CHAPTER 60: HELICOBACTER PYLORI INFECTIONS

Helicobacter pylori colonizes the stomach in ~50% of the world’s human population, essentially for life unless eradicated by antibiotic treatment. Colonization with this organism is the main risk factor for peptic ulceration as well as for gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Treatment for H. pylori has revolutionized the management of peptic ulcer disease, providing a permanent cure in most cases. Such treatment also represents first-line therapy for patients with low-grade gastric MALT lymphoma. Treatment of H. pylori is of no benefit in the treatment of gastric adenocarcinoma, but prevention of H. pylori colonization could potentially prevent gastric malignancy and peptic ulceration. In contrast, increasing evidence indicates that lifelong H. pylori colonization may offer some protection against complications of gastroesophageal reflux disease (GERD), including esophageal adenocarcinoma. Recent research has focused on whether H. pylori colonization is also a risk factor for some extragastric diseases and whether it is protective against some recently emergent medical problems, such as childhood-onset asthma and obesity.

Helicobacter pylori

H. pylori is a gram-negative bacillus that has naturally colonized humans for at least 100,000 years, and probably throughout human evolution. It lives in gastric mucus, with a small proportion of the bacteria adherent to the mucosa and possibly a very small number of the organisms entering cells or penetrating the mucosa; the organism’s distribution is never systemic. Its spiral shape and flagella render H. pylori motile in the mucus environment. The organism has several acid-resistance mechanisms, most notably a highly expressed urease that catalyzes urea hydrolysis to produce buffering ammonia. H. pylori is microaerophilic (i.e., requires low levels of oxygen), is slow-growing, and requires complex growth media in vitro.

Other Helicobacter species

A very small proportion of gastric Helicobacter infections are due to species other than H. pylori, possibly acquired as zoonoses. These non-pylori gastric helicobacters are associated with low-level inflammation and occasionally with disease. In immunocompromised hosts, several nongastric (intestinal) Helicobacter species can cause disease with clinical features resembling those of Campylobacter infections; these species are covered in Chap. 64.

Prevalence and risk factors

The prevalence of H. pylori among adults is <30% in most parts of the United States and in other developed countries as opposed to >80% in most developing countries. In the United States, prevalence varies with age: up to 50% of 60-year-old persons, ~20% of 30-year-old persons, and fewer than 10% of children are colonized. H. pylori is usually acquired in childhood. The age association is due mostly to a birth-cohort effect whereby current 60-year-olds were more commonly colonized as children than are current children. Spontaneous acquisition or loss of H. pylori in adulthood is uncommon. Childhood acquisition explains why the main risk factors for infection are markers of crowding and social deprivation in childhood.

Transmission

Humans are the only important reservoir of H. pylori. Children may acquire the organism from their parents (most often the primary caregiver) or from other children. The former is more common in developed countries and the latter in less developed countries. Whether transmission takes place more often by the fecal-oral or the oral-oral route is unknown, but H. pylori is easily cultured from vomitus and gastroesophageal refluxate and is less easily cultured from stool.

H. pylori colonization induces chronic superficial gastritis, a tissue response in the stomach that includes infiltration of the mucosa by both mononuclear and polymorphonuclear cells. (The term gastritis should be used specifically to describe histologic features; it has also been used to describe endoscopic appearances and even symptoms, but these features do not correlate with microscopic findings or even with the presence of H. pylori.) Although H. pylori is capable of numerous adaptations that prevent excessive stimulation of the immune system, colonization is accompanied by a considerable persistent local and systemic immune response, including the production of antibodies and cell-mediated responses. However, these responses are ineffective in clearing the bacterium. This inefficient clearing appears to be due in part to H. pylori’s downregulation of the immune system, which fosters its own persistence.

Most H. pylori–colonized persons do not develop clinical sequelae. That some persons develop overt disease whereas others do not is related to a combination of factors: bacterial strain differences, host susceptibility to disease, and environmental factors.

Bacterial virulence factors

Several H. pylori virulence factors are more common among strains that are associated with disease than among those that are not. The cag island is a group of genes that encodes a bacterial type IV secretion system. Through this system, an effector protein, CagA, is translocated into epithelial cells, where it may be transformed by phosphorylation and induces host cell signal transduction; proliferative, cytoskeletal, and inflammatory changes in the cell result. The protein at the tip of the secretory apparatus, CagL, binds to integrins on the cell surface, transducing further signaling. Finally, soluble components of the peptidoglycan cell wall enter the cell, mediated by the same secretory system. These components are recognized by the emergency intracellular bacterial receptor Nod1, which stimulates a proinflammatory cytokine response resulting in enhanced gastric inflammation. Carriage of cag-positive strains increases the risk of peptic ulcer or gastric adenocarcinoma. A second major virulence factor is the vacuolating cytotoxin VacA, which forms pores in cell membranes. VacA is polymorphic, and carriage of more active forms also increases the risk of disease. Other bacterial factors that are associated with increased disease risk include adhesins, such as BabA (which binds to blood group antigens on epithelial cells), and incompletely characterized factors, such as another recently described bacterial type 4 secretion system.

Host genetic and environmental factors

The best-characterized host determinants of disease are genetic polymorphisms leading to enhanced activation of the innate immune response, including polymorphisms in cytokine genes or in genes encoding bacterial recognition proteins such as Toll-like receptors. For example, colonized people with polymorphisms in the interleukin 1 gene that increase the production of this cytokine in response to H. pylori infection are at increased risk of gastric adenocarcinoma. In addition, environmental cofactors are important in pathogenesis. Smoking increases the risks of duodenal ulcers and gastric cancer in H. pylori–positive individuals. Diets high in salt and preserved foods increase cancer risk, whereas diets high in antioxidants and vitamin C are modestly protective.

Distribution of gastritis and differential disease risk

The pattern of gastric inflammation is associated with disease risk: antral-predominant gastritis is most closely linked with duodenal ulceration, whereas pan-gastritis is linked with gastric ulceration and adenocarcinoma. This difference probably explains why patients with duodenal ulceration are not at high risk of developing gastric adenocarcinoma later in life, despite being colonized by H. pylori.

Pathogenesis of duodenal ulceration

How gastric colonization causes duodenal ulceration is now becoming more clear. H. pylori–induced inflammation of the gastric antrum diminishes the number of somatostatin-producing D cells. Because somatostatin inhibits gastrin release, gastrin levels are higher than in H. pylori–negative persons, and these higher levels lead to increased meal-stimulated acid secretion from the relatively spared gastric corpus. How this situation increases duodenal ulcer risk remains controversial, but the increased acid secretion may contribute to the formation of the potentially protective gastric metaplasia found in the duodenum of duodenal ulcer patients. Gastric metaplasia in the duodenum may become colonized by H. pylori and subsequently inflamed and ulcerated.

Pathogenesis of gastric ulceration and gastric adenocarcinoma

The pathogenesis of these conditions is less well understood, although both arise in association with pan- or corpus-predominant gastritis. The hormonal changes described above still occur, but the inflammation in the gastric corpus means that it produces less acid (hypochlorhydria) despite hypergastrinemia. Gