Invited review
Functional dyspepsia
Tomica Milosavljevic, Ivan Jovanovic
Institute of Digestive Diseases, Clinic of Gastroenterology and Hepatology,
University Clinical Center of Serbia, Belgrade
Address of correspondence to:
Professor Dr Tomica Milosavljevic
Institute of Digestive Disease
6 Koste Todorovic St, Yu - 11000 Belgrade ,
Yugoslavia
FAX: ( 381 11 ) 361 54 32
FUNCTIONAL GASTROINTESTINAL DISORDERS
A large group of patients seen by gastroenterologists in clinical practice present with chronic or recurrent gastrointestinal symptoms that continue to defy explanation, despite structural and biochemical studies. These patients are generally labeled as having a functional gastrointestinal disorder. Up to 50% of outpatients referred to gastroenterologists, in fact, receive this diagnosis. Functional gastrointestinal disorders are common conditions in otherwise healthy persons. Up to two thirds of such persons have one or more symptom (1).
Table 1 and Table 2 (2). The Rome II classification of functional gastrointestinal disorders
For unknown reasons, the reporting of symptoms slightly declines with age. Woman tend to report more functional (upper) gut symptoms than men do and more likely to be diagnosed as having functional disorder in Western countries (3,4), but in our study we did not observe this postulated gender associated difference (5).
APPROACH TO THE PATIENTS WITH SYMPTOMS OF DYSPEPSIA
General consideration
Dyspeptic symptoms are prevalent in one-fourth of the adult population (4). The majority of people, however, never seek medical attention for their symptoms. In medical practice, it is among the most common complaints evaluated by both general practitioners and gastroenterologists. The direct and indirect costs of dyspepsia, including diagnostic evaluation, drug therapy and days lost from work are staggering (6)
Definition
Dyspepsia is a vague, imprecise term that encompasses variety of upper abdominal or epigastric symptoms. According to the Rome II Multinational Consensus (2). Minimum criteria of diagnosis are:
Dyspepsia may arise from variety of causes. (Table 3)(7).
Certain kind of food such as tomatoes, spices, fatty food and coffee can cause symptoms of dyspepsia. Mechanisms underlying include abdominal distention, delayed gastric emptying (cholecystokinin -induced), direct mucosal irritation and the provocation of the gastroesophageal reflux.
Luminal gastrointestinal tract
A number of organic and functional disorders of the upper gastrointestinal tract may cause dyspepsia. Approximately 20% of patients with dyspepsia have peptic (gastric) or duodenal) ulcer disease (8,9). (Table 4).
Gastric cancer is a rare cause of dyspepsia in patients under age 45. However, it should be considered in the elderly patients with new-onset dyspepsia (up to 5%)(8,9). Gastroesophageal reflux disease is most likely if patients represent with symptoms of substernal burning and regurgitation. (Table 5).
A great number of medications may cause dyspepsia and should not be overlooked. A trial of a potentially offending drug withdrawal may often result in symptomatic relief (10,11,12,13,14).
Pancreatic (pancreatic carcinoma, chronic pancreatitis) and biliary tract diseases (cholelithiasis, choledocholithiasis, sphincter of Oddi dysfunction) can also be confused with other causes of dyspepsia.
Systemic conditions including pregnancy, diabetes mellitus (gastroparesis diabeticorum or diabetic radiculopathy of the thoracic nerve root), intra-abdominal malignancy, coronary ischemia, thyroid dysfunction.
Functional dyspepsia is present in up to one-half of dyspeptic patients (8,11). A cause of the symptoms cannot be determined from endoscopy or abdominal echosonography. In these patients symptoms may arise from a complex interaction of psychological factors, abnormal visceral pain perception and motility disorders. Dyspepsia may also be associated with other functional gastrointestinal disorders, such as irritable bowel syndrome (15).
Clinical findings
Symptoms and signs: The clinical history is of limited value in distinguishing the causes of dyspepsia. A complete drug and dietary history (including lactose) should be taken. The primary goal should be identifying patients at high risk for organic disease.
Patient should be asked about the character and location of pain its pattern of radiation, whether it is constant or intermittent, and factors that alleviate it. Predominant substernal burning (heartburn) and regurgitation is highly specific for gastroesophageal reflux disease. The epigastrium is the most common site of pain in dyspepsia of all causes, including biliary tract disease. Peptic ulcer disease is more likely when episodic bouts of rhythmic, gnawing epigastric pain occurs between meals or at night (16). Approximately two thirds of duodenal ulcer patients and one third of gastric ulcer patients experience nocturnal pain that awakens them from sleep. Antacids or food relieves the pain; however at least one-half of ulcer patients do not give this classical history. Furthermore, up to 20% of people with peptic ulcers have pain-free "silent ulcers", which may manifest with bleeding, perforation, obstruction, or other complications (13,16,17). (Table 6) .
Nonulcer dyspepsia patients are more likely to experience an exacerbation of symptoms after meals and seldom have nocturnal pain. Severe epigastric pain or pain that radiates to the back should suggest other diseases (acute pancreatitis), or a complicated peptic ulcer (with perforation or penetration). Irregular, intermittent right upper quadrant or epigastric pain precipitated by meals with crescendo-decrescendo pattern is suggestive of biliary disease. Constant, vague epigastric pain associated with weight losses possibly indicates pancreatic disease. Finally, nonulcer dyspepsia is more likely in younger patients with chronic, vague epigastric pain associated with a variety of other complaints such as bloating and distention. Although these clinical features of dyspepsia may provide clues to the cause, they are nonspecific and cannot be relied upon to make anything other than a speculative diagnosis.
