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Peptic ulcer disease and current approaches to Helicobacter pylori
MEDICAL PROGRESS
Peptic ulcer disease and current approaches to Helicobacter pylori Eric Hassall, MBChB, FRCP(C), FACG The most exciting recent development in the area of peptic ulcer disease has been the discovery that a bacterial infection, Helicobacter pylori, is a major factor in its pathogenesis. The fascinating story of this discovery is colorfully recounted elsewhere.1 Because of its importance, H pylori dominates any discussion of PUD, but there are many other causes. This article provides an overview of ulcer disease, focusing on areas of progress, especially those of importance in the care of children; because PUD in children differs in some respects from that in adults, there are important practical implications for pediatric practitioners. In this regard, recently published consensus guidelines are presented.
DEFINITIONS Gastritis and Gastropathy Peptic ulceration of the stomach or duodenum is often accompanied by abnormalities of the gastric mucosa, and the key to determining the cause of ulcer disease often lies in histologic diagnosis of the associated gastritis (inflammation present in biopsy specimens) or gastropathy (inflammation not
prominent).2 There are many gastropathies and gastritides that are not accompanied by peptic ulceration.2 In both gastritis and gastropathy, endoscopic findings may be normal or abnormal. The term gastritis is often misused. For example, not infrequently, clinicians will refer to a patient with epigastric pain or dyspepsia as having “gastritis,” whereas radiologists may diagnose “gastritis” on the basis of nonspecific changes on x-ray films. However, gastritis is neither a clinical nor a radiologic diagnosis; most often it is a purely histologic diagnosis, made by the use of multiple random or targeted endoscopic biopsies.
Erosions, Ulcers, and Other Terms An erosion is a mucosal break that does not penetrate the muscularis mucosae, whereas an ulcer is deeper, extending through the muscularis into the submucosa. Acid peptic diseases or acid-related disorders are mucosal disorders of the esophagus, stomach, or duodenum that primarily involve gastric acid (and pepsin) in their pathogenesis. We use the terms ulcer disease
From the Division of Gastroenterology, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada.
Submitted for publication July 29, 1999; revisions received Aug 10, 2000, Oct 18, 2000, and Nov 21, 2000; accepted Dec 4, 2000. Reprint requests: Eric Hassall, MBChB, FRCP(C), Division of Gastroenterology, British Columbia Children’s Hospital, 4480 Oak St, Room 1K2, Vancouver, British Columbia V6H 3V4, Canada.
J Pediatr 2001;138:462-8. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/19/113621 doi:10.1067/mpd.2001.113621
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and peptic ulcer synonymously to refer to erosions or ulcers of the stomach and duodenum. GI Gastrointestinal NSAIDs Nonsteroidal anti-inflammatory drugs PUD Peptic ulcer disease
PRIMARY AND SECONDARY ULCER DISEASE Conceptually, it is useful to categorize PUD by cause into primary and secondary types (Table).3 Secondary ulcers are usually related to underlying disease or drugs. Although the categorization is based on cause or mechanism, there are other general qualities consistent with this approach. For example, primary peptic ulcers are usually chronic, with fibrinopurulent debris overlying active inflammatory infiltrate, granulation tissue, and fibrosis.3 In contrast, secondary peptic ulcers are usually more acute in onset, without signs of chronicity, with the exception of the hypergastrinemic disorders. Primary peptic ulcers are more often duodenal, whereas secondary ulcers are more often gastric than duodenal; again, hypergastrinemic disorders are excepted. Most primary peptic ulcers in children occur between the ages of 8 and 17 years (mean age, 11.5 years),4,5 whereas secondary ulcers occur at all ages.
Clinical Presentation In the pediatric age group, abdominal pain is a very common reason for seeking medical advice, and it is also the most common presenting symptom
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THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 4 of PUD. However, peptic and other erosive/ulcerative gastritides and gastropathies of the stomach and duodenum are relatively uncommon, accounting for perhaps 15% to 20% of abdominal pain in children in a subspecialty practice, and less in a general pediatric practice. Other upper gastrointestinal disorders such as erosive gastroduodenal disease caused by Crohn’s disease, nonsteroidal anti-inflammatory drugs , allergic gastritis, and other entities in the Table may present with similar symptoms, as may the many causes of esophagitis. In children aged 10 to 12 years and older, symptoms may be similar to those in adults. Although epigastric pain or discomfort that is meal-related or -exacerbated or that wakes the child from sleep is often a symptom of PUD (or of other gastric mucosal disorders), it is sometimes a presenting symptom of more common disorders such as non-ulcer dyspepsia, or so-called recurrent abdominal pain, or constipation. Younger children may not be able to localize pain to the epigastrium and may present with discomfort or bloating, especially with meals. Other symptoms include anorexia, nausea, early satiety, recurrent vomiting, and anemia. Weight loss occurs less often. GI bleeding may occur with antecedent epigastric pain or other symptoms, but painless bleeding may be the only manifestation of ulcer disease; up to 25% of children with primary duodenal ulcers have this “silent” presentation, whereas some 25% present with bleeding and antecedent pain, and the rest present with abdominal pain or recurrent vomiting.4,5 Epigastric tenderness is an unreliable physical sign of gastritis or ulcer disease.
PRIMARY PEPTIC ULCER DISEASE Although there is a paucity of prevalence figures for children, it is well accepted that primary PUD is much less
Table. Causes of peptic ulcers in children Primary peptic ulcers H pylori–associated H pylori–negative/idiopathic Secondary peptic ulcers Physiologic stress (decreased gastric blood flow) Burns, sepsis, shock, hypoxemia, head injury, uremia, exercise-induced Traumatic gastropathy Forceful retching, nasogastric tubes, foreign bodies Drugs NSAIDS, alcohol, valproic acid, chemotherapy, potassium chloride Immune-mediated Celiac gastritis, allergic gastritis, eosinophilic gastritis, graft-versus-host disease Infections Cytomegalovirus, herpes simplex, anisakiasis, influenza A, Candida albicans, syphilis, histoplasmosis, mucormycosis, phlegmonous gastritis, emphysematous gastritis Corrosive gastropathy Iron overdose, acid indigestion Autoimmune Diabetes mellitus, connective tissue disease Granulomatous gastritides Crohn’s disease, foreign body reaction, idiopathic, histiocytosis X, tuberculosis Hypersecretory states Zollinger-Ellison syndrome, G-cell hyperplasia/hyperfunction, systemic mastocytosis, cystic fibrosis, short bowel syndrome, hyperparathyroidism Vascular insufficiency Sickle cell disease, Henoch-Schönlein disease Hepatic cirrhosis Radiation gastropathy
common in children than in adults. For example, in our unit in a tertiary care children’s hospital with a referral population of some 4 million, we diagnose only about 4 to 6 new primary ulcers per year. Of these, duodenal ulcers are much more prevalent than gastric ulcers; in our experience over some 15 years, with all ulcers diagnosed endoscopically, duodenal ulcers were some 30 times more prevalent than gastric ulcers (when NSAID-related ulcers are excluded). Most primary peptic ulcers are H pylori–related, though a significant and increasing proportion are H pylori–negative or “idiopathic” (Table).
