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HELICOBACTER PYLORI
Guidelines for Healthcare Providers
Introduction
Helicobacter pylori (H. pylori) is the most common bacterial infection worldwide and infects about one third of adult Australians. It
causes gastritis and peptic ulcer, and is strongly linked to gastric cancer. This booklet provides a current consensus statement about
this organism, its role in disease and its diagnosis and treatment
What is H. pylori?
H. pylori is a gram-negative bacterium that has evolved to inhabit the hostile environment of the human stomach. A spiral/helical shape
and specialised motility allow the organism to swim in a corkscrew-like fashion through the viscous gastric mucus down to the gastric
mucosa. It resists the effect of gastric acidity by breaking down endogenous urea via the activity of the enzyme, urease, creating a
protective cloud of alkaline ammonia. At the gastric surface, some H. pylori adhere to the epithelium via specific adhesion molecules
although large numbers of organisms swim freely in the mucus gel. The preferred ecological niche of H. pylori is the gastric antrum but
bacteria are also found in the body and fundus.
Various bacterial products such as enzymes and cytotoxins cause structural damage and induce an inflammatory response with both
polymorphonuclear leucocytes and mononuclear cells. This active chronic gastritis is the underlying lesion of all H. pylori infections. The
bacterium has learnt to successfully evade the cellular and humoral responses against it and may infect the stomach of its host for life.
H. pylori is the human adapted helicobacter; many other animal species have their own special helicobacter (indeed there are now
more than 20 species).
How prevalent is H. pylori infection in Australia?
The prevalence of H. pylori increases with age and is greater in certain ethnic populations. In some countries it may be as high as 7080%. In general, the prevalence is higher in people from lower socio-economic groups, institutionalised individuals and those who have
migrated from the developing world.
Sero-epidemiological studies show that about 30% of the Australian-born adult population are infected with H. pylori. There is no
difference between the sexes but prevalence of infection is higher in older age groups. About 40% of persons over 40 are infected while
less than 10% of children are currently H. pylori positive. As the bacterium is known to be primarily acquired in childhood, the increase
in prevalence with age is probably a cohort effect, i.e. 40 years ago many more children were infected than is the case today. There is
intrafamilial clustering of infection. Transmission appears to be between parents and children rather than between spouses. Reinfection rates after successful treatment are very low (0.5 - 1% per year) suggesting that the infection is rarely contracted in adulthood.
There is still controversy over the dominant mode of transmission. Humans are the only reservoir. Whether the main route of transfer is
faecal/oral or oral/oral is unknown. Oral/oral transmission via infected vomitus or refluxate is consistent with transmission in childhood.
Gastric juice contains viable bacteria and transmission via inadequately disinfected endoscopes has been documented. The bacterium
is not normally found in faeces. Comparative epidemiological studies with Hepatitis A in China suggest faecal/oral spread is not the
norm.
What diseases does H. pylori cause?
H. pylori is now accepted as a cause of:
•
•
•
•
Histological gastritis
Duodenal ulcer disease
Gastric ulcer disease
Gastric malignancy
Histological gastritis
H. pylori causes chronic gastritis. All infected patients have histological gastritis but most are asymptomatic. The gastritis slowly
resolves with successful treatment of the infection but this may take years. About a third of infected subjects develop some degree of
gastric atrophy and/or intestinal metaplasia over many years.
It is unclear whether these later changes are reversible with successful treatment of the bacteria. H. pylori gastritis is distinct from the
auto-immune gastritis that causes pernicious anaemia.
Duodenal ulcer disease
H. pylori is a major causal factor in up to 90% of duodenal ulcers. Successful treatment of the infection alters the natural history of the
disease, promoting ulcer healing and preventing relapse and complications. Other causes of duodenal ulcer include ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) and the rare Zollinger-Ellison syndrome. There are some patients where no cause is
identified. The overall proportion of ulcers not due to H. pylori infection is increasing as the prevalence of H. pylori in Australia declines.
Gastric ulcer disease
About 70% of patients with gastric ulcer are infected with H. pylori, and eradication of the organism markedly lowers the ulcer relapse
rate. Most H. pylori negative gastric ulcers are caused by NSAIDs. Some patients have both risk factors.
