Just over 20 years have elapsed since Warren and Marshall discovered Helicobacter pylori and suggested that, by causing chronic gastritis, this microorganism might play a pivotal role in the aetiology of peptic ulcer disease and gastric cancer.1 Up to that point, peptic ulcer disease was looked on as a condition primarily caused by excess gastric acid, for which antisecretory therapy was the mainstay of treatment. Gastric cancer, on the other hand, was viewed as a multifactorial disease where environmental and dietary factors such as high salt diet and nitrate intake, but not bacterial infection, were viewed as important in the aetiology. The management of peptic ulcer disease has been revolutionized by the discovery of H. pylori and is now focused on antibiotic rather than antisecretory therapy, and elimination of H. pylori has become a key element in the global effort to prevent gastric cancer. Given the link between H. pylori infection and peptic ulcer disease and gastric cancer, the infection should be looked on as a major public health issue and an understanding of the epidemiology and transmission of H. pylori infection is therefore important.2 There are worldwide differences in the epidemiology of H. pylori infection. The prevalence of H. pylori infection has fallen quite rapidly in Western countries over the past few decades. About 20% of the population under the age of 40 years and about 50% of those over the age of 60 years carry the infection. The prevalence of H. pylori infection in Western countries appears to increase with age. This finding is explained to a large extent by a cohort effect whereby older people acquired H. pylori infection in childhood when the infection was considerably more prevalent than it is now.3 The actual rate of the acquisition of H. pylori infection is as low as 0.3–0.5% per patient per year in developed countries. H. pylori infection shows an inverse relationship with socio-economic status, and the infection is more prevalent in groups with low income and poor education.4 Education and wealth may, in fact, be indirect markers of hygiene, which might in turn determine whether H. pylori is transmitted or not. Living conditions during childhood may also determine the risk of acquiring H. pylori infection. Larger, poorer families where children share beds are more likely to become infected.5 The spread of H. pylori infection probably involves person-to-person contact, but whether the spread of infection is by a faecal–oral, oral–oral, or gastro–oral route remains to be resolved.6 The infection tends to cluster within families. No important animal reservoir of H. pylori infection has been found but animal sources have been suspected, including the domestic cat.7 The epidemiology of H. pylori infection appears to be different in developing countries. Firstly, the infection is far more common, with upwards of 80% of subjects carrying the infection by the age of 20 years.2 Presumably this finding is accounted for by poor hygiene and sanitation, and overcrowding. There is some evidence that H. pylori infection in developing countries is spread by contaminated drinking water, taken from a municipal supply or from community wells.8 In that context, H. pylori has been cultured from the faeces of children in Africa.2 Similar factors probably account for the higher reinfection rates seen in developing countries after patients have had effective eradication therapy. Reinfection in adults in developed countries is quite rare but has been found in 20% of patients in Brazil within 18 months of eradication.9 This finding has clear clinical implications for the value of treating H. pylori infection in developed vs. developing countries. At a global level, public health measures to improve sanitation, and eliminate poverty and overcrowding are likely to be key factors in reducing the worldwide prevalence of H. pylori. The most important impact of the discovery of H. pylori has been in the management of duodenal and gastric ulcer disease. Over 90% of duodenal ulcer and 70% of gastric ulcer patients are infected with H. pylori.10 Duodenal ulcer is a common condition with a lifetime prevalence of 10% in males and 4% in females. The incidence of duodenal ulcer is approximately 0.2% in males and 0.1% in females.11 The incidence of duodenal ulcer increases with age, and peaks at about 60 years of age. Interestingly, the incidence of duodenal ulcer has declined in recent years in developed countries, and seems to parallel the falling prevalence of H. pylori infection. In most countries, duodenal ulcer is more common than gastric ulcer but exceptions to this rule occur in countries such as Japan, where gastric ulcer is more common. Only a minority of H. pylori-infected patients develop peptic ulcers, and a combination of host factors and bacterial factors are probably critical to the development of peptic ulcer in infected individuals. For instance, genetic susceptibility to duodenal ulcer is increased in individuals of blood group O, and men are more prone to duodenal ulcer than women.12 Smokers are more at risk of peptic ulcer than nonsmokers. The single most important piece of evidence linking H. pylori and duodenal ulcer is the finding that