Etiology Ulcer disease was long assumed to be idiopathic, caused by acid hyper-
secretion, and/or psychologic stress. The Helicobacter relationship gained acceptance only after Marshall produced acute gastritis in himself by ingesting the organism6 and later showed that H pylori–related ulcers could be cured by antimicrobial agents and remain in remission, unlike those treated with acid suppression alone.7 A subsequent deluge of research has proved and extended his findings. In the process, opinion swung to the belief that virtually all primary ulcer disease was H pylori–related. However, more recently, there has been increasing recognition of the entity of non Helicobacter-associated (idiopathic) primary PUD, with reports that up to 39% of ulcers (most duodenal) may be in this category.8-10 There are conflicting results as to whether psychologic stress plays a signif463
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THE JOURNAL OF PEDIATRICS APRIL 2001 adults, particularly in developing countries, multifocal atrophic gastritis with intestinal metaplasia develops22; the latter is a risk factor for gastric ulcer and gastric adenocarcinoma when it is extensive. No significant increase in inflammation nor development of atrophy or metaplasia was found in a pediatric study of H pylori gastritis.23
Gastric Carcinoma
Fig 1. Anatomic regions of the stomach. From, Rudolph AM, Hoffman JIE, Rudolph CD editors. Rudolph’s pediatrics. 20th ed. Stamford (CT): Appleton & Lange; Copyright 1996. Reprinted with permission of The McGraw-Hill Companies.
icant role in causing ulcer disease,11-13 reflecting the difficulties in defining and quantitating stress and studying its interactions with different personalities. In addition, PUD has long been regarded as a heterogeneous disorder,12 and data from the “pre-H pylori era” almost certainly involved a mixed bag of Helicobacter-positive and -negative subjects. Although there are no controlled data on psychologic stress and ulcer disease in children, it is recognized that stress plays a role in causing symptoms (eg, dysmotility disorders such as irritable bowel syndrome, recurrent abdominal pain, nonulcer dyspepsia), though not necessarily ulcer disease. Acid hypersecretion occurs in some patients with ulcers, but overlap with normal subjects is present.14
Sequelae of H pylori Infection The sequelae of H pylori infection include chronic gastritis, PUD, mucosaassociated lymphoid tumors (MALT lymphoma), and gastric adenocarcinoma: this is H pylori disease. However, while some 50% of the world’s popula464
tion is infected with H pylori, the vast majority of individuals are asymptomatic, with chronic gastritis: this is H pylori infection.15-17 Why different manifestations occur is just beginning to be understood, and early evidence indicates roles for certain genotypic and phenotypic bacterial and host factors.18-21
Gastritis Acute infection with H pylori is often asymptomatic but may cause nausea, vomiting, and halitosis. An acute (neutrophilic) gastritis develops, with a brief period of acid hypersecretion, followed by a profound hypochlorhydria. Symptoms resolve within about a week. Over some 3 to 6 months, the gastritis severity lessens, and basal acid secretion returns to near pre-morbid levels.6,13 The great majority of infected individuals develop an asymptomatic chronic nonulcer pan-gastritis of no consequence.18 In the Western world, most commonly this is “antral predominant” and attended by a lifetime risk of duodenal ulcer disease of only 10%.13 In a small minority of
H pylori is but one risk factor, and then not always. For example, in two areas of China, both with a high prevalence of H pylori infection, one area has a low prevalence of gastric adenocarcinoma, and the other has a high prevalence.24 In addition, the presence of H pylori–associated duodenal ulcer disease appears to protect against gastric adenocarcinoma.25 Thus environmental and genetic factors in addition to H pylori appear to determine whether gastric carcinoma develops.18,25 Data do not support early (childhood) acquisition of H pylori infection as a cause.18 Fortunately, gastric adenocarcinoma is extremely rare before the age of 21 years.26
MALToma H pylori is also a co-factor in the development of the very slow growing gastric B-cell lymphoma arising from mucosa-associated lymphoid tissue. This lymphoma has been reported in only a handful of children and is usually cured by H pylori eradication.27
Other Conditions Many non-GI conditions have been ascribed to H pylori, such as cardiovascular disease, hypertension, Raynaud’s phenomenon, migraine, diabetes mellitus, psoriasis, chronic urticaria, connective tissue diseases, and other disorders. The evidence for such a link is not credible, weak at best, or absent.28
Helicobacter-Negative or Idiopathic Ulcer Disease H pylori–negative duodenal ulcer has features different from those of H py-
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THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 4 lori–associated ulcer disease.8-10 It is present in about 20% of children with duodenal ulcers who have not taken NSAIDs and have no serologic or histologic evidence of H pylori10; the figure may be higher, as has recently been shown in adults.8,9 Before making the diagnosis of “true” H pylori–negative ulcer disease, recent antibiotic use, NSAIDs, Crohn’s disease, and hypersecretory conditions must be ruled out as causes. An increasing proportion of H pylori–negative duodenal ulcers, at entry to various studies, has been observed, as well as a high recurrence rate after cure of the infection.29
DIAGNOSIS OF PEPTIC ULCER DISEASE: GENERAL APPROACHES As in adults, the differential diagnosis of ulcer disease includes the different causes of such, in addition to esophagitis, gastritis, or gastropathy (many causes), nonulcer dyspepsia, gallbladder or liver disease, pneumonia, pancreatitis, among others. In children, although abdominal pain is relatively common, pain that is truly localized to the epigastrium is relatively uncommon, and endoscopy with biopsies has a high yield in such cases.30 As in adults, definitive diagnosis of ulcer disease is made with upper GI endoscopy, which can confirm or exclude the presence of ulcers and effect hemostasis in cases of active bleeding.
