Dyspepsia is a problem commonly seen by primary

Concise Review for Clinicians Nonulcer Dyspepsia: What It Is and What It Is Not G. RICHARD LOCKE III, MD Nonulcer dyspepsiais a description of persistent or recurrent upper abdominal pain or discomfort with no structural or biochemical explanation for the patient's symptoms. The exact cause of nonulcer dyspepsia is not known, but many myths have evolved regarding its etiology and treatment. The goal of this reviewis to evaluate the potential causesof nonulcer dyspepsia.bydetermining what it is Dyspepsia is a problem commonly seen by primary care physicians. Most patients with dyspepsia do not have ulcers or cancers. In fact, the majority do not have a structural or biochemical explanation for their symptoms. Such patients are diagnosed as having nonulcer dyspepsia (NUD). Multiple potential pathogeneses have been postulated for NUD. Similarly, many different therapies have been tried. This multitude of diagnostic and therapeutic options simply underscores the fact that the true cause of dyspepsia is not known. At present, there is no clear consensus as to how best to manage patients with NUD. The goal of this article is to review the etiologic and therapeutic options and recommend management approaches for this common condition. DEFINITION Dyspepsia is not a condition, it is a symptom complex. Dyspepsia can be defined as persistent or recurrent abdominal pain or abdominal discomfort centered in the upper abdomen. I This discomfort may include symptoms of nausea, vomiting, early satiety, postprandial fullness, and upper abdominal bloating. Symptoms are typically associated with eating but not with bowel movements. Heartburn and acid regurgitation are often included as symptoms of dyspepsia; yet if these are the main symptoms, the patient should be considered to have reflux rather than dyspepsia. Patients with symptoms or signs typical of biliary tract or pancreatic disease should not be considered to have NUD. From the Division of Gastroenterology and Hepatology and Internal Medicine, Mayo Clinic Rochester, Rochester, Minn. Dr Locke is the recipient of an American College of Gastroenterology Institute Junior Faculty Development Award. Address reprint requests and correspondence to G. Richard Locke III, MD, Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905. Mayo Clin Proc. 1999;74:1011-1015 1011 and what it is not, we can be more selective in our approach to diagnosisand our choiceof empiric therapies. Mayo Clin Proc. 1999;74:1011-1015 GERD =gastroesophageal reflux disease; NSAIDs =nonsteroidal anti-inflammatory drugs; NUD = nonulcer dyspepsia; PUD =peptic ulcer disease Thus, right upper quadrant pain or epigastric pain radiating to the back should not be included in the definition of dyspepsia. Nonulcer dyspepsia can then be defined as dyspepsia symptoms of more than 3 months' duration without an anatomical or biochemical abnormality. Typically, this means normal blood test results and a negative evaluation of the upper gastrointestinal tract with either endoscopy or barium radiography. However, defining a negative endoscopy can be difficult. Does this include biopsies of the esophagus for esophagitis or biopsies of the stomach for gastritis or Helicobacter pylori infection? Are erythema, erosions, or histologic inflammation meaningful findings? These controversial issues are discussed subsequently. What about other diagnostic tests such as ultrasonography, computed tomographic scans, gastric-emptying studies, or ambulatory ph monitoring? Do these have to be done before a diagnosis of NUD is made? These are the issues that need to be addressed. EPIDEMIOLOGY Many surveys have evaluated how many people experience symptoms of dyspepsia in the community. The rates vary in large part because of the definitions used. Some surveys include the symptom of heartburn in the definition of dyspepsia and report a prevalence of 40%. Other surveys exclude subjects with symptoms of heartburn or irritable bowel syndrome and report prevalence rates of less than 5%. Nonetheless, it is probably reasonable to estimate that 15% (about 1 in 7) of the adult population has dyspepsia.' Not all these people have NUD, however. In 1 study, a random sample of the population with dyspepsia underwent endoscopy"; 53% had normal endoscopy. The remarkable findings were esophagitis, peptic ulcer disease (PUD), duodenitis, and duodenogastric reflux. Of note, only 66% of the asymptomatic controls in this study had 1999 Mayo Foundation/or Medical Education and Research