A complete physical examination is mandatory in dyspeptic patients including stool occult blood testing. The majority of patients are clinically normal. Signs of organic disease such as weight loss, organomegaly, abdominal mass, or positive fecal occult blood merits further investigation.
Initial laboratory work includes a complete blood cell count, serum electrolyte measurements, amylase and liver function tests. In the patients with uncomplicated ulcer disease or functional dyspepsia these tests are usually normal. Anemia may occur from acute or chronic upper gastrointestinal blood loss and should prompt an endoscopic evaluation. An elevated serum amylase may suggest acute or chronic pancreatitis, a penetrating ulcer or choledocholithiasis. Abnormal liver function tests may suggest acute hepatitis or biliary tract disease. Other laboratory tests, such as blood alcohol levels, pregnancy test, and thyroid function tests, should be performed if necessary.
Special examinations: Because the history and physical examination are nonspecific, a diagnosis of dyspepsia in most cases requires special examinations. Upper GI endoscopy is highly accurate in diagnosing peptic ulcer disease, and gastric neoplasms. However, at least one-half of patients with dyspepsia have normal or non-specific findings on endoscopy (16). Although barium upper gastrointestinal series is less expensive, it is less accurate and suboptimal means of evaluating patients with dyspepsia. Therefore, upper GI endoscopy should be the study of first choice in the evaluation of most patients with dyspepsia. The decision as to when and how to investigate the dyspeptic patient depends on a number of factors. Patients who are older than 45 years with new onset symptoms of dyspepsia, have physical or laboratory abnormalities, or are from region endemic for gastric cancer should undergo a diagnostic endoscopy. In patients younger than 45 years of age with normal physical and laboratory examinations (in whom the risk of malignancy is low) the optimal approach is controversial (18). Until recently, an empiric trial of therapy with H2-receptors antagonists was recommended (19). In patients who failed to improve or had persistent symptoms, further diagnostic evaluation with endoscopy was recommended (20). With the recognition of the pivotal role of Helicobacter pylori in peptic ulcer disease, the merits of these guidelines are called into question ( 21 ). Some clinicians now recommend early endoscopy in patients with acute dyspepsia to diagnose peptic ulcer disease and Helicobacter pylori infection so that definitive antibacterial therapy can be given and the ulcer diathesis eliminated (22).
Other clinicians recommend screening patients with dyspepsia for Helicobacter pylori infection with noninvasive tests, such as serology or urease breath tests (23). Patients with evidence of Helicobacter pylori infection could be treated empirically with antibacterial therapy. Patients who are negative for Helicobacter pylori infection or who fail to respond to anti Helicobacter pylori treatment likely have functional dyspepsia. Further diagnostic tests are unlikely to reveal significant abnormalities.
Abdominal ultrasonography should be made only when biliary or pancreatic disease is suspected. Computed tomography (CT) or magnetic resonance imaging (MRI) should only be performed when there is a strong suspicion of intra-abdominal disease or to pursue abdominal findings on ultrasonography.
Differential diagnosis of dyspepsia should include chronic intestinal ischemia, intermittent or partial bowel obstruction, aortic dissection, ruptured aortic aneurysm, incarcerated internal or abdominal wall hernia, ureteral colic, myocardial infarction, acute intermittent porphyria, intermittent intestinal obstruction and diabetic radiculopathy
FUNCTIONAL DYSPEPSIA
Diagnostic criteria
Besides being a very common disorder, functional dyspepsia is very budget targeted. Cost of clinical evaluation and treatment of functional dyspepsia appear to be enormous. It is estimated that the direct costs are $2 billion per year in the United States (3). The indirect costs also appear to be high. Since functional dyspepsia is the most prevalent in working population, indirect costs are expected to be also high in our population. (Figure 1)(5).
Patients with functional dyspepsia take as much as 2.5 times more sickdays per year compared with other workers (24).
Dyspepsia has frequently been categorized as ulcer-like, and dysmotility-like (Table 5)(2,5). Patients with symptoms that cannot be categorized are said to have non-specific dyspepsia. Also, there is considerable overlap between the dyspepsia categories, bringing into question the validity of such classifications.
Pathophysiology
The causes of functional dyspepsia are poorly understood, and appear to be heterogeneous. As it is with other functional disorders it encompasses a number of physiologic and physiological abnormalities:
Environmental factors and dietary habits: as it was mentioned earlier, many dyspeptic patients report exacerbation of dyspeptic symptoms after ingestion of certain kind of food (tea, coffee, tomatoes, spices, etc.)
Gastric acid secretion appears to be normal in patients with functional dyspepsia. (25-29).
Motility disorders are present in up to half patients with functional dyspepsia. Solid phase gastric emptying is the most prominent disorder along with abnormal antroduodenal motility, detected in about 50% of the patients (30-34, 35). Although sympathetic and parasympathetic gut dysfunction probably underlay or at least precipitate observed motor abnormalities, the clinical importance of these findings and its relationship to symptoms is uncertain (33). There is a poor correlation between the presence of symptoms and the finding of motor abnormalities. In the relation to the absence of Helicobacter pylori infection, dysmotility-like functional dyspepsia is the most prevalent (36).