DIAGNOSIS OF SUSPECTED H PYLORI INFECTION/DISEASE Association Between H pylori and Symptoms When H pylori–associated PUD is present, the presentation is similar to that of ulcer disease from any cause. There are no symptoms specific to H pylori infection.4,31 In addition, several lines of evidence indicate that, in the absence of
PUD, chronic H pylori gastritis (ie, infection) is very seldom a cause of abdominal pain in children.32,33 An analysis of 45 pediatric reports showed evidence of an association that was strong for H pylori gastritis and duodenal ulcer, weak for gastric ulcer, and weak or absent for recurrent abdominal pain.34
Whom to Test/Not to Test: How to Test Given the important distinction between H pylori infection and H pylori disease, it follows that the optimal care of the child depends on determination of the cause of the presenting symptoms, rather than the mere presence of H pylori infection. The prevalence of gastric infection with H pylori varies between countries and socioeconomic groups, but even where it is common, children are considerably less susceptible to peptic ulcers and other sequelae than adults. As a result, the risk-to-benefit ratios of diagnostic studies and treatments for H pylori are likely different in adult and pediatric populations. In order to optimize the care of children, guidelines have been developed by pediatric consensus groups in North America and Europe.15-17 Although abdominal pain and other GI symptoms or signs are common in children, the prevalence of pediatric H pylori infection in developed countries is low, and, in the absence of peptic ulceration, H pylori is only rarely a cause of such symptoms.32-34 Therefore H pylori should be considered as a potential cause of the child’s symptoms only after other more common causes have been explored; that is, testing for H pylori infection should not be part of the initial investigative strategy. Although certain diagnostic tests have greater up-front costs than others, the expense is often more apparent than real, because significant financial and social costs result from failure to reach an accurate diagnosis promptly. These include the costs of more tests and doctor visits, inappropriate treatment, and missed school or work. A more expensive test that is definitive
Fig 2. All ulcers are not the same. This endoscopic photograph shows a “classic” primary duodenal ulcer (arrow indicates white exudate in depressed ulcer base); a clot is present at the edge of the ulcer (X marks the clot).There is no active bleeding.The patient, a 12-year-old boy, presented with hematemesis and melena and required a 14-unit blood transfusion. Initially, the ulcer was missed because the boy was under-sedated for the procedure and struggling, and the duodenum was in spasm.When repeat endoscopy was perfomed at our institution, duodenal spasm was overcome by the administration of intravenous glucagon, allowing adequate visualization of the duodenal bulb. Endoscopic hemostasis was not required. Multiple biopsy specimens from the stomach revealed no evidence of gastritis, nor any Helicobacter pylori. Endoscopic appearance of ulcers cannot differentiate Helicobacter-negative ulcers from those not associated with Helicobacter; multiple biopsy specimens are required.The ulcer healed with acid-suppressing medication and no antibiotic treatment. NonHelicobacter-associated ulcers have assumed increasing importance. may result in overall cost savings.35 Given the large numbers of children with abdominal pain and the relatively few peptic ulcers occurring in children, the cost of diagnosing ulcer disease with non-definitive testing is likely higher than that for adults. Pediatric guidelines have been published by 3 multidisciplinary groups, convened independently by separate organizations.15-17 The groups included experts in pediatric and adult gastroenterology, infectious diseases, general pediatrics, epidemiology, family practice, and others; thus, the guidelines represent the collective views of some 90 individuals from both sides of the Atlantic. Despite this diversity, the guidelines are in almost total agreement with each other. 465
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The major specific recommendations for the diagnostic approach are summarized as follows. • The goal of diagnostic testing should be to determine the cause of presenting symptoms rather than the presence of H pylori infection. • A test-and-treat strategy is not advised for the optimal care of children. • Antibody tests with whole blood, serum, or saliva are not recommended. Antibody levels may remain elevated for years after eradication or resolution of infection. Therefore a positive test result does not necessarily mean that infection is present at the time of testing. Tests for antibodies are of low specificity and sensitivity, and the cutoff values for children are different from those for adults. Added to this is the low prevalence of H pylori–related diseases in children. Although antibody tests are useful for population studies, they are not useful in the care of individual patients. • Upper GI endoscopy with biopsies is the optimal test for the child with chronic upper abdominal symptoms or suspected PUD. The differential diagnosis of upper GI symptoms in a child is extensive. Endoscopy with biopsy specimens obtained from different zones of the upper GI tract allows for rapid and definitive diagnosis of upper GI mucosal diseases; prompt, accurate diagnosis allows for appropriate therapy, cessation of further testing, and a rapid return of the child to school and social activities. Endoscopy is the only acceptable diagnostic test in children with upper GI bleeding, recurrent vomiting, or persistent undiagnosed abdominal pain. • Children previously suspected of having a peptic ulcer, as determined by barium studies, should undergo endoscopy if their symptoms persist or recur. Endoscopy 466
THE JOURNAL OF PEDIATRICS APRIL 2001 with biopsies should be performed to confirm or rule out the presence of an ulcer and to determine whether H pylori is present. • The urea breath test is not an appropriate alternative to upper endoscopy for initial diagnosis of H pylori infection in children. The sensitivity and specificity of labeled UBTs, which are noninvasive, are close to those of endoscopic biopsies for the presence of H pylori infection. However, a positive breath test result does not confirm or exclude the presence of a disease causing symptoms. It only indicates the presence or absence of H pylori. Similarly, in the event of a negative result, this indirect testing cannot rule out alternative diagnoses. Results of the UBT are affected by current or recent use of antibiotics, bismuth salts, and acid-suppressing medications and by the presence of other non-urease-producing organisms, including flora resident in the oral cavity. Breath testing is expensive, but less so than endoscopy. Use of the UBT is usually more appropriate than repeat endoscopy to confirm successful eradication of H pylori. • Screening for H pylori infection in asymptomatic individuals is not warranted. Screening for H pylori infection is costly and has no established public health benefits in asymptomatic children. • Testing for H pylori is appropriate only when treatment is planned if the test result is positive.
