. Clinical trials in NUD do not have an objective endpoint. Symptom improvement is the main outcome measure, which is subjective, and it is essential that a validated method of quantifying dyspepsia symptoms is employed. The duration of follow-up also is important because there is a considerable placebo response to treatment in the short-term (30% to 60%).46Many studies have had an insufficient follow-up to determine the true effect of eradication therapy versus placebo.
Table 3. POSSIBLE HELlCOBACTER PYLORFINDUCED PATHOPHYSIOLOGICAL MECHANISMS IN NONULCER DYSPEPSIA Smooth muscle dysfunction Gastric peptides Nociception Central nervous dysfunction
Altered gastric emptying T Acid secretion T Substance P J. Somatostatin f Prostanoids Gut-brain-gut axis
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Table 4. HELlCOBACTER PYLORl TREATMENT STUDIES IN NONULCER DYSPEPSIA Study
No. Subjects
FoIIow-UP (mo)
Symptom Improvement
TrespP7 Veldhuyzen van Zanten69 Fertolaniso FrazzonP McCarthp EltaZo Sheus Gilvarry" Blum (OCAY)* Talley (ORCHID)" McCol14'
20 49 48 20 75 26 41 49 328 237 308
6 6 8 10 12 34 12 12 12 12 12
Yes No Yes No Yes No Yes Yes No No Yes
Previously, several studies were reported and examined in a meta-analysis by Laheij et a133in which 10 adequately structured studies were identified. Overall, 73% of patients who became H. pylori negative and 45% who remained H. pylori positive after treatment had significant symptom improvement. Symptom improvement was observed in the short term in patients with persistent irifection, consistent with a placebo effect. Large multicenter placebo-controlled trials have since been published2Of22 40, 50, 53, 67, 69 The OCAY (Omeprazole plus Clarithromycin and Amoxicillin: Effect one year after treatment) study involved 328 patients, and the treatment group received proton-pump inhibitor-based triple therapy. Patients were followed for 1 year. There was no significant difference in symptom improvement between the two groups (27.4% versus 20.7%). In the treatment group, there was no difference in outcome between those who were treated successfully and those who remained H. pylori positive.* Similar results were reported by the ORCHID group. Complete symptom resolution occurred in 24% who received treatment and in 22% of the placebo group. Further analysis based on symptom subgroup revealed no benefit from active treatment. The ORCHID study did report a sigruficant symptom improvement for patients with no or mild gastritis at the end of 1 year (32% and 17%; R0.008). Forty-one patients had mild or no gastritis; as expected, most were in the active treatment group.6oConflicting evidence is provided by another welldesigned single-center study from Glasgow. McColl et a141reported a sigruficant difference in symptom resolution between treatment and placebo groups (21% and 7%). Patients with a symptom duration before study entry of less than 5 years were more likely to respond to treatment? Work performed in the authors' institution involving a 1-year follow-up found results similar to the Glasgow group with regard to complete symptom res0lution.2~ The role of H. pylori in NUD is not as definite as for other diseases, such as peptic ulcer, and treatment cannot guarantee improvement. The evidence suggests that using eradication therapy results in a sigruficant resolution of symptoms, compared with placebo, for a proportion of patients, possibly as a result of healing associated gastritis. As yet, it is not possible based on symptom subtype or by any other means to identify patients who would benefit. MANAGEMENT
The treatment of NUD is difficult and involves instigating changes in lifestyle and symptomatic treatment with antacids, prokinetics, or antiserotonin-
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ergic agents, the initial choice depending on the predominant symptom group. Patients with NUD present with dyspepsia. With the increasing availability of noninvasiv H. pylori tests and the economic benefits of empiric treatment of dyspepsia, the management of NUD is related integrally to how one treats dyspepsia. Several management strategies have been explored. The underlying diagnosis reported in young patients (<45 years old) who have undergone endoscopy is gastroesophageal reflux (32%),peptic ulcer (18%), NUD (43%),and gastric cancer (0.05%). The prevalence of serious underlying pathology, such as gastric cancer, increases with age and is infrequent in young patient^.^, 12,26, 38, 57 H. pylori infection is associated with peptic ulcer and NUD. The management of dyspepsia should include strategies to diagnose and treat H. pylori infection. Empiric Therapy
Previously the standard management of dyspepsia on first presentation depended on addressing lifestyle issues and a therapeutic trial of acid-lowering agents. Although the rationale for this approach is not evidence based, there is evidence to indicate that greater acid suppression is beneficial to some patients.49 Early Endoscopy
