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Roundtable discussion: Differences between Japan and Western countries in the treatment of dyspepsia
CLINICAL THERAPEUTICS®/VOL. 20, SUPPLEMENT D, 1998
Roundtable Discussion: Differences Between Japan and Western Countries in the Treatment of Dyspepsia
Participants: Ken Haruma, MD, 1 Michio Hongo, MD, 2 Kei Matsueda, MD, 3 Takeshi Miwa, MD, 4 and Vincenzo Stanghellini, M D s 1First Department of Internal Medicine, Hiroshima University, Hiroshima, Japan, 2Department of Comprehensive Medicine, Tohoku University, Sendai, Japan, 3Department of Gastroenterology, International Medical Center of Japan, Tokyo, Japan, 4Tokai University, Isehara, Japan, 51nstitute of Clinical Medicine and Gastroenterology, University of Bologna, Bologna, Italy
Dr. Miwa: The first topic for consideration is dyspepsia in general, which involves some difficult issues. The majority relate to the subjectivity of symptoms, but there are also issues regarding the interpretation of the term "dyspepsia." In this regard, the concept of dyspepsia is perhaps a little abstract, so we will discuss the differences in understanding and perspective between Japan, Europe, and the United States. Dr. Stanghellini: I mentioned during my presentation that the semantic issue is very important when dealing with dyspepsia. If you look at some of the recently published data, there do not appear to be different subgroups of patients with functional dyspepsia or with dyspepsia in general. However, if you examine the methods and the questionnaires used in these studies, it becomes apparent that epigastric pain was present in all the dif0149-2918198/$19.00
ferent subgroups they considered. This means that only patients with pain or burning pain arising from the gastric area were included. Thus it is not surprising that by subdividing patients with different types of stomach pain you end up with small differences among different groups. In contrast, in other studies designed to evaluate the role of prokinetic agents, only patients with dysmotility-like dyspepsia were included. I do not believe that we need to become obsessive about terminology, but we do need to be precise in what we do. We must carefully describe each symptom that is reported by our patients. This practice is particularly important because upper gastrointestinal symptoms often overlap, and many patients may have gastroesophageal reflux disease (GERD) with dyspepsia and irritable bowel syndrome (IBS) at the same time. They may have prevalent epigastric symptoms for a certain period, but D23
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then GERD becomes the most relevant condition. I think it is important to realize that IBS, GERD, and dyspepsia are different entities, as well as to describe in greater detail each individual complaint that patients have. Dr. Miwa: I think the issue of terminology involves many subtle problems, particularly from the standpoint of definitions. Dr. Matsueda, what is your opinion? Dr. Matsueda: The definitions involved in this discussion are very subtle. Although dyspepsia describes the central concept, patients' descriptions of symptoms differ from country to country. Even with different descriptions based on the same concept, we have the problem that patients in Japan are reluctant to complain of pain. For example, both IBS patients and dyspepsia patients describe abdominal discomfort as the main symptom, with few complaining of abdominal pain. I believe that this is a country-specific problem stemming from the concept that concealing emotions is a virtue in some countries. I do not know whether there is any consensus on whether pain and discomfort are treated equally. However, it is important to obtain the proper perspective and determine the views of specialists in this area. Dr. Miwa: I believe that this is a very difficult problem to deal with, and I often use the terms "epigastric pain," "discomfort," and "distress" without really understanding their difference. The difference between English and Japanese is so great--and terminology also differs within the Japanese language--that you can imagine how difficult it becomes when dealing with expressions in differD24
ent languages worldwide. In this sense, I believe we need some degree of consensus from country to country, as well as within countries. How do you feel about this, Dr. Haruma? Dr. H a r u m a : I believe that the terms need to be more clearly defined for general practitioners. Disease descriptions are essential for medical examinations, and without proper definitions I believe it will be difficult to provide proper medical care for dyspepsia. In general, "dyspepsia" has been used in Japan in place of "chronic gastritis" or "gastritis," which is the disease name used for insurance purposes. However, I think that dyspepsia needs to be used as a description for insurance purposes in Japan before it will be accepted clinically. Dr. Miwa: In addition to the issue of what dyspepsia is, there is also the issue of its Japanese equivalent. Can you comment on this, Dr. Hongo? Dr. Hongo: The term used internationally to describe the subjective symptomatology of dyspepsia is "functional dyspepsia." If considered to be a dysfunction of the epigastric area or upper gastrointestinal tract, this can be translated into Japanese as functional dyspepsia. However, I would like to have a Japanese term for "dyspepsia," the understanding of which is different for an upper gastrointestinal dysfunction. We have tentatively considered a term corresponding to "gastrointestinal disease," but in terms of a higher scale of pain and discomfort, I believe that diffusion of the concept of dyspepsia is important for its understanding. Even pain, as we heard from Dr. Matsueda, is characteristically hidden by Japanese patients, although it may be that
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the Japanese vocabulary does not use the word pain to describe the feelings experienced in dyspepsia. In this sense, pain cannot be considered as being distinct from discomfort. Without establishing this understanding first or educating physicians through workshops and other means, I think it will be difficult to accurately convey the concept of functional dyspepsia. Dr. Matsueda: May I interrupt? Japanese patients do complain of pain. When it is dominant, for example in the case of peptic ulcer disease, pain is the major complaint. But dull pain generally tends to be expressed as "discomfort." In the case of acute abdomen, their complaints are the same as complaints in Europe and the United States. I am saying that if treated equivocally as discomfort, cases of dull pain and pain might be more easily understood internationally. Dr. Miwa: This is obviously a difficult issue. Whatever the case, I believe it is necessary to obtain a consensus of opinion worldwide and in Japan. A lack of consensus can produce a lack of understanding, and I think that this will be a major topic for specialists to deal with in the future. Dr. Stanghellini, do you have anything you wish to add?