1012 Nonulcer Dyspepsia normal endoscopic findings. Only PUD and duodenitis were more common in the patients with dyspepsia than in the controls. Dyspepsia accounts for a significant number of medical visits. Unfortunately, the National Center for Health Statistics does not use a specific code for dyspepsia. More than 2 million office visits occur each year for gastritis and duodenitis, and most of these are to general practitioners and internists. In 1 study, patients presenting to primary care physicians with dyspepsia underwent endoscopy prior to therapy.' Twenty-two percent had peptic ulcer disease, 10% had esophagitis, 1% had cancer, and the remaining 67% had NUD. To summarize, symptoms of dyspepsia are common and result in a high number of physician visits. Most people presenting with dyspepsia have negative evaluations, and thus, they are diagnosed as having NUD. WHAT IT IS AND WHAT IT IS NOT Table I lists the most frequently mentioned etiologic possibilities for NUD. In some ways, the thinking has been divided into 2 worlds: patients have either an acid or H pylori problem or a motility disorder. This led investigators to try to identify specific symptom subtypes such as reflux-like, ulcer-like, or dysmotility-like dyspepsia. The idea was that symptoms of dyspepsia could result from multiple etiologies; however, by refining the symptom criteria, more specific etiologies would be identified. Although the reasoning was sound, this has not proved true. Symptoms and specific test findings do not correlate well, and this is just 1 of the problems in identifying the cause of NUD. Table 2 lists some others. The clinician must be careful before attributing any cause-and-effect relationship. Is NUD Caused by Gastritis or H pylorn Traditional teaching in the 1980s was that the differential diagnosis of dyspepsia included PUD, esophagitis, gastric cancer, and gastritis. Patients were empirically treated with acid inhibitors as these were thought to be effective for the 3 benign conditions. However, the identification of H pylori has forced reanalysis of this issue. Fifty percent of adults older than 60 years are infected with H pylori. The rates are lower in younger people, closer to 15%. H pylori infection is synonymous with type B chronic active gastritis. Thus, most of the elderly have gastritis, yet they do not all have symptoms of dyspepsia. In the communitybased endoscopy study mentioned previously,' the majority of asymptomatic controls had histologically proved gastritis. The prevalence of gastritis was only slightly more common in dyspeptic patients. Still, the idea that the histologic inflammation gives rise to symptoms is an interesting Mayo Clin Proc, October 1999, Vol 74 Table 1. Nonulcer Dyspepsia: The Possibilities Acid-H pylori H pylori infection Gastritis, duodenitis Overlooked peptic ulcer disease Acid sensitivity Occult gastroesophageal reflux disease Motility Gastroparesis Abnormal relaxation Visceral hypersensitivity Brain-gut disorder Psychological disorder one. The early findings and reports of H pylori eradication in NUD disagreed. Examination of specific subtypes of H pylori, such as those that express the CagA gene, has not clarified this issue. Fortunately, 2 multicenter, placebocontrolled clinical trials were recently ' published.v" In both studies, 20% of the subjects had resolution of their dyspeptic symptoms at I year. What differed between the studies was the placebo response rate, which was 20% in I study and 8% in the other. Therefore, the 2 studies came to conflicting conclusions. Thus, the role of H pylori eradication in the treatment of NUD remains controversial. Since H pylori treatment may help one fifth of patients and H pylori has been declared a carcinogen by the World Health Organization, this treatment remains worthy of consideration. Although the role of H pylori in NUD is controversial, its role in PUD is clear. At times, however, the boundary between PUD and NUD becomes fuzzy. Specifically, some patients have duodenitis or duodenal erosions. They may have a history of PUD but negative endoscopic findings at the time of presentation. Overall, these patients should be managed as having PUD rather than NUD. Many patients have minor erosions or erythema of the stomach at endoscopy. The endoscopist cannot distinguish whether this represents gastritis or gastropathy. The determination requires histologic evaluation. Gastropathy is primarily associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs). The role of NSAIDs, like that of H pylori, in causing dyspepsia without PUD is somewhat controversial. NSAIDs certainly cause erosions, many of which are asymptomatic. The development of dyspepsia in NSAID users is associated with psychological distress. Patients who take NSAIDs and have gastric erosions can still be considered to have NUD. Typically, when patients develop dyspepsia while taking NSAIDs, the NSAID is temporarily discontinued to see if the dyspepsia resolves.

