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Focus on H. pylori

Helicobacter pylori is a bug in the news! It has been implicated as one causative agent in gastric and duodenal ulcer formation, and as one factor involved in gastric cancer. New diagnostic tests for H. pylori antibodies are becoming available, and drug therapies for eradication are being extensively tested.

Bandolier does not have the resources to cover all these issues in depth, but the focus on H. pylori this month will give the reader a strong feel of what is coming.

H. pylori and ulcers

In 1975 it was estimated at about 4,000,000 Americans had gastric or duodenal ulcers with a total estimated cost of $3.2 billion per year. While gastric ulcer, duodenal ulcer and gastrointestinal inflammation are clearly separate disease entities, they share a common pathophysiology - an imbalance between mucosal aggressive and defensive factors.

In the late '70s a pathologist (J R Warren) from the Royal Perth Hospital in Western Australia described finding spiral bacilli in biopsy specimens from inflamed gastric mucosa. In 1982 the organism was isolated by Barry Marshall, also at Perth. Marshall elegantly fulfilled Koch's postulates for the role of H. pylori in antral gastritis with self administration of H. pylori. The last decade has seen a considerable effort, not without controversy, which has brought H. pylori to the forefront as a major causative agent in gastric and duodenal ulceration.

How does H. pylori cause ulcers?

A speculative sequence of events which describes the way in which H. pylori has these effects is as follows. The bacterium, introduced into a normal stomach, has the ability to survive the acid pH because of an intense urease activity. Its motility allows it to penetrate the thick protective layer of gastric mucus and attach to the gastric epithelium. The release of cytotoxins and the weakening of the gastric mucus layer all contribute to tissue damage and inflammation. Interference with the normal negative feedback that acid exerts on the gastrin-secreting cells can lead to hypergastrinaemia, increased acid secretion, and gastric metaplasia. Hyperacidity and H. pylori then work synergistically to produce an ulcer.

There is currently no direct proof that H. pylori infection actually causes duodenal ulcer. The compelling indirect evidence includes almost 100% infection rates of H. pylori in duodenal ulcers and much reduced long term recurrence rates when the organism is eradicated.

Serological tests for H. pylori infection (circulating IgG and IgA antibodies measured by immunological methods) show that H. pylori infection is low in children, but rises dramatically in fifth and subsequent decades, and that more than half of the population over 50 years is infected.

Eradication of H. pylori is curative

Eradication of H. pylori has been suggested by using a number of therapeutic regimens, many of which appear to be successful. One randomised controlled trial, reported from Baylor College of Medicine, used the so-called "triple-therapy" regimen of tetracycline (2 g), metronidazole (750 mg) and bismuth (about 2 g) daily. The treatment is continued for two weeks. It has been shown that while bismuth and metronidazole both have a small effect on killing H. pylori, there is a much larger effect when they are administered together. The Baylor study examined 83 patients (83 with duodenal ulcers and 26 with gastric ulcers). They were randomised into a group treated with ranitidine alone (300 mg once daily in the evening) or ranitidine plus triple therapy. After ulcer healing had been documented, patients were followed for up to two years, during which time patients received no antiulcer therapy (including antacids). Follow-up visits were at one month and three months after therapy, and then at three month intervals. The endoscopist was blinded to the treatment of the patients. Patients receiving ranitidine with a recurrence of ulcer were crossed-over to ranitidine and triple therapy at recurrence.


  • All patients had H. pylori infection at the start of treatment.
  • All 47 treated with ranitidine alone were still infected at the end of therapy.
  • The bacterium was eradicated in 55 of 62 patients receiving triple therapy.
Half the patients who experience healing with ranitidine alone had a recurrence within 12 weeks, and 44 of 47 (96%) had recurrence by the end of the study period (median about 44 weeks). The figures for triple therapy plus ranitidine were 10% and 12% (Figure). No patient in whom H. pylori was eradicated became reinfected, and only three (all of whom were taking NSAID drugs) experienced ulcer recurrence. Fourteen patients who experienced ulcer recurrence after ranitidine alone were crossed to triple therapy and ranitidine. After ulcer healing none experienced a further recurrence after a median of 42 weeks. In this study the only factors associated with ulcer recurrence were H. pylori infection and continued use of nonsteroidal anti-inflammatory drugs. A very recent publication in the Lancet has demonstrated that 92% of patients treated with H. pylori eradication remained free of ulcers after a mean of 7.1 years. The rate of H. pylori reinfection was about 1% per year. Triple therapy for eradication of H. pylori is not without its problems. The treatments have an unpleasant taste, antibiotic associated diarrhoea is not an uncommon effect, and there is some evidence of metronidazole resistance in some strains of H. pylori - about 20% of ulcer patients in the UK.

When to treat

DTB recommends that attempts to eradicate H. pylori should be limited to patients in whom duodenal ulceration is a management problem. This would include those with frequent recurrences, and who would need maintenance treatment with H2-antagonists or proton pump inhibitors. It would also include those being considered for elective surgery and those who have bled or perforated in the past.

References:

  1. Graham et al. Annals of Internal Medicine 1992 116: 705-8.
  2. Flier & Underhill. New England Journal of Medicine 1990 322: 909-16.
  3. Forbes et al. Lancet 1994 343: 258-60.
  4. Drug & Therapeutic Bulletin 1993 31: 13-15.

