Clinical Review ABC of the upper gastrointestinal tract

Management of Helicobacter pylori infection

BMJ 2001; 323 doi: http://dx.doi.org/10.1136/bmj.323.7320.1047 (Published 03 November 2001) Cite this as: BMJ 2001;323:1047
  1. Adam Harris,
  2. J J Misiewicz

    This article discusses the current management of Helicobacter pylori infection in patients with dyspepsia with or without endoscopic abnormalities. We take an evidence based approach when possible and consider recent guidelines from national and international bodies pertaining to primary and secondary care.

    Figure1

    Microanatomy of gastric mucosa indicating the pH gradient

    Duodenal ulcer disease

    In patients who are not taking non-steroidal anti-inflammatory drugs (NSAIDs) duodenal ulcer will be due to H pylori infection in 95% of cases, and eradication treatment can be prescribed without testing for H pylori. If there is any doubt about the diagnosis, such as a possible ulcer crater on a barium meal, endoscopic confirmation of duodenal ulcer and H pylori infection should be sought before prescribing treatment.

    Figure2

    Management plan for uncomplicated duodenal ulcer in patients not taking NSAIDs

    H pylori eradication treatment, if successful, will be effective in curing the ulcer diathesis regardless of whether a patient is seen at the initial presentation of the disease or at a recurrence. Patients taking long term (maintenance) treatment with H2 receptor antagonists or proton pump inhibitors should also be offered H pylori eradication treatment regardless of whether they are free of symptoms or still experiencing indigestion. In most cases eradication of H pylori cures the duodenal ulcer disease, and maintenance treatment can be stopped.

    After eradication treatment

    Uncomplicated duodenal ulcers heal quickly and completely after eradication of H pylori. Further antisecretory treatment, repeat endoscopy, or formal assessment of eradication is not necessary, and one can await the clinical outcome.

    Recurrent symptoms indicate either eradication failure or the presence of some other disease. Subsequent management will not be clear unless the outcome of eradication treatment is known, and this is best assessed by a 13C-urea breath test performed more than four weeks after the antimicrobial treatment. Recurrent symptoms after documented H pylori eradication are often due to gastro-oesophageal reflux disease, the symptoms of which may be misattributed to duodenal ulcer.

    Complicated duodenal ulcer

    Complicated duodenal ulcers (such as bleeding or perforated) are associated with appreciable morbidity and mortality, especially in elderly people. Therefore, in patients with complicated duodenal ulcers, eradication of H pylori and complete epithelialisation of the ulcer crater need to be confirmed by the 13C-urea breath test and endoscopy, after which maintenance antisecretory treatment can be stopped. The prevalence of H pylori infection in patients with complicated duodenal ulcer may be lower than in those with simple duodenal ulcer, and H pylori status should therefore be assessed before prescribing eradication treatment.

    Causes of duodenal ulcer

    Common causes
    • H pylori infection

    • Non-steroidal anti-inflammatory drugs

    Rare causes
    • Zollinger-Ellison syndrome

    • Hypercalcaemia

    • Granulomatous diseases (Crohn's disease, sarcoidosis)

    • Neoplasia (carcinoma, lymphoma, leiomyoma, leiomyosarcoma)

    • Infections (tuberculosis, syphilis, herpes simplex, cytomegalovirus)

    • Ectopic pancreatic tissue

    Duodenal ulcers recur in about 5% of patients initially infected with H pylori even after eradication and in the absence of reinfection or use of NSAIDs. Duodenal ulcers are also found occasionally in people not infected with H pylori. After exclusion of surreptitious use of ulcerogenic drugs and the rarer causes of duodenal ulcer, such patients need long term maintenance treatment with antisecretory drugs.

    Gastric ulcer

    Diagnosis

    The main difference in the management of gastric ulcers from that of duodenal ulcers is the need to exclude malignancy in an apparently benign gastric ulcer. Endoscopy is mandatory, with targeted biopsies of the ulcer rim and base. About eight weeks after treatment is started, endoscopy should be repeated to confirm healing, obtain further biopsies from the original ulcer site, and if clinically indicated ascertain H pylori infection status.