Mayo Clio Proc, October 1999, Vol 74 Is NUD an Acid Problem? Patients commonly take antacids for relief of dyspepsia, yet gastric acid secretion is normal in patients with NUD. One hypothesis is that patients with NUD may be more sensitive to acid. However, studies in which acid secretion has been stimulated with pentagastrin have yielded conflicting results. Other investigators infused acid or saline directly into the stomach in a blinded fashion, and these results were also conflicting. Placebo-controlled trials have not shown that antacids are more effective than placebo in relieving NUD. However, since patients can take antacids on their own, those who seek medical care may be those for whom the antacids were not helpful. Similarly, histamine receptor antagonists have been used widely in the treatment of NUD. A meta-analysis done in 1989 reported that histamine blockers had a mean success rate 20% higher than placebo.' Are proton pump inhibitors any better? The data on proton pump inhibition and NUD are mostly directed toward H pylori eradication. In 1 of the H pylori eradication trials mentioned previously, omeprazole was used with antibiotic placebos, and 8% of patients were symptom free at 1 year. The omeprazole, however, was given for only 4 weeks. Thus, the role of proton pump inhibitor therapy in NUD is not clear. Is NUD Occult Gastroesophageal Reflux? Gastroesophageal reflux disease (GERD) encompasses all the manifestations of gastric acid moving into the esophagus. The typical symptoms of reflux are heartburn and acid regurgitation. These symptoms are experienced by 20% of the population on a weekly basis. Some investigators include these symptoms in their definition of dyspepsia (reflux-like dyspepsia). Others believe that this is inappropriate. Patients with typical symptoms of heartburn or acid regurgitation are usually treated empirically without investigation and should be considered to have GERD. However, not all patients with GERD have typical symptoms. Studies have performed ambulatory ph monitoring in patients with epigastric pain and found that 50% to 60% have excessive acid exposure. Thus, there is likely a subset of dyspeptic patients who do, in fact, have occult GERD. Unfortunately, these patents are difficult to identify. Ambulatory ph monitoring may be considered, or alternatively, empiric treatment trials directed toward reflux can be used. 'S NUD a Motility Disorder? Although clinicians often focus on epigastric pain as the cardinal symptom of NUD, most investigators include other symptoms such as nausea, fullness, early satiety, and the like. These symptoms suggest that motor abnormalities Nooulcer Dyspepsia 1013 Table 2. Nonulcer Dyspepsia: The Problems Symptomscome and go (and change) Placebo response rate is high (30%+) No findings are present in all patients with nonulcer dyspepsia Findings are present in asymptomatic patients Symptoms and findings do not correlate No therapy is universallyeffective Response to therapy is hard to predict may play a role in this condition. Between one third and one half of patients with NUD seen in the gastroenterology clinics of referral centers will have delayed gastric emptying. Multiple studies, primarily in Europe, have evaluated the role of prokinetics in NUD. In general, prokinetics are 30% more effective than placebo, although the rates between studies have been quite variable. Only 1 study has directly compared a prokinetic with a histamine blocker, and the prokinetic was slightly more effective." Most of the studies have been with cisapride at low doses (10 mg, 2 to 4 times daily). Domperidone is available in Europe but not in the United States. Metoclopramide has been shown to be helpful, which may in part be due to its antiemetic effects. Still, long-term use of metoclopramide needs to be avoided because of the risk of tardive dyskinesia. Recently, the prokinetic agent cisapride has been associated with torsades