Gastric malignancy
H. pylori is now classified as a group 1 (definite) biological carcinogen analogous to Hepatitis B virus. Gastric cancer is a multi-factorial
disease in which H. pylori is not the only risk factor. Other factors (such as a high salt diet and low vitamin C intake) are known to be
important in some populations. Gastric adenocarcinoma is becoming less common in Australia, presumably reflecting the declining
prevalence of infection.
A causal link has now been found between H. pylori infection and the rare low-grade MALT (mucosa-associated lymphoid tissue)
lymphomas. More than 90% of these patients have H. pylori infection. Regression of the lymphoma occurs with H. pylori treatment in
75%.
H. pylori and non-ulcer dyspepsia (NUD)
Patients with NUD are a very diverse group and this diagnosis should be considered descriptive only. About 25-50% of patients with
non-ulcer dyspepsia (NUD) have H. pylori infection. However, many uninfected patients have NUD and therefore infection is bound to
be incidental to symptoms in many cases. H. pylori may play a role in the genesis of symptoms in a minority of patients but identification
of this subset pre-treatment is not reliable. Thus, although some patients (up to 15% more than placebo) improve symptomatically, most
infected patients with NUD will not have symptom resolution after successful H. pylori eradication, although their risk of subsequent
gastroduodenal disease (particularly ulcers) will be reduced by treatment.
H. pylori in children
Fewer studies have been performed in paediatric populations. In infected children an antral nodular gastritis is observed with few
progressing to develop ulcer disease. An Australian study has found that 14% of paediatric patients sent for gastroscopy were positive
for H. pylori infection - 50% of these had nodular gastritis and 5% had peptic ulcer disease. H. pylori infection can be considered as an
infection of children that may last for most, if not all, of the child's life. In some subjects, because of other risk factors that remain to be
defined, it will eventually contribute to the development of significant adult disease.
. pylori and extradigestive diseases
At this time there are no convincing data linking H. pylori with extradigestive diseases such as ischaemic heart disease, skin diseases
(e.g. acne rosacea) or short stature.
How is H. pylori diagnosed?
Helicobacter pylori can be detected using a range of non-invasive or invasive tests.
1.
Non-invasive tests (endoscopy not required)
o
Breath tests
Validated breath tests are very accurate (95-98% sensitivity and specificity) and simple tests for H. pylori that are now widely available.
They involve giving the fasting patient a 13C or 14C-urea solution. If the organism is present, its urease enzyme breaks down urea to
produce labeled CO2, which can be detected in breath samples collected over the next 10-60 minutes. 13C has the advantage of being
non-radioactive so it is preferred for children or pregnant women. Many centres that use the 14C test now use a very low dose, with a
radiation exposure of about one tenth of a chest X-ray.
When used to assess the outcome of treatment, the test should not be done sooner than one month after the completion of therapy.
Antibiotics and bismuth should be avoided during the 4 weeks before breath testing. Because proton pump inhibitors can suppress the
organism they should be suspended for two weeks beforehand to minimize false negative results. Standard doses of histamine H2blockers have little effect on the accuracy of the test.
o
Serology
Serology is now widely available. The accuracy of tests vary, with the least accurate usually being office based tests (their sensitivity
may be as low as 60%). To be clinically useful for decision-making about individual patients, the sensitivity and specificity need to be
high - of the order of 90% or greater. Few serology tests reach this standard. A small number of national reference laboratories provide
tests of this quality.
Serology is currently of no value for checking the success of treatment since the fall in titre is slow and variable, usually taking at least 6
months to fall by a half.
o
Local validation of test accuracy
There is variability in the accuracy of the non-invasive tests. It is reasonable to request evidence of local validation from the provider.
2.
Invasive tests (endoscopy and biopsy required)
Biopsies at endoscopy should ideally be taken from both the antrum and body of the stomach, since the organism can sometimes be
found in one and not the other. Although the antrum is the main reservoir of infection, H. pylori may move its major location to the body
during therapy with PPIs. As with breath tests, a negative result in patients taking PPIs or antibiotics may be unreliable (because of
suppression but not eradication of the organisms).
o
Rapid urease tests
Like the breath tests, these rely on the massive amounts of urease generated by the organisms. The biopsy is placed in a urea solution
or gel containing a pH indicator. Both in-house and commercial tests are satisfactory, and sensitivity and specificity are around 90-95%.