Some reports show that prompt endoscopy is beneficial to patients and is more effective than empiric treatment. In one report, patients who underwent early endoscopic investigation benefited from positive reassurance, which resulted in less time lost from work, a reduced need for medications, and an overall improvement in symptoms.59This study was performed without reference to H. pylori status. The availability and cost of endoscopy services promotes the use of empiric therapy initially. Test and Treat or Test and Scope
The availability of effective and affordable noninvasive tests for H. pylori, including I3C-ureabreath testing, laboratory or office-based serologic tests, and stool antigen assays, has led to the development of new approaches to dyspepsia management (Fig. 1).66 Strategies that have been proposed include a test and scope policy. This policy involves noninvasive H. pylori testing followed by empiric treatment for H. pylori-negative patients and endoscopy for H. pyloripositive patients to document significant underlying pathologyll. 48 One report of a test and scope policy revealed that endoscopy workload was reduced by one third, while being safe and effective. Subsequently a test and treat strategy has been advocated and examined based on the premise that a large proportion of young patients with dyspepsia who are H. pylori positive have peptic ulcer disease or NUD and would benefit from empiric eradication therapy; endoscopy is reserved for patients who are negative for H. pylori infection. A similar reduction in endoscopy workload has been reported for test and treat and test and scope regimens (37%).3,9, 72 Cost-Effectiveness
The aforementioned management strategies have been shown to result in significant cost savings.18 Silverstein et a154showed that noninvasive H. pylori
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Dyspepsia
No
7 r--
symptomatic therapy
11
c Treat ABx
Figure 1. Test and treat management strategy. Hp = He/icobacterpy/ori,ABx = antibiotics; UBT = urea breath test.
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testing and subsequent treatment of H. pylori-positive patients is less costly when compared with endoscopy for all but more expensive than global empiric treatment of dyspepsia. There was little difference in the overall long-term cost between endoscopy or empiric therapy for all subjects. An additional report by S ~ n n e n b e r gconcluded ~~ that if only 10% of patients with NUD responded to H. pylori eradication, noninvasive testing and treatment would be cost-effective, as a result of symptom improvement and the prevention of peptic ulcer development. Consensus Three consensus meetings have reported findings on how a patient with dyspepsia should be managed: Maastricht/ European, Canadian, and American. The Maastricht group examined the best currently available data and were in favor of a test and treat strategy for younger patients without alarm symptoms.65 The Canadian and American groups were less definite.lS3O In their view, the evidence for a significant benefit being obtained by H. pylori treatment in NUD was equivocal, and the risk of side effects from treatment and the development of resistant strains was considerable. The suggestion was that possible benefits and problems should be considered on a case-by-case basis. The success of any particular approach depends on the incidence of H. pylori in the community, the availability of endoscopy and noninvasive H. pylori tests, and referral practices. There is evidence to support a selective (based on H. pylori status) empiric treatment regimen. SUMMARY
NUD is a common heterogeneous condition with a multifactorial cause. NUD is a cause of considerable morbidity with an annual incidence of 8% and similar incidence of spontaneous resolution.& Its economic effects are considerable. The estimated annual cost to the community of NLJD is $431 per patient for the initial 6 months after diagnosis. The annual Health Maintenance Organization (HMO) expenditure on acid-related disorders in one Northern California HMO was estimated to be $59.4 million, of whch NUD represented a significant proportion.34The association of H. pylori infection with NUD is controversial. There are strong epidemiologic evidence and supportive pathophysiological mechanisms to implicate H. pylori causally in a subset of cases. Treatment studies are likewise conflicting. Evidence suggests that treatment cannot guarantee improvement in all cases of H. pylori-related NUD but that a subset would benefit with complete symptom resolution in the long term. It is not possible currently to predict which patients would or would not respond to eradication therapy. The strength of evidence is such that empiric eradication therapy, based on noninvasive H. pylori testing, can be advocated in young patients with dyspepsia safely and effectively with resultant financial savings. References 1. American Gastroenterological Association: American Gastroenterological Association medical position statement Evaluation of dyspepsia. Gastroenterology 114:579, 1998 2. Armstrong D: Helicobacter pylori infection and dyspepsia. Scand J Gastroenterol 3l(suppl215):38, 1996