Dr. Stanghellini: I think most of the important issues have been touched on. I would like to summarize what has been achieved internationally so far and maybe give some advice for the future. First, dyspepsia is different from IBS and GERD, and this fact is recognized internationally. Second, the concept of dyspepsia includes two main kinds of symptoms. One is pain, and the other is an unpleasant but not painful sensation. I think that Dr. Mat-
sueda's definition of pain is fairly good: pain is similar to what is most commonly reported by patients with peptic ulcer; discomfort is different from pain regardless of symptom severity. For example, one can have extremely severe nausea without perceiving any pain at all; quality of life can be completely destroyed by nausea, but nobody would ever describe this as a painful sensation. We now know that different receptors, at least to a certain extent, through different afferent pathways bring painful and nonpainful messages to the central nervous system. The last concept that I would like to suggest for future consideration is to introduce greater emphasis on the severity of individual symptoms and the concept that some symptoms are more bothersome to patients than others. These concepts were not present in the first Roman criteria on dyspepsia, but they are being introduced in the new ones that were discussed in Rome in June 1998. I think these are the main criteria that I would like to suggest that you follow when defining dyspepsia in Japan. Dr. Miwa: Thank you very much. I would like to move on to the next issue, which involves the differences between epidemiologic surveys of dyspepsia in Japan, Europe, and the United States, because it is not clear exactly what the differences are. Dr. I-Iongo: The Domestic International Gastroenterology Study (DIGEST) showed that approximately 26% of Japanese subjects experience symptoms of dyspepsia, which is slightly lower than the incidence in other countries. However, these are common symptoms found in more than 25% of the population and thus cannot be explained simply by eating D25
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habits. In support of this is the fact that although diet is very different in Switzerland and Japan, the incidence of symptoms is similar. The severity of dyspepsia symptoms among Japanese subjects is also slightly milder than that in other countries. However, I think that because so many people display so many symptoms, it indicates that there is a serious problem, even if these symptoms are not very severe. Interestingly, the average number of times a Japanese patient receives treatment for dyspepsia symptoms at a medical institution indicates a higher requirement for medical attention than in other countries. It appears that it is typical for Japanese patients to consult physicians immediately on experiencing symptoms. Because medical care is particularly expensive in the United States, it is possible that patients do not seek medical attention despite the high frequency of dyspepsia symptoms. Accordingly, when the type of medication taken is examined, over-thecounter drugs are used widely in the United States, whereas prescription drugs are more common in Japan: Approximately 40% of Japanese patients with dyspepsia take prescription drugs. In conclusion, although symptom severity appears to be mild, Japanese patients tend to consult physicians and take prescription drugs. Because the incidence of dyspepsia symptoms is high in Japan, although lower than that in other countries, it is a serious problem that cannot be ignored.
Dr. Stanghellini: I was surprised to learn how often Japanese subjects visit physicians. There is a consensus in Western countries that only about 25% of dyspepsia patients consult their physicians. The D26
observation that Japanese subjects consult physicians frequently regarding dyspepsia is to me in contrast to what Dr. Matsueda said about Japanese people being ashamed to show their feelings. It would seem to me that if they were really ashamed, they would not discuss their illnesses with physicians more often than in other countries. One may wonder whether Japanese physicians are better than those in other countries and whether a better patient-doctor relationship exists in Japan. In Western newspapers it is becoming increasingly common to have medical sections in which simple medical concepts are explained. Furthermore, despite digestive cancers being among the leading causes of death in most Western countries, people still feel confident that indigestion, constipation, and diarrhea are mild clinical conditions that they can handle without the help of physicians. Dr. Miwa: A comprehensive discussion of the unique aspects of different countries might be difficult, but in the earlier lecture by Dr. Stanghellini we heard that the relationship between dyspepsia and gastric motility is well established, especially in women. Do you have any comments on the ratio of men to women in the DIGEST study? Dr. Hongo: The ratio of men to women was roughly equal in the DIGEST study, and in no country was there a clear majority of men or women. I do not believe that differences in men:women ratios affected this survey. Dr. Miwa: I do not believe that there are any special circumstances in Japan, but I think that the tendency to consult physicians in Japan might be attributable to
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large populations living in close proximity, with a general practitioner clinic always nearby and accessible. When people live far from their physicians, the number of consultations probably decreases. Italy is also a quite densely populated country, and I wonder if you have any comments, Dr. Stanghellini? Dr. Stanghellini: I think that this is a good point. In Italy, we have a different organization. Outpatients must pay for endoscopy and for consultations with specialists, which certainly affects the attitude of many patients toward consulting hospital doctors. In general, consultation often takes place if the symptoms are severe or if patients become aware that these symptoms may be suggestive of a serious disease. In these cases patients want to consult doctors to be reassured about their situation. I think cultural, social, and economic factors strongly influence the attitudes of patients.
ease, particularly malignant disease, and endoscopy is the most conclusive means of eliminating those concerns. However, cost remains a problem, and in view of the available evidence and considering the various risk factors, it is not always necessary for endoscopy to be the first step. Also, not all patients visit specialists first. Thus the most efficient approach is first to note the patient's age and whether alarm symptoms exist. I believe that this is a practical concept, but I think that it is very important, not only for specialists but for all health care professionals, to take into account the need for examinations as part of treatment.
Dr. Miwa: Thank you very much. Now we should consider diagnosis and treatment of dyspepsia. We are currently studying draft guidelines for Japan prepared with reference to the European guidelines. Could you comment on the differences between them, and especially on the importance of endoscopy and the relationship between primary care physicians and specialists, Dr. Hongo?
Dr. Miwa: Regarding the importance of endoscopy, as we know, Japan still has a high incidence of stomach cancer. From this standpoint, there is a tendency to try to rule out the possibility of stomach cancer by immediate endoscopic examination. For better or worse, the major manufacturer of gastrointestinal endoscopes is Japanese, which makes these instruments easy to obtain. The guidelines described by Dr. Matsueda might be difficult to implement because when considering step 1 of the guidelines, the general practitioner, due to concerns about serious disease, may tend to refer patients to specialists. Thus it may not be helpful to adhere strictly to the guidelines. Dr. Stanghellini, what is the situation in Italy?
