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An international consensus conference has defined dyspepsia as chronic or recurrent pain or discomfort that is centered in the upper abdomen.1 This discomfort includes such symptoms as early satiety, fullness, bloating, and nausea. Up to 50% of people in community surveys in the United States and Europe report having dyspepsia.2 Although only a minority of people with dyspepsia seek care,3,4 this complaint still accounts for 2% to 3% of visits to family physicians.5 Patients with dyspepsia report lower quality of life than asymptomatic people; in one report, they had a quality of life similar to patients with angina.6 This review discusses the evaluation of dyspepsia and will be followed next month by a review of the treatment of dyspepsia.
Differential diagnosis
Information about the differential diagnosis of this condition largely comes from studies in which patients with dyspepsia were referred for upper endoscopy Table 1.7 The most common identifiable conditions were esophagitis, gastric ulcer, and duodenal ulcer. Most patients in these studies did not have any abnormalities on endoscopy and were considered to have functional dyspepsia. The pathophysiology of functional dyspepsia is not well understood and is likely to be multifactorial. Gastroduodenal dysmotility, increased gastric acid secretion, increased visceral sensation to distention and/or gastric acid, psychological distress, and environmental factors such as smoking and Helicobacter pylori infection all may play a role.8
When dyspeptic patients undergo more extensive evaluations and/or are followed up for longer periods of time, a large variety of other conditions have been identified. These include gastroesophageal reflux without esophagitis, lactose intolerance, cholelithiasis, gastroparesis, chronic pancreatitis, pancreatic cancer, celiac disease, giardiasis, and ischemic heart disease.9-11 However, it is not always clear that these diagnoses are completely responsible for a patient’s dyspeptic symptoms. Finally, a variety of medications or other ingestions (such as alcohol) can lead to dyspepsia.12
Using the history and physical examination
The history and physical examination are important in detecting red flags for potentially fatal conditions, such as cancer or complicated ulcers. Alarm symptoms include dysphagia, gastrointestinal bleeding, acute abdominal pain, jaundice, or an abdominal mass. The presence of 1 or more of these symptoms should trigger a consultation with a surgeon or a gastroenterologist and possible endoscopy.
A patient’s age is of some help in diagnosis; older patients are more likely to have identifiable causes for dyspepsia than those who are younger.7,9 This is particularly true for gastric cancer, which is rare in people younger than 45 years in Europe and North America. In 1 study that identified all cases of gastric cancer in a population of 280,500, only 25 of 319 gastric cancers occurred in patients younger than 55 years. Of these patients, 24 of 25 had symptoms or signs of gastric cancer: weight loss (14), dysphagia (8), anemia (7), gastrointestinal bleed (3), previous gastric surgery (3), palpable mass (3), gastrointestinal perforation (1), and cerebral metastases (1).13 Historical and demographic factors that are more likely to be seen in patients with ulcers than in those with functional dyspepsia are male sex, smoking, and nonsteroidal anti-inflammatory drug (NSAID) use.14
Table 2 shows the results of 3 large prospective studies of patients with dyspepsia who were referred for endoscopy.12,15,16 Although certain symptoms are more likely to occur in some conditions than in others, no single item from the history and physical examination clearly establishes a diagnosis. Compared with patients with normal endoscopic examinations, those with ulcers are more likely to have relief of pain with food or antacids; those with gastric cancer are more likely to have lost weight; and those with esophagitis are more likely to have heartburn and pain relief with antacids. Symptoms such as nausea, distinct localization of pain, and nocturnal pain overlap to a large degree among patients with different diagnoses and are therefore not helpful.
Investigators have tried to develop more complicated scoring systems that employ a combination of these different symptoms. Although some of these clinical scores have some value in distinguishing the various causes of dyspepsia in patients who are referred for endoscopy,17-19 they are cumbersome and have not been validated in unselected patients with dyspepsia in primary care.18
The usefulness of the physical examination has been questioned in 2 studies of patients undergoing endoscopy for dyspepsia. In one study, epigastric tenderness did not accurately distinguish patients with abnormal endoscopy findings from those with normal findings.20 The likelihood ratio (LR) for tenderness to light or deep palpation was near 1, meaning that this maneuver had no diagnostic value. A second study found that an abnormal physical examination was equally likely in patients with an ulcer as in those without one.18
A recent study examined the accuracy of general practitioners’ overall impression based on the history and physical examination.21 Four hundred consecutive unselected patients with dyspepsia were evaluated by their general practitioners and then underwent endoscopy, upper abdominal ultrasonography, and laboratory tests. The physicians’ overall clinical impressions had a low sensitivity for diagnosing organic diseases or functional dyspepsia but were fairly specific for organic diseases Table 3. Note from the LRs that while suspicion of gallstone disease or malignancy significantly increased the likelihood of these conditions, an absence of suspicion in no way ruled them out (negative LR near 1).
Imaging studies and endoscopy
Definitively diagnosing the cause of a patient’s dyspepsia usually requires either upper endoscopy or an upper gastrointestinal (UGI) series. The former is more expensive, may not be readily available in some communities, and has a slight risk of complications (such as a 0.05% perforation rate22). Endoscopy is generally believed to be more accurate than a UGI series. However, most studies that compared the accuracy of these tests have used endoscopy as the gold standard, which creates a bias in favor of endoscopy. The few studies that have used repeat endoscopy for lesions detected by radiography but not the initial endoscopy have still shown that radiography is less accurate than endoscopy, especially for lesions smaller than 5 mm Table 4.23,24 Another advantage of endoscopy is the ability to biopsy lesions suspicious for malignancy and to perform invasive tests for H pylori infection. A patient who has a gastric ulcer detected by a UGI series should be referred for endoscopic biopsy, since up to 3% of these ulcers can harbor malignancy.9
Other imaging studies are not routinely recommended for evaluation of dyspepsia. In the absence of typical symptoms of biliary colic, abdominal ultrasonography has a very low yield11; even if gallstones are detected in a patient with dyspepsia, this may be incidental, and cholecystectomy may not improve the patient’s symptoms. Gastric-emptying studies may be abnormal in nearly 40% of patients with functional dyspepsia,25 but basing therapy on the results of these studies has not been consistently shown to benefit patients.1
Detecting H pylori
Patients with dyspepsia should be evaluated for the presence of H pylori, because this infection has been found in up to 95% of patients with duodenal ulcer and 80% with a gastric ulcer. It occurs in approximately 30% to 40% of patients without an ulcer.26 Patients with ulcers who are H pylori–positive have a markedly reduced recurrence rate after successful eradication therapy.27,28 Therefore, patients with gastric or duodenal ulcers who are infected with H pylori should be treated with a combination of antibiotics and acid suppressive agents to eradicate the infection. Noninvasive options for diagnosing H pylori include immunoglobulin G (IgG) antibody testing in serum or whole blood, urea breath tests, and stool antigen tests Table 4.