    Figure3

    Management plan for gastric ulcer

    Treatment

    As with duodenal ulcer, eradication of H pylori leads to healing of gastric ulcer and markedly decreases the incidence of relapse. Eradication of H pylori also seems to reduce the complications associated with gastric ulcer, but the supporting evidence is less strong than for duodenal ulcer. Maintenance treatment with antisecretory drugs should therefore be started after successful eradication of H pylori in those patients with gastric ulcer who have a history of haemorrhage or perforation until complete healing of the ulcer is confirmed at endoscopy.

    Ulcers associated with H pylori and NSAIDs

    Most gastric ulcers associated with H pylori infection or with use of NSAIDs occur in elderly women. Despite several studies, no clearly defined guidelines have emerged. NSAIDs and H pylori seem to be independent risk factors for increased risk of gastrointestinal bleeding. If a patient infected with H pylori has ulceration then H pylori should be eradicated before treatment with NSAIDs is started. There is no evidence that H pylori eradication relieves NSAID induced dyspepsia.

    Causes of gastric ulcer

    • H pylori infection

    • Non-steroidal anti-inflammatory drugs

    • Neoplasia (carcinoma, lymphoma, leiomyosarcoma)

    • Stress

    • Crohn's disease

    • Infections (herpes simplex, cytomegalovirus)

    Gastro-oesophageal reflux disease

    The interaction between H pylori, gastro-oesophageal reflux disease (GORD), and treatment with antisecretory drugs is extremely complex and highly contentious. Epidemiological studies have shown that the prevalence of H pylori infection is no higher in patients with GORD than in healthy controls matched for age and sex. Indeed, H pylori infection may be less common in patients with GORD, particularly those with more severe (erosive) disease, suggesting that the bacterium may have a protective role, perhaps by producing corpus gastritis and thus decreasing the output of acid. Moreover, proton pump inhibitors used to treat GORD seem to be more effective at suppressing acid and healing oesophagitis in the presence of H pylori. After eradication of the bacterium, patients with GORD may require higher doses and longer duration of proton pump inhibitor treatment.



    Embedded Image

    Benign gastric ulcer (arrow) in upper part of stomach

    Figure4

    Interactions between H pylori, GORD, and antisecretory drugs

    However, patients with GORD and H pylori infection who need prolonged treatment with standard doses of proton pump inhibitors may be at increased risk of developing atrophic gastritis. It is well recognised that chronic atrophic pangastritis is associated with increased risk of proximal gastric adenocarcinoma. During profound acid suppression with proton pump inhibitors, H pylori infection spreads from the antrum to the gastric body and fundus and causes a chronic active pangastritis that, with time, may progress to atrophic gastritis. The actual lifetime risk of subsequent gastric cancer is unknown and needs to be evaluated against the potentially detrimental effects of eradicating H pylori infection in patients with GORD. Further studies are needed before these contradictory considerations can be resolved.

    Functional dyspepsia

    In the absence of NSAID treatment, about 60% of young patients (<45 years old) with dyspepsia have functional dyspepsia, about 25% have GORD, and 15% have peptic ulcer disease. Although the evidence unequivocally supports H pylori eradication in peptic ulcer disease, the role of H pylori in functional dyspepsia and the evidence to support its treatment are much less clear.

    Figure5

    Possible reasons for failure of H pylori eradication

    Asymptomatic H pylori infection

    This presentation is becoming more common because of the increasing use of commercial, non-invasive tests for H pylori. A positive test often causes concern about the risk of developing stomach cancer; but we don't know when H pylori has to be eradicated to prevent the progression to cancer, and there is no evidence yet that eradication of H pylori decreases this risk.

    H pylori eradication treatment

    The aim of treating H pylori is to eradicate the organism from the stomach. Eradication is defined as negative tests for the bacterium four weeks or longer after treatment has finished. Premature assessments may give false negative results because of temporary clearance or suppression of H pylori. The best test to confirm eradication is the 13C-urea breath test. The recently described stool antigen test may be an alternative in future. “Near patient tests” or laboratory based blood serology tests are not suitable because antibody titres take at least six months to decrease.