eradication of infection prevents ulcer relapse, effectively altering the natural history. This vital finding was first highlighted by the study of Coghlan et al. and has since been reproduced in several studies.13, 14 Effective H. pylori eradication therapy also accelerates duodenal ulcer healing.15 About 1 in 10 duodenal ulcers bleed for reasons that remain unclear, but of critical importance is the fact that eradication of H. pylori dramatically reduces the occurrence of rebleeding from both duodenal and gastric ulcers.16 Curiously, a similar beneficial impact has not been demonstrated for H. pylori eradication in the management of peptic ulcer perforation.17 The prevalence of H. pylori-negative peptic ulcer disease appears to be on the increase.18 Nonsteroidal anti-inflammatory drug (NSAID) ingestion and prophylactic aspirin ingestion are important factors in H. pylori-negative peptic ulcer disease. Despite this, some H. pylori-negative peptic ulcers remain unexplained and perhaps related to factors such as excess gastric acid secretion. Nonulcer dyspepsia is defined as a syndrome of digestive symptoms referable to the upper gastrointestinal tract for which no focal lesion or systemic disease can be identified. Nonulcer dyspepsia seems remarkably common in developed countries, with a prevalence of 20–30%, and is at least three times as common as peptic ulcer disease.19 The aetiology of nonulcer dyspepsia is unclear, and several factors have been considered including H. pylori infection, abnormal motility, abnormal acid secretion and psychological factors. Similarly, a variety of treatments including acid blockers, anticholinergics and prokinetics have been tried in the treatment of non-ulcer dyspepsia, and no therapy has been found to be universally effective.20 Between 50 and 70% of patients with nonulcer dyspepsia have H. pylori infection, but no significant differences in symptoms have been detected between H. pylori-positive andnegative nonulcer dyspepsia patients. There have been several placebo-controlled trials of H. pylori therapy in the management of nonulcer dyspepsia,21 which show consistent improvement in gastritis associated with eradication of infection. The trials differ in methodology, therapy, H. pylori assessment, and methods of symptom assessment. Despite these difficulties, a recent meta-analysis suggests that H. pylori eradication provides modest but significant symptom benefit in nonulcer dyspepsia. It has been calculated, however, that 15 nonulcer dyspepsia patients might need H. pylori therapy to achieve symptom resolution in one patient.22 Escalating demand for upper gastrointestinal endoscopy, coupled with continued pressure on healthcare resources, has driven the search for alternative noninvasive management of dyspepsia. An important offshoot of clinical trials in nonulcer dyspepsia has been the increasing acceptance that uncomplicated dyspepsia in younger patients can be safely managed by noninvasive testing for H. pylori, followed by eradication therapy in H. pylori-positive patients.23 Upper GI endoscopy can then be reserved for H. pylori-negative patients, patients whose symptoms fail to resolve with H. pylori therapy, and of course for patients presenting with alarm symptoms.13 Despite advances in diagnosis and treatment, gastric cancer remains one of the most important human cancers, with a poor prognosis. Worldwide, gastric cancer remains the second most prevalent cancer, behind lung cancer.24 Although the incidence of gastric cancer has fallen rapidly in developed countries in recent decades, gastric cancer still occurs frequently in developing countries, and shows remarkable variation in incidence both between and within countries. Perhaps the most important clinical aspect of H. pylori infection is its important link with gastric cancer. The Eurogast study showed a significant correlation between the prevalence of gastric cancer and H. pylori infection in different countries worldwide.25 Prospective case–control studies have shown a clear association between H. pylori infection and the subsequent development of gastric cancer.26 Long-term follow-up studies have shown progression from H. pylori gastritis to intestinal metaplasia, dysplasia and on to cancer.27 The World Health Organization has included H. pylori on its list of known carcinogens.28 A variety of bacterial and host factors have been implicated in the link between H. pylori and gastric cancer.28,29H. pylori infection is associated with prolonged inflammation, which of itself is known to increase the likelihood of cancer. Release of oxygen free radicals from neutrophils infiltrating the gastric mucosa might be involved in carcinogenesis. H. pylori gastritis can progress to gastric atrophy, which in turn elevates intragastric pH. Hypochlorhydria facilitates the growth of nitrosating bacteria to produce so-called double infection in the stomach, which can then catalyse the production of carcinogenic N-nitroso compounds.30 Vitamin C is an important scavenger of N-nitroso compounds and oxygen free radicals, and H. pylori infection is known to inhibit the secretion of ascorbic acid into gastric juice.31 An important host factor linking H. pylori and gastric cancer