TREATMENT General Treatment of specific types of peptic ulcers in children is similar to that in adults. Some have even proposed that, in view of an ancient symbiosis between humans and H pylori, perhaps not all H pylori strains are harmful, and not all should be eliminated.36 In any
case, to attempt elimination of H pylori from some 50% of the world’s population is unrealistic, and there are significant negative consequences from indiscriminate use of eradication therapy. Large-scale use of antibiotics would lead to antibiotic resistance of H pylori and other organisms, diminishing the usefulness of antibiotics for infections other than H pylori as well.37 In addition, in some patients, treatment of H pylori may unmask reflux disease, once the acid-suppressing effect of H pylori gastritis is removed.38,39 The treatment of most ulcer diseases involves use of an acid-suppressing drug, either a histamine-2-receptor antagonist or a proton pump inhibitor.40 Proton pump inhibitors are highly effective drugs, but there are some caveats about their use. In general, they should not be used as empiric therapy for symptomatic relief in children, in the absence of an established diagnosis. Being such effective acid suppressors, they may partially treat an underlying acid peptic disorder and thereby remove or significantly modify diagnostic signs such as would be found at endoscopy and biopsy; they may also mask the presence of H pylori.30,41 Once empirically given, when the time comes to stop the drug, and symptoms recur, the patient is left without a diagnosis or prognosis. Then a diagnosis may be difficult to reach by endoscopy and biopsy until the patient has not received any acid-suppressing medications for some weeks.
H pylori: Whom to Treat, How to Treat Treatment should be given only after accurate diagnosis of H pylori disease (ie, PUD proven to be associated with a current H pylori infection) or MALToma. Abdominal pain that is not due to PUD is not an indication for eradication therapy. However, when the result of any test for H pylori is positive, even if performed by a method or for an indication unadvised by the guidelines, treatment should be offered to
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THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 4 the child. The family should be informed that this may or may not help and that there may be adverse effects of the treatment. Although there is currently no evidence to support treating or not treating in this circumstance, the Canadian and North American consensus groups15,17 regarded this as a prudent approach. The rationale is that although a test-and-treat strategy is not advocated for children (ie, we are not on a “search and destroy” mission for H pylori in every child who presents to a physician), the field is evolving, and new knowledge may indicate a different strategy. The European group advocated treatment of H pylori gastritis diagnosed by means of endoscopy and biopsies but did not broach the issue of treating on the basis of other positive test results.16
How to Treat For non-H pylori ulcer disease proven by endoscopy and biopsy, acid suppression alone is indicated. For H pylori–associated PUD, an acid suppressing-agent is used together with antibiotics. Acid suppression helps heal the ulcer and afford pain relief rapidly. The currently recommended regimens generally include a proton pump inhibitor in combination with antibiotics. In children, dosing regimens, efficacy, long-term safety (up to 2 years or more), and pharmacokinetics have been established for omeprazole in the treatment of erosive esophagitis,40,42,43 but at this time, there is a relative paucity of data for other PPIs. Although the H pylori eradication regimens have not been well tested in children, one currently in favor includes omeprazole, 1 to 2 mg/kg/d, given in 2 divided doses, plus clarithromycin with either metronidazole or amoxycillin in age-appropriate therapeutic doses, for 2 weeks.44 Although 1-week therapy has been used, its efficacy in children requires further validation.17 Failure of treatment is most often due to poor compliance, but antibiotic resistance may also be a fac-
tor. High rates of metronidazole resistance are already present, and rates of amoxicillin and clarithromycin resistance are increasing.37
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FUTURE DIRECTIONS 8.
The recent description of the genome of H pylori allows recognition of many characteristics of the organism, such as its nutritional requirements and its variable surface antigenicity. This allows for logical selection of key targets for novel specific antimicrobial agents, which could avoid resistance, and for vaccine development.45 Elucidation of the genetics of different strains of H pylori may help explain their different effects; for example, different members of one family, with gastric cancer and duodenal ulcer disease, respectively, had H pylori strains with different DNA fingerprints.20 Host genetic factors that affect interleukin-1-β may determine why some individuals infected with H pylori develop hypochlorhydria and gastric cancer and others do not.21 Further investigation of this and other host and organism factors and successful vaccine development are likely to change our approaches to H pylori infection in the future.
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Koch’s postulates for pyloric campylobacter. Med J Aust 1985;142:436-9. Marshall BJ, Goodwin CS, Warren JR, Murray R, Blincow ED, Blackbourn SJ, et al. Prospective doubleblind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988;2:1437-42. Jyotheeswaran S, Shah AN, Jin HO, Potter GD, Ona FV, Chey WY. Prevalence of Helicobacter pylori in peptic ulcer patients in Greater Rochester, NY: is empirical triple therapy justified? Am J Gastroenterol 1998;93: 574-8. Peura DA. The problem of Helicobacter pylori-negative idiopathic ulcer disease. Baillieres Best Pract Res Clin Gastroenterol 2000;14:109-17. Hassall E, Hiruki T, Dimmick JE. True Helicobacter pylori-negative duodenal ulcer disease in children [abstract]. Gastroenterology 1993;104:A96. Levenstein S. Stress and peptic ulcer: life beyond Helicobacter. BMJ 1998;3: 538-41. Feldman EJ, Sabovich KA. Stress and peptic ulcer disease. Gastroenterology 1980;78:1087-9. Soll AH. Peptic ulcer and its complications. In: Feldman M, Sleisenger MH, Scharsmidt BF, editors. Sleisenger & Fordtran’s gastrointestinal and liver disease. 