Dr. Hongo: Dyspepsia symptoms indicate that there is a disorder of the digestive organs, and patients therefore present with some concerns. Dr. Stanghellini outlined how to deal effectively with these concerns, but in summary the motivation for consulting a physician with gastrointestinal symptoms is concern about dis-
Dr. Stanghellini: Regardless of the country in which you live, there is a consensus that if dyspepsia starts in relatively old patients--that is, older than 40 or 45 y e a r s - - w h o were previously asymptomatic, they should undergo immediate endoscopy. Similarly, if clinical features such as anemia, weight loss, or jaundice D27
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suggest serious disease, patients should be investigated fully. The problem, at least in the West, is restricted to younger patients without alarm features. There is much debate about the management of this group, and it is necessary to distinguish family doctors from specialists who have quick access to endoscopy. In the real world, family doctors will not refer young patients for endoscopy. We could ask them to refer the high-risk group for endoscopy, but we cannot ask them to refer everybody because many governments will not support this. We already have long waiting lists at endoscopy laboratories, and we do not want to perform negative endoscopies in young dyspeptic patients. Therefore family doctors basically treat young dyspeptic patients on a symptomatic basis. Whether they look for Helicobacterpylori depends on the situation. If symptoms recur after early treatment, family doctors would probably test noninvasively for H pylori before referring. In terms of the specialist, in my view, at least in Italy, when patients are referred to a specialist they need immediate endoscopy. I do not see any reason why a specialist should delay endoscopy, because patients have already consulted different doctors and had different treatments. Such patients need to have endoscopy at least once in their life. 1 trust that the respective roles of family physicians and specialists in the treatment of dyspepsia will be clarified in the near future.
Dr. I-Iaruma: Although no definite conclusions have been reached, based on published trials of different treatments, eradication of Hpylori shows 80% efficacy in terms of symptom improvement. Dr. Miwa: Is this the effect of eradication of bacteria or some other effect?
H pylori infection. I think that H pylori
Dr. I t a r u m a : There is still much controversy regarding whether it is the effect of eradication, as there is regarding whether dyspepsia symptoms are present in infected and uninfected people. Conflicting data have also been presented. However, when we combined data from our institution, the results were positive. There was a significant difference, with a high rate of infection in patients with dyspepsia symptoms. There was also a difference, based on the severity of symptoms, between outpatients with dyspepsia and people with no symptoms, and based on age <40 years. I am of the opinion that treatment measures must be considered on the basis of age. In addition, about 95 % of Japanese with gastric cancer are positive for H pylori, whereas 95% of gastrointestinal ulcer patients are also positive. Thus it is a very convenient tool for screening, and in Japan screening by endoscopy might also be useful. In Europe and North America, 60% to 70% of gastric cancer patients are H pylori positive, so perhaps it is not as useful for screening there. A problem that remains is that H pylori screening is not covered by insurance, although the test is becoming less expensive.
may be a cause of functional dyspepsia in many patients. I would like to ask Dr. Haruma for his comments on how to interpret the effect of H pylori infection at this time.
Dr. Matsueda: My view on H pylori is somewhat different from that of Dr. Hamma because I believe that with the high prevalence in Japan, no data will emerge to
Dr. Miwa: Thank you. Our next topic is
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change treatment policy purely on that basis. For example, even in patients aged <40 years, the prevalence of H pylori infection in Japan is still higher than in Europe and the United States. If H pylori were to be used in the guidelines as a tool for decision making, there would be problems in terms of their rationality and cost effectiveness. Furthermore, even with eradication of H pylori in H pylori-positive younger patients, symptomatic relief is achieved in only about 20%. Thus, as we have been shown today, the issue of how to deal with Hpylori in younger patients requires a more open mind. I think that considering H pylori in the discussion of dyspepsia is not worthwhile at the present time.
Dr. Itaruma: In adults, particularly those aged >_40 years, the infection rate is 70% to 80%, so I agree completely with Dr. Matsueda. However, the infection rate is only 50% in people in their 30s, 25% to 26% in those in their 20s, and only 12% in those in their teens, at least at our institution. Consequently, I think that in younger age groups H pylori infection is a significant factor. We have about 100 patients who developed gastroduodenal ulcers in their young teens, and the H pylori positivity rate is 95%; we can use this fact for endoscopic screening. In addition, although not confirmed in randomized studies, I think it is well known that physicians faced with H pylori infection always attempt to eradicate the bacteria. In many cases treatment is definitely effective. I believe in this treatment. It is most effective for nodular gastritis in younger women, and I believe that you will be convinced if you try eradication once. Dr. Miwa: I do not believe that we have any results from epidemiologic surveys
on the causal relationship between H pylori and dyspepsia at this point. However, this was briefly touched on earlier: Because symptoms have disappeared in persons after elimination of the bacteria, we might conclude that some people exhibit symptoms of dyspepsia as a result of H pylori infection alone. Dr. Stanghellini, could we have your opinion on this?
Dr. Stanghellini: I think that we will know much more about this a year or so from now because 3 or 4 major controlled trials on Hpylori eradication in dyspepsia are ongoing. For the time being, my guess is that 20% to 30% of patients with functional dyspepsia and H pylori infection will see their symptoms markedly improve or disappear after eradication. I do not know whether these patients belong to the ulcer-like dyspepsia group. Preliminary, uncontrolled trials seem to suggest that pain and burning in the stomach are the symptoms that respond best to H pylori eradication. However, the problem is wider than this because sometimes science is overcome by social factors. In Italy, the potential role of Hpylori infection in the etiology of gastric cancer has been so stressed in the nonmedical literature that most patients will say at consultation, "Please, doctor, check if I have these germs in my stomach." If we find Hpylot4, we are forced to eradicate it. We must be aware that widespread eradication will produce a number of side effects. It will cause an increase in the already rapidly expanding problem of antibiotic resistance, and it will increase the number of colonic problems and intestinal diseases. Family doctors eradicate H pylori in patients with functional dyspepsia more often than specialists, not only in Italy, but also in the United Kingdom and GerD29
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many. This treatment is done without using a specific therapeutic approach; in one published paper, 116 different therapeutic approaches were used by specialists and family doctors to eradicate H pylori. What we will see in the near future is a huge population of either individuals in whom H pylori has been eradicated or individuals in whom eradication is no longer possible because the bacteria are resistant to all antibiotic therapies. These patients will still be symptomatic, and doctors will have to develop strategies to deal with this group, which comprises at least 70% of the current dyspepsia population. Dr. Miwa: Thank you. Although much work is needed to make a proper judgment, I would like to move on to the final issue of treatment--in particular, the issue of drug treatment. Dr. Hongo: Data from the DIGEST study on symptoms of postprandial fullness show that in Japanese and Italian patients, prescription drugs are effective in about 80% and 70% of patients, respectively. This finding indicates that people with distention are being treated and respond well to therapy. I think that this is one typical aspect of dyspepsia treatment and that concern about symptoms will probably lead to more patients seeking treatment. As was discussed earlier, endoscopy can help ease patients' concerns, and I believe that endoscopy is also important in this sense. Other data show that a high percentage of people with gastrointestinal symptoms consult physicians for nongastrointestinal symptoms such as weakness, chills, or dizziness, as well as gastrointestinal symptoms. Thus they are likely to be visD30
iting medical institutions frequently, again indicating that there is considerable concern regarding the meaning of symptoms. I believe that active treatment is necessary for such people. The nongastrointestinal symptoms are not necessarily related to the gastrointestinal symptoms, but I think that many related symptoms will be found. Although there are many different symptoms of functional dyspepsia, disorders of gastric emptying occur with high prevalence in patients with functional dyspepsia. Approximately 50% of patients-and perhaps more---have delayed gastric emptying; such symptoms are suitable for treatment with prokinetic agents, with which satisfactory results have been obtained. For example, we have shown in an open trial that cisapride improved symptom scores in all patients and that gastric emptying was accelerated in most patients. Thus, although cisapride ameliorated most symptoms, the fact that improvements in gastric motility do not necessarily parallel symptom improvement requires further consideration. I think the message here is that, although prokinetic agents are clinically effective, interpreting the mechanism for this effectiveness is difficult. Dr. Miwa: Gastric emptying is not delayed in all patients, and those with normal and accelerated gastric emptying also experience dyspepsia. What is the effect of prokinetic agents in these patients? Dr. Hongo: The general opinion from the treatment results obtained using prokinetic agents to date is that significant improvement in symptoms has been achieved, although gastric motility is often not directly measured.