There are at least 40 commercially available IgG serologic tests. The median sensitivity and specificity are 92% and 83%, respectively, but the accuracy varies considerably.29 Whole blood serologic tests can be performed on capillary blood obtained from finger sticks, and are therefore more convenient than serum tests that require venipuncture but are not recommended because they are less sensitive.30,31 Because patients may have persistently positive IgG antibodies for many months after eradication therapy, a serologic test will often give a false-positive result during that period.32
Urea breath tests are able to detect an active H pylori infection. Patients ingest a specific food or drink that contains carbon-labeled urea. Gastric urease activity, which is highly specific for active H pylori infection, converts the carbon-labeled urea to labeled carbon dioxide and ammonia. The patient breathes into a container, and a positive test occurs when the labeled carbon dioxide exceeds a threshold level. Both 13Carbon and 14Carbon are used. The latter exposes patients to a negligible amount of radioactivity, but is simple, rapid, and less expensive than the 13 carbon tests. In comparative studies, the urea breath tests are more accurate than serologic tests.33,34
Stool antigen is involved in the most recently developed noninvasive test. The few studies that have been conducted to date have demonstrated that these tests are highly accurate.35 The stool antigen has recently been recommended by the European Helicobacter Pylori Study Group as the preferred initial noninvasive diagnostic test.36
Approach to the patient
There are a variety of possible approaches to the initial management of patients with dyspepsia. These include (1) prompt endoscopy (or UGI) for all patients, (2) prompt endoscopy (or UGI) for patients at highest risk for organic disease, (3) empiric acid suppression therapy for all patients with testing reserved for patients who remain symptomatic, (4) empiric H pylori eradication therapy for all patients, and (5) noninvasive H pylori testing for all patients, followed by empiric eradication therapy for those with positive results and empiric treatment of functional dyspepsia for those with negative results (a “test and treat” approach).
The most recent American, Canadian, and European consensus-based guidelines all recommend that patients younger than 45 years with dyspepsia and no alarm symptoms should be tested for H pylori infection and then given eradication therapy if positive; patients older than 45 years and those with alarm symptoms should have prompt endoscopy.37-39 H pylori–negative patients younger than 45 years and without alarm symptoms should be managed empirically for functional dyspepsia. H pylori–positive or negative patients who do not undergo endoscopy initially should do so if their symptoms persist. An algorithm depicting this approach is presented in the Figure 1. Cost-effectiveness analyses generally support this approach.22,40,41
Direct evidence for these approaches from randomized controlled trials has recently become available.42-45 These studies show that outcomes are similar whether patients received prompt endoscopy or follow a test and treat strategy. Note that patients older than 45 years, using NSAIDs, or with any alarm symptoms for complicated disease were either excluded from these trials or underwent prompt endoscopy.
Although the current evidence supports a test and treat strategy, the results may not be generalizable to all areas. The effectiveness of this approach depends on the prevalence of H pylori infection in patients with ulcers in the community; in some areas, this prevalence may be too low to make this approach effective.46,47 Also, patients not undergoing prompt endoscopy may be less satisfied with their care,42 which is related to the observation that patients with dyspepsia are more likely than physicians to value diagnostic certainty.48 Other data suggest, however, that patient satisfaction is more closely associated with symptom improvement than with having procedures performed.49 With these caveats in mind, it seems most reasonable to inform your patients about the evidence regarding the advantages and disadvantages of the various approaches and allow them to share in the decision-making process.
1. Talley N, Stanghellini V, Heading R, et al. Functional gastroduodenal disorders. Gut 1999;45:1137-42.
2. Heading RC. Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol 1999;34(suppl):3-8.
3. Jones RH, Lydeard SE, Hobbs FDR, Kenkre JE, Williams EI, Jones SJ. Dyspepsia in England and Scotland. Gut 1990;31:401-05.
4. Talley NJ, Zinsmeister AR, Schleck CD, Melton LJ. Dyspepsia and dyspepsia subgroups: a population-based study. Gastroenterology 1992;102:1259-68.
5. Marsland DW, Wood M, Mayo F. Content of family practice. Part I: rank order of diagnoses by frequency. Part II: diagnoses by disease category and age/sex distribution. J Fam Pract 1976;3:37-68.
6. Dimenas E. Methodological aspects of evaluation of quality of life in upper gastrointestinal diseases. Scand J Gastroenterol 1993;28(suppl):18-21.
7. Rabeneck L, Wray NP, Graham DY. Managing dyspepsia: what do we know and what do we need to know? Am J Gastroenterol 1998;93:920-24.
8. McNamara DA, Buckley M, O’Morain CA. Nonulcer dyspepsia: current concepts and management. Gastroenterol Clin N Am 2000;29:807-18.
9. Talley NJ, Silverstein MD, Agreus L, Nyren O, Sonnenberg A, Holtmann G. AGA technical review: evaluation of dyspepsia. Gastroenterology 1998;114:582-95.
10. Lundquist P, Seensalu R, Linden B, Nilsson LH, Lindberg G. Symptom criteria do not distinguish between functional and organic dyspepsia. Eur J Surg 1998;164:345-52.
11. Heikkinen MT, Pikkarainen PH, Takala JK, Rasanen HT, Eskelinen MJ, Julkunen RJK. Diagnostic methods in dyspepsia: the usefulness of upper abdominal ultrasound and gastroscopy. Scand J Prim Health Care 1997;15:82-86.
12. Crean GP, Holden RJ, Knill-Jones RP, et al. A database on dyspepsia. Gut 1994;35:191-202.
13. Christie J, Shepherd NA, Codling BW, Valori RM. Gastric cancer below the age of 55: implications for screening patients with uncomplicated dyspepsia. Gut 1997;41:513-17.
14. Kurata JH, Nogawa AN. Meta-analysis of risk factors for peptic ulcer: nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997;24:2-17.
15. Johannessen T, Petersen H, Kleveland PM, et al. The predictive value of history in dyspepsia. Scand J Gastroenterol 1990;25:689-97.
16. Mansi C, Savarino V, Mela GS, Picciotto A, Mele MR, Cele G. Are clinical patterns of dyspepsia a valid guideline for appropriate use of endoscopy? A report on 2253 dyspeptic patients. Am J Gastroenterol 1993;88:1011-15.
17. Talley NJ, McNeil D, Piper DW. Discriminant value of dyspeptic symptoms: a study of the clinical presentation of 221 patients with dyspepsia of unknown cause, peptic ulceration, and cholelithiasis. Gut 1987;28:40-46.
18. Numans M, van der Graaf Y, de Wit NJ, Touw-otten FWMM, de Melker RA. How much ulcer is ulcer-like? Diagnostic determinates of peptic ulcer in open access gastroscopy. Fam Pract 1994;11:382-88.
19. Bytzer P, Moller Hansen J, de Muckadell OBS, Malchow-Moller A. Predicting endoscopic diagnosis in the dyspeptic patient: the value of predictive score models. Scand J Gastroenterol 1997;32:118-25.
20. Priebe WM, DaCosta LR, Beck IT. Is epigastric tenderness a sign of peptic ulcer disease? Gastroenterology 1982;82:16-19.
21. Heikkinen M, Pikkarainen P, Eskelinen M, Julkunen R. GPs’ ability to diagnose dyspepsia based only on physical examination and patient history. Scand J Prim Health Care 2000;18:99-104.
22. Ofman JJ, Etchason J, Fullerton S, Kahn KL, Soll AH. Management strategies for Helicobacter pylori–seropositive patients with dyspepsia: clinical and economic consequences. Ann Intern Med 1997;126:280-91.
23. Shaw PC, van Romunde LKJ, Griffioen G, Janssens AR, Kreuning J, Eilers GAM. Peptic ulcer and gastric carcinoma: diagnosis with biphasic radiography compared with fiberoptic endoscopy. Radiology 1987;163:39-42.
24. Dooley CP, Larson AW, Stace NH, Renner IG, Valenzuela JE, Eliasoph J. Double-contrast barium meal and upper gastrointestinal endoscopy: a comparative study. Ann Intern Med 1984;101:538-45.