6th ed. Philadelphia: WB Saunders Co; 1998. p. 620-78. Euler AR, Byrne WJ, Campbell MF. Basal and pentagastrin-stimulated gastric acid secretory rates in normal children and in those with peptic ulcer disease. J Pediatr 1983;103:766-8. Sherman P, Hassall E, Hunt RH, Fallone CA, Veldhuyzen van Zanten S, Thomson ABR, et al. Canadian Helicobacter Study Group Consensus Conference on the approach to H. pylori infection in children and adolescents. Can J Gastroenterol 1999;13:553-9. Drumm B, Koletzko S, Oderda G, and the European Task Force on Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr 2000;31:207-14. Gold BD, Abbott M, Colletti R, Czinn SJ, Elitsur Y, Hassall E, et al. Evidence-based guidelines for an approach to the diagnosis and treatment of Helicobacter pylori infection in children: recommendations for diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2000;31:490-7. Graham DY. Helicobacter pylori infection in the pathogenesis of duodenal ulcer and gastric cancer: a model. Gastroenterology 1997;113:1983-91. 467
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19. Nedrud JG, Czinn SJ. Host, heredity and Helicobacter. Gut 1999;45:323-4. 20. Miehlke S, Genta RM, Graham DY, Go MF. Molecular relationships of Helicobacter pylori strains in a family with gastroduodenal disease. Am J Gastroenterol 1999;94:364-8. 21. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000;404: 398-402. 22. Rubin CE. Are there three types of Helicobacter pylori gastritis? Gastroenterology 1997;112:2108-10. 23. Ganga-Zandzou PS, Michaud L, Vincent P, Husson M-O, Witzler Derambure N, Delassalle EM, et al. Natural outcome of Helicobacter pylori infection in asymptomatic children. Pediatrics 1999;104:216-21. 24. Hu PJ, Li YY, Lin HL, Zhou SM, Du G, Chen MH, et al. Gastric atrophy and regional variation in upper gastrointestinal disease. Am J Gastroenterol 1995;90:1102-6. 25. Hansson LE, Nyren O, Hsing AW, Bergstrom R, Josefsson S, Chow WH, et al. The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med 1996; 335:242-9. 26. McGill TW, Downey EC, Westbrook J, Wade D, de la Garza J. Gastric carcinoma in children. J Pediatr Surg 1993;28:1620-1. 27. Blecker U, McKeithan TW, Hart J, Kirschner BS. Resolution of Helicobacter pylori-associated gastric lymphoproliferative disease in a child. Gastroenterology 1995;109:973-7. 28. Leontiadis GI, Sharma VK, Howden
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Peptic ulcer disease and current approaches to Helicobacter pylori Eric Hassall, MBChB, FRCP(C), FACG The most exciting recent development in the area of peptic ulcer disease has been the discovery that a bacterial infection, Helicobacter pylori, is a major factor in its pathogenesis. The fascinating story of this discovery is colorfully recounted elsewhere.1 Because of its importance, H pylori dominates any discussion of PUD, but there are many other causes. This article provides an overview of ulcer disease, focusing on areas of progress, especially those of importance in the care of children; because PUD in children differs in some respects from that in adults, there are important practical implications for pediatric practitioners. In this regard, recently published consensus guidelines are presented.
DEFINITIONS Gastritis and Gastropathy Peptic ulceration of the stomach or duodenum is often accompanied by abnormalities of the gastric mucosa, and the key to determining the cause of ulcer disease often lies in histologic diagnosis of the associated gastritis (inflammation present in biopsy specimens) or gastropathy (inflammation not
prominent).2 There are many gastropathies and gastritides that are not accompanied by peptic ulceration.2 In both gastritis and gastropathy, endoscopic findings may be normal or abnormal. The term gastritis is often misused. For example, not infrequently, clinicians will refer to a patient with epigastric pain or dyspepsia as having “gastritis,” whereas radiologists may diagnose “gastritis” on the basis of nonspecific changes on x-ray films. However, gastritis is neither a clinical nor a radiologic diagnosis; most often it is a purely histologic diagnosis, made by the use of multiple random or targeted endoscopic biopsies.
Erosions, Ulcers, and Other Terms An erosion is a mucosal break that does not penetrate the muscularis mucosae, whereas an ulcer is deeper, extending through the muscularis into the submucosa. Acid peptic diseases or acid-related disorders are mucosal disorders of the esophagus, stomach, or duodenum that primarily involve gastric acid (and pepsin) in their pathogenesis. We use the terms ulcer disease
From the Division of Gastroenterology, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada.
Submitted for publication July 29, 1999; revisions received Aug 10, 2000, Oct 18, 2000, and Nov 21, 2000; accepted Dec 4, 2000. Reprint requests: Eric Hassall, MBChB, FRCP(C), Division of Gastroenterology, British Columbia Children’s Hospital, 4480 Oak St, Room 1K2, Vancouver, British Columbia V6H 3V4, Canada.
J Pediatr 2001;138:462-8. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/19/113621 doi:10.1067/mpd.2001.113621
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and peptic ulcer synonymously to refer to erosions or ulcers of the stomach and duodenum. GI Gastrointestinal NSAIDs Nonsteroidal anti-inflammatory drugs PUD Peptic ulcer disease
PRIMARY AND SECONDARY ULCER DISEASE Conceptually, it is useful to categorize PUD by cause into primary and secondary types (Table).3 Secondary ulcers are usually related to underlying disease or drugs. Although the categorization is based on cause or mechanism, there are other general qualities consistent with this approach. For example, primary peptic ulcers are usually chronic, with fibrinopurulent debris overlying active inflammatory infiltrate, granulation tissue, and fibrosis.3 In contrast, secondary peptic ulcers are usually more acute in onset, without signs of chronicity, with the exception of the hypergastrinemic disorders. Primary peptic ulcers are more often duodenal, whereas secondary ulcers are more often gastric than duodenal; again, hypergastrinemic disorders are excepted. Most primary peptic ulcers in children occur between the ages of 8 and 17 years (mean age, 11.5 years),4,5 whereas secondary ulcers occur at all ages.