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Dr. Miwa: Is the improvement significant even if emptying is not delayed? Dr. Hongo: Symptom improvement is seen even in patients where delayed emptying has not been confirmed. Dr. Matsueda: I would like to comment from the perspective of the development of the Japanese guidelines. Although there are many reasons why prokinetic agents are the main therapy in the guidelines, one is that dysmotility-like symptoms are dominant in about 60% of dyspepsia patients in Japan. Also, as Dr. Hongo pointed out, 50% of all patients have dysmotility. If these two points are considered properly, I believe that it is correct to include prokinetic agents as the main treatment. Another important point for Japan is that patients with gastric cancer often present with symptoms similar to those of patients with dysmotility-like symptoms. In the two trials of the draft guidelines that we have conducted, although the number of patients was small, there were two cases of stomach cancer. Both were patients initially included in the group with dysmotility-like symptoms, and prokinetic therapy did not ameliorate their symptoms. In other words, the symptoms were not masked by prokinetic agents. This finding is very important. When these three points are considered and because in Japan we have observed that strict control of gastric acid production sometimes produces symptomatic improvements in patients with gastric cancer, I think prokinetic agents are the treatment of choice in patients with dysmotility-like symptoms. Dr. H a r u m a : I have my own classification of dyspepsia that I interpret quite literally.
I also evaluate gastrointestinal motility based on ultrasonography. Thus I use ultrasonography to examine gastric motility in dyspepsia patients. If they have not eaten on that day, I then do endoscopy. Then, if there are symptoms of delayed gastric emptying, I prescribe prokinetic agents. If emptying is normal, I combine prokinetic treatment with mild tranquilizers. Using this method, routine ultrasonography takes 5 minutes and checking gastrointestinal motility takes 15 minutes; thus the total screening period is about 20 minutes. Another advantage is that liquid loading allows the stomach to be seen very clearly, and any tumor >2 cm in diameter should be detectable using this technique. Therefore I think that the two patients with gastric cancer included in Dr. Matsueda's studies would probably have been detected using our screening protocol.
Dr. Stanghellini: Once again, I would like to say some words of caution about how difficult it is, for a number of reasons, to draw firm conclusions when dealing with dyspepsia. In terms of therapy, you must always take into consideration that dyspepsia fluctuates over time. Symptoms become worse or better spontaneously, and interpretation of the effect of a drug is difficult. There is a large placebo effect because patients tend to consult physicians when their symptoms are bad, at the top of the fluctuating curve of symptom severity. Therefore patients tend to improve spontaneously when they have consulted their physician or undergone endoscopy. On top of that, there is the reassurance factor, which plays an important role. We need to know whether a drug influences the natural history of dyspeps i a - t h a t is, does it change the rhythm or the frequency of recurrences? D31
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Based on the published literature, I think that, overall, prokinetic agents have been proved to be better than antisecretory drugs. Two meta-analytical studies of which I am aware reached this conclusion. Looking at all placebo-controlled studies, prokinetic agents are significantly better than histamine 2 antagonists. Finally, a word about cancer. I think that prokinetic agents are safer than antisecretory drugs because prokinetic agents tend to mask symptoms in patients with gastric cancer less effectively. Therefore, if prescribing a drug for the average dyspeptic patient, I would recommend starting with a prokinetic agent. Dr. Miwa: I think that you have summarized the issue very well. Do you have any further comments, Dr. Hongo? Dr. H o n g o : There are many different factors to consider when dealing with dyspepsia, and functional d y s p e p s i a appears in tandem with many problems, including stomach conditions, H p y l o r i infection, duodenal motility dysfunction, subjective sensations, and psychological p r o b l e m s . There are also many problems with regard to continuing treatment, and 1 think that it is necessary to consider at all times that the patient's environment, the information
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available, education, and family, are all factors. Dr. Miwa: Dr. Haruma, do you have any final comments? Dr. I t a r u m a : Symptoms in patients with Hpylori-posifive nonulcer dyspepsia are not
always eliminated, even using prokinetic agents. However, it is my impression that treatment is now quite effective. Dr. Miwa: Treatment for the chronic symptoms of dyspepsia should probably focus on supporting patient quality of life, and I think that one problem with this approach will be that it is difficult to determine whether one drug is sufficient. Selection of the appropriate drug(s) for individual patients should be possible, but as a general approach the basic firstchoice treatment for functional dyspepsia should be prokinetic agents. I think that I am correct in saying that this approach is the general opinion. In conclusion, I would like to thank you for your input. These are very difficult issues, and I do not believe that it is possible to predict what a discussion of these issues 1 year from now would conclude. Very significant points were made, and I learned a great deal. I wish to thank all of you for your comments.