25. Quartero AO, de Wit NJ, Lodder AC, Numans ME, Smout AJPM, Hoes AW. Disturbed solid-phase gastric emptying in functional dyspepsia: a meta-analysis. Dig Dis Sci 1998;43:2028-33.
26. Peterson W, Fendrick AM, Cave DR, Peura DA, Garabedian-Ruffalo SM, Laine L. Helicobacter pylori–related disease: guidelines for testing and treatment. Arch Intern Med 2000;160:1285-91.
27. Moore RA. Helicobacter pylori and peptic ulcer: a systematic review of effectiveness and an overview of the economic benefits of implementing what is known to be effective. Oxford: Pain Relief Research Unit, 1995; vii:37.
28. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110:1244-52.
29. Laheij RJF, Straatman H, Jansen JBMJ, Verbeek ALM. Evaluation of commercially available Helicobacter pylori serology kits: a review. J Clin Microbiol 1998;36:2803-09.
30. Chey WD, Murthy U, Shaw S, et al. A comparison of three fingerstick, whole blood antibody tests for Helicobacter pylori infection: a United States, multicenter trial. Am J Gastroenterol 1999;94:1512-16.
31. Faigel DO, Magaret N, Corless C, Lieberman DA, Fennerty MB. Evaluation of rapid antibody tests for the diagnosis of Helicobacter pylori infection. Am J Gastroenterol 2000;95:72-77.
32. Ho B, Marshall BJ. Accurate diagnosis of Helicobacter pylori: serologic testing. Gastroenterol Clin N Am 2000;29:853-62.
33. Cutler AF, Havstad S, Ma CK, Blaser MJ, Perez-Perez GI, Schubert TT. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology 1995;109:136-41.
34. Thijs JC, van Zwet AA, Thijs WJ, et al. Diagnostic tests for Helicobacter pylori: a prospective evaluation of their accuracy, without selecting a single test as the gold standard. Am J Gastroenterol 1996;91:2125-29.
35. Vaira D, Malfertheiner P, Megraud F, et al. Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based assay. Lancet 1999;354:30-33.
36. Vaira D, Vakil N. Blood, urine, stool, breath, money, and Helicobacter pylori. Gut 2001;48:287-89.
37. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 1998;114:579-81.
38. Hunt RH, Fallone CA, Thomson ABR. Canadian Helicobacter Study Group. Canadian Helicobacter pylori consensus conference update: infection in adults. Can J Gastroenterol 1999;13:213-17.
39. The European Helicobacter Pylori Study Group (EHPSG). Current European concepts in the management of Helicobacter pylori infection: the Maastricht Consensus Report. Gut 1997;41:8-13.
40. Fendrick AM, Chernew ME, Hirth RA, Bloom BS. Immediate endoscopy or initial Helicobacter pylori serological testing for suspected peptic ulcer disease: estimating cost-effectiveness using decision analysis. Yale J Biol Med 1996;69:187-95.
41. Ebell MH, Warbasse L, Brenner C. Evaluation of the dyspeptic patient: a cost-utility study. J Fam Pract 1997;44:545-55.
42. Lassen AT, Pedersen FM, Bytzer P, de Muckadell OBS. Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356:455-60.
43. Jones R, Tait C, Sladen G, Weston-Baker J. A trial of test-and-treat strategy for Helicobacter pylori–positive dyspeptic patients in general practice. Int J Clin Pract 1999;53:413-16.
44. Heaney A, Collins JSA, Watson RGP, McFarland RJ, Bamford KB, Tham TCK. A prospective randomised trial of a “test and treat” policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut 1999;45:186-90.
45. Asante MA, Mendall M, Patel P, Ballam L, Northfield TC. A randomized trial of endoscopy vs no endoscopy in the management of seronegative Helicobacter pylori dyspepsia. Eur J Gastroenterol Hepatol 1998;10:983-89.
46. Tovey FI, Hobsley M. Is Helicobacter pylori the primary cause of duodenal ulceration? J Gastroenterol Hepatol 1999;14:1053-56.
47. Xia HHX, Kalantar JS, Mitchell HM, Talley NJ. Can Helicobacter pylori serology still be applied as a surrogate marker to identify peptic ulcer disease in dyspepsia? Aliment Pharmacol Ther 2000;14:615-24.
48. Hirth RA, Bloom BS, Chernew ME, Fendrick AM. Patient, physician, and payer perceptions and misperceptions of willingness to pay for diagnostic certainty. Int J Technol Assess Health Care 2000;16:35-49.
49. Kurata JH, Nogawa AN, Chen YK, Parker CE. Dyspepsia in primary care: perceived causes, reasons for improvement, and satisfaction with care. J Fam Pract 1997;44:281-88.
50. Peura DA, Pambianco DJ, Dye KR, et al. Microdose 14C-urea breath test offers diagnosis of Helicobacter pylori in 10 minutes. Am J Gastroenterol 1996;91:233-38.
51. Raju GS, Smith MJ, Morton D, Bardhan KD. Mini-dose (1-microCi) 14C-urea breath test for the detection of Helicobacter pylori. Am J Gastroenterol 1994;89:1027-31.
An international consensus conference has defined dyspepsia as chronic or recurrent pain or discomfort that is centered in the upper abdomen.1 This discomfort includes such symptoms as early satiety, fullness, bloating, and nausea. Up to 50% of people in community surveys in the United States and Europe report having dyspepsia.2 Although only a minority of people with dyspepsia seek care,3,4 this complaint still accounts for 2% to 3% of visits to family physicians.5 Patients with dyspepsia report lower quality of life than asymptomatic people; in one report, they had a quality of life similar to patients with angina.6 This review discusses the evaluation of dyspepsia and will be followed next month by a review of the treatment of dyspepsia.
Differential diagnosis
Information about the differential diagnosis of this condition largely comes from studies in which patients with dyspepsia were referred for upper endoscopy Table 1.7 The most common identifiable conditions were esophagitis, gastric ulcer, and duodenal ulcer. Most patients in these studies did not have any abnormalities on endoscopy and were considered to have functional dyspepsia. The pathophysiology of functional dyspepsia is not well understood and is likely to be multifactorial. Gastroduodenal dysmotility, increased gastric acid secretion, increased visceral sensation to distention and/or gastric acid, psychological distress, and environmental factors such as smoking and Helicobacter pylori infection all may play a role.8
When dyspeptic patients undergo more extensive evaluations and/or are followed up for longer periods of time, a large variety of other conditions have been identified. These include gastroesophageal reflux without esophagitis, lactose intolerance, cholelithiasis, gastroparesis, chronic pancreatitis, pancreatic cancer, celiac disease, giardiasis, and ischemic heart disease.9-11 However, it is not always clear that these diagnoses are completely responsible for a patient’s dyspeptic symptoms. Finally, a variety of medications or other ingestions (such as alcohol) can lead to dyspepsia.12
Using the history and physical examination
The history and physical examination are important in detecting red flags for potentially fatal conditions, such as cancer or complicated ulcers. Alarm symptoms include dysphagia, gastrointestinal bleeding, acute abdominal pain, jaundice, or an abdominal mass. The presence of 1 or more of these symptoms should trigger a consultation with a surgeon or a gastroenterologist and possible endoscopy.