Clinical Presentation In the pediatric age group, abdominal pain is a very common reason for seeking medical advice, and it is also the most common presenting symptom
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THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 4 of PUD. However, peptic and other erosive/ulcerative gastritides and gastropathies of the stomach and duodenum are relatively uncommon, accounting for perhaps 15% to 20% of abdominal pain in children in a subspecialty practice, and less in a general pediatric practice. Other upper gastrointestinal disorders such as erosive gastroduodenal disease caused by Crohn’s disease, nonsteroidal anti-inflammatory drugs , allergic gastritis, and other entities in the Table may present with similar symptoms, as may the many causes of esophagitis. In children aged 10 to 12 years and older, symptoms may be similar to those in adults. Although epigastric pain or discomfort that is meal-related or -exacerbated or that wakes the child from sleep is often a symptom of PUD (or of other gastric mucosal disorders), it is sometimes a presenting symptom of more common disorders such as non-ulcer dyspepsia, or so-called recurrent abdominal pain, or constipation. Younger children may not be able to localize pain to the epigastrium and may present with discomfort or bloating, especially with meals. Other symptoms include anorexia, nausea, early satiety, recurrent vomiting, and anemia. Weight loss occurs less often. GI bleeding may occur with antecedent epigastric pain or other symptoms, but painless bleeding may be the only manifestation of ulcer disease; up to 25% of children with primary duodenal ulcers have this “silent” presentation, whereas some 25% present with bleeding and antecedent pain, and the rest present with abdominal pain or recurrent vomiting.4,5 Epigastric tenderness is an unreliable physical sign of gastritis or ulcer disease.
PRIMARY PEPTIC ULCER DISEASE Although there is a paucity of prevalence figures for children, it is well accepted that primary PUD is much less
Table. Causes of peptic ulcers in children Primary peptic ulcers H pylori–associated H pylori–negative/idiopathic Secondary peptic ulcers Physiologic stress (decreased gastric blood flow) Burns, sepsis, shock, hypoxemia, head injury, uremia, exercise-induced Traumatic gastropathy Forceful retching, nasogastric tubes, foreign bodies Drugs NSAIDS, alcohol, valproic acid, chemotherapy, potassium chloride Immune-mediated Celiac gastritis, allergic gastritis, eosinophilic gastritis, graft-versus-host disease Infections Cytomegalovirus, herpes simplex, anisakiasis, influenza A, Candida albicans, syphilis, histoplasmosis, mucormycosis, phlegmonous gastritis, emphysematous gastritis Corrosive gastropathy Iron overdose, acid indigestion Autoimmune Diabetes mellitus, connective tissue disease Granulomatous gastritides Crohn’s disease, foreign body reaction, idiopathic, histiocytosis X, tuberculosis Hypersecretory states Zollinger-Ellison syndrome, G-cell hyperplasia/hyperfunction, systemic mastocytosis, cystic fibrosis, short bowel syndrome, hyperparathyroidism Vascular insufficiency Sickle cell disease, Henoch-Schönlein disease Hepatic cirrhosis Radiation gastropathy
common in children than in adults. For example, in our unit in a tertiary care children’s hospital with a referral population of some 4 million, we diagnose only about 4 to 6 new primary ulcers per year. Of these, duodenal ulcers are much more prevalent than gastric ulcers; in our experience over some 15 years, with all ulcers diagnosed endoscopically, duodenal ulcers were some 30 times more prevalent than gastric ulcers (when NSAID-related ulcers are excluded). Most primary peptic ulcers are H pylori–related, though a significant and increasing proportion are H pylori–negative or “idiopathic” (Table).
Etiology Ulcer disease was long assumed to be idiopathic, caused by acid hyper-
secretion, and/or psychologic stress. The Helicobacter relationship gained acceptance only after Marshall produced acute gastritis in himself by ingesting the organism6 and later showed that H pylori–related ulcers could be cured by antimicrobial agents and remain in remission, unlike those treated with acid suppression alone.7 A subsequent deluge of research has proved and extended his findings. In the process, opinion swung to the belief that virtually all primary ulcer disease was H pylori–related. However, more recently, there has been increasing recognition of the entity of non Helicobacter-associated (idiopathic) primary PUD, with reports that up to 39% of ulcers (most duodenal) may be in this category.8-10 There are conflicting results as to whether psychologic stress plays a signif463
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THE JOURNAL OF PEDIATRICS APRIL 2001 adults, particularly in developing countries, multifocal atrophic gastritis with intestinal metaplasia develops22; the latter is a risk factor for gastric ulcer and gastric adenocarcinoma when it is extensive. No significant increase in inflammation nor development of atrophy or metaplasia was found in a pediatric study of H pylori gastritis.23
Gastric Carcinoma
Fig 1. Anatomic regions of the stomach. From, Rudolph AM, Hoffman JIE, Rudolph CD editors. Rudolph’s pediatrics. 20th ed. Stamford (CT): Appleton & Lange; Copyright 1996. Reprinted with permission of The McGraw-Hill Companies.
icant role in causing ulcer disease,11-13 reflecting the difficulties in defining and quantitating stress and studying its interactions with different personalities. In addition, PUD has long been regarded as a heterogeneous disorder,12 and data from the “pre-H pylori era” almost certainly involved a mixed bag of Helicobacter-positive and -negative subjects. Although there are no controlled data on psychologic stress and ulcer disease in children, it is recognized that stress plays a role in causing symptoms (eg, dysmotility disorders such as irritable bowel syndrome, recurrent abdominal pain, nonulcer dyspepsia), though not necessarily ulcer disease. Acid hypersecretion occurs in some patients with ulcers, but overlap with normal subjects is present.14
Sequelae of H pylori Infection The sequelae of H pylori infection include chronic gastritis, PUD, mucosaassociated lymphoid tumors (MALT lymphoma), and gastric adenocarcinoma: this is H pylori disease. However, while some 50% of the world’s popula464
tion is infected with H pylori, the vast majority of individuals are asymptomatic, with chronic gastritis: this is H pylori infection.15-17 Why different manifestations occur is just beginning to be understood, and early evidence indicates roles for certain genotypic and phenotypic bacterial and host factors.18-21
Gastritis Acute infection with H pylori is often asymptomatic but may cause nausea, vomiting, and halitosis. An acute (neutrophilic) gastritis develops, with a brief period of acid hypersecretion, followed by a profound hypochlorhydria. Symptoms resolve within about a week. Over some 3 to 6 months, the gastritis severity lessens, and basal acid secretion returns to near pre-morbid levels.6,13 The great majority of infected individuals develop an asymptomatic chronic nonulcer pan-gastritis of no consequence.18 In the Western world, most commonly this is “antral predominant” and attended by a lifetime risk of duodenal ulcer disease of only 10%.13 In a small minority of