Roundtable Discussion: Differences Between Japan and Western Countries in the Treatment of Dyspepsia
Participants: Ken Haruma, MD, 1 Michio Hongo, MD, 2 Kei Matsueda, MD, 3 Takeshi Miwa, MD, 4 and Vincenzo Stanghellini, M D s 1First Department of Internal Medicine, Hiroshima University, Hiroshima, Japan, 2Department of Comprehensive Medicine, Tohoku University, Sendai, Japan, 3Department of Gastroenterology, International Medical Center of Japan, Tokyo, Japan, 4Tokai University, Isehara, Japan, 51nstitute of Clinical Medicine and Gastroenterology, University of Bologna, Bologna, Italy
Dr. Miwa: The first topic for consideration is dyspepsia in general, which involves some difficult issues. The majority relate to the subjectivity of symptoms, but there are also issues regarding the interpretation of the term "dyspepsia." In this regard, the concept of dyspepsia is perhaps a little abstract, so we will discuss the differences in understanding and perspective between Japan, Europe, and the United States. Dr. Stanghellini: I mentioned during my presentation that the semantic issue is very important when dealing with dyspepsia. If you look at some of the recently published data, there do not appear to be different subgroups of patients with functional dyspepsia or with dyspepsia in general. However, if you examine the methods and the questionnaires used in these studies, it becomes apparent that epigastric pain was present in all the dif0149-2918198/$19.00
ferent subgroups they considered. This means that only patients with pain or burning pain arising from the gastric area were included. Thus it is not surprising that by subdividing patients with different types of stomach pain you end up with small differences among different groups. In contrast, in other studies designed to evaluate the role of prokinetic agents, only patients with dysmotility-like dyspepsia were included. I do not believe that we need to become obsessive about terminology, but we do need to be precise in what we do. We must carefully describe each symptom that is reported by our patients. This practice is particularly important because upper gastrointestinal symptoms often overlap, and many patients may have gastroesophageal reflux disease (GERD) with dyspepsia and irritable bowel syndrome (IBS) at the same time. They may have prevalent epigastric symptoms for a certain period, but D23
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then GERD becomes the most relevant condition. I think it is important to realize that IBS, GERD, and dyspepsia are different entities, as well as to describe in greater detail each individual complaint that patients have. Dr. Miwa: I think the issue of terminology involves many subtle problems, particularly from the standpoint of definitions. Dr. Matsueda, what is your opinion? Dr. Matsueda: The definitions involved in this discussion are very subtle. Although dyspepsia describes the central concept, patients' descriptions of symptoms differ from country to country. Even with different descriptions based on the same concept, we have the problem that patients in Japan are reluctant to complain of pain. For example, both IBS patients and dyspepsia patients describe abdominal discomfort as the main symptom, with few complaining of abdominal pain. I believe that this is a country-specific problem stemming from the concept that concealing emotions is a virtue in some countries. I do not know whether there is any consensus on whether pain and discomfort are treated equally. However, it is important to obtain the proper perspective and determine the views of specialists in this area. Dr. Miwa: I believe that this is a very difficult problem to deal with, and I often use the terms "epigastric pain," "discomfort," and "distress" without really understanding their difference. The difference between English and Japanese is so great--and terminology also differs within the Japanese language--that you can imagine how difficult it becomes when dealing with expressions in differD24
ent languages worldwide. In this sense, I believe we need some degree of consensus from country to country, as well as within countries. How do you feel about this, Dr. Haruma? Dr. H a r u m a : I believe that the terms need to be more clearly defined for general practitioners. Disease descriptions are essential for medical examinations, and without proper definitions I believe it will be difficult to provide proper medical care for dyspepsia. In general, "dyspepsia" has been used in Japan in place of "chronic gastritis" or "gastritis," which is the disease name used for insurance purposes. However, I think that dyspepsia needs to be used as a description for insurance purposes in Japan before it will be accepted clinically. Dr. Miwa: In addition to the issue of what dyspepsia is, there is also the issue of its Japanese equivalent. Can you comment on this, Dr. Hongo? Dr. Hongo: The term used internationally to describe the subjective symptomatology of dyspepsia is "functional dyspepsia." If considered to be a dysfunction of the epigastric area or upper gastrointestinal tract, this can be translated into Japanese as functional dyspepsia. However, I would like to have a Japanese term for "dyspepsia," the understanding of which is different for an upper gastrointestinal dysfunction. We have tentatively considered a term corresponding to "gastrointestinal disease," but in terms of a higher scale of pain and discomfort, I believe that diffusion of the concept of dyspepsia is important for its understanding. Even pain, as we heard from Dr. Matsueda, is characteristically hidden by Japanese patients, although it may be that
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the Japanese vocabulary does not use the word pain to describe the feelings experienced in dyspepsia. In this sense, pain cannot be considered as being distinct from discomfort. Without establishing this understanding first or educating physicians through workshops and other means, I think it will be difficult to accurately convey the concept of functional dyspepsia. Dr. Matsueda: May I interrupt? Japanese patients do complain of pain. When it is dominant, for example in the case of peptic ulcer disease, pain is the major complaint. But dull pain generally tends to be expressed as "discomfort." In the case of acute abdomen, their complaints are the same as complaints in Europe and the United States. I am saying that if treated equivocally as discomfort, cases of dull pain and pain might be more easily understood internationally. Dr. Miwa: This is obviously a difficult issue. Whatever the case, I believe it is necessary to obtain a consensus of opinion worldwide and in Japan. A lack of consensus can produce a lack of understanding, and I think that this will be a major topic for specialists to deal with in the future. Dr. Stanghellini, do you have anything you wish to add?