A patient’s age is of some help in diagnosis; older patients are more likely to have identifiable causes for dyspepsia than those who are younger.7,9 This is particularly true for gastric cancer, which is rare in people younger than 45 years in Europe and North America. In 1 study that identified all cases of gastric cancer in a population of 280,500, only 25 of 319 gastric cancers occurred in patients younger than 55 years. Of these patients, 24 of 25 had symptoms or signs of gastric cancer: weight loss (14), dysphagia (8), anemia (7), gastrointestinal bleed (3), previous gastric surgery (3), palpable mass (3), gastrointestinal perforation (1), and cerebral metastases (1).13 Historical and demographic factors that are more likely to be seen in patients with ulcers than in those with functional dyspepsia are male sex, smoking, and nonsteroidal anti-inflammatory drug (NSAID) use.14
Table 2 shows the results of 3 large prospective studies of patients with dyspepsia who were referred for endoscopy.12,15,16 Although certain symptoms are more likely to occur in some conditions than in others, no single item from the history and physical examination clearly establishes a diagnosis. Compared with patients with normal endoscopic examinations, those with ulcers are more likely to have relief of pain with food or antacids; those with gastric cancer are more likely to have lost weight; and those with esophagitis are more likely to have heartburn and pain relief with antacids. Symptoms such as nausea, distinct localization of pain, and nocturnal pain overlap to a large degree among patients with different diagnoses and are therefore not helpful.
Investigators have tried to develop more complicated scoring systems that employ a combination of these different symptoms. Although some of these clinical scores have some value in distinguishing the various causes of dyspepsia in patients who are referred for endoscopy,17-19 they are cumbersome and have not been validated in unselected patients with dyspepsia in primary care.18
The usefulness of the physical examination has been questioned in 2 studies of patients undergoing endoscopy for dyspepsia. In one study, epigastric tenderness did not accurately distinguish patients with abnormal endoscopy findings from those with normal findings.20 The likelihood ratio (LR) for tenderness to light or deep palpation was near 1, meaning that this maneuver had no diagnostic value. A second study found that an abnormal physical examination was equally likely in patients with an ulcer as in those without one.18
A recent study examined the accuracy of general practitioners’ overall impression based on the history and physical examination.21 Four hundred consecutive unselected patients with dyspepsia were evaluated by their general practitioners and then underwent endoscopy, upper abdominal ultrasonography, and laboratory tests. The physicians’ overall clinical impressions had a low sensitivity for diagnosing organic diseases or functional dyspepsia but were fairly specific for organic diseases Table 3. Note from the LRs that while suspicion of gallstone disease or malignancy significantly increased the likelihood of these conditions, an absence of suspicion in no way ruled them out (negative LR near 1).
Imaging studies and endoscopy
Definitively diagnosing the cause of a patient’s dyspepsia usually requires either upper endoscopy or an upper gastrointestinal (UGI) series. The former is more expensive, may not be readily available in some communities, and has a slight risk of complications (such as a 0.05% perforation rate22). Endoscopy is generally believed to be more accurate than a UGI series. However, most studies that compared the accuracy of these tests have used endoscopy as the gold standard, which creates a bias in favor of endoscopy. The few studies that have used repeat endoscopy for lesions detected by radiography but not the initial endoscopy have still shown that radiography is less accurate than endoscopy, especially for lesions smaller than 5 mm Table 4.23,24 Another advantage of endoscopy is the ability to biopsy lesions suspicious for malignancy and to perform invasive tests for H pylori infection. A patient who has a gastric ulcer detected by a UGI series should be referred for endoscopic biopsy, since up to 3% of these ulcers can harbor malignancy.9
Other imaging studies are not routinely recommended for evaluation of dyspepsia. In the absence of typical symptoms of biliary colic, abdominal ultrasonography has a very low yield11; even if gallstones are detected in a patient with dyspepsia, this may be incidental, and cholecystectomy may not improve the patient’s symptoms. Gastric-emptying studies may be abnormal in nearly 40% of patients with functional dyspepsia,25 but basing therapy on the results of these studies has not been consistently shown to benefit patients.1
Detecting H pylori
Patients with dyspepsia should be evaluated for the presence of H pylori, because this infection has been found in up to 95% of patients with duodenal ulcer and 80% with a gastric ulcer. It occurs in approximately 30% to 40% of patients without an ulcer.26 Patients with ulcers who are H pylori–positive have a markedly reduced recurrence rate after successful eradication therapy.27,28 Therefore, patients with gastric or duodenal ulcers who are infected with H pylori should be treated with a combination of antibiotics and acid suppressive agents to eradicate the infection. Noninvasive options for diagnosing H pylori include immunoglobulin G (IgG) antibody testing in serum or whole blood, urea breath tests, and stool antigen tests Table 4.
There are at least 40 commercially available IgG serologic tests. The median sensitivity and specificity are 92% and 83%, respectively, but the accuracy varies considerably.29 Whole blood serologic tests can be performed on capillary blood obtained from finger sticks, and are therefore more convenient than serum tests that require venipuncture but are not recommended because they are less sensitive.30,31 Because patients may have persistently positive IgG antibodies for many months after eradication therapy, a serologic test will often give a false-positive result during that period.32
Urea breath tests are able to detect an active H pylori infection. Patients ingest a specific food or drink that contains carbon-labeled urea. Gastric urease activity, which is highly specific for active H pylori infection, converts the carbon-labeled urea to labeled carbon dioxide and ammonia. The patient breathes into a container, and a positive test occurs when the labeled carbon dioxide exceeds a threshold level. Both 13Carbon and 14Carbon are used. The latter exposes patients to a negligible amount of radioactivity, but is simple, rapid, and less expensive than the 13 carbon tests. In comparative studies, the urea breath tests are more accurate than serologic tests.33,34
Stool antigen is involved in the most recently developed noninvasive test. The few studies that have been conducted to date have demonstrated that these tests are highly accurate.35 The stool antigen has recently been recommended by the European Helicobacter Pylori Study Group as the preferred initial noninvasive diagnostic test.36
Approach to the patient
There are a variety of possible approaches to the initial management of patients with dyspepsia. These include (1) prompt endoscopy (or UGI) for all patients, (2) prompt endoscopy (or UGI) for patients at highest risk for organic disease, (3) empiric acid suppression therapy for all patients with testing reserved for patients who remain symptomatic, (4) empiric H pylori eradication therapy for all patients, and (5) noninvasive H pylori testing for all patients, followed by empiric eradication therapy for those with positive results and empiric treatment of functional dyspepsia for those with negative results (a “test and treat” approach).
The most recent American, Canadian, and European consensus-based guidelines all recommend that patients younger than 45 years with dyspepsia and no alarm symptoms should be tested for H pylori infection and then given eradication therapy if positive; patients older than 45 years and those with alarm symptoms should have prompt endoscopy.37-39 H pylori–negative patients younger than 45 years and without alarm symptoms should be managed empirically for functional dyspepsia. H pylori–positive or negative patients who do not undergo endoscopy initially should do so if their symptoms persist. An algorithm depicting this approach is presented in the Figure 1. Cost-effectiveness analyses generally support this approach.22,40,41
Direct evidence for these approaches from randomized controlled trials has recently become available.42-45 These studies show that outcomes are similar whether patients received prompt endoscopy or follow a test and treat strategy. Note that patients older than 45 years, using NSAIDs, or with any alarm symptoms for complicated disease were either excluded from these trials or underwent prompt endoscopy.
Although the current evidence supports a test and treat strategy, the results may not be generalizable to all areas. The effectiveness of this approach depends on the prevalence of H pylori infection in patients with ulcers in the community; in some areas, this prevalence may be too low to make this approach effective.46,47 Also, patients not undergoing prompt endoscopy may be less satisfied with their care,42 which is related to the observation that patients with dyspepsia are more likely than physicians to value diagnostic certainty.48 Other data suggest, however, that patient satisfaction is more closely associated with symptom improvement than with having procedures performed.49 With these caveats in mind, it seems most reasonable to inform your patients about the evidence regarding the advantages and disadvantages of the various approaches and allow them to share in the decision-making process.