Abnormal visceral perception has been registered in patients with dyspepsia (37,38). This could explain onset of epigastric pain after intravenous injection of pentagastrin even though an H2-receptor antagonist blocks acid secretion. Several studies report that patients with functional dyspepsia develop pain when balloons are inflated in the proximal stomach (39,40). In these patients, pain occurs at significantly lower levels of balloon inflation than in control subjects. These findings are analogous to those found in irritable bowel syndrome, in which there is lower pain threshold to rectal balloon inflation, and noncardiac chest pain, in which there is a lower threshold to esophageal balloon inflation. The underlying pathophysiological mechanism of abnormal perception is unknown. Some investigators suggest abnormal processing of afferent gut sensation at the spinal or central nervous system level (35, 41). In addition it has been proven that abnormal visceral sensation is not related to the presence of gastric motor abnormalities (34, 35, 41). Furthermore, somatic pain sensation appears to be normal in those patients.
There is no convincing evidence that functional dyspepsia is related to psychological abnormalities or chronic stress. Personality profiles happen to be similar to those of patients with other functional gastrointestinal disorders (such as irritable bowel syndrome) or peptic ulcer disease (42). Patients in all of these groups have higher degrees of neurosis, depression, anxiety and hypochondriasis on standard testing (42). However, these differences are small and unlikely to be of clinical importance, in most cases. Similarly, dyspeptic patients often report onset of symptoms after an acute or chronic stress, but not to a greater extent than other patients do (42). However, the perceived magnitude of this stress may be greater. In other words, stress, objectively defined, may not be greater but may subjectively be perceived as being more deleterious to persons with functional dyspepsia. Therefore, psychological factors are likely to be important in at least some patients with dyspepsia. To understand a patient's illness, clinician must recognize the interplay of personality traits, life events and social structure that may be important in the way a patient perceives and reports symptoms.
Aerophagia due to the excessive amounts of swallowed air may causes distention, bloating, flatulence and belching. Consciously or unconsciously this occurs often secondary to stress or anxiety. There is a large overlap between functional dyspepsia and other functional disorders. approximately, one third of patients with irritable bowel syndrome also report dyspepsia (38).
Although heartburn and regurgitation are highly specific symptoms for gastroesophageal reflux, many patients experience also symptoms of dyspepsia, making a problem more complex. Whether these upper abdominal symptoms are due to acid reflux or concomitant functional dyspepsia is not clear. Most likely it is a combination of underlying motor disturbances and impaired acid secretion, which, as it was described earlier, may precipitate both dyspepsia and reflux symptoms.
Helicobacter pylori
Helicobacter pylori is the major cause of chronic antral gastritis, a condition that is prevalent in over 65% of asymtomatic adults in our population (5, 43, 44). (Overall prevalence is count to be little over 35% in asymptomatic population in developed countries).
It has become quite clear that Helicobacter pylori plays a major role in the pathogenesis of peptic ulcer disease. The organism is present in over 90% of the patients with duodenal ulcer and over 70% of those with gastric ulcer. Successful eradication of the organism with proton pump inhibitor and antibiotics in combination not only resolves histologic gastritis but decreases ulcer recurrence rates from over 80% to less than 10% per year. Antibiotic treatment is now recommended for all patients with peptic ulcer diseases who have Helicobacter pylori infection documented (18). The role of Helicobacter pylori infection in functional dyspepsia is much more controversial.
Acute infection with Helicobacter pylori causes transient nausea, abdominal pain, vomiting and hypochlorhydria. However, it has not been convincingly demonstrated that this organism can cause chronic dyspepsia, although long-term infection resulting in chronic active inflammation could produce symptoms.
Variations in definitions of dyspepsia, non-blinded, not-randomized trials, lack of validation in the scoring systems and unclear endpoints of often short follow-up studies make interpretation of the available data difficult (45,46)
Assessment of symptoms (Table 7)
There is a suggestion that Helicobacter pylori infected patients have higher ulcer-like dyspepsia scores and lower dysmotility-like scores, than do Helicobacter pylori negative patients, and there is higher prevalence of Helicobacter pylori infection in ulcer-like dyspepsia than in dysmotility-like dyspepsia (47,48). In our study (49), we also reported that ulcer disease like symptoms occur more often in Helicobacter pylori positive patients, but this was of no significant value.
It would be extremely useful if, in clinical practice, dyspepsia patients could be divided into simple subgroups as a basis for determining management. But, the major problem is that dyspepsia is not disease entity, and the term dyspepsia encompasses a variety of symptoms and symptom clusters that could reflect diversity of potential underlying diseases. Furthermore, the patient expectation, prior life, ethic background, medications taken and sometimes doctors often modify symptoms themselves. The subjectivities of the different origin could be overcome by means of objective symptom scales. Thus, there is no individual symptom that is pathognomonic of Helicobacter pylori related dyspepsia.
Epidemiological studies
If we assume that Helicobacter pylori can cause dyspepsia, one would expect to find a higher prevalence of Helicobacter pylori infection in patients with dyspepsia, than in those who have no symptoms. Analysis of Armstrong et of data from all reports showed that the prevalence of Helicobacter pylori is greater in patients with dyspepsia than in controls.
Unfortunately, we were unable to confirm this results, since the prevalence of Helicobacter pylori in investigated group of dyspeptics (64%) did not differ at all from the prevalence in overall population (65%-earlier conducted serology based study on volunteer blood donors) (5,43).