Dr. Stanghellini: I think most of the important issues have been touched on. I would like to summarize what has been achieved internationally so far and maybe give some advice for the future. First, dyspepsia is different from IBS and GERD, and this fact is recognized internationally. Second, the concept of dyspepsia includes two main kinds of symptoms. One is pain, and the other is an unpleasant but not painful sensation. I think that Dr. Mat-
sueda's definition of pain is fairly good: pain is similar to what is most commonly reported by patients with peptic ulcer; discomfort is different from pain regardless of symptom severity. For example, one can have extremely severe nausea without perceiving any pain at all; quality of life can be completely destroyed by nausea, but nobody would ever describe this as a painful sensation. We now know that different receptors, at least to a certain extent, through different afferent pathways bring painful and nonpainful messages to the central nervous system. The last concept that I would like to suggest for future consideration is to introduce greater emphasis on the severity of individual symptoms and the concept that some symptoms are more bothersome to patients than others. These concepts were not present in the first Roman criteria on dyspepsia, but they are being introduced in the new ones that were discussed in Rome in June 1998. I think these are the main criteria that I would like to suggest that you follow when defining dyspepsia in Japan. Dr. Miwa: Thank you very much. I would like to move on to the next issue, which involves the differences between epidemiologic surveys of dyspepsia in Japan, Europe, and the United States, because it is not clear exactly what the differences are. Dr. I-Iongo: The Domestic International Gastroenterology Study (DIGEST) showed that approximately 26% of Japanese subjects experience symptoms of dyspepsia, which is slightly lower than the incidence in other countries. However, these are common symptoms found in more than 25% of the population and thus cannot be explained simply by eating D25
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habits. In support of this is the fact that although diet is very different in Switzerland and Japan, the incidence of symptoms is similar. The severity of dyspepsia symptoms among Japanese subjects is also slightly milder than that in other countries. However, I think that because so many people display so many symptoms, it indicates that there is a serious problem, even if these symptoms are not very severe. Interestingly, the average number of times a Japanese patient receives treatment for dyspepsia symptoms at a medical institution indicates a higher requirement for medical attention than in other countries. It appears that it is typical for Japanese patients to consult physicians immediately on experiencing symptoms. Because medical care is particularly expensive in the United States, it is possible that patients do not seek medical attention despite the high frequency of dyspepsia symptoms. Accordingly, when the type of medication taken is examined, over-thecounter drugs are used widely in the United States, whereas prescription drugs are more common in Japan: Approximately 40% of Japanese patients with dyspepsia take prescription drugs. In conclusion, although symptom severity appears to be mild, Japanese patients tend to consult physicians and take prescription drugs. Because the incidence of dyspepsia symptoms is high in Japan, although lower than that in other countries, it is a serious problem that cannot be ignored.
Dr. Stanghellini: I was surprised to learn how often Japanese subjects visit physicians. There is a consensus in Western countries that only about 25% of dyspepsia patients consult their physicians. The D26
observation that Japanese subjects consult physicians frequently regarding dyspepsia is to me in contrast to what Dr. Matsueda said about Japanese people being ashamed to show their feelings. It would seem to me that if they were really ashamed, they would not discuss their illnesses with physicians more often than in other countries. One may wonder whether Japanese physicians are better than those in other countries and whether a better patient-doctor relationship exists in Japan. In Western newspapers it is becoming increasingly common to have medical sections in which simple medical concepts are explained. Furthermore, despite digestive cancers being among the leading causes of death in most Western countries, people still feel confident that indigestion, constipation, and diarrhea are mild clinical conditions that they can handle without the help of physicians. Dr. Miwa: A comprehensive discussion of the unique aspects of different countries might be difficult, but in the earlier lecture by Dr. Stanghellini we heard that the relationship between dyspepsia and gastric motility is well established, especially in women. Do you have any comments on the ratio of men to women in the DIGEST study? Dr. Hongo: The ratio of men to women was roughly equal in the DIGEST study, and in no country was there a clear majority of men or women. I do not believe that differences in men:women ratios affected this survey. Dr. Miwa: I do not believe that there are any special circumstances in Japan, but I think that the tendency to consult physicians in Japan might be attributable to
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large populations living in close proximity, with a general practitioner clinic always nearby and accessible. When people live far from their physicians, the number of consultations probably decreases. Italy is also a quite densely populated country, and I wonder if you have any comments, Dr. Stanghellini? Dr. Stanghellini: I think that this is a good point. In Italy, we have a different organization. Outpatients must pay for endoscopy and for consultations with specialists, which certainly affects the attitude of many patients toward consulting hospital doctors. In general, consultation often takes place if the symptoms are severe or if patients become aware that these symptoms may be suggestive of a serious disease. In these cases patients want to consult doctors to be reassured about their situation. I think cultural, social, and economic factors strongly influence the attitudes of patients.
ease, particularly malignant disease, and endoscopy is the most conclusive means of eliminating those concerns. However, cost remains a problem, and in view of the available evidence and considering the various risk factors, it is not always necessary for endoscopy to be the first step. Also, not all patients visit specialists first. Thus the most efficient approach is first to note the patient's age and whether alarm symptoms exist. I believe that this is a practical concept, but I think that it is very important, not only for specialists but for all health care professionals, to take into account the need for examinations as part of treatment.
Dr. Miwa: Thank you very much. Now we should consider diagnosis and treatment of dyspepsia. We are currently studying draft guidelines for Japan prepared with reference to the European guidelines. Could you comment on the differences between them, and especially on the importance of endoscopy and the relationship between primary care physicians and specialists, Dr. Hongo?
Dr. Miwa: Regarding the importance of endoscopy, as we know, Japan still has a high incidence of stomach cancer. From this standpoint, there is a tendency to try to rule out the possibility of stomach cancer by immediate endoscopic examination. For better or worse, the major manufacturer of gastrointestinal endoscopes is Japanese, which makes these instruments easy to obtain. The guidelines described by Dr. Matsueda might be difficult to implement because when considering step 1 of the guidelines, the general practitioner, due to concerns about serious disease, may tend to refer patients to specialists. Thus it may not be helpful to adhere strictly to the guidelines. Dr. Stanghellini, what is the situation in Italy?