An international consensus conference has defined dyspepsia as chronic or recurrent pain or discomfort that is centered in the upper abdomen.1 This discomfort includes such symptoms as early satiety, fullness, bloating, and nausea. Up to 50% of people in community surveys in the United States and Europe report having dyspepsia.2 Although only a minority of people with dyspepsia seek care,3,4 this complaint still accounts for 2% to 3% of visits to family physicians.5 Patients with dyspepsia report lower quality of life than asymptomatic people; in one report, they had a quality of life similar to patients with angina.6 This review discusses the evaluation of dyspepsia and will be followed next month by a review of the treatment of dyspepsia.
Differential diagnosis
Information about the differential diagnosis of this condition largely comes from studies in which patients with dyspepsia were referred for upper endoscopy Table 1.7 The most common identifiable conditions were esophagitis, gastric ulcer, and duodenal ulcer. Most patients in these studies did not have any abnormalities on endoscopy and were considered to have functional dyspepsia. The pathophysiology of functional dyspepsia is not well understood and is likely to be multifactorial. Gastroduodenal dysmotility, increased gastric acid secretion, increased visceral sensation to distention and/or gastric acid, psychological distress, and environmental factors such as smoking and Helicobacter pylori infection all may play a role.8
When dyspeptic patients undergo more extensive evaluations and/or are followed up for longer periods of time, a large variety of other conditions have been identified. These include gastroesophageal reflux without esophagitis, lactose intolerance, cholelithiasis, gastroparesis, chronic pancreatitis, pancreatic cancer, celiac disease, giardiasis, and ischemic heart disease.9-11 However, it is not always clear that these diagnoses are completely responsible for a patient’s dyspeptic symptoms. Finally, a variety of medications or other ingestions (such as alcohol) can lead to dyspepsia.12
Using the history and physical examination
The history and physical examination are important in detecting red flags for potentially fatal conditions, such as cancer or complicated ulcers. Alarm symptoms include dysphagia, gastrointestinal bleeding, acute abdominal pain, jaundice, or an abdominal mass. The presence of 1 or more of these symptoms should trigger a consultation with a surgeon or a gastroenterologist and possible endoscopy.
A patient’s age is of some help in diagnosis; older patients are more likely to have identifiable causes for dyspepsia than those who are younger.7,9 This is particularly true for gastric cancer, which is rare in people younger than 45 years in Europe and North America. In 1 study that identified all cases of gastric cancer in a population of 280,500, only 25 of 319 gastric cancers occurred in patients younger than 55 years. Of these patients, 24 of 25 had symptoms or signs of gastric cancer: weight loss (14), dysphagia (8), anemia (7), gastrointestinal bleed (3), previous gastric surgery (3), palpable mass (3), gastrointestinal perforation (1), and cerebral metastases (1).13 Historical and demographic factors that are more likely to be seen in patients with ulcers than in those with functional dyspepsia are male sex, smoking, and nonsteroidal anti-inflammatory drug (NSAID) use.14
Table 2 shows the results of 3 large prospective studies of patients with dyspepsia who were referred for endoscopy.12,15,16 Although certain symptoms are more likely to occur in some conditions than in others, no single item from the history and physical examination clearly establishes a diagnosis. Compared with patients with normal endoscopic examinations, those with ulcers are more likely to have relief of pain with food or antacids; those with gastric cancer are more likely to have lost weight; and those with esophagitis are more likely to have heartburn and pain relief with antacids. Symptoms such as nausea, distinct localization of pain, and nocturnal pain overlap to a large degree among patients with different diagnoses and are therefore not helpful.
Investigators have tried to develop more complicated scoring systems that employ a combination of these different symptoms. Although some of these clinical scores have some value in distinguishing the various causes of dyspepsia in patients who are referred for endoscopy,17-19 they are cumbersome and have not been validated in unselected patients with dyspepsia in primary care.18
The usefulness of the physical examination has been questioned in 2 studies of patients undergoing endoscopy for dyspepsia. In one study, epigastric tenderness did not accurately distinguish patients with abnormal endoscopy findings from those with normal findings.20 The likelihood ratio (LR) for tenderness to light or deep palpation was near 1, meaning that this maneuver had no diagnostic value. A second study found that an abnormal physical examination was equally likely in patients with an ulcer as in those without one.18
A recent study examined the accuracy of general practitioners’ overall impression based on the history and physical examination.21 Four hundred consecutive unselected patients with dyspepsia were evaluated by their general practitioners and then underwent endoscopy, upper abdominal ultrasonography, and laboratory tests. The physicians’ overall clinical impressions had a low sensitivity for diagnosing organic diseases or functional dyspepsia but were fairly specific for organic diseases Table 3. Note from the LRs that while suspicion of gallstone disease or malignancy significantly increased the likelihood of these conditions, an absence of suspicion in no way ruled them out (negative LR near 1).
Imaging studies and endoscopy
Definitively diagnosing the cause of a patient’s dyspepsia usually requires either upper endoscopy or an upper gastrointestinal (UGI) series. The former is more expensive, may not be readily available in some communities, and has a slight risk of complications (such as a 0.05% perforation rate22). Endoscopy is generally believed to be more accurate than a UGI series. However, most studies that compared the accuracy of these tests have used endoscopy as the gold standard, which creates a bias in favor of endoscopy. The few studies that have used repeat endoscopy for lesions detected by radiography but not the initial endoscopy have still shown that radiography is less accurate than endoscopy, especially for lesions smaller than 5 mm Table 4.23,24 Another advantage of endoscopy is the ability to biopsy lesions suspicious for malignancy and to perform invasive tests for H pylori infection. A patient who has a gastric ulcer detected by a UGI series should be referred for endoscopic biopsy, since up to 3% of these ulcers can harbor malignancy.9
Other imaging studies are not routinely recommended for evaluation of dyspepsia. In the absence of typical symptoms of biliary colic, abdominal ultrasonography has a very low yield11; even if gallstones are detected in a patient with dyspepsia, this may be incidental, and cholecystectomy may not improve the patient’s symptoms. Gastric-emptying studies may be abnormal in nearly 40% of patients with functional dyspepsia,25 but basing therapy on the results of these studies has not been consistently shown to benefit patients.1
Detecting H pylori
Patients with dyspepsia should be evaluated for the presence of H pylori, because this infection has been found in up to 95% of patients with duodenal ulcer and 80% with a gastric ulcer. It occurs in approximately 30% to 40% of patients without an ulcer.26 Patients with ulcers who are H pylori–positive have a markedly reduced recurrence rate after successful eradication therapy.27,28 Therefore, patients with gastric or duodenal ulcers who are infected with H pylori should be treated with a combination of antibiotics and acid suppressive agents to eradicate the infection. Noninvasive options for diagnosing H pylori include immunoglobulin G (IgG) antibody testing in serum or whole blood, urea breath tests, and stool antigen tests Table 4.