    Risk factors for nitroimidazole resistance in H pylori

    • Previous use of nitroimidazoles, such as for gynaecological infections, infective diarrhoeas

    • Failed eradication of H pylori with treatment regimen containing a nitroimidazole

    • Urban or inner city areas

    • Patients born in developing countries

    Low dose triple therapy for H pylori eradication

    View this table:

    Treatment of H pylori is difficult because of the rapid development of resistance to antibacterial drugs, especially to nitroimidazoles, which occurs more commonly in women and patients from developing countries because of previous treatment for gynaecological infections or infective diarrhoeas. Resistance to clarithromycin may occur after failed treatment or after use of this drug for other indications such as respiratory tract infections. Resistance to antibiotics other than nitroimidazoles can also develop but is less common

    Low dose triple therapy—The most overall effective H pylori eradication regimens reported to date combine a proton pump inhibitor with two of the following—amoxicillin, clarithromycin, or a nitroimidazole—for a week. There are few side effects (the commonest being nausea, diarrhoea, and taste disturbance). Results from large randomised controlled trials have shown H pylori eradication in about 90% of patients.

    Ranitidine-bismuth-citrate has been developed specifically for treating H pylori infection. It retains both the antisecretory and antibacterial properties of the parent compounds but achieves acceptable eradication rates only when used as an alternative to a proton pump inhibitor in combination with clarithromycin and either metronidazole or amoxicillin for a week.

    Quadruple therapy—Classic bismuth based triple therapy is more effective when coprescribed with a proton pump inhibitor (80-90% H pylori eradication). Efficacy is highly dependent on compliance with the complicated regimen, and there are numerous side effects. It is best reserved for use by hospital specialists to treat patients in whom triple therapy has failed.

    Quadruple therapy for H pylori eradication

    View this table:

    What to tell patients?

    There has been much discussion of H pylori in the media, and many patients are aware of its ulcerogenic and carcinogenic potential and may request antibacterial treatment if they are found to be infected. Eradication treatment is of proved benefit only in patients with duodenal or gastric ulcer associated with H pylori infection. At present there is no evidence to suggest that screening and treating patients without risk factors will prevent gastric cancer. The risk of transmission to partners is low in adults, and treatment of the entire family is not warranted.

    Indications for H pylori eradication treatment

    View this table:

    Counselling patients

    Whatever treatment is chosen, patients need careful counselling. The reasons for embarking on the treatment and the importance of compliance despite possible side effects need to be emphasised, and the possible side effects must be carefully discussed. The need for good compliance needs special attention, as it is crucial to the success of treatment.

    Figure6

    Choosing a treatment regimen for H pylori eradication

    First line treatment—In areas with a low prevalence (<30%) of metronidazole resistant strains of H pylori one week of low dose triple therapy consisting of a proton pump inhibitor, metronidazole, and clarithromycin is currently recommended. Patients' compliance with treatment is likely to be good because of twice daily dosing and few side effects. If metronidazole resistance is likely a proton pump inhibitor in combination with amoxicillin and clarithromycin given for one week is preferable.

    Second line treatment—After a proved failure with a treatment containing metronidazole, a patient is likely to be colonised by a resistant strain of H pylori. In this case a proton pump inhibitor should be given in combination with amoxicillin and clarithromycin for a week, with about 90% success. If H pylori eradication is unsuccessful after a treatment containing clarithromycin and the patient is likely to harbour a metronidazole resistant strain of H pylori, then either omeprazole in combination with amoxicillin and metronidazole or quadruple therapy are the only logical options, with roughly 75% success.

    Summary

    Despite a vast amount of research, the only evidence based indications for eradication of H pylori are for patients with duodenal ulcer or gastric ulcer who are not taking NSAIDs and for patients with the extremely rare MALT lymphoma. Low dose triple therapy given for one week will cure most patients of their infection: failures are due to bacterial resistance or poor compliance. The importance of H pylori in NSAID associated ulceration is uncertain. Although H pylori is strongly associated with gastric cancer, there is no proof that eradication treatment decreases an individual's risk of that disease.

    Acknowledgments

    The endoscopic image of benign gastric ulcer is reproduced with permission of Gastrolab Image Gallery.

    Footnotes

    • Adam Harris is consultant physician and gastroenterologist at Kent and Sussex Hospital, Tunbridge Wells. J J Misiewicz is honorary consultant physician and honorary joint director of the department of gastroenterology and nutrition, Central Middlesex Hospital, London,

      The ABC of upper gastrointestinal tract is edited by Robert Logan, senior lecturer in the division of gastroenterology, University Hospital, Nottingham, Adam Harris, J J Misiewicz, and J H Baron, honorary professorial lecturer at Mount Sinai School of Medicine, New York, USA, and former consultant gastroenterologist, St Mary's Hospital, London.