Dr. Hongo: Dyspepsia symptoms indicate that there is a disorder of the digestive organs, and patients therefore present with some concerns. Dr. Stanghellini outlined how to deal effectively with these concerns, but in summary the motivation for consulting a physician with gastrointestinal symptoms is concern about dis-
Dr. Stanghellini: Regardless of the country in which you live, there is a consensus that if dyspepsia starts in relatively old patients--that is, older than 40 or 45 y e a r s - - w h o were previously asymptomatic, they should undergo immediate endoscopy. Similarly, if clinical features such as anemia, weight loss, or jaundice D27
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suggest serious disease, patients should be investigated fully. The problem, at least in the West, is restricted to younger patients without alarm features. There is much debate about the management of this group, and it is necessary to distinguish family doctors from specialists who have quick access to endoscopy. In the real world, family doctors will not refer young patients for endoscopy. We could ask them to refer the high-risk group for endoscopy, but we cannot ask them to refer everybody because many governments will not support this. We already have long waiting lists at endoscopy laboratories, and we do not want to perform negative endoscopies in young dyspeptic patients. Therefore family doctors basically treat young dyspeptic patients on a symptomatic basis. Whether they look for Helicobacterpylori depends on the situation. If symptoms recur after early treatment, family doctors would probably test noninvasively for H pylori before referring. In terms of the specialist, in my view, at least in Italy, when patients are referred to a specialist they need immediate endoscopy. I do not see any reason why a specialist should delay endoscopy, because patients have already consulted different doctors and had different treatments. Such patients need to have endoscopy at least once in their life. 1 trust that the respective roles of family physicians and specialists in the treatment of dyspepsia will be clarified in the near future.
Dr. I-Iaruma: Although no definite conclusions have been reached, based on published trials of different treatments, eradication of Hpylori shows 80% efficacy in terms of symptom improvement. Dr. Miwa: Is this the effect of eradication of bacteria or some other effect?
H pylori infection. I think that H pylori
Dr. I t a r u m a : There is still much controversy regarding whether it is the effect of eradication, as there is regarding whether dyspepsia symptoms are present in infected and uninfected people. Conflicting data have also been presented. However, when we combined data from our institution, the results were positive. There was a significant difference, with a high rate of infection in patients with dyspepsia symptoms. There was also a difference, based on the severity of symptoms, between outpatients with dyspepsia and people with no symptoms, and based on age <40 years. I am of the opinion that treatment measures must be considered on the basis of age. In addition, about 95 % of Japanese with gastric cancer are positive for H pylori, whereas 95% of gastrointestinal ulcer patients are also positive. Thus it is a very convenient tool for screening, and in Japan screening by endoscopy might also be useful. In Europe and North America, 60% to 70% of gastric cancer patients are H pylori positive, so perhaps it is not as useful for screening there. A problem that remains is that H pylori screening is not covered by insurance, although the test is becoming less expensive.
may be a cause of functional dyspepsia in many patients. I would like to ask Dr. Haruma for his comments on how to interpret the effect of H pylori infection at this time.
Dr. Matsueda: My view on H pylori is somewhat different from that of Dr. Hamma because I believe that with the high prevalence in Japan, no data will emerge to
Dr. Miwa: Thank you. Our next topic is
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change treatment policy purely on that basis. For example, even in patients aged <40 years, the prevalence of H pylori infection in Japan is still higher than in Europe and the United States. If H pylori were to be used in the guidelines as a tool for decision making, there would be problems in terms of their rationality and cost effectiveness. Furthermore, even with eradication of H pylori in H pylori-positive younger patients, symptomatic relief is achieved in only about 20%. Thus, as we have been shown today, the issue of how to deal with Hpylori in younger patients requires a more open mind. I think that considering H pylori in the discussion of dyspepsia is not worthwhile at the present time.
Dr. Itaruma: In adults, particularly those aged >_40 years, the infection rate is 70% to 80%, so I agree completely with Dr. Matsueda. However, the infection rate is only 50% in people in their 30s, 25% to 26% in those in their 20s, and only 12% in those in their teens, at least at our institution. Consequently, I think that in younger age groups H pylori infection is a significant factor. We have about 100 patients who developed gastroduodenal ulcers in their young teens, and the H pylori positivity rate is 95%; we can use this fact for endoscopic screening. In addition, although not confirmed in randomized studies, I think it is well known that physicians faced with H pylori infection always attempt to eradicate the bacteria. In many cases treatment is definitely effective. I believe in this treatment. It is most effective for nodular gastritis in younger women, and I believe that you will be convinced if you try eradication once. Dr. Miwa: I do not believe that we have any results from epidemiologic surveys
on the causal relationship between H pylori and dyspepsia at this point. However, this was briefly touched on earlier: Because symptoms have disappeared in persons after elimination of the bacteria, we might conclude that some people exhibit symptoms of dyspepsia as a result of H pylori infection alone. Dr. Stanghellini, could we have your opinion on this?
Dr. Stanghellini: I think that we will know much more about this a year or so from now because 3 or 4 major controlled trials on Hpylori eradication in dyspepsia are ongoing. For the time being, my guess is that 20% to 30% of patients with functional dyspepsia and H pylori infection will see their symptoms markedly improve or disappear after eradication. I do not know whether these patients belong to the ulcer-like dyspepsia group. Preliminary, uncontrolled trials seem to suggest that pain and burning in the stomach are the symptoms that respond best to H pylori eradication. However, the problem is wider than this because sometimes science is overcome by social factors. In Italy, the potential role of Hpylori infection in the etiology of gastric cancer has been so stressed in the nonmedical literature that most patients will say at consultation, "Please, doctor, check if I have these germs in my stomach." If we find Hpylot4, we are forced to eradicate it. We must be aware that widespread eradication will produce a number of side effects. It will cause an increase in the already rapidly expanding problem of antibiotic resistance, and it will increase the number of colonic problems and intestinal diseases. Family doctors eradicate H pylori in patients with functional dyspepsia more often than specialists, not only in Italy, but also in the United Kingdom and GerD29
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many. This treatment is done without using a specific therapeutic approach; in one published paper, 116 different therapeutic approaches were used by specialists and family doctors to eradicate H pylori. What we will see in the near future is a huge population of either individuals in whom H pylori has been eradicated or individuals in whom eradication is no longer possible because the bacteria are resistant to all antibiotic therapies. These patients will still be symptomatic, and doctors will have to develop strategies to deal with this group, which comprises at least 70% of the current dyspepsia population. Dr. Miwa: Thank you. Although much work is needed to make a proper judgment, I would like to move on to the final issue of treatment--in particular, the issue of drug treatment. Dr. Hongo: Data from the DIGEST study on symptoms of postprandial fullness show that in Japanese and Italian patients, prescription drugs are effective in about 80% and 70% of patients, respectively. This finding indicates that people with distention are being treated and respond well to therapy. I think that this is one typical aspect of dyspepsia treatment and that concern about symptoms will probably lead to more patients seeking treatment. As was discussed earlier, endoscopy can help ease patients' concerns, and I believe that endoscopy is also important in this sense. Other data show that a high percentage of people with gastrointestinal symptoms consult physicians for nongastrointestinal symptoms such as weakness, chills, or dizziness, as well as gastrointestinal symptoms. Thus they are likely to be visD30
iting medical institutions frequently, again indicating that there is considerable concern regarding the meaning of symptoms. I believe that active treatment is necessary for such people. The nongastrointestinal symptoms are not necessarily related to the gastrointestinal symptoms, but I think that many related symptoms will be found. Although there are many different symptoms of functional dyspepsia, disorders of gastric emptying occur with high prevalence in patients with functional dyspepsia. Approximately 50% of patients-and perhaps more---have delayed gastric emptying; such symptoms are suitable for treatment with prokinetic agents, with which satisfactory results have been obtained. For example, we have shown in an open trial that cisapride improved symptom scores in all patients and that gastric emptying was accelerated in most patients. Thus, although cisapride ameliorated most symptoms, the fact that improvements in gastric motility do not necessarily parallel symptom improvement requires further consideration. I think the message here is that, although prokinetic agents are clinically effective, interpreting the mechanism for this effectiveness is difficult. Dr. Miwa: Gastric emptying is not delayed in all patients, and those with normal and accelerated gastric emptying also experience dyspepsia. What is the effect of prokinetic agents in these patients? Dr. Hongo: The general opinion from the treatment results obtained using prokinetic agents to date is that significant improvement in symptoms has been achieved, although gastric motility is often not directly measured.