Pathophysiological studies
The mechanism(s) responsible for dyspeptic symptoms are unknown. Earlier discussed possible pathophisiological mechanisms so far can not be successfully implicated to the Helicobacter pylori infection itself. It was reported that patients with functional dyspepsia have acid output comparable to that of healthy patients regardless of whether the patients were infected with Helicobacter pylori or not.
Likewise, studies of gastric mucosal sensitivity have found no clear indication that
Helicobacter pylori infection renders dyspeptic patients uniformly sensitive to the instillation of acid or autologous duodenal content (50). Similarly, Helicobacter pylori infection has not been shown to be associated with increased sensitivity to luminal distention (51).
There was no difference observed with respect to gastric or fundal emptying, although it was reported a prolonged lag time in Helicobacter pylori negative patients (52-55). In the study of Minocha et al. (54) Helicobacter pylori infection was associated with a significantly shorter orocaecal transit time, but the many subjects did not complete the study. Thus, the effect of Helicobacter pylori infection on upper gastrointestinal transit time is unclear, as is its effect on motor activity.
Also there was no significant difference between Helicobacter pylori positive and negative patients regarding postprandial antral motor index and migrating motor complex (MMC) duration (56,57).
On the other hand in the study of Testoni et an absence of phase III in dyspeptic patients was significantly associated with higher prevalence of Helicobacter pylori infection (56). If proved, prolonged MMC phase II and specially phase III among Helicobacter pylori positive patients could induce more HCl, pepsin and bile acid impact on stomach mucosa.
Interesting study was conducted by Konturek et al in which gastric emptying rate, postprandial motility index (MI=number of contractions x mmHg/min) significantly improved as well as amplitude of postprandial gastric electric activity six weeks after the eradication of Helicobacter pylori infection (58).
Helicobacter pylori infection is associated with increased production of neuropeptides such as somatostatin and substance P (59). There is also increased productions of some cytokines, including tumor necrosis factor alpha (TNF), interleukin 8 (IL-8), and IL-1 and nitric oxide (NO) in both, ulcer disease and functional dyspepsia (60). IL-1, for example, has been shown to increase enteric neural sensitivity mediating through increased prostaglandin E2 level. Nitric oxide also acts as an inhibitory neurotransmitter.
Treatment studies
Other then detecting the underlying pathophysiological mechanism, the role of Helicobacter pylori infection in functional dyspepsia can also be determined by monitoring the changes in symptomatology resulting from the cure of Helicobacter pylori and associated inflammation. Hypothetically, dyspeptic symptoms may be due to the associated gastritis or infection itself. If we assume that inflammation causes the symptoms of dyspepsia, even if the infection is eradicated it could take many months for the chronic inflammation to resolve. In this case, the symptoms may persist for months or even years, analogous to the prolonged persistence of symptoms in the post-infectious form of irritable bowel syndrome. Many of the trials to date have evaluated symptoms within 1-2 months of completion of treatment and this may be too soon to assess final outcome (61-64). The extended follow-up is mandatory in patients with functional digestive disorders, primarily due to the magnitude of placebo response.
Two recent studies with 12 month follow-up after attempted Helicobacter pylori eradication reported symptomatic improvement and subsequent decrease in drug consumption in successfully treated patients (65,66).
These studies were criticized because they were non-randomized and the patients were informed about their Helicobacter pylori status (67).
The most important unresolved clinical question is whether eradication of the infection leads to a sustained improvement in the symptoms of functional dyspepsia. The published data are conflicting, and most studies before 1998 have been small.
Dyspeptic symptoms are probably the result of a number of different mechanisms, some unrelated to the presence of Helicobacter pylori and some related to the treatment. Indeed, both dyspepsia and Helicobacter pylori infection are so prevalent that one would expect many patients to have multiple causes for their symptoms. Thus eradication of Helicobacter pylori cannot be expected to render all patients completely symptom-free. As it may take up to 6-12 months before Helicobacter pylori associated gastritis returns to normal, there is agreement that the follow-up period in clinical trials needs to be at least 6-12 months (18,68).
An important problem in treatment trials of functional dyspepsia is the lack of consensus on how best to measure outcome.
A few validated outcome measures for use in dyspepsia trials have recently become
available, but non of them is generally accepted. The gastrointestinal Symptom Rating Scale (GSRS) measures the severity of 15 upper and lower gastrointestinal symptoms and was used in the OCAY and ORCHID studies (69,67).
The Glasgow Dyspepsia Severity Score (GDSS) includes measurement of the severity and frequency of symptoms and the number of investigations, doctors visits and treatments for dyspepsia over the previous 6 months (70). At the moment there is no single questionnaire that can be unequivocally recommended for use in dyspepsia trials (71).
One of the recent trials, the FROSCH study involved 205 Helicobacter pylori positive patients who did not respond to treatment with either omeprazole or ranitidine or who had relapse of symptoms within 6 months of stopping the treatment (72).
The methodologically strong UK Medical Research Council (MRC) trial of Helicobacter pylori eradication therapy for functional dyspepsia improvement was achieved in 21% of anti-Helicobacter pylori treated patients and in 7% of the control group (p<0.001)(66).
On the contrary, in a double-blind, placebo-controlled trial (ORCHID) involving 275 patients, randomized to receive omeprazole-amoxycillin-clarithromycin (OAC) or placebo, relief from the symptoms of dyspepsia was evaluated over 12 months (67). Treatment success (no more than minimal symptom at 1 year) occurred in 24% of patients in the OAC group compared with 22% in the placebo group, a non-significant difference. In the secondary analysis, the treatment success rate was significantly higher in patients in whom gastritis had healed than in those in whom gastritis had not healed (32% versus 17%, respectively, p<0.05). Dyspepsia subgrouping were not of value in predicting treatment success, and quality-of-life scores were similar in both treatment groups.