There are at least 40 commercially available IgG serologic tests. The median sensitivity and specificity are 92% and 83%, respectively, but the accuracy varies considerably.29 Whole blood serologic tests can be performed on capillary blood obtained from finger sticks, and are therefore more convenient than serum tests that require venipuncture but are not recommended because they are less sensitive.30,31 Because patients may have persistently positive IgG antibodies for many months after eradication therapy, a serologic test will often give a false-positive result during that period.32
Urea breath tests are able to detect an active H pylori infection. Patients ingest a specific food or drink that contains carbon-labeled urea. Gastric urease activity, which is highly specific for active H pylori infection, converts the carbon-labeled urea to labeled carbon dioxide and ammonia. The patient breathes into a container, and a positive test occurs when the labeled carbon dioxide exceeds a threshold level. Both 13Carbon and 14Carbon are used. The latter exposes patients to a negligible amount of radioactivity, but is simple, rapid, and less expensive than the 13 carbon tests. In comparative studies, the urea breath tests are more accurate than serologic tests.33,34
Stool antigen is involved in the most recently developed noninvasive test. The few studies that have been conducted to date have demonstrated that these tests are highly accurate.35 The stool antigen has recently been recommended by the European Helicobacter Pylori Study Group as the preferred initial noninvasive diagnostic test.36
Approach to the patient
There are a variety of possible approaches to the initial management of patients with dyspepsia. These include (1) prompt endoscopy (or UGI) for all patients, (2) prompt endoscopy (or UGI) for patients at highest risk for organic disease, (3) empiric acid suppression therapy for all patients with testing reserved for patients who remain symptomatic, (4) empiric H pylori eradication therapy for all patients, and (5) noninvasive H pylori testing for all patients, followed by empiric eradication therapy for those with positive results and empiric treatment of functional dyspepsia for those with negative results (a “test and treat” approach).
The most recent American, Canadian, and European consensus-based guidelines all recommend that patients younger than 45 years with dyspepsia and no alarm symptoms should be tested for H pylori infection and then given eradication therapy if positive; patients older than 45 years and those with alarm symptoms should have prompt endoscopy.37-39 H pylori–negative patients younger than 45 years and without alarm symptoms should be managed empirically for functional dyspepsia. H pylori–positive or negative patients who do not undergo endoscopy initially should do so if their symptoms persist. An algorithm depicting this approach is presented in the Figure 1. Cost-effectiveness analyses generally support this approach.22,40,41
Direct evidence for these approaches from randomized controlled trials has recently become available.42-45 These studies show that outcomes are similar whether patients received prompt endoscopy or follow a test and treat strategy. Note that patients older than 45 years, using NSAIDs, or with any alarm symptoms for complicated disease were either excluded from these trials or underwent prompt endoscopy.
Although the current evidence supports a test and treat strategy, the results may not be generalizable to all areas. The effectiveness of this approach depends on the prevalence of H pylori infection in patients with ulcers in the community; in some areas, this prevalence may be too low to make this approach effective.46,47 Also, patients not undergoing prompt endoscopy may be less satisfied with their care,42 which is related to the observation that patients with dyspepsia are more likely than physicians to value diagnostic certainty.48 Other data suggest, however, that patient satisfaction is more closely associated with symptom improvement than with having procedures performed.49 With these caveats in mind, it seems most reasonable to inform your patients about the evidence regarding the advantages and disadvantages of the various approaches and allow them to share in the decision-making process.
1. Talley N, Stanghellini V, Heading R, et al. Functional gastroduodenal disorders. Gut 1999;45:1137-42.
2. Heading RC. Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol 1999;34(suppl):3-8.
3. Jones RH, Lydeard SE, Hobbs FDR, Kenkre JE, Williams EI, Jones SJ. Dyspepsia in England and Scotland. Gut 1990;31:401-05.
4. Talley NJ, Zinsmeister AR, Schleck CD, Melton LJ. Dyspepsia and dyspepsia subgroups: a population-based study. Gastroenterology 1992;102:1259-68.
5. Marsland DW, Wood M, Mayo F. Content of family practice. Part I: rank order of diagnoses by frequency. Part II: diagnoses by disease category and age/sex distribution. J Fam Pract 1976;3:37-68.
6. Dimenas E. Methodological aspects of evaluation of quality of life in upper gastrointestinal diseases. Scand J Gastroenterol 1993;28(suppl):18-21.
7. Rabeneck L, Wray NP, Graham DY. Managing dyspepsia: what do we know and what do we need to know? Am J Gastroenterol 1998;93:920-24.
8. McNamara DA, Buckley M, O’Morain CA. Nonulcer dyspepsia: current concepts and management. Gastroenterol Clin N Am 2000;29:807-18.
9. Talley NJ, Silverstein MD, Agreus L, Nyren O, Sonnenberg A, Holtmann G. AGA technical review: evaluation of dyspepsia. Gastroenterology 1998;114:582-95.
10. Lundquist P, Seensalu R, Linden B, Nilsson LH, Lindberg G. Symptom criteria do not distinguish between functional and organic dyspepsia. Eur J Surg 1998;164:345-52.
11. Heikkinen MT, Pikkarainen PH, Takala JK, Rasanen HT, Eskelinen MJ, Julkunen RJK. Diagnostic methods in dyspepsia: the usefulness of upper abdominal ultrasound and gastroscopy. Scand J Prim Health Care 1997;15:82-86.
12. Crean GP, Holden RJ, Knill-Jones RP, et al. A database on dyspepsia. Gut 1994;35:191-202.
13. Christie J, Shepherd NA, Codling BW, Valori RM. Gastric cancer below the age of 55: implications for screening patients with uncomplicated dyspepsia. Gut 1997;41:513-17.
14. Kurata JH, Nogawa AN. Meta-analysis of risk factors for peptic ulcer: nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997;24:2-17.
15. Johannessen T, Petersen H, Kleveland PM, et al. The predictive value of history in dyspepsia. Scand J Gastroenterol 1990;25:689-97.
16. Mansi C, Savarino V, Mela GS, Picciotto A, Mele MR, Cele G. Are clinical patterns of dyspepsia a valid guideline for appropriate use of endoscopy? A report on 2253 dyspeptic patients. Am J Gastroenterol 1993;88:1011-15.
17. Talley NJ, McNeil D, Piper DW. Discriminant value of dyspeptic symptoms: a study of the clinical presentation of 221 patients with dyspepsia of unknown cause, peptic ulceration, and cholelithiasis. Gut 1987;28:40-46.
18. Numans M, van der Graaf Y, de Wit NJ, Touw-otten FWMM, de Melker RA. How much ulcer is ulcer-like? Diagnostic determinates of peptic ulcer in open access gastroscopy. Fam Pract 1994;11:382-88.
19. Bytzer P, Moller Hansen J, de Muckadell OBS, Malchow-Moller A. Predicting endoscopic diagnosis in the dyspeptic patient: the value of predictive score models. Scand J Gastroenterol 1997;32:118-25.
20. Priebe WM, DaCosta LR, Beck IT. Is epigastric tenderness a sign of peptic ulcer disease? Gastroenterology 1982;82:16-19.
21. Heikkinen M, Pikkarainen P, Eskelinen M, Julkunen R. GPs’ ability to diagnose dyspepsia based only on physical examination and patient history. Scand J Prim Health Care 2000;18:99-104.
22. Ofman JJ, Etchason J, Fullerton S, Kahn KL, Soll AH. Management strategies for Helicobacter pylori–seropositive patients with dyspepsia: clinical and economic consequences. Ann Intern Med 1997;126:280-91.
23. Shaw PC, van Romunde LKJ, Griffioen G, Janssens AR, Kreuning J, Eilers GAM. Peptic ulcer and gastric carcinoma: diagnosis with biphasic radiography compared with fiberoptic endoscopy. Radiology 1987;163:39-42.