Questions to be Answered

Q: What need is met by this treatment?
A: More effective treatment of duodenal or gastric ulcers with much lowered rate of recurrence.
Q: What happens at present?
A: Patients are treated with H2 receptor antagonists or proton pump inhibitors (cimetidine, ranitidine, omeprazole). Maintenance therapy is used in patients with a history of recurrence.
Q: How does this approach improve effectiveness or quality?
A: Patients treated to eradicate H. pylori will suffer many fewer episodes of recurrence.
Q: What are the cost implications?
A: The cost of a two-week standard triple therapy is about £15. There may be other initial costs (test to establish infection, plus triple therapy drugs), followed by lower costs as many fewer of H2-receptor antagonists are needed. Overall cost should be lower.
Q: Is more information needed
A: Yes, this issue is worthy of a full effectiveness and cost review, and urgently.

Advice to purchasers

  • This is likely to increase effectiveness.
  • This is likely to reduce costs.
  • Will decrease total cost of care for this problem.
  • Should consider inclusion in specification, and could form part of a RCT for formal evaluation of cost effectiveness.

H. pylori and gastric cancer

Two studies published in the New England Journal of Medicine in 1991 associated H. pylori infection with increased risk of gastric cancer. Both studies looked at H. pylori infection in patients with gastric cancer and matched controls. H. pylori infection was high in gastric cancer patients (approaching 90%), and was lower in the controls (40 - 60%). Odds ratios for the association between gastric cancer and H. pylori infection were 3.6 and 6.0. The EUROGAST study, published last year, confirmed these findings. The study looked at the relation between the prevalence of H. pylori infection and gastric cancer rates in 17 populations from 13 countries. A significant correlation was found between the infection rate and gastric cancer incidence and mortality. The study concluded that a population with a 100% infection rate with H. pylori would have a six-fold increased risk of gastric cancer. In the UK gastric cancer accounts for about 10% of all deaths from malignant disease. When diagnosed early, and treated with radical surgery, the 5-year survival rates are good (>70% for stage I and II).

Screening for gastric cancer?

Considerations such as these have led to suggestions that screening for H. pylori infection using antibody tests (especially in high risk groups), together with eradication using triple therapy, may lead to reductions in cancer rates. There are many problems associated with such a strategy. H. pylori seropositivity is high in the elderly population and high-risk ethnic groups - so making follow-up tests like endoscopy impractical because of the large numbers that would be needed. Moreover, treatment itself is associated with unwanted affects in up to 30% of patients; antibiotic resistant strains of H. pylori would be likely to appear. Gastric cancer has a complicated aetiology. H. pylori infection is certainly an associated factor, but there is no reason at present to consider its use in screening for gastric cancer.

References:

  1. Parsonnet et al. New England Journal of Medicine 1991 325: 1127-31.
  2. Nomura et al. New England Journal of Medicine 1991 325: 1132-6.
  3. EUROGAST Study. Lancet 1993 341: 1359-62. Goodwin. Lancet 1993 341: 507-8.

Advice to Purchasers

  • No evidence whatever for increased quality or effectiveness for H. pylori screening for gastric cancer.
  • Should exclude specifically from specifications.

H. pylori: testing

Persons infected with H. pylori develop serum antibodies to the organism. These antibodies can be detected in serum by binding the antibodies to purified H. pylori antigen, followed by detection of the human immunoglobulins. Both IgG and IgA immunoglobulin classes are found, and can be used diagnostically. However, the IgG subclass decreases after eradication, and high titres are usually associated with acute infections. Serological testing for H. pylori is only one of a number of diagnostic techniques that can be used. Culturing the organism is probably the gold standard, but the method is slow and expensive. Histology and CLO (campylobacter-like organism) testing are more simple, but depend upon invasive techniques to obtain samples. Breath testing for isotopes of carbon after urea ingestion is non-invasive, but has a high capital cost. Serological methods of identifying circulating antibodies to H. pylori are cheap, quick and non invasive (other than blood collection).



A number of ELISA assays for laboratory use have become available in recent years. Typical reagent costs are £2-3, though they have to be conducted in a laboratory with trained personnel and special laboratory equipment.

H. pylori testing in the clinic

The Quidel company in the USA have produced an enzymeimmunoassay for the rapid qualitative detection of IgG antibodies to H. pylori. The QuickVue test uses only 30 uL of serum and can be performed without laboratory facilities in any clinic or office in about 7 - 10 minutes, and has a simple visual end-point. The assay has sensitivity and specificity of between 93 and 100%, with accuracy of approaching 90 - 100%, depending on the population studied. The cost of each test is about £6, but it does need blood samples to be centrifuged or stood for some hours before serum or plasma can be obtained. The value of testing for H. pylori infection is not fully established. It is almost certainly worthwhile in establishing H. pylori infection before treatment for eradicating the organism to eliminate those patients where infection is not the cause of duodenal or gastric ulceration. Information: Quidel QuickVue test is distributed in the UK by Allerayde, Queens Head Court, 42 Kirk Gate, Newark.

Questions to be Answered

Q: Will serological testing for H. pylori be effective.
A: Yes, if it forms part of a service for gastroenterologists and GPs, and if eradication therapies are being used.
Q: Are laboratory or near-patient testing facilities needed.
A: Overall costs differences are not great. The argument is balanced on present information. The immediate results, and need mainly for qualitative information probably favour near-patient testing.

Advice to purchasers

  • Support of H. pylori testing services should be part of a strategy for dealing with duodenal and gastric ulcers.
  • Unrestrained testing, especially for screening, is not indicated.
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