Similarly, Blum et al. in the OCAY trial found non-significant difference in active compared to placebo treatment (69). Overall, 27% of patients on active treatment and 21% of those on placebo had symptom relief. These results suggest that, overall, eradication of Helicobacter pylori does not relieve the symptoms of functional dyspepsia.
Results of our study suggest that Helicobacter pylori is associated more with ulcer-like than dysmotility-like symptoms and, although this is not a useful discriminate in the diagnosis of Helicobacter pylori-related dyspepsia, it may help to predict which patients will respond to therapy or which patients will respond to therapy or which symptoms will improve following therapy (49). In 12-month follow-up, eradication of Helicobacter pylori resulted in a fall in the total dyspepsia score. (Figure 3).
Gilvarry et alperformed a prospective, long-term, double-blind study in 100 patients with functional dyspepsia and Helicobacter pylori infection randomized to bismuth-based triple therapy or bismuth plus placebo therapy (65). In patients with treated with the bismuth-triple therapy those who became Helicobacter pylori negative had a significant symptomatic response at 8 weeks, 6 months and 1 year. The symptomatic improvement was evident in the ulcer-like dyspepsia subgroup at all times, whereas it was only evident in the reflux-like and dysmotility-like group at 6 months. The individuals who remained Helicobacter pylori positive had no symptomatic improvement at 8 weeks, 6 months and 1 year. Those who remained Helicobacter pylori negative had an insignificant improvement in the dysmotility and non-specific subgroups only.
In the study of McColl et al after 1 year, 21% of the patients treated with proton pump inhibitors (PPI)- based triple therapy versus 7% of those treated with PPI-placebo therapy (p<0.05) had resolution of symptoms (66). The severity of patient's symptoms was quantified using the validated Glasgow Dyspepsia Severity Score.
Talley et al. performed a similar study with use of daily diary cards of seven point-graded scales (67). This group of investigators didn't confirm previously reported studies of positive Helicobacter pylori infection role in functional dyspepsia. (one year after treatment, patients treated with PPI triple and placebo had no significant reduction in dyspeptic symptoms: 24.1 and 21.8%, respectively).
On the basis of the results of all these studies including ours, we cannot categorically dismiss Helicobacter pylori eradication therapy in functional dyspepsia. The critical questions are:
Despite the controversy, many clinicians have already adopted the policy of "test and treat" with or without diagnostic endoscopy. In one study from 1996 it was reported that 25% of general practitioners and 17% of gastroenterologists were already using Helicobacter pylori serology as a screening test for young dyspeptics (73). Eventhough, this "test-and-treat" policy has expanded over the past couple of years, it is recommended that patients with alarming symptoms should promptly referred for further investigation (18).
Subgrouping of symptoms to ulcer-like, dysmotility-like, and nonspecific is neither useful in diagnosis of Helicobacter pylori positive dyspeptics nor should be guide for empirical treatment of dyspepsia.
Empirical treatment with acid-reducing or prokintic drugs for all patients with dyspepsia is considered to be inappropriate as peptic ulcer disease will be inadequately treated (i.e. Helicobacter pylori will not be eradicated)(74).
Eradication of Helicobacter pylori in dyspeptic patients is considered preferable to other empirical treatment if prompt endoscopy is not an option.
In conference of the American Digestive Health Initiative, Peura reported that based on available data, the panel concluded that testing for and treating Helicobacter pylori infection has not been adequately investigated in terms of effectiveness, symptom relief, patient's satisfaction and cost (75). It was advised that patients older than 50 years of age with previously uninvestigated dyspepsia and patients at any age with alarm symptoms should be referred for further investigation. In patients younger than 50 years of age, the clinician should consider either testing for Helicobacter pylori or performing endoscopy; the decision should be assessed on a case by case basis.
Asante et al proposed as a cost-effective approach, to prescribe empirical eradication therapy to men aged under 45 years without alarm symptoms if they either smoke heavily and/or have a positive family history of peptic ulcer (76). Endoscopy, as he advised, should be performed only in those less likely to have peptic ulcer or those whose symptoms fail to resolve after empirical therapy. But as many clinicians criticized, the family history of peptic ulcer disease is unreliable and the strategy is quite complicated for the general practice.
The message from recent studies is clear. If Helicobacter pylori does cause symptoms in confirmed functional dyspepsia, it does so in a very small proportion of patients.
Treatment for patients with functional dyspepsia
At last but not the least, results from morphological studies on topographic distribution of Helicobacter pylori associated gastritis would help clinicians making their decision.
References:
1. Armstrong D. Helicobacter pylori infection and dyspepsia. Scand J Gastroenterol 1996;31 Suppl 215:38-47.
2. Drossman DA. The functional gastrointestinal disorders and the Rome II proces; A multinational Consensus Document on Functional Gastrointestinal Disorders. Gut 1999;45(suppl II):II1-II5.
3. Graham DY, Malaty HM, Evans DG, Evans DJ, Klein PD JR, Adam E. Epidemiology of Helicobacter pylori in an asymptomatic population in the United States: effect of age, race, and socioeconomic status. Gastroenterology 1991;100:1495-1501.