24. Dooley CP, Larson AW, Stace NH, Renner IG, Valenzuela JE, Eliasoph J. Double-contrast barium meal and upper gastrointestinal endoscopy: a comparative study. Ann Intern Med 1984;101:538-45.
25. Quartero AO, de Wit NJ, Lodder AC, Numans ME, Smout AJPM, Hoes AW. Disturbed solid-phase gastric emptying in functional dyspepsia: a meta-analysis. Dig Dis Sci 1998;43:2028-33.
26. Peterson W, Fendrick AM, Cave DR, Peura DA, Garabedian-Ruffalo SM, Laine L. Helicobacter pylori–related disease: guidelines for testing and treatment. Arch Intern Med 2000;160:1285-91.
27. Moore RA. Helicobacter pylori and peptic ulcer: a systematic review of effectiveness and an overview of the economic benefits of implementing what is known to be effective. Oxford: Pain Relief Research Unit, 1995; vii:37.
28. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110:1244-52.
29. Laheij RJF, Straatman H, Jansen JBMJ, Verbeek ALM. Evaluation of commercially available Helicobacter pylori serology kits: a review. J Clin Microbiol 1998;36:2803-09.
30. Chey WD, Murthy U, Shaw S, et al. A comparison of three fingerstick, whole blood antibody tests for Helicobacter pylori infection: a United States, multicenter trial. Am J Gastroenterol 1999;94:1512-16.
31. Faigel DO, Magaret N, Corless C, Lieberman DA, Fennerty MB. Evaluation of rapid antibody tests for the diagnosis of Helicobacter pylori infection. Am J Gastroenterol 2000;95:72-77.
32. Ho B, Marshall BJ. Accurate diagnosis of Helicobacter pylori: serologic testing. Gastroenterol Clin N Am 2000;29:853-62.
33. Cutler AF, Havstad S, Ma CK, Blaser MJ, Perez-Perez GI, Schubert TT. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology 1995;109:136-41.
34. Thijs JC, van Zwet AA, Thijs WJ, et al. Diagnostic tests for Helicobacter pylori: a prospective evaluation of their accuracy, without selecting a single test as the gold standard. Am J Gastroenterol 1996;91:2125-29.
35. Vaira D, Malfertheiner P, Megraud F, et al. Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based assay. Lancet 1999;354:30-33.
36. Vaira D, Vakil N. Blood, urine, stool, breath, money, and Helicobacter pylori. Gut 2001;48:287-89.
37. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 1998;114:579-81.
38. Hunt RH, Fallone CA, Thomson ABR. Canadian Helicobacter Study Group. Canadian Helicobacter pylori consensus conference update: infection in adults. Can J Gastroenterol 1999;13:213-17.
39. The European Helicobacter Pylori Study Group (EHPSG). Current European concepts in the management of Helicobacter pylori infection: the Maastricht Consensus Report. Gut 1997;41:8-13.
40. Fendrick AM, Chernew ME, Hirth RA, Bloom BS. Immediate endoscopy or initial Helicobacter pylori serological testing for suspected peptic ulcer disease: estimating cost-effectiveness using decision analysis. Yale J Biol Med 1996;69:187-95.
41. Ebell MH, Warbasse L, Brenner C. Evaluation of the dyspeptic patient: a cost-utility study. J Fam Pract 1997;44:545-55.
42. Lassen AT, Pedersen FM, Bytzer P, de Muckadell OBS. Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356:455-60.
43. Jones R, Tait C, Sladen G, Weston-Baker J. A trial of test-and-treat strategy for Helicobacter pylori–positive dyspeptic patients in general practice. Int J Clin Pract 1999;53:413-16.
44. Heaney A, Collins JSA, Watson RGP, McFarland RJ, Bamford KB, Tham TCK. A prospective randomised trial of a “test and treat” policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut 1999;45:186-90.
45. Asante MA, Mendall M, Patel P, Ballam L, Northfield TC. A randomized trial of endoscopy vs no endoscopy in the management of seronegative Helicobacter pylori dyspepsia. Eur J Gastroenterol Hepatol 1998;10:983-89.
46. Tovey FI, Hobsley M. Is Helicobacter pylori the primary cause of duodenal ulceration? J Gastroenterol Hepatol 1999;14:1053-56.
47. Xia HHX, Kalantar JS, Mitchell HM, Talley NJ. Can Helicobacter pylori serology still be applied as a surrogate marker to identify peptic ulcer disease in dyspepsia? Aliment Pharmacol Ther 2000;14:615-24.
48. Hirth RA, Bloom BS, Chernew ME, Fendrick AM. Patient, physician, and payer perceptions and misperceptions of willingness to pay for diagnostic certainty. Int J Technol Assess Health Care 2000;16:35-49.
49. Kurata JH, Nogawa AN, Chen YK, Parker CE. Dyspepsia in primary care: perceived causes, reasons for improvement, and satisfaction with care. J Fam Pract 1997;44:281-88.
50. Peura DA, Pambianco DJ, Dye KR, et al. Microdose 14C-urea breath test offers diagnosis of Helicobacter pylori in 10 minutes. Am J Gastroenterol 1996;91:233-38.
51. Raju GS, Smith MJ, Morton D, Bardhan KD. Mini-dose (1-microCi) 14C-urea breath test for the detection of Helicobacter pylori. Am J Gastroenterol 1994;89:1027-31.
1. Talley N, Stanghellini V, Heading R, et al. Functional gastroduodenal disorders. Gut 1999;45:1137-42.
2. Heading RC. Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol 1999;34(suppl):3-8.
3. Jones RH, Lydeard SE, Hobbs FDR, Kenkre JE, Williams EI, Jones SJ. Dyspepsia in England and Scotland. Gut 1990;31:401-05.
4. Talley NJ, Zinsmeister AR, Schleck CD, Melton LJ. Dyspepsia and dyspepsia subgroups: a population-based study. Gastroenterology 1992;102:1259-68.
5. Marsland DW, Wood M, Mayo F. Content of family practice. Part I: rank order of diagnoses by frequency. Part II: diagnoses by disease category and age/sex distribution. J Fam Pract 1976;3:37-68.
6. Dimenas E. Methodological aspects of evaluation of quality of life in upper gastrointestinal diseases. Scand J Gastroenterol 1993;28(suppl):18-21.
7. Rabeneck L, Wray NP, Graham DY. Managing dyspepsia: what do we know and what do we need to know? Am J Gastroenterol 1998;93:920-24.
8. McNamara DA, Buckley M, O’Morain CA. Nonulcer dyspepsia: current concepts and management. Gastroenterol Clin N Am 2000;29:807-18.
9. Talley NJ, Silverstein MD, Agreus L, Nyren O, Sonnenberg A, Holtmann G. AGA technical review: evaluation of dyspepsia. Gastroenterology 1998;114:582-95.
10. Lundquist P, Seensalu R, Linden B, Nilsson LH, Lindberg G. Symptom criteria do not distinguish between functional and organic dyspepsia. Eur J Surg 1998;164:345-52.
11. Heikkinen MT, Pikkarainen PH, Takala JK, Rasanen HT, Eskelinen MJ, Julkunen RJK. Diagnostic methods in dyspepsia: the usefulness of upper abdominal ultrasound and gastroscopy. Scand J Prim Health Care 1997;15:82-86.
12. Crean GP, Holden RJ, Knill-Jones RP, et al. A database on dyspepsia. Gut 1994;35:191-202.
13. Christie J, Shepherd NA, Codling BW, Valori RM. Gastric cancer below the age of 55: implications for screening patients with uncomplicated dyspepsia. Gut 1997;41:513-17.