In many infected patients the test becomes positive within an hour or two, but sometimes this takes longer, so the test is not finally
declared negative till 24 hours later. The practitioner needs to be aware of this, to follow up tests that may not have had the result
recorded at the time the patient is sent home with their endoscopy report.
o
Histology
Histological examination of biopsy sections has the advantage that the histopathology of gastritis can be assessed as well as the
presence of the organisms. The pathologist needs to be experienced and sometimes to use special stains and some patience in
searching for the organism. When these conditions are met, histology is a very accurate way of detecting the presence or absence of
the organism (specificity and sensitivity both around 95%). Histology is substantially more expensive than the rapid urease test.
o
Culture
The bacteria may be hard to grow in culture if inappropriate conditions are used. Culture has a limited role in routine diagnosis but is
useful if antibiotic susceptibilities need to be monitored - either as part of a national monitoring program, or to help in the choice of
repeat treatment for patients who have already failed therapy.
Which patients should be tested and treated?
In general, treatment of H. pylori should be considered in all patients found to be infected. In some of the diseases listed below, this
treatment should be a high priority. In other situations, the potential risks and benefits of treatment should normally be discussed with
the patient, and an individual decision made to treat or not. In most cases, testing should be done only if there is intention to treat if
infection is found.
Duodenal ulcer disease
All H. pylori infected patients with duodenal ulcer should have treatment to cure the infection. An attempt should be made to
demonstrate H. pylori infection by antral biopsy using a rapid urease test with or without histology. In patients who have recently
received treatment with a proton pump inhibitor, a negative test is not reliable. Similarly, all patients with a history of previous duodenal
ulcer disease should have their H. pylori status assessed and if positive, be treated. Clinical judgement should of course be exercised in
some circumstances where the risk of future ulceration is considered irrelevant, e.g. severe dementia, terminal illness. Assessment of
H. pylori status initially could be either by a locally validated serology assay or a urea breath test. Evaluation of success of therapy in
these patients is important before maintenance therapy is ceased. This is best done using a urea breath test if, as is usually the case,
there is no clinical indication for follow up endoscopy.
Gastric ulcer disease
All patients with proven H. pylori infection and documented gastric ulcer (past or present), that are not taking NSAIDs, should be
treated. (with the exceptions discussed above). In gastric ulcer patients who are both infected and taking NSAIDs, either factor or both
may be important. Eliminating both factors appears logical, hence H. pylori treatment together with stopping the NSAID (whenever
possible) is recommended.
In those patients with the infection who require long-term NSAID therapy but do not have a documented ulcer, the evidence for a
benefit from treating H. pylori is controversial
Gastric MALT lymphoma
Patients should be given a course of eradication therapy and carefully monitored by endoscopy at frequent intervals until evidence of
resolution of both the infection and lymphoma has occurred. Surgery or chemotherapy may still be required in some cases.
Unendoscoped dyspepsia (excluding those with predominant reflux symptoms)
A non-invasive test for H. pylori followed by treatment in infected cases may aid in management. If the patient with dyspepsia is
infected, the probability that they have peptic ulcer disease is substantially increased. If the patient has no evidence of infection (or
NSAID use), the risk of ulcer is very low. It is reasonable therefore to consider treating H. pylori-positive dyspeptic patients younger
than 50 years without further investigations if there are no alarm features. Alarm features include weight loss, vomiting, dysphagia,
bleeding, anorexia, or an abdominal mass. Follow-up should be arranged. However, this strategy will often not relieve symptoms, as
many patients have non-ulcer dyspepsia and some ulcer patients, even after cure of the ulcer disease, have continued dyspepsia.
The decision to test and treat for H. pylori is also influenced by the potential benefits of reducing lifetime ulcer (and complications of
ulcer) risk and possibly cancer risk in some patients. There are data suggesting cost effectiveness with this approach also. Clinical
outcomes have been shown to be the same at 1 year compared to patients referred for early endoscopy. Four consensus statements
worldwide have endorsed the test and treatment strategy.
Family history of gastric cancer
Some patients with a family history of gastric cancer will request H. pylori testing. This is reasonable, after appropriate counselling. This
may have reassurance value. The rationale is that treatment of H. pylori might reduce the risk of subsequent gastric cancer, although
this is unproven. If there is any benefit, it might be expected to be greatest in younger patients as cancer is thought to be a
consequence of H. pylori-induced histological changes (intestinal metaplasia) which may take decades to develop. Currently there is no
evidence as to which H. pylori-induced premalignant changes might be reversible
Asymptomatic patients
Asymptomatic patients should not routinely be tested for H. pylori. However, patients sometimes request this and the decision to test,
and treat if positive, should be made on a case by case basis after discussion of risks and benefits. The risks include those of 1-2
weeks of combined antibiotics. The benefits are unproven, but may include reduction of long-term ulcer risk and perhaps cancer risks in
a small subset of infected patients. Routine testing for H. pylori in family members of infected patients is not recommended but
considered in the same way if requested.