4. Knill-Jones Rp. Geographical differences in the prevalence of dyspepsia. Scand J Gastroenterol 1991;26 Suppl 182:17-24.
5. Jovanovic I. Kilnicka studija povezanosti Helicobacter pylori infekcije i sindroma gornje dispepsije. Magistarska teza, Medicinski fakultet Univerziteta u Beogradu, Beograd, Jun 1998.
6. Deltenre Mal. Economics of Helicobacter pylori eradication therapy. Eur J Gastroenterol Hepatol 1997;9(suppl 1):S23-S26.
7. McQuaid. Dyspepsia
8. Talley NJ, Phillips SF. Non-Ulcer Dyspepsia: Potential causes and pathophysiology. Ann Intern Med 1988;108:865-879.
9. slezinger
10. Talley Nj, Collin- Jones D, Koch Kl, Koch M,Nyren O, Stanghellini V. Functional dyspepsia: a classification with guidelines for management. Gastroenterol Int 1991; 4:145- 60.
11. Rokass T, Pursey C, Uzoechina E, Dorrington L, Simmons Na, Fillipe Mi. Campylobacter pylori and non- ulcer dyspepsia. Am J Gastroenterol 1987, 11:1149-1152.
12. Richter Je. Stress and psychologic and environmental factros in functional dyspepsia. Scand J Gastroenterol 1991;26 Suppl 182:40-46.
13. Talley Nj, Weaver Al, Zinsmeister Ar, Melton Iii Lj. Onset and disappearance of gastrointestinal symptoms and functional gastrointestinal disorders. Am J Epidemiol 1992; 136:165- 77.
14. Smith A, Gillen D, Cochran K, El- Omar E, Mccoll KEL. Ranitidine treatment induces dyspepsia in previousl asymptomatic healthy volunteers. Gut 1997, 40 (Suppl 1):A3.
15. Talley Nj. Spectrum of chronic dyspepsia in the presence of the irritabile bowel syndrome. Scand J Gastroenterol 1991;26 Suppl 182:7-10.
16. Strauss Rm, Wang Tc, Kelsey Pb, Compton Cc, Ferraro Mj, Perez Gp, Parsonnet J, Blaser Mj. Association of Helicobacter pylori infection with dyspeptic symptoms in patients undergoing gastroduodenoscopy. Am J Med 1990;89:4649.
17. tabela slezinger
18. Malfertheiner P, O Morain C, Michetti P. The Maastricht guidelines and other innovation. Curr Opin Gastroenterol 1997;13:1-7.
19. Colin Jones DG. Mangement of dyspepsia: report of a Working Party. Lancet 1988; 1:576- 9.
20. Malagelada Jr. When and how to investigate the dyspeptic patient. Scand J Gastroenterol 1991;26 Suppl 182:70-74.
21. Marshall B. Unindentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983; i:1273-5.
22. Labenz J, Rokkas T. Helicobacter pylori and dyspepsia. Curr Opin Gastroenterol 1997;13:48-51.
23. Pachett S, Beattie S, Leen E, Keane C, O Morain C. Eradicating Helicobacter pylori and symptoms of non-ulcer dyspepsia. BMJ 1991;303:1238-1240.
24. Penston Jg, Pounder Re. A survey of dyspepsia in Great Britain. Aliment Pharmacol Ther 1996, 10:83-89.
25. Brady Ce, Hadfield Tl, Hyatt Jr, Utts Sj. Acid secretion and serum gastrin levels in individuals with Campylobacter pylori. Gastroenterology 1988;94:923-927.
26. Deluca Va. No acid, no polyps. No active gastritis no dyspepsia. A proposal. J Clin gastroenterol 1989, 11:127-131.
27. El-Omar E, Penman I, Ardill Je, Mccoll Ke. A substantial proportion of non- ulcer dyspepsia patients have the same abnormality of acid secretion as duodenal ulcer patients. Gut 1995; 36 (4): 534- 8.
28. El-Omar E, Penman Id, Ardhill Jes, Chittajallu Rs, Howie C, Mccoll Kel. Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 1995, 109:681-691.
29. Nyren O. Secretory abnormalities in functional dyspepsia. Scand J Gastroenterol 1991;26 Suppl 182:25-28
30.Undeland Ka, Hausken T, Gilja Oh, Ropert A, Galmische Jp, Berstad A. Gastric relaxation in response to a soup meal in healthy subjects. A study using barostat in the proximal stomach. Scand J Gastroenterol 1995; 30:1069- 76.
31. Undeland Ka, Hausken T, Svebak S, Anderud S, Berstad A. Wide gastric antrum and low vagal tone in patients with diabetes mellitus type I compared to patients with functional dyspepsia and healthy individuals. Dig Dis Sci 1996; 41:9-16.
32. Troncon Le, Bennett Rj, Ahluwalia Nk, Thompson Dg. Abnormal intragastric distribution of food during gastric emptying in functional dyspepsia patients. Gut 1994; 35:327- 32.
33. Troncon Lea, Thompson Dg, Ahluwalia Nk, Barlow J, Heggie L. Relations between upper abdominal symptoms and gastric distension abnormalities in dysmotility like functional dyspepsia and after vagotomy. Gut 1995; 37:17- 22.
34. Salet Gam, Samsom M, Roelofs Jmm, Van Berge Henegouwen Gp, Smout Ajpm, Akkermans Lma. Responses to gastric distension in functional dyspepsia. Gastroenterology 1995; 108:A681.
