Helicobacter pylori
A Doctor's Guide to detection and treatment

H pylori ? Helicobacter pylori is a gram negative, microaerophilic, curved bacillus. It is motile, has flagellae and has a special affinity for human gastric mucosa.

Since its initial discovery it has been implicated in the pathogenesis of a number of gastroduodenal disorders including acute and chronic gastritis, gastric and duodenal ulceration, gastric cancer and gastric MALT lymphoma.

Up to 50% of the population in developed countries such as Australia will have evidence of H. pylori infection by the age of 50 years. The organism is present in up to 92% of patients with active chronic gastritis, 88-100% with duodenal ulceration, 58-100% with gastric ulceration and 46-94% with gastric cancer. In duodenal ulcer disease eradication of the organism has been shown to markedly reduce ulcer recurrence rates and possibly change the natural history of the disease.

Methods of detection of H. pylori

The organism is usually present in the gastric antrum and lives beneath the mucus layer. One of its special characteristics is its ability to produce urease, an enzyme that is not normally found in the human stomach.

Various methods have been developed for detecting H. pylori, including :

All the methods have a high sensitivity and specificity in the detection of H. pylori
(Thijs et al, 1996; 105 patients).
Method Sensitivity Specificity
Histology   96   98
Culture   98 100
Urease test   90 100
PCR   96 100
Serology 100   94
CUBT 100 100

Methods of detection using endoscopic antral biopsies

1. Histological identification

Histological examination is performed on endoscopic antral biopsy specimens. Numerous stains can be used including Haematoxylin & Eosin, Warthin-Starry, Giemsa. However,  the results are not known immediately. Histological examination has the advantage of providing information on other mucosal abnormalities. This is particularly useful in the case of gastric ulceration, when the exclusion of malignancy is important.

2. H. pylori culture

The organism can be successfully cultured from antral biopsy specimens and grown in various media with enrichment at 37oC in a microaerobic atmosphere. The technique is very specific and permits strain typing of the organism. In addition to this antimicrobial susceptibility testing can be performed. The results however may take up to three days to be completed. At present H. pylori culture is mainly used in research and in assessing bacterial resistance after failed eradication therapy.

3. Molecular methods

The polymerase chain reaction (PCR) has been used in identifying the organism accurately. This technique has a high specificity and again allows for detailed identification of the organism's strain. It is a complicated technique and no commercial kits are available, confining it to research. It has been used to distinguish treatment failure with recurrence of the same strain of organism from reinfection with a new strain.

4. The rapid urease test (CLO, HP fast, pyloritec tests)

This is the least expensive test that can be performed on endoscopic biopsy specimens. It is based on the ability of the H. pylori to produce urease which is not usually present in the stomach. The urease produced by the organism converts urea to ammonia resulting in a PH change detected by phenol red. The tests usually give a rapid result but typical sensitivity at 1 hour is 71% which increases to 96% at 6 hours. Some of this delay can be overcome by warming the specimen which speeds up the reaction.

With all the endoscopic biopsy tests there is some potential for sampling error particularly following eradication therapy. Following treatment with acid inhibiting drugs and antibiotics bacterial suppression in the antrum can occur with inhibition of urease activity and redistribution of the organism to the gastric fundus. Thus antral biopsy specimens alone may not detect the organism. Further, as the organism usually resides beneath the intact mucus layer, biopsies from areas of intestinal metaplasia and gastric carcinoma may also result in low detection rates. If H. pylori eradication is being assessed on endoscopic biopsies, in addition to performing antral biopsies one should also take specimens from the gastric body.

Serological tests for H. pylori


These are non invasive laboratory tests for antibody against H. pylori. Various methods exist, including : Tests for IgG antibodies are the most sensitive as once infected with the organism an IgG response is seen in 95%, an IgA response in 68-80% and IgM response in only 14% of infected patients. The majority of tests are performed on blood and the sensitivity of salivary antibody tests is low, probably as the majority of salivary antibodies are IgA rather than IgG. It is important that serological tests are locally validated.

The serological test offered by the IMVS is the pyloritest (Orion Diagnostica). This is a total antibody latex agglutination test for the detection of H. pylori antibodies. When compared to histology and rapid urease test and culture in 90 patients it was shown to have a sensitivity of 93% and specificity of 95%.

H. pylori serology is useful in screening the population but a small proportion of elderly patients do not mount an IgG response and up to 31% of patients with positive serology may not have active infection. Antibody levels drop very slowly following eradication of the organism and up to 65% of patients may remain positive for 12 months post treatment. Serology is thus not useful in assessing eradication.

The Carbon urea breath test (CUBT)

The breath tests are performed by asking the patient to swallow carbon- labelled urea which is metabolised by H. pylori produced urease to produce labelled carbon dioxide. This is absorbed into the blood stream and then exhaled in the breath of infected individuals as illustrated.Principles of urea breath testing

Broadly, two forms of urea breath tests are available, using 13C urea which is Testing for H pyloria stable (non radioactive) isotope or 14C urea which is radioactive.