de pointes. Thus, electrocardiographic monitoring and careful consideration of drug-drug interactions have become necessary. More recently, attention has shifted from gastric emptying to gastric accommodation. That is, just like the heart, the stomach has both systolic and diastolic functions. Recent studies have shown that gastric accommodation (the relaxation of the stomach in response to a meal) is abnormal in patients with functional dyspepsia." Medications such as nitroglycerin, calcium channel blockers, and anticholinergics are being evaluated to see if they improve the accommodation response. However, at present their effectiveness is not known. Is NUD a Functional Disorder? The functional disorders are a continuum of illnesses characterized by gastrointestinal symptoms with negative diagnostic evaluations. There is significant overlap among these disorders.'? Specifically, at least one third of people with NUD also have symptoms of irritable bowel syndrome, including a lower threshold for rectal distention. In NUD, a similar phenomenon is noted for distention of the stomach. Patients with NUD report pain at a lower volume when a gastric balloon is inflated in the gastric cavity. More recently, central nervous system imaging has highlighted

Mayo Clin Proc, October 1999, Vol 74 1014 Nonulcer Dyspepsia the activation of different parts of the brain in subjects with functional gastrointestinal disorders. Thus, the concept of visceral hypersensitivity remains a strong consideration in all functional gastrointestinal disorders, including NUD. At present, however, there is not a specific medication for visceral hypersensitivity, although newer agents such as fedotozine and serotonin receptor antagonists are being investigated. Clinically, low-dose antidepressants are being used, although formal clinical trial data are lacking. Is NUD a Psychiatric Disease? Like the other functional gastrointestinal disorders, patients with NUD do report higher levels of psychological distress as well as higher rates of anxiety and depression. The question remains as to whether the psychiatric distress is the cause of the NUD or rather promotes health care-seeking behavior. Psychological and psychiatric interventions are being investigated in NUD, although, once again, clinical trial data are not yet available. Furthermore, there is little benefit in arguing with the patient whether the NUD is organic or psychiatric. Clinicians need to take the patient's symptoms seriously; however, if a psychiatric disease is present, it needs to be treated, and this may affect the gastrointestinal symptoms. diagnostic testing or referral to a gastroenterologist may be considered. Tests to consider include abdominal imaging with computed tomography or ultrasonography, gastric emptying studies, or ambulatory ph monitoring. In the future, simpler tests of gastric function may become available. Often the diagnostic tests can be interfaced with therapeutic trials of H pylori eradication, proton pump inhibitors, prokinetics, mucosal protectants such as sucralfate, anticholinergics, or, finally, use of low-dose antidepressants. In one third to one half of patients with dyspepsia, symptoms resolve spontaneously. Yet, some will be plagued by this problem chronically. The hope for the future is that new medications to treat visceral hypersensitivity or gastric accommodation prove useful and strengthen the clinician's armamentarium against this common disorder. ACKNOWLEDGMENT I wish to thank Karen A. Kruger for her assistance in preparing the submitted manuscript. REFERENCES I. Talley NJ, Colin-Jones D, Koch KL, Koch M, Nyren 0, Stanghellini V. Functional dyspepsia: a classification with guidelines for diagnosis and management. Gastroenterol Int. 1991;4: 2. Locke GR III. Prevalence, incidence and natural history of dyspepsia and functional dyspepsia. Bail/ieres Clin Gastroenterol. 