14. Kurata JH, Nogawa AN. Meta-analysis of risk factors for peptic ulcer: nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997;24:2-17.
15. Johannessen T, Petersen H, Kleveland PM, et al. The predictive value of history in dyspepsia. Scand J Gastroenterol 1990;25:689-97.
16. Mansi C, Savarino V, Mela GS, Picciotto A, Mele MR, Cele G. Are clinical patterns of dyspepsia a valid guideline for appropriate use of endoscopy? A report on 2253 dyspeptic patients. Am J Gastroenterol 1993;88:1011-15.
17. Talley NJ, McNeil D, Piper DW. Discriminant value of dyspeptic symptoms: a study of the clinical presentation of 221 patients with dyspepsia of unknown cause, peptic ulceration, and cholelithiasis. Gut 1987;28:40-46.
18. Numans M, van der Graaf Y, de Wit NJ, Touw-otten FWMM, de Melker RA. How much ulcer is ulcer-like? Diagnostic determinates of peptic ulcer in open access gastroscopy. Fam Pract 1994;11:382-88.
19. Bytzer P, Moller Hansen J, de Muckadell OBS, Malchow-Moller A. Predicting endoscopic diagnosis in the dyspeptic patient: the value of predictive score models. Scand J Gastroenterol 1997;32:118-25.
20. Priebe WM, DaCosta LR, Beck IT. Is epigastric tenderness a sign of peptic ulcer disease? Gastroenterology 1982;82:16-19.
21. Heikkinen M, Pikkarainen P, Eskelinen M, Julkunen R. GPs’ ability to diagnose dyspepsia based only on physical examination and patient history. Scand J Prim Health Care 2000;18:99-104.
22. Ofman JJ, Etchason J, Fullerton S, Kahn KL, Soll AH. Management strategies for Helicobacter pylori–seropositive patients with dyspepsia: clinical and economic consequences. Ann Intern Med 1997;126:280-91.
23. Shaw PC, van Romunde LKJ, Griffioen G, Janssens AR, Kreuning J, Eilers GAM. Peptic ulcer and gastric carcinoma: diagnosis with biphasic radiography compared with fiberoptic endoscopy. Radiology 1987;163:39-42.
24. Dooley CP, Larson AW, Stace NH, Renner IG, Valenzuela JE, Eliasoph J. Double-contrast barium meal and upper gastrointestinal endoscopy: a comparative study. Ann Intern Med 1984;101:538-45.
25. Quartero AO, de Wit NJ, Lodder AC, Numans ME, Smout AJPM, Hoes AW. Disturbed solid-phase gastric emptying in functional dyspepsia: a meta-analysis. Dig Dis Sci 1998;43:2028-33.
26. Peterson W, Fendrick AM, Cave DR, Peura DA, Garabedian-Ruffalo SM, Laine L. Helicobacter pylori–related disease: guidelines for testing and treatment. Arch Intern Med 2000;160:1285-91.
27. Moore RA. Helicobacter pylori and peptic ulcer: a systematic review of effectiveness and an overview of the economic benefits of implementing what is known to be effective. Oxford: Pain Relief Research Unit, 1995; vii:37.
28. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110:1244-52.
29. Laheij RJF, Straatman H, Jansen JBMJ, Verbeek ALM. Evaluation of commercially available Helicobacter pylori serology kits: a review. J Clin Microbiol 1998;36:2803-09.
30. Chey WD, Murthy U, Shaw S, et al. A comparison of three fingerstick, whole blood antibody tests for Helicobacter pylori infection: a United States, multicenter trial. Am J Gastroenterol 1999;94:1512-16.
31. Faigel DO, Magaret N, Corless C, Lieberman DA, Fennerty MB. Evaluation of rapid antibody tests for the diagnosis of Helicobacter pylori infection. Am J Gastroenterol 2000;95:72-77.
32. Ho B, Marshall BJ. Accurate diagnosis of Helicobacter pylori: serologic testing. Gastroenterol Clin N Am 2000;29:853-62.
33. Cutler AF, Havstad S, Ma CK, Blaser MJ, Perez-Perez GI, Schubert TT. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology 1995;109:136-41.
34. Thijs JC, van Zwet AA, Thijs WJ, et al. Diagnostic tests for Helicobacter pylori: a prospective evaluation of their accuracy, without selecting a single test as the gold standard. Am J Gastroenterol 1996;91:2125-29.
35. Vaira D, Malfertheiner P, Megraud F, et al. Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based assay. Lancet 1999;354:30-33.
36. Vaira D, Vakil N. Blood, urine, stool, breath, money, and Helicobacter pylori. Gut 2001;48:287-89.
37. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 1998;114:579-81.
38. Hunt RH, Fallone CA, Thomson ABR. Canadian Helicobacter Study Group. Canadian Helicobacter pylori consensus conference update: infection in adults. Can J Gastroenterol 1999;13:213-17.
39. The European Helicobacter Pylori Study Group (EHPSG). Current European concepts in the management of Helicobacter pylori infection: the Maastricht Consensus Report. Gut 1997;41:8-13.
40. Fendrick AM, Chernew ME, Hirth RA, Bloom BS. Immediate endoscopy or initial Helicobacter pylori serological testing for suspected peptic ulcer disease: estimating cost-effectiveness using decision analysis. Yale J Biol Med 1996;69:187-95.
41. Ebell MH, Warbasse L, Brenner C. Evaluation of the dyspeptic patient: a cost-utility study. J Fam Pract 1997;44:545-55.
42. Lassen AT, Pedersen FM, Bytzer P, de Muckadell OBS. Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356:455-60.
43. Jones R, Tait C, Sladen G, Weston-Baker J. A trial of test-and-treat strategy for Helicobacter pylori–positive dyspeptic patients in general practice. Int J Clin Pract 1999;53:413-16.
44. Heaney A, Collins JSA, Watson RGP, McFarland RJ, Bamford KB, Tham TCK. A prospective randomised trial of a “test and treat” policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut 1999;45:186-90.
45. Asante MA, Mendall M, Patel P, Ballam L, Northfield TC. A randomized trial of endoscopy vs no endoscopy in the management of seronegative Helicobacter pylori dyspepsia. Eur J Gastroenterol Hepatol 1998;10:983-89.
46. Tovey FI, Hobsley M. Is Helicobacter pylori the primary cause of duodenal ulceration? J Gastroenterol Hepatol 1999;14:1053-56.
47. Xia HHX, Kalantar JS, Mitchell HM, Talley NJ. Can Helicobacter pylori serology still be applied as a surrogate marker to identify peptic ulcer disease in dyspepsia? Aliment Pharmacol Ther 2000;14:615-24.
48. Hirth RA, Bloom BS, Chernew ME, Fendrick AM. Patient, physician, and payer perceptions and misperceptions of willingness to pay for diagnostic certainty. Int J Technol Assess Health Care 2000;16:35-49.
49. Kurata JH, Nogawa AN, Chen YK, Parker CE. Dyspepsia in primary care: perceived causes, reasons for improvement, and satisfaction with care. J Fam Pract 1997;44:281-88.
50. Peura DA, Pambianco DJ, Dye KR, et al. Microdose 14C-urea breath test offers diagnosis of Helicobacter pylori in 10 minutes. Am J Gastroenterol 1996;91:233-38.
51. Raju GS, Smith MJ, Morton D, Bardhan KD. Mini-dose (1-microCi) 14C-urea breath test for the detection of Helicobacter pylori. Am J Gastroenterol 1994;89:1027-31.