H pylori is but one risk factor, and then not always. For example, in two areas of China, both with a high prevalence of H pylori infection, one area has a low prevalence of gastric adenocarcinoma, and the other has a high prevalence.24 In addition, the presence of H pylori–associated duodenal ulcer disease appears to protect against gastric adenocarcinoma.25 Thus environmental and genetic factors in addition to H pylori appear to determine whether gastric carcinoma develops.18,25 Data do not support early (childhood) acquisition of H pylori infection as a cause.18 Fortunately, gastric adenocarcinoma is extremely rare before the age of 21 years.26
MALToma H pylori is also a co-factor in the development of the very slow growing gastric B-cell lymphoma arising from mucosa-associated lymphoid tissue. This lymphoma has been reported in only a handful of children and is usually cured by H pylori eradication.27
Other Conditions Many non-GI conditions have been ascribed to H pylori, such as cardiovascular disease, hypertension, Raynaud’s phenomenon, migraine, diabetes mellitus, psoriasis, chronic urticaria, connective tissue diseases, and other disorders. The evidence for such a link is not credible, weak at best, or absent.28
Helicobacter-Negative or Idiopathic Ulcer Disease H pylori–negative duodenal ulcer has features different from those of H py-
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THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 4 lori–associated ulcer disease.8-10 It is present in about 20% of children with duodenal ulcers who have not taken NSAIDs and have no serologic or histologic evidence of H pylori10; the figure may be higher, as has recently been shown in adults.8,9 Before making the diagnosis of “true” H pylori–negative ulcer disease, recent antibiotic use, NSAIDs, Crohn’s disease, and hypersecretory conditions must be ruled out as causes. An increasing proportion of H pylori–negative duodenal ulcers, at entry to various studies, has been observed, as well as a high recurrence rate after cure of the infection.29
DIAGNOSIS OF PEPTIC ULCER DISEASE: GENERAL APPROACHES As in adults, the differential diagnosis of ulcer disease includes the different causes of such, in addition to esophagitis, gastritis, or gastropathy (many causes), nonulcer dyspepsia, gallbladder or liver disease, pneumonia, pancreatitis, among others. In children, although abdominal pain is relatively common, pain that is truly localized to the epigastrium is relatively uncommon, and endoscopy with biopsies has a high yield in such cases.30 As in adults, definitive diagnosis of ulcer disease is made with upper GI endoscopy, which can confirm or exclude the presence of ulcers and effect hemostasis in cases of active bleeding.
DIAGNOSIS OF SUSPECTED H PYLORI INFECTION/DISEASE Association Between H pylori and Symptoms When H pylori–associated PUD is present, the presentation is similar to that of ulcer disease from any cause. There are no symptoms specific to H pylori infection.4,31 In addition, several lines of evidence indicate that, in the absence of
PUD, chronic H pylori gastritis (ie, infection) is very seldom a cause of abdominal pain in children.32,33 An analysis of 45 pediatric reports showed evidence of an association that was strong for H pylori gastritis and duodenal ulcer, weak for gastric ulcer, and weak or absent for recurrent abdominal pain.34
Whom to Test/Not to Test: How to Test Given the important distinction between H pylori infection and H pylori disease, it follows that the optimal care of the child depends on determination of the cause of the presenting symptoms, rather than the mere presence of H pylori infection. The prevalence of gastric infection with H pylori varies between countries and socioeconomic groups, but even where it is common, children are considerably less susceptible to peptic ulcers and other sequelae than adults. As a result, the risk-to-benefit ratios of diagnostic studies and treatments for H pylori are likely different in adult and pediatric populations. In order to optimize the care of children, guidelines have been developed by pediatric consensus groups in North America and Europe.15-17 Although abdominal pain and other GI symptoms or signs are common in children, the prevalence of pediatric H pylori infection in developed countries is low, and, in the absence of peptic ulceration, H pylori is only rarely a cause of such symptoms.32-34 Therefore H pylori should be considered as a potential cause of the child’s symptoms only after other more common causes have been explored; that is, testing for H pylori infection should not be part of the initial investigative strategy. Although certain diagnostic tests have greater up-front costs than others, the expense is often more apparent than real, because significant financial and social costs result from failure to reach an accurate diagnosis promptly. These include the costs of more tests and doctor visits, inappropriate treatment, and missed school or work. A more expensive test that is definitive
Fig 2. All ulcers are not the same. This endoscopic photograph shows a “classic” primary duodenal ulcer (arrow indicates white exudate in depressed ulcer base); a clot is present at the edge of the ulcer (X marks the clot).There is no active bleeding.The patient, a 12-year-old boy, presented with hematemesis and melena and required a 14-unit blood transfusion. Initially, the ulcer was missed because the boy was under-sedated for the procedure and struggling, and the duodenum was in spasm.When repeat endoscopy was perfomed at our institution, duodenal spasm was overcome by the administration of intravenous glucagon, allowing adequate visualization of the duodenal bulb. Endoscopic hemostasis was not required. Multiple biopsy specimens from the stomach revealed no evidence of gastritis, nor any Helicobacter pylori. Endoscopic appearance of ulcers cannot differentiate Helicobacter-negative ulcers from those not associated with Helicobacter; multiple biopsy specimens are required.The ulcer healed with acid-suppressing medication and no antibiotic treatment. NonHelicobacter-associated ulcers have assumed increasing importance. may result in overall cost savings.35 Given the large numbers of children with abdominal pain and the relatively few peptic ulcers occurring in children, the cost of diagnosing ulcer disease with non-definitive testing is likely higher than that for adults. Pediatric guidelines have been published by 3 multidisciplinary groups, convened independently by separate organizations.15-17 The groups included experts in pediatric and adult gastroenterology, infectious diseases, general pediatrics, epidemiology, family practice, and others; thus, the guidelines represent the collective views of some 90 individuals from both sides of the Atlantic. Despite this diversity, the guidelines are in almost total agreement with each other. 465
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The major specific recommendations for the diagnostic approach are summarized as follows. • The goal of diagnostic testing should be to determine the cause of presenting symptoms rather than the presence of H pylori infection. • A test-and-treat strategy is not advised for the optimal care of children. • Antibody tests with whole blood, serum, or saliva are not recommended. Antibody levels may remain elevated for years after eradication or resolution of infection. Therefore a positive test result does not necessarily mean that infection is present at the time of testing. Tests for antibodies are of low specificity and sensitivity, and the cutoff values for children are different from those for adults. Added to this is the low prevalence of H pylori–related diseases in children. Although antibody tests are useful for population studies, they are not useful in the care of individual patients. • Upper GI endoscopy with biopsies is the optimal test for the child with chronic upper abdominal symptoms or suspected PUD. The differential diagnosis of upper GI symptoms in a child is extensive. Endoscopy with biopsy specimens obtained from different zones of the upper GI tract allows for rapid and definitive diagnosis of upper GI mucosal diseases; prompt, accurate diagnosis allows for appropriate therapy, cessation of further testing, and a rapid return of the child to school and social activities. Endoscopy is the only acceptable diagnostic test in children with upper GI bleeding, recurrent vomiting, or persistent undiagnosed abdominal pain. • Children previously suspected of having a peptic ulcer, as determined by barium studies, should undergo endoscopy if their symptoms persist or recur. Endoscopy 466