3. Johnsen R, Bemersen B, Straume B, Forde OH, Bostad L, Burhol PG. Prevalences of endoscopic and histological findings in subjects with and without dyspepsia. BMJ. 1991;302:749-752. Bytzer P, Hansen JM, Schaffalitzky de Muckadell OB. Empirical H,-blocker therapy or prompt endoscopy in management of dyspepsia. Lancet. 1994;343:811-816. Blum AL, Talley NJ, O'Moniin C, et al, Omeprazole Plus Clarithromycin and Amoxicillin Effect One Year After Treatment (OCAY) Study Group. Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med. RECOMMENDATIONS FOR EVALUATION AND THERAPY Given all the controversy with conflicting study results and inadequate data, how is the clinician to proceed? By definition, patients with NUD have a diagnostic evaluation, either upper gastrointestinal tract radiography or endoscopy, to exclude PUD and malignancy. Since current practice guidelines recommend either a trial of acid inhibition or testing for H pylori prior to any diagnostic investigation for dyspepsia, most patients have I or both of these done prior to the diagnosis of NUD. The first step is to provide reassurance. Some patients with NUD simply want to be sure they do not have cancer. They find their symptoms tolerable and require no further intervention. The most difficult decision is whether to perform further diagnostic testing. The alternative is to proceed directly with empirical treatment trials. Initially, investigators hoped that symptom subgroups of dyspepsia such as motility-like, ulcer-like, or reflux-like groups could be identified, and this would help guide decisions. To date, however, these subgroups have not proven useful. At present, the decision regarding diagnostic tests vs treatment trials depends on the patient's preferences and the physician's practice style. If the physician and patient are comfortable with the diagnosis of NUD, then diagnostic testing can be kept to a minimum. However, if either party is uncertain, then further 145-160. 1998; 12:435-442. 4. 5. 1998;339: 1875-1881. 6. 7. 8. McColl K, Murray L, El-Omar E, et a1. Symptomatic benefit from eradicating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med. 1998;339:1869-1874. Dobrilla G, Comberlato M, Steele A, Vallaperta P. Drug treatment of functional dyspepsia: a meta-analysis of randomized controlled clinical trials. J Clin Gastroenterol. 1989;11: 169-177. Finney JS, Kinnersley N, Hughes M, O'Bryan-Tear CG, Lothian J. Meta-analysis of antisecretory and gastrokinetic compounds in functional dyspepsia. J Clin Gastroenterol. 1998;26:312320. 9. 10. Camilleri M. Nonulcer dyspepsia: a look into the future. Mayo Clin Proc. 1996;71:614-622. Agreus L, Svardsudd K, Nyren 0, Tibblin G. Irritable bowel syndrome and dyspepsia in the general population: overlap and lack of stability over time. Gastroenterology. 1995;109:671680.

Mayo Clin Proc, October 1999, Vol 74 Nonulcer Dyspepsia 1015 Questions About Nonulcer Dyspepsia (See article, pages 1011 to 1014) 1. What percentage of patients presenting with symptoms of dyspepsia have NUD? a.5% b. 15% c. 33% d.67% e. 85% 2. What percentage of elderly patients have histologically proved gastritis? a. 0% to 1% b. 5% to 10% c. 20% to 30% d. 50% to 70% e. 90% to 100% 3. Which one of the following is the first step in the management of a patient with NUD? a. Provide reassurance b. Order additional imaging studies c. Initiate empiric treatment d. Refer to a gastroenterologist e. Refer to a psychiatrist 4. Which one of the following is found in less than 10% of patients presenting with dyspepsia? a. H pylori infection b. Delayed gastric emptying c. Excess gastric acid production d. Symptoms of irritable bowel syndrome e. Gastroesophageal reflux on ph monitoring 5. Which one of the following treatments has not been shown to be effective in some patients with NUD? a. Histamine receptor antagonists b. Prokinetics c. H pylori eradication regimens d. Low-dose tricyclic antidepressants e. Calcium channel blockers Correct answers: a. d, 2. d, 3. a, 4. c, 5. e