How should H. pylori be treated?
Currently, first line therapy in Australia is either a proton pump inhibitor (PPI) or ranitidine-bismuth-citrate combined with amoxycillin and
clarithromycin. These one week, twice daily combinations have high efficacy and are available as 'single script' triple therapies,
(containing either omeprazole or ranitidine-bismuth-citrate). They are relatively simple to take and are generally well tolerated. Common
adverse effects include taste disturbance, nausea and mild diarrhoea. Patients should not take cisapride or some antihistamines with
these combinations because of the possibility of interaction with clarithromycin. Eradication rates above 85% are achievable in clinical
practice. These combinations are less effective if there is pre-treatment clarithromycin resistance (CR). However, in Australia the
primary CR rate is only about 5% because clarithromycin until recently, has rarely been used as monotherapy for other infections.
When treatment fails, secondary clarithromycin resistance commonly emerges and retreatment with a clarithromycin-containing
regimen has a low rate of success.
Where there is penicillin allergy or intolerance, metronidazole may be substituted for amoxycillin in either combination. These regimens
also have proven efficacy in trials. Pre-treatment metronidazole resistance (MR) reduces the efficacy of these combinations modestly
but eradication rates above 80% are achievable in Australia.
A two week omeprazole, amoxycillin, metronidazole combination has been available as a 'single script' therapy. This regimen has
moderate efficacy but pre-treatment metronidazole resistance (MR) reduces efficacy. A clarithromycin containing combination is now
preferred when PPI triple therapy is to be used.
The original triple therapy consisted of bismuth subcitrate, tetracycline and metronidazole. This is also available as a 'single script'
therapy. Dosage is four times daily for two weeks. The bismuth should be crushed or chewed rather than swallowed whole. This
regimen is rather clumsy because of the number of tablets and the frequency of dosing as well as the duration of treatment. Sideeffects are common and include nausea, taste disturbance, diarrhoea and black tongue and stools. Although good eradication rates are
achievable with this combination, its effectiveness is markedly impaired when there is pre-treatment metronidazole resistance.
Unfortunately, studies across Australia reveal a primary MR rate of 40-60% which reduces the efficacy of this treatment. Quadruple
therapy combines a proton pump inhibitor twice daily with bismuth, tetracycline and metronidazole. One week courses of this treatment
have shown promising results and the impact of metronidazole resistance appears to be reduced. However, the treatment is clumsy
which may impair compliance. Where there has been failure of a clarithromycin containing triple therapy, quadruple therapy is a good
choice as second line treatment. Similarly, where a bismuth, tetracycline, metronidazole combination has failed, a PPI, amoxycillin,
clarithromycin combination has been shown to be a good second choice of therapy.
Efficacy, local antibiotic resistance rates, simplicity, tolerability and cost should guide the choice of therapy. Only therapies that have
had their efficacy proven in well-conducted clinical trials should be used. Unproven, ad hoc therapies should be avoided. Detailed
explanation of the importance of compliance and the possibility of adverse effects should accompany any prescription for eradication
therapy. Patients forewarned about self-limiting adverse effects are more likely to complete the course of therapy.
Cost-effectiveness studies show that the regimens that achieve the highest rates of successful eradication are generally the most costeffective, because they reduce the costs of managing treatment failures.