At the Royal Adelaide Hospital we offer the following techniques :

1. 13C urea breath test
The procedure is :

The RAPID-13 urea breath test kitThe 13C urea breath test is more expensive than the 14C urea breath test due to the cost of  the mass spectrometer and substrate.

The RAPID-13 kit is a 13C urea breath test kit.

2. 14C urea breath test
The procedure is :

RAPID-14 urea breath test kitAt the Royal Adelaide Hospital we have validated the RAPID-14 14CUBT in 130 subjects using a single 15 minute sample resulting in a sensitivity and specificity of up to 100% when compared to histology and the rapid urease test (CLO) on endoscopic biopsies. When compared to the RAPID-14 test the RAPID-13 13CUBT using a simplified method and a single 20 minute sample resulted in a sensitivity of 92% and specificity of 98% . This is shown in adjacent graph.

Limitations


False negative breath test results can occur through suppression of urease activity if the breath tests are performed too soon after antibiotic or acid suppression therapy.

In assessing eradication the CUBT should be performed at least 4 weeks following cessation of antibiotics or antibacterials. The optimal length of cessation of H2 antagonists and proton pump inhibitors (PPI's) is not fully known and may range from 2 days to 2 weeks.

At present we follow the recommendation of ceasing H2 antagonists for 9 hours (during the fasting period) and PPI's for 7 days prior to CUBT, if possible. Other possible causes of false negative and positive CUBT's are shown below:

Result type Possible cause
False negative Test performed too soon after antibiotics, acid suppression therapy 
(should wait at least 1 month after eradication therapy)
Rapid gastric emptying (post surgery)
False positive Contamination with oral commensals (ie non-fasting)
Achlorhydria, gastric atrophy

Estimated costs of the tests

Test Cost  ($AUD)
Endoscopy
132 -
with
Histopathology
+ 79 -
with
Culture
+ 33 -
with
Rapid urease test
 + 3 -
Serology
13 -
13/14C Urea breath test
78 -

Application of the tests for H. pylori


All the tests for H. pylori have a high sensitivity and specificity, however it is important that the tests used be locally validated and have a sensitivity and specificity of well over 90%.

Medicare

The HIC will pay a rebate for 13/14C urea breath tests for the following indications

MBS Item 12533, 1 Nov. 2008
CARBON-LABELLED UREA BREATH TEST using oral C-13 or C-14 urea, performed by a specialist or consultant physician, including the measurement of exhaled 13CO2 or 14CO2, for either:-

  1. the confirmation of Helicobacter pylori colonisation, OR
  2. the monitoring of the success of eradication of Helicobacter pylori.

Indications for H. pylori eradication

Established reasons for H. pylori eradication are :

  1. All gastric and duodenal ulcer patients who are H. pylori positive whether the ulcer is active or in remission.
  2. Patients with low grade mucosa-associated lymphoid tissue lymphoma (MALT). These are usually managed in specialist centres.
  3. Patients who have undergone resection of early gastric cancer.
H. pylori eradication may have a role in patients with gastritis and non ulcer dyspepsia and in patients with a family history of gastric cancer but this is not firmly established at present. Treatment of asymptomatic spouses and family members is not currently recommended.

Treatment regimens

The 7 day treatment regimen available through the PBS for the treatment of H. pylori is:


Nexium Hp7 (Astra)
This consists of

It is available on restricted PBS benefit for the eradication of H. pylori associated with peptic ulcer disease
This regime has superior eradication rates compared to the earlier regimens such as HELIDAC (Pharmacia & Upjohn) and LOSEC HELICOPAK (Astra)


In some countries, including Australia, high rates of metronidazole resistance have been found and studies have shown eradication rates greater than 90% with well tolerated 7 day regimens using clarithromycin.

Treatment Failure

Following treatment based on a PPI, a clarithromycin/metronidazole combination regimen could be repeated.

Other breath tests

13C-Triolein breath test

This is a test for fat malabsorption. Following an overnight fast the patient is given a 40ml liquid meal comprising a mixed fat meal (Calogen) and 200 mg 13C-Triolein. The triolein is digested, absorbed and metabolized in the body and 13CO2 produced that is exhaled and then measured in the breath.
In this test breath samples are collected hourly for 6 hours following the meal. The activity in the breath sample is measured in a mass spectrometer and the rate of fat absorption calculated. If there is fat malabsorption the amount of the ingested dose absorbed and 13CO2 exhaled is reduced. The test has a reported sensitivity of up to 100% and 96% specificity for fat malabsorption (Newcomer et al 1979). However diabetic gastroparesis, thyroid disease and severe respiratory insufficiency may affect the test.

14C-Xylose breath test

This is a sensitive and specific test for bacterial overgrowth in the small intestine. It depends on the ability of anaerobic bacteria to metabolize 14C-Xylose resulting in the production in the body of 14CO2 that can be measured in the breath. If there is bacterial overgrowth more 14CO2 is exhaled. For this test, following an overnight fast the patient is given 370KBq oral 14C-Xylose. A single breath sample is then taken at 30 minutes and analyzed. Bacterial overgrowth is confirmed if >0.00014% of the ingested dose is exhaled in the breath at 30 minutes.


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