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Dr. Miwa: Is the improvement significant even if emptying is not delayed? Dr. Hongo: Symptom improvement is seen even in patients where delayed emptying has not been confirmed. Dr. Matsueda: I would like to comment from the perspective of the development of the Japanese guidelines. Although there are many reasons why prokinetic agents are the main therapy in the guidelines, one is that dysmotility-like symptoms are dominant in about 60% of dyspepsia patients in Japan. Also, as Dr. Hongo pointed out, 50% of all patients have dysmotility. If these two points are considered properly, I believe that it is correct to include prokinetic agents as the main treatment. Another important point for Japan is that patients with gastric cancer often present with symptoms similar to those of patients with dysmotility-like symptoms. In the two trials of the draft guidelines that we have conducted, although the number of patients was small, there were two cases of stomach cancer. Both were patients initially included in the group with dysmotility-like symptoms, and prokinetic therapy did not ameliorate their symptoms. In other words, the symptoms were not masked by prokinetic agents. This finding is very important. When these three points are considered and because in Japan we have observed that strict control of gastric acid production sometimes produces symptomatic improvements in patients with gastric cancer, I think prokinetic agents are the treatment of choice in patients with dysmotility-like symptoms. Dr. H a r u m a : I have my own classification of dyspepsia that I interpret quite literally.
I also evaluate gastrointestinal motility based on ultrasonography. Thus I use ultrasonography to examine gastric motility in dyspepsia patients. If they have not eaten on that day, I then do endoscopy. Then, if there are symptoms of delayed gastric emptying, I prescribe prokinetic agents. If emptying is normal, I combine prokinetic treatment with mild tranquilizers. Using this method, routine ultrasonography takes 5 minutes and checking gastrointestinal motility takes 15 minutes; thus the total screening period is about 20 minutes. Another advantage is that liquid loading allows the stomach to be seen very clearly, and any tumor >2 cm in diameter should be detectable using this technique. Therefore I think that the two patients with gastric cancer included in Dr. Matsueda's studies would probably have been detected using our screening protocol.
Dr. Stanghellini: Once again, I would like to say some words of caution about how difficult it is, for a number of reasons, to draw firm conclusions when dealing with dyspepsia. In terms of therapy, you must always take into consideration that dyspepsia fluctuates over time. Symptoms become worse or better spontaneously, and interpretation of the effect of a drug is difficult. There is a large placebo effect because patients tend to consult physicians when their symptoms are bad, at the top of the fluctuating curve of symptom severity. Therefore patients tend to improve spontaneously when they have consulted their physician or undergone endoscopy. On top of that, there is the reassurance factor, which plays an important role. We need to know whether a drug influences the natural history of dyspeps i a - t h a t is, does it change the rhythm or the frequency of recurrences? D31
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Based on the published literature, I think that, overall, prokinetic agents have been proved to be better than antisecretory drugs. Two meta-analytical studies of which I am aware reached this conclusion. Looking at all placebo-controlled studies, prokinetic agents are significantly better than histamine 2 antagonists. Finally, a word about cancer. I think that prokinetic agents are safer than antisecretory drugs because prokinetic agents tend to mask symptoms in patients with gastric cancer less effectively. Therefore, if prescribing a drug for the average dyspeptic patient, I would recommend starting with a prokinetic agent. Dr. Miwa: I think that you have summarized the issue very well. Do you have any further comments, Dr. Hongo? Dr. H o n g o : There are many different factors to consider when dealing with dyspepsia, and functional d y s p e p s i a appears in tandem with many problems, including stomach conditions, H p y l o r i infection, duodenal motility dysfunction, subjective sensations, and psychological p r o b l e m s . There are also many problems with regard to continuing treatment, and 1 think that it is necessary to consider at all times that the patient's environment, the information
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available, education, and family, are all factors. Dr. Miwa: Dr. Haruma, do you have any final comments? Dr. I t a r u m a : Symptoms in patients with Hpylori-posifive nonulcer dyspepsia are not
always eliminated, even using prokinetic agents. However, it is my impression that treatment is now quite effective. Dr. Miwa: Treatment for the chronic symptoms of dyspepsia should probably focus on supporting patient quality of life, and I think that one problem with this approach will be that it is difficult to determine whether one drug is sufficient. Selection of the appropriate drug(s) for individual patients should be possible, but as a general approach the basic firstchoice treatment for functional dyspepsia should be prokinetic agents. I think that I am correct in saying that this approach is the general opinion. In conclusion, I would like to thank you for your input. These are very difficult issues, and I do not believe that it is possible to predict what a discussion of these issues 1 year from now would conclude. Very significant points were made, and I learned a great deal. I wish to thank all of you for your comments.