Biology of Disease CH0576 Peptic Ulceration Role of H. pylori

Helicobacter pylori A spiral bacterium with several flagellae at one end. First recognised as a cause of G.I.T disease and successfully cultured in Originally classified as Campylobacter pylori. It is a microaerophilic organism, with a potent urease activity.

Helicobacter pylori Microaerophilic organism is one which can readily grow in minimal O 2 environments. Urease activity is an enzyme which is capable of hydrolysing urea to form ammonia.

Helicobacter pylori The resultant ammonia causes an increase in the immediate surrounding environment’s pH. This urease activity then affords the organism protection from the potentially damaging gastric acid. Ammonia generated by the activity is directly toxic to mucosal cells.

Helicobacter pylori It is thought that around 50% of the world’s population is infected with this organism. Fortunately, most individuals infected show no symptoms or adverse effects of the infection. Outcome of the infection seems to be dependent on multiple factors ~ both host and bacterial.

Helicobacter pylori Generally infection with H.pylori is long standing. Individuals being infected for several decades. Epidemiological studies have indicated that the vast majority of cases of gastritis are accompanied by infection with H.pylori.

Helicobacter pylori In the U.K and U.S.A the infection is most common in adults, with the incidence  with age:- Around 5-20% below age of 20 years. Around 30-60% over the age of 50 years. In the African and Asian continents rates of infection are generally much higher: Between 60-90% of the population.

H. pylori Infection In Africa and Asia the individuals generally become infected at an earlier age. Generally the poorer the population, the higher the incidence, and the younger the age of onset. The likelihood of new infection is greatly reduced due to improved hygeine and the development of effective new antibiotics.

H.pylori Infection No clear relationship exists between H.pylori infection and smoking or alcohol intakes. There are no clear specific dietary links. Vegetarians are equally susceptible to infection. Transmission of H.pylori is via the oral-faecal route, rather like Hep A infection. Contaminated water supplies would seem to be the most likely source of infection and serves as a vehicle for its transmission.

H.pylori:Development of Peptic Ulcers Both urea and HCO 3 - are chemotactic for the organism. Hence they migrate through the mucus layer in an organised fashion, towards the mucosal surface In the infected stomach the organism adheres to the surface of normal gastric epithelial cells.

H.pylori:Development of Peptic Ulcers The adherence to the mucosal cell surface is mediated by specific glycolipid receptors. These are present on the surface of epithelial cells in the antral region of the stomach. The organism hence populates an area beneath the mucus layer, in an alkaline environment.

H.pylori:Development of Peptic Ulcers Evidence suggests that the H.pylori remains attached to the cell surface, and does not penetrate into the epithelial layer itself. The organism is, however, still capable of exerting a damaging effect on the cells. The organism releases cytotoxins into the cells on which it is attached. Direct toxic effect of NH 3 –Hence an inflammatory response is initiated

H.pylori Taken from: Yoshiyama & Nakazawa: Unique mechanism of Helicobacter pylori for colonizing the gastric mucus: Microbes and Infection, 2, 2000, p 55-60

H.pylori:Development of Peptic Ulcers The glycolipid receptors are not a feature of intestinal cells. Hence H. pylori is unable to attach to this new form of epithelium ~ the attachment is specific for antral epithelial cells. As a result the infection episode in the stomach is generally self limiting, as the gastric mucosa undergoes intestinal metaplasia.

H.pylori:Development of Peptic Ulcers In most cases total intestinal metaplasia will not occur. The immune response to the organism is generally able to eliminate it before this point is reached. The production of duodenal ulcers is generally thought to be related to injury to the mucosa, induced by HCl.

H.pylori:Development of Peptic Ulcers The adaptive response to an excess of acid in the duodenum is metaplasia. Gastric metaplasia occurs in the duodenum. These areas are now susceptible to infection with H. pylori. The infection with H. pylori induces further damage to the intestinal mucosa and leads to ulceration

H.pylori:Development of Peptic Ulcers An unanswered question still remains:- Is infection with H.pylori essential to the development of duodenal ulceration?

H.pylori:Development of Peptic Ulcers There is a very low yield of organisms from duodenal biopsies. However, >90% of duodenal ulcer patients also have H.pylori associated gastritis. Inflammatory mediators which are released in the stomach, in the response to gastritis, are washed into the duodenum, where they initiate a local response and mucosal damage.

H.pylori:Development of Peptic Ulcers Alternatively it is clear that the majority of individuals who are infected with H.pylori don’t develop ulcers, they remain healthy. Why is this organism completely harmless in some individuals and yet is associated with ulceration and gastric carcinoma in others? The answer is uncertain, multifactorial, and dependent on host and bacterial features.

H.pylori:Development of Peptic Ulcers The outcome of the inflammatory response is gastritis. With continuing and persistent infection the tissue responds to the inflammation by mounting an adaptive response, as covered in Cellular Basis of Disease. Metaplastic change occurs. The response of the gastric mucosa is that it is converted to an intestinal type.

Diagnosis of Infection A number of diagnostic tests are available, grouped into two categories: –Invasive biopsy based methods –Non-invasive methods. Various methods have different sensitivities and specificities. Some methods are good screening tests whilst others are employed to assess the eradication following treatment

Diagnosis of Infection Biopsy based tests: –Culture on selective media; considered as the ‘gold standard’ method which gives indisputable identification of the organism (provides antibiotic sensitivity). –Histology of gastric biopsy; identification relatively simple, slides can be retained for second opinion.