35. Hausken T, Berstad A. Wide gastric antrum in patients with non- ulcer dyspepsia. Effect of cisapride. Scand J Gastroenterol 1992; 27:427-32.
36. Tucci A, Corinaldesi R, Stanghellini V, Tosetti C, Febo Gd, Paparo Gf,Varoli O. Helicobacter pylori infection and gastric function in patients with chronic idiopathic dyspepsia. Gastroenterology 1992;103:768-74.
37. Lemann M, Dedering Jp, Flourie B, Franchisseur C, Rambaud Jc, Jian R. Abnormal perception of visceral pain in response to gastric distension in chronic idiopathic dyspepsia. Dig Dis Sci 1991; 36:1249- 54.
38. Malagelada Jr. Gastrointestinal motor disturbances in functional dyspepsia. Scand J Gastroenterol 1991;26 Suppl 182:29-32.
39. Gilja Oh, Hausken T, Berstad A. Effect of glyceryl trinitrate on gastric accomodation and symptoms in functional dyspepsia. Gastroenterology 1996; 110:A669.
40. Gilja Oh, Hausken T, Wilhelmsen I, Berstad A. Impaired accomodation of proximal stomach to a meal in functional dyspepsia. Dig Dis Sci 1996; 41:689- 96.
41. Haug Tt, Wilhelmsen I, Berstad A, Ursin H. Life- events and sress in patients with functional dyspepsia compared to patients with duodenal ulcer and healthy controls. Scand J Gastroenterol 1995; 30:524- 30.
42. Talley Nj, Fung Lh, Gilligan Ij, Mcneil D, Piper Dw. Association of anxiety, neuroticism, and depression with dyspepsia of unknown cause. A case- control study. Gastroenterology 1986; 90:886- 92.
43. Milosavljevic T. Helicobacter pylori u klini~koj praksi. Vreme knjige, Beograd 1996.
44. Milosavljevic T, Jovanovic I. Helicobacter pylori, CDrom, Medicinski fakultet u saradnji sa DanDesign, Beograd mart 1999.
45. Heading Rc. Definitions of dyspepsia. Scand J Gastroenterol 1991;26 Suppl 182:1-6.
46. Talley Nj. A critique of therapeutic trials in Helicobacter pylori positive functional dyspepsia. Gastroenterology 1994; 106:1174-1183.
47. Scott Am, Kellow Je, Shuter B, Cowan H, Corbett A- M, Riley Jw, Lunzer Mr, Eckstein Rp, Hoschl R, Lam Sk. Intragastric distribution and gastric emptying of solids and liquids in functional dyspepsia. Lack of influence of symptom subgroups and H. pylori- associated gastritis. Dig Dis Sci 1993; 38(12): 2247- 54.
48. Veldhuyzen Van Zanten Sjo, Tytgat Kmaj, Pollak Pt, Goldie J, Goodacre Rl, Riddell Rh, Hunt Rh. Can severity of symptoms be used as an outcome measure in trials of non-ulcer dyspepsia and Helicobacter pylori associated gastritis ? J Clin Epidemiol 1993;46:273-279.
49.. Symtom clusters are not helpful in diagnosis of Helicobacter pylori positive dyspepsia. Arch Gastroenterohepatol 1999;18 (No 3-4): 51-54.
50. Mearin F, De Ribot X, Balboa A, Salas A, Varas Mj, Cucala M, Bartolome R, Armengol Jr, Malagelada Jr. Does Helicobacter pylori infection increase gastric sensitivity in functional dyspepsia ? Gut 1995;37 (1): 47- 51.
51. Holtmann G, Goebell H, Huber J, Talley Nj. H.pylori and sensory dysfunction in patients with functional dyspepsia and healthy controls. Gastroenterology 1995; 108:A615.
52. Pieramico O, Ditschuneit H, Malfertheiner P. Gastrointestinal motility in patients with non- ulcer dyspepsia: a role for Helicobacter pylori infection? Am J Gastroenterol 1993; 88:364- 8.
53. Caballero- Plasencia Am, Muros- Navarro Mc, Martin- Ruiz Jl, Valenzuela- Barranco M, Delos- Reyes- Garcia Mc, Casado- Caballro Fj, Rodriguez- Tellez M, Lopez- Manas Jg. Dyspeptic symptoms and gastric emptying of solids in patients with functional dyspepsia. Role of Helicobacter pylori infection. Scand J Gastroenterol 1995; 30(8): 745- 51.
54. Minocha A, Mokshagundam S, Gallo Sh, Rahal Ps. Alterations in upper gastrointestinal motility in Helicobacter pyloi- positive non- ulcer dyspepsia. Am J Gastroenterol 1994; 89:1797- 1800.
55. Marzio L, Facucci M, Ciccaglione Af, Malatesta Mg, Lapenna D, Ballone E, Antonelli C, Grossi L. Relationship between gastric and gallbladder emptying and refilling in normal subjects and patients with H. pylori- positive and - negative idiopathic dyspepsia and correlation wih symptoms. Dig Dis Sci 1996; 41:26-31.
56. Testoni Pa, Bagnolo F, Colombo E, Bonassi U, Tosi T. The correlation in dyspeptic patients of Helicobacter pylori infection with changes in interdigestive gastroduodenal motility patterns but not in gastric emptying. Helicobacter 1996; 4 (1): 229- 237.