is the presence of T polymorphisms in the host genetic makeup of the cytokine interleukin-1. These polymorphisms promote inflammation and inhibit gastric acid, and may increase the relative risk of gastric cancer.32 World-wide elimination of H. pylori infection might well be the ultimate method of preventing the majority of gastric cancer. This utopian ideal, however, might be difficult to achieve, particularly in developing countries, where treatment agents are not readily available, and re-infection rates are high. Efforts to improve socio-economic status and sanitation might ultimately reduce the prevalence of H. pylori infection and thus gastric cancer. Acquisition of infection in early childhood seems to be an important risk factor for gastric cancer, and the development of an effective vaccine might ultimately prove the most effective cancer-prevention strategy at a global level.33 At an individual level, it is probably worthwhile eradicating H. pylori on the assumption that this will reduce the long-term risk of gastric cancer. This particularly applies in family members of gastric cancer patients.34 It is unclear, however, whether precancerous changes such as gastric atrophy or intestinal metaplasia are reversible after H. pylori eradication.35 Long-term follow up studies on this important topic are ongoing. The lymphocytes found in the gastric mucosa in response to H. pylori infection represent an example of so-called mucosa-associated lymphoid tissue. In rare instances, the B cells infiltrate the epithelium in a neoplastic manner, and the lesion is then called a mucosa-associated lymphoid tissue lymphoma. Eradication of H. pylori leads to the disappearance and even cure of low-grade gastric mucosa-associated lymphoid tissue lymphoma.36H. pylori infection is also known to increase the risk of gastric non-Hodgkin's lymphoma.37 These tumours account for about 3% of all gastric neoplasms and about 10% of all lymphomas. The strong links between H. pylori infection and gastric neoplasms argue strongly in favour of eradication of the infection even in asymptomatic persons. H. pylori infection is generally easy to diagnose using either invasive or noninvasive methods. Invasive methods utilize gastric biopsies obtained by upper gastrointestinal endoscopy. The most widely used biopsy-based test is the rapid urease test or the so-called CLO test, which was originally devised by Dr Barry Marshall, the clinician responsible for discovering H. pylori originally. The rapid urease test depends on the fact that H. pylori has copious amounts of the enzyme urease, the presence of which causes alkali production to change the colour of a pH indicator from yellow to red, indicating a positive result. Most results from rapid urease tests declare themselves within a few hours, and an appropriate prescription can then be given to the patient after their endoscopy procedure.38 Diagnosis of H. pylori infection by histology has the advantage of providing additional information on histopathological changes in the gastric mucosa, which might include intestinal metaplasia, dysplasia, or even occasionally, early gastric cancer.39 Most histopathologists can identify H. pylori bacteria on routine haematoxylin and eosin staining but special stains can also be used to increase sensitivity. Bacterial culture of gastric biopsies can also be used to diagnose H. pylori infection. Culture is highly specific and allows assessment of antibiotic sensitivity. Culture of H. pylori infection is not widely used as a diagnostic method largely because of the technical difficulties involved at laboratory level and the fastidious nature of the infection.40 False-negative results can occur with all three biopsy-based diagnostic tests. The commonest scenario is where patients undergo endoscopy and biopsies while on continued therapy with proton pump inhibitors or antibiotics.41 A false-negative histology result can also occur where there is extensive gastric atrophy and intestinal metaplasia. The principal noninvasive test for the diagnosis of H. pylori infection is the urea breath test. This clever test, like the rapid urease test, depends on the fact that H. pylori has copious amounts of the enzyme urease. The patient drinks a urea solution containing a labelled carbon atom, usually 13C, and the detection of labelled carbon dioxide in the breath indicates that the patient is positive for H. pylori infection. The test has excellent sensitivity and specificity but does require an expensive mass spectrometer for analysis. Some centres use a 14C-based test, which is cheaper but has the significant disadvantage of radiation for the patient.42 Similar to biopsy-based tests, false-negative urea breath tests can occur in patients on treatment with proton pump inhibitors or antibiotics. H. pylori infection elicits a vigorous host immune response, and the presence of H. pylori antibodies in the blood can be used to diagnose the presence of the infection. Several commercial test kits are available, some of which are laboratory-based and some are automated with the result available almost immediately in the doctor's surgery.43 Serological tests vary in their accuracy but in practice they are extensively