Table 1: Currently recommended therapies for H. pylori in Australia
Therapy
Dosages
Duration
twice daily
1 week
Proton pump inhibitor-based triple therapies:
1
PPI standard dose
2
Amoxycillin 1000mg
twice daily
Clarithromycin 500mg
twice daily
PPI double standard dose
Once in the morning
Amoxycillin 500mg
three times daily
Metronidazole 400mg
three times daily
2 weeks
Ranitidine-bismuth-citrate triple therapy:
3
Ranitidine-bismuth-citrate 400mg
twice daily
Amoxycillin 1000mg
twice daily
Clarithromycin 500mg
twice daily
1 week
When there is penicillin allergy or intolerance:
4
PPI or ranitidine-bismuth-citrate
twice daily
Metronidazole 400mg
twice daily
Clarithromycin 500mg
twice daily
1 week
Bismuth based triple therapy:
5
Colloidal bismuth subcitrate 120mg
times daily (chewed or crus
Tetracycline 500mg
four times daily
Metronidazole 200mg
three times daily
Metronidazole 400mg
at bedtime
2 weeks
Quadruple therapy:
6
Bismuth triple therapy as above
four times daily
+ PPI in standard dose
twice daily
1
6
1-2 weeks
Available as single script omeprazole combination as Klacid Hp7® or Losec Hp7®.
2
Available as single script omeprazole combination as Losec HelicoPak 2®.
3
Available as single script ranitidine-bismuth-citrate combination as Pylorid KA®.
4
Currently no single script therapy available.
5
Available as a single script triple therapy as Helidac®.
Currently no single script therapy. Any PPI (lansoprazole, omeprazole or pantoprazole) may be used.
How should patients be followed up?
Assessment of the outcome of eradication is highly desirable in complicated ulcer disease, or where cessation of maintenance therapy
for previous ulcer is contemplated. In patients with uncomplicated ulcer disease, it is recommended that the outcome of H. pylori
treatment be assessed as this guides subsequent management and provides reassurance when testing is negative. There is evidence
that the rate of successful H. pylori eradication in practice is considerably lower that that reported in controlled trials, increasing the
importance of outcome assessment.
Post-treatment testing is best done with a breath test. Prior to testing, no antibiotics should be taken for at least one month. Because
proton pump inhibitors can suppress the organism, they should be suspended for 2 weeks beforehand to minimise false negative
results. Follow-up endoscopy (and biopsy) is usually not required except for gastric ulcers ( to exclude) malignancy ad document
healing) and for some complicated duodenal ulcers. Serology is not a reliable way of assessing outcome after treatment and is not
recommended.
Acknowledgements
This booklet is a publication of the Digestive Health Foundation - the educational arm of GESA (Gastroenterological Society of
Australia). It was prepared by:
Neville Yeomans
Professor of Medicine and Head of Gastroenterology, The University of Melbourne at Western Hospital
Helen Dooley
Family Medicine Physician, Footscray, Melbourne
Adrian Lee
Professor of Microbiology, The University of New South Wales
Nicholas Talley
Professor of Medicine, Head Division of Medicine, The University of Sydney at Nepean Hospital
Peter Katelaris
Clinical Senior Lecturer, The University of Sydney, Senior Staff Specialist, Concord Hospital, Sydney
Disclaimer
This document has been prepared by the Digestive Health Foundation, of the Gastroenterological Society of Australia and every care
has been taken in its compilation. The booklet is intended to be used as a guide only and not as an authoritative statement of every
conceivable step or circumstance which may or could relate to the management of diseases related to H. pylori.
The Gastroenterological Society of Australia and the compilers of this document shall not be liable to users of the document nor to any
other person, firm, company or other body for loss, direct or consequential, on whatsoever account for any omission or negligent
misstatement contained therein, or by reason of, arising from or in relation to any such user, by any other person, company or body
relying or acting upon or purporting to rely or act upon any matter contained therein or arising thereout. Information leaflets on
Helibactor pylori for patients and the general public are available through the Digestive Health Foundation, 145 Macquarie Street,
Sydney, NSW, 2000
The Digestive Health Foundation (DHF) is an educational body committed to promoting better health for all Australians by promoting
education and community health programs relate to the digestive system.
The DHF is the educational arm of the Gastroenterological Society of Australia (GESA), the professional body representing the
Specialty of gastrointestinal and liver disease in Australia. Members of the Society are drawn from physicians, surgeons, scientists and
other medical specialties with an interest in GI disorders. Since its establishment in 1990 the DHF has been involved in the
development of programs to improve community awareness and the understanding of digestive diseases. Research and education into
gastrointestinal disease are essential to contain the effects of these disorders on all Australians.Guidelines for General Practitioners
and patient leaflets are available on a range of topics related to GI disorders. Copies are available by contacting the Secretariat at the
address below:
GESA
145 Macquarie Street
SYDNEY NSW 2000
Telephone: 02 9256 5454
Facsimile: 02 9241 4586
Email: [email protected]
Website: http://www.gesa.org.au