57. Qvist N, Rasmussen L, Axelsson Ck. Heliobacter pylori associated gastritis and dyspepsia. The influence on migrating motor complexes. Scand J Gastroenterol 1996; 29:133- 7.
58. Konturek Jw, Fischer H, Riemann B, Domschke W. Effect of eradication of Helicobacter pylori on gastric Secretory And Motor Function In Patients With Non-Ulcer Dyspepsia. Gastroenterology 1997;112:A181.
59. Moss Sf, Legon S, Bishop Ae, Polak Jm, Calam J. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease. Lancet 1992, 340:930-932.
60. Trespi E, Broglia F, Villani L, Luinetti O, Fiocca R, Solcia E. Distinct profiles of gastritis in dyspepsia subgroups. Their different clinical responses to gastric healing after Helicobacter pylori eradication. Scand J Gastroenterol 1994;29:884-888.
61. Tytgat Gnj, Noach La, Rauws Aj. Is gastroduodenitis a cause of chronic dyspepsia. Scand J Gastroenterol 1991;26 Suppl 182:33-39.
62. Bernersen B, Johnsen R, Bostad L, Straume B, Sommer Ai, Burhol Pg. Is Helicobacter pylori the cause of dyspepsia? BMJ 1992;304:1276-9.
63. Borody T, Daskalopoulos G, Brandl S, Carrick J, Hazell S. Dyspeptic symptoms improve following eradication of gastric Campylobacter pyloridis. (abstr.) Gastroenterology 1987;92:1324.
64. Laheij Rjf, Jansen Jbmj, Van De Klisdonk Eh, Severens Jl, Verbeek Alm. Review article: symptom improvement through eradication of Helicobacter pylori in patients with non- ulcer dyspepsia. Aliment Pharmacol Ther 1996; 10:843- 850.
65. Gilvarry J, Buckley Hj, Beattie S Et Al. Eradication of Helicobacter pylori affects symptoms in non-ulcer dyspepsia. Scand J Gastroenterol 1997;32:35-40.
66. Mccoll Kel, Murray Ls, El-Omar E Et Al. UK MRC trial of Helicobacter pylori eradication therapy for non-ulcer dyspepsia. Gastroenterology 1998;114:A222(G0908)
67. Talley Nj, Janssens J, Lauritsen K Et Al. Long-term follow-up of patients with non-ulcer dyspepsia after Helicobacter pylori eradication. A randomized double-blind placebo controlled trial. Gastroenterology 1998;114:A305.
68. Valle J, Sppala K, Sipponen P, Kosunen T. Disappearance of gastritis after eradication of Helicobacter pylori: a morphometric study. Scand J Gastroenterol 1991;26:1057-1065.
69. Blum AL, O'Morain C, Talley NJ et al. Does eradication of Helicobacter pylori cure dyspeptic symptoms in patients with functional dyspepsia 12 months after cessation of treatment? A randomized double-blind controlled trial. Abstract. World Congresses of Gastroenterology, Vienna, Austria, 6-11 September 1998.
70. El-Omar Em, Banerjee S, Wirz A, Mccoll Kel. The Glasgow Dyspepsia Severity Score- a tool for the global measurement of dyspepsia. Eur J Gastroenterol Hepatol 1996;8:967-71.
71. Nyren O, Adami Ho, Bates S, Bergstrom R, Gustavsson S, Loof L, Sjoden Po. Self-rating of pain in nonulcer dyspepsia: a methodological study comparing a new fixed-point scale and visual analogue scale. J Clin Gastroenterol 1987;9:408-414.
72. Koelz Hr, Arnold R, Stolte M Et Al. Frosch Study: Treatment of Helicobacter pylori does not improve symptoms of functional dyspepsia (FD). Gastroenetrology 1998;114:A182-3.
73. brun j. Managing patients in general practice. Scand J Gastroenterol 1996;31 Suppl 215:116-117.
74. NYREN O. Therapeutic trial in dyspepsia: Its role in the primary care setting. Scand J Gastroenterol 1991;26 Suppl 182:61-69.
75. Lambert Jr. The role of Helicobacter pylori in nonulcer dyspepsia. A debate- for. Gastroenterol Clin North Am. 1993; 22 (1): 141- 51.
76. Talley Nj. The role of Helicobacter pylori in nonulcer dyspepsia. A debate against. Gastroenterol Clin North Am. 1993; 22 (1): 153- 67
77. Dimenas E, Glise H, Hallerback B Et Al. Quality of life in patients with upper gastrointestinal symptoms. An improved evaluation of treatment regimens. Scand J Gastroenterol 1993;28:681-7.
78. Lai St, Fung Kp, Ng Fh, Lee Kc. A quantitative analysis of symptoms of non-ulcer dyspepsia as related to age, pathology, and Helicobacter infection. Scand J Gastroenterol 1996, 31:1078-1082.
79. Talley Nj. Drug treatment of functional dyspepsia. Scand J Gastroenterol 1991;26 Suppl 182:47-60.
80. De Groot G, De Both Psm. Cisapride in functional dyspepsia in general practice. A placebo- controlled, randmized, double- blind study. Alimen Pharmacol Ther 1997, 11:193-199.
81. Dixon Mf, Path Frc, Genta Rm, Yardley Jh, Correa P And The Participants In The International Workshop On The Histopatology Of Gastritis, Houston 1994. Classification and Grading of gastritis (The Updated Sydney System). Am J Surg Pathol 1996;20 (10):1161-1181.