used, particularly in primary care, to guide decisions on treatment.44H. pylori infection can also be diagnosed by the detection of H. pylori antigens in stool samples.45 The stool antigen test is accurate but may not be attractive or user-friendly for routine use. The strongest clinical indication for eradication of H. pylori infection is in the treatment of peptic ulcer disease, where eradication of infection prevents peptic ulcer relapse and effectively cures both duodenal and gastric ulceration.46 Furthermore, successful eradication accelerates ulcer healing, gives excellent symptom relief and prevents rebleeding in patients with bleeding peptic ulcer. H. pylori eradication therapy has truly become the treatment of choice for peptic ulcer disease. A minority of peptic ulcers are H. pylori-negative and often related to ingestion of NSAIDs.47 Under these circumstances, withdrawal of the NSAIDs and continued antisecretory therapy is the treatment of choice.48 H. pylori eradication also has a role in the treatment of nonulcer dyspepsia but the results of H. pylori eradication in this patient population are not as impressive as in peptic ulcer disease.49H. pylori eradication is also advocated in relatives of patients with gastric cancer as a means of preventing gastric cancer.50 Treatment regimens for H. pylori infection have evolved rapidly over the past decade. Initially, single-agent treatment with bismuth was the treatment of choice, but since the mid-1990s, a combination of a proton pump inhibitor with two antibiotics, so-called triple therapy, has become the gold standard.51 European guidelines recommend triple therapy combining a proton pump inhibitor with clarithromycin and amoxicillin as first-line treatment.50, 52 Eradication rates approaching 90% can be achieved with this regimen.53 Some patients harbour antibiotic-resistant H. pylori infection, which is difficult to eradicate. Where first-line triple therapy has failed, recommended second-line treatment consists of quadruple therapy, combining a proton pump inhibitor, bismuth and alternative antibiotics including metronidazole and tetracycline.50 The extent of antibiotic resistance among H. pylori strains varies considerably between countries and within countries. About 28% of H. pylori infection in Europe is metronidazole-resistant compared with almost 75% in Africa.54 Primary resistance to clarithromycin is less common but seems to be on the increase. Interestingly, penicillin resistance is very unusual in H. pylori infection.55 The search continues for alternative agents to eradicate H. pylori. Alternative antibiotics such as furazolidone and the anti-tuberculosis agent rifabutin have shown promising results but clinical experience is limited to date.56 The ideal treatment for H. pylori infection should be easy to comply with, cheap, widely available, and effective. Our current treatment regimens are still quite a long way from that ideal. The socio-economic costs of H. pylori related peptic ulcer disease is considerable. Peptic ulcer is a chronic disorder characterized by frequent recurrences, which may be complicated by life-threatening bleeding or perforation. The direct costs of peptic ulcer disease include consultations, diagnostic tests, hospitalization and drug therapy, whereas indirect costs include absenteeism, poor work performance and quality of life. Prior to the advent of H. pylori eradication therapy, continuous acid-blocker treatment was the treatment of choice for peptic ulcer, which entailed considerable cumulative expense for the patient. By minimizing ulcer relapse and preventing complications without the need for expensive maintenance therapy, H. pylori eradication has emerged as the most cost-effective treatment for peptic ulcer. The socio-economic burden of gastric cancer is also considerable. It has been calculate that H. pylori infection might account for approximately 60% of all gastric cancer world-wide. Using a cost-effectiveness model, Parsonnet et al. have shown that screening and treatment of H. pylori infection is potentially cost-effective in the prevention of gastric cancer, particularly in high-risk populations. The development of an effective H. pylori vaccine also seems a reasonable prospect in the next few years. The widespread application of an effective H. pylori vaccine could help prevent gastric cancer and be of enormous socio-economic benefit. The discovery of H. pylori infection ranks as one of the most important medical discoveries of the 20th century. The most dramatic impact of H. pylori infection has been in the treatment of peptic ulcer disease, which has now become a curable condition, no longer requiring long-term antacid therapy or surgery. H. pylori infection has emerged as a key factor in gastric cancer, and treatment and prevention of H. pylori infection might well prevent this lethal disease. The search continuous for the ideal H. pylori eradication regimen but at present, proton pump inhibitor-based triple therapy is the treatment of choice. Finally, we are moving closer to an effective H. pylori vaccine, which could have enormous worldwide benefit.
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O’Connor et al. (2003) studied this question.