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3. Asante MA, Mendall M, Pate1 P, et al: A randomised trial of endoscopy versus no endoscopy in the treatment of seronegative Helicobacter pylori dyspepsia. Eur J Gastroenterol Hepatol 10:983, 1998 4. Ayoola EA, al-Rashed RS, al-Mofleh IA, et al: Diagnostic yield of upper gastrointestinal endoscopy in relation to age and gender: A study of 10,112 Saudi patients. Hepatogastroenterology 43:405, 1996 5. Barbara L, Camilleri M, Corinalesi R, et al: Definition and investigation of dyspepsia: Consensus of an international adhoc working party. Dig Dis Sci 34:1272, 1989 6. Bemeasen 8, Johnsen R, Straume B: Non-ulcer dyspepsia and peptic ulcer: Their distribution in a population and their relation to risk factors. Gut 38:822, 1996 7. Besherdus K, Leahy A, Mason I, et al: The effect of cisapride on dyspepsia symptoms and the electrogastrogram in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther 12:755, 1998 8. Blum AL, Talley NJ, OMorain C, et al: Lack of effect of treating Helicobacter pylori infection in patients with non-ulcer dyspepsia: Omeprazole plus Clarithromycin and Amoxicillin: Effect one year after treatment (OCAY) study group. N Engl J Med 3391875, 1998 9. Breslin NP, Lee J, Buckley M, et ak Rapid serological tests in the assessment of young dyspeptic patients. Gut 39(suppl2):A117, 1996 10. Buckley M, OMorain C A Prevalence of Helicobacter pylori in non-ulcer dyspepsia. Aliment Pharmacol Ther 9(suppl2):53, 1995 11. Buckley MJ, Scanlon C, McGurgan P, et al: A validated dyspepsia symptom score. Ital J Gastroenterol29495, 1997 12. Bytzer P, Hansen JM, Schaffalizky de Muckadell OB: Empirical H2 blocker therapy or prompt endoscopy in management of dyspepsia. Lancet 343:811, 1994 13. Bytzer P, Schaffalizky de Muckadell 08: Prediction of major pathological conditions in dyspeptic patients referred for endoscopy: A prospective validation study of a scoring system. Scand J Gastroenterol27987, 1992 14. Camilleri M Gastric and autonomic response to stress and functional dyspepsia. Dig Dis Sci 31:1169, 1986 15. Caldwell RH, Malenalla G, Marshall BJ, et al: Helicobacter pylori infection and gastric emptying of series in humans. J Gastrointest Motil4111, 1992 16. Chen TS, Chang FY, Lee SO, et al: Recurrence of H. pylori infection and dyspeptic symptoms after successful eradication in patients cured of duodenal ulcer disease. Hepatogastroenterology 46:252, 1999 17. Chua A, Kealing NJ, Hamilton D, et al: Central serotonin receptors and delayed gastric emptying in non-ulcer dyspepsia. BMJ 305:280, 1992 18. Ebell MH, Warbasse L, Brenner C: Evaluation of the dyspeptic patient: A cost utility study. J Fam Pract 44:545, 1997 19. El-Omar E, Penman J, Ardill JE, et al: A substantial proportion of non-ulcer dyspepsia patients have the same abnormality of acid secretion as duodenal ulcer patients. Gut 36:534, 1995 20. Elta CH, Scheiman JM, Barrett JL, et al: Long term follow up of Helicobacter pylori eradication in non-ulcer dyspepsia patients. Am J Gastroenterol90:1089, 1995 21. Fobat FM, Gribble RJ, Baron J H Gastrointestinal endoscopy in the young. BMJ 295:365, 1987 22. Frazzoni M, Lonardo A, Grisendi A, et al: Are routine duodenal and antral biopsies useful in the management of functional dyspepsia? A diagnostic and therapeutic study. J Clin Gastroenterol 17101, 1993 23. George AA, Iahghtuosa M, Dooley CP: Sensitivity of the gastric mucosa to acid and duodenal contents in patients with non-ulcer dyspepsia. Gastroenterology 101:3, 1991 24. Gilvarry J, Buckley MJM, Beattie S, et al: Eradication of Helicobacter pylori affects symptoms in NUD. Scand J Gastroenterol32:535, 1997 25. Goh KL, Paramsothy M, Azian M, et al: Does Helicobacter pylori infection affect gastric emptying in patients with functional dyspepsia? J Gastroenterol Hepatol 12:790, 1997 26. Heikkinen M, Pikkarainen P, Takula J, et al: Etiology of dyspepsia in four hundred unselected consecutive patients in general practice. Scand J Gastroenterol30:519, 1995 27. Holtmann G, Goebell H, Holtmann H, et al: Dyspepsia in healthy blood donors: Patterns of symptoms and associations with Helicobacter pylori. Dig Dis S a 39:1090,1994
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Address reprint requests to Deirdre A. Mc Namara, MB, MRCPI Adelaide and Meath Hospitals Trinity College Tallaght Dublin 24 Ireland