Diagnosis of Infection - Rapid Urease test; ‘bedside’ test in which a change in pH causes colour change in medium is detected by a suitable indicator e.g. Phenol Red. pH is raised due to ammonia production. –Gastric biopsy PCR; very sensitive technique, false positives can occur due to contamination. All biopsy based techniques may give false negatives due to sampling error!

Diagnosis of Infection Non-invasive methods: –Serology; detection of antibodies to H.pylori ~ useful in epidemiological studies but not suitable for eradication confirmation – indicates past as well as current infection. –Urea Breath Test; Patient is fed C 13 or C 14 labelled urea. Urease activity generates labelled CO 2 which is expired and detected by scintillography after collection of expired air in a respiratory chamber.

Diagnosis of Infection –C 14 urea breath test exposes individual to low radiation ~ about 1/10 of level of abdominal X- ray. –The test lacks sensitivity especially if treatment has decreased density of the organism but has not completely eradicated it. –If used as a means of assessing success of treatment it should only be used at least one month after completion of treatment.

Diagnosis of Infection –Stool culture; can be technically difficult but can provide antibiotic sensitivity information. –Stool EIA; again prone to technical sampling errors. –‘Non-invasive’ PCR; allows amplification of bacterial DNA to allow identification in:- Dental plaque Saliva sample Stool sample

Treatment of H.pylori Infection Before the recognition of the significance of H.pylori in the pathogenesis of ulceration the treatment for peptic ulcers were essentially aimed at: –Reducing acid secretion from the stomach –Enhancing the defensive barriers against both enzymatic and acid attack. –Nowadays an additional treatment regime is aimed at eradication of H.pylori infection

H.pylori Eradication The eradication of H.pylori from ulcer patients alleviates their symptoms. Re-infection with the organism leads to a renewal of their symptoms. The organism can be fairly difficult to completely eradicate from the system. A varied range of anti-microbial agents have been employed with varied success.

H.pylori Eradication Success and effectiveness of the various regimes depends upon a number of factors, including:- –The particular strain of the organism. –The pH of the gastric environment –Immunological status of the individual. The course of treatment can be quite long, and the potential side effects unpleasant.

H.pylori Eradication As with most prolonged treatment regimes, with side effects, this can cause a problem with patient compliance. Developing therapies are aimed at a shorter treatment period, in an effort to improve compliance. A dual therapy exists, employing the use of both omeprazole and amoxycillin.

H.pylori Eradication Omeprazole is an inhibitor of the proton pump, responsible for the transport of H + from the parietal cells. Hence this drug down regulates acid output into the stomach. A 6 week dual therapy with these two drugs can eradicate the organism in around 80% of cases.

H.pylori Eradication A triple therapy employing bismuth chelate, metronidazole and tetracycline administered over a 2 week period is effective in >90% of cases. –Unfortunately, the bismuth is unpleasant to take and the metronidazole can cause side- effects, including diarrhoea and possible allergic reactions. –Incidence of resistance to metrinidazole is high

H.pylori Eradication Unfortunately, the eradication of the organism is no guarantee that the problem will not re-occur. Re-infection rates of around 20% have been found, following a full course of the triple therapy. The treatments do not immediately change the environment of the duodenum.

H.pylori Eradication Gastric metaplasia will persist for some time and will be susceptible to re- infection, or more likely, the regrowth of colonies which were not completely eradicated. –Duodenal ulcers do not occur without gastric metaplasia.**** –Until the metaplasia is reversed, the patient is vulnerable to re-infection.****

Gastric Cancer Among the malignant tumours which can occur in the stomach, carcinoma is the most important and most common. –It forms between 90-95% of malignancies. –In most countries there has been a steady decline in both the incidence and mortality of gastric cancer. –It is responsible for around 3% of cancer deaths.

Gastric Cancer It has a fairly low 5 year survival rate - at less than 10%. The most common form of gastric cancer is adenocarcinoma (about 95% of cases). There are two principal forms of adenocarcinoma - diffuse and intestinal. It is the latter which is associated with H.pylori infection.

Gastric Cancer The two forms have different histological appearances. Intestinal type adenocarcinomas are mainly found in the body and antral regions of the stomach. Diffuse adenocarcinomas are most often associated with the cardia region, a small part of the fundus, near the oesophageal- gastric junction.

Gastric Cancer There are a number of risk factors which are associated with the development of gastric cancer. One of the associated risk factors is infection by H.pylori. Correa, in 1988, proposed a model for the chain of events leading to the development of adenocarcinoma - as illustrated.

Gastric Cancer The adenocarcinoma is preceded by a series of pre-neoplastic lesions which may start with infection by this organism, causing a superficial gastritis. This initiates inflammatory changes in the gastric mucosa. As the lesion becomes metaplastic infection disappears from the lesion, as it is unable to bind to intestinal mucosa.

Gastric Cancer Conditions within the stomach start to favour the conversion of nitrites in food into carcinogenic nitrosamines. –These may lead to the development of dysplasia and ultimately neoplasia. –Evidence suggests that the progression from H.pylori positive gastritis to gastric cancer may take several decades. –This probably occurs in only a small percentage of cases of gastric cancer.

Conclusion It would seem reasonable to suggest that many peptic ulcers and at least some gastric cancers could be avoided by the prevention and eradication of infection with H.pylori.