THE JOURNAL OF PEDIATRICS APRIL 2001 with biopsies should be performed to confirm or rule out the presence of an ulcer and to determine whether H pylori is present. • The urea breath test is not an appropriate alternative to upper endoscopy for initial diagnosis of H pylori infection in children. The sensitivity and specificity of labeled UBTs, which are noninvasive, are close to those of endoscopic biopsies for the presence of H pylori infection. However, a positive breath test result does not confirm or exclude the presence of a disease causing symptoms. It only indicates the presence or absence of H pylori. Similarly, in the event of a negative result, this indirect testing cannot rule out alternative diagnoses. Results of the UBT are affected by current or recent use of antibiotics, bismuth salts, and acid-suppressing medications and by the presence of other non-urease-producing organisms, including flora resident in the oral cavity. Breath testing is expensive, but less so than endoscopy. Use of the UBT is usually more appropriate than repeat endoscopy to confirm successful eradication of H pylori. • Screening for H pylori infection in asymptomatic individuals is not warranted. Screening for H pylori infection is costly and has no established public health benefits in asymptomatic children. • Testing for H pylori is appropriate only when treatment is planned if the test result is positive.
TREATMENT General Treatment of specific types of peptic ulcers in children is similar to that in adults. Some have even proposed that, in view of an ancient symbiosis between humans and H pylori, perhaps not all H pylori strains are harmful, and not all should be eliminated.36 In any
case, to attempt elimination of H pylori from some 50% of the world’s population is unrealistic, and there are significant negative consequences from indiscriminate use of eradication therapy. Large-scale use of antibiotics would lead to antibiotic resistance of H pylori and other organisms, diminishing the usefulness of antibiotics for infections other than H pylori as well.37 In addition, in some patients, treatment of H pylori may unmask reflux disease, once the acid-suppressing effect of H pylori gastritis is removed.38,39 The treatment of most ulcer diseases involves use of an acid-suppressing drug, either a histamine-2-receptor antagonist or a proton pump inhibitor.40 Proton pump inhibitors are highly effective drugs, but there are some caveats about their use. In general, they should not be used as empiric therapy for symptomatic relief in children, in the absence of an established diagnosis. Being such effective acid suppressors, they may partially treat an underlying acid peptic disorder and thereby remove or significantly modify diagnostic signs such as would be found at endoscopy and biopsy; they may also mask the presence of H pylori.30,41 Once empirically given, when the time comes to stop the drug, and symptoms recur, the patient is left without a diagnosis or prognosis. Then a diagnosis may be difficult to reach by endoscopy and biopsy until the patient has not received any acid-suppressing medications for some weeks.
H pylori: Whom to Treat, How to Treat Treatment should be given only after accurate diagnosis of H pylori disease (ie, PUD proven to be associated with a current H pylori infection) or MALToma. Abdominal pain that is not due to PUD is not an indication for eradication therapy. However, when the result of any test for H pylori is positive, even if performed by a method or for an indication unadvised by the guidelines, treatment should be offered to
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THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 4 the child. The family should be informed that this may or may not help and that there may be adverse effects of the treatment. Although there is currently no evidence to support treating or not treating in this circumstance, the Canadian and North American consensus groups15,17 regarded this as a prudent approach. The rationale is that although a test-and-treat strategy is not advocated for children (ie, we are not on a “search and destroy” mission for H pylori in every child who presents to a physician), the field is evolving, and new knowledge may indicate a different strategy. The European group advocated treatment of H pylori gastritis diagnosed by means of endoscopy and biopsies but did not broach the issue of treating on the basis of other positive test results.16
How to Treat For non-H pylori ulcer disease proven by endoscopy and biopsy, acid suppression alone is indicated. For H pylori–associated PUD, an acid suppressing-agent is used together with antibiotics. Acid suppression helps heal the ulcer and afford pain relief rapidly. The currently recommended regimens generally include a proton pump inhibitor in combination with antibiotics. In children, dosing regimens, efficacy, long-term safety (up to 2 years or more), and pharmacokinetics have been established for omeprazole in the treatment of erosive esophagitis,40,42,43 but at this time, there is a relative paucity of data for other PPIs. Although the H pylori eradication regimens have not been well tested in children, one currently in favor includes omeprazole, 1 to 2 mg/kg/d, given in 2 divided doses, plus clarithromycin with either metronidazole or amoxycillin in age-appropriate therapeutic doses, for 2 weeks.44 Although 1-week therapy has been used, its efficacy in children requires further validation.17 Failure of treatment is most often due to poor compliance, but antibiotic resistance may also be a fac-
tor. High rates of metronidazole resistance are already present, and rates of amoxicillin and clarithromycin resistance are increasing.37
7.
FUTURE DIRECTIONS 8.
The recent description of the genome of H pylori allows recognition of many characteristics of the organism, such as its nutritional requirements and its variable surface antigenicity. This allows for logical selection of key targets for novel specific antimicrobial agents, which could avoid resistance, and for vaccine development.45 Elucidation of the genetics of different strains of H pylori may help explain their different effects; for example, different members of one family, with gastric cancer and duodenal ulcer disease, respectively, had H pylori strains with different DNA fingerprints.20 Host genetic factors that affect interleukin-1-β may determine why some individuals infected with H pylori develop hypochlorhydria and gastric cancer and others do not.21 Further investigation of this and other host and organism factors and successful vaccine development are likely to change our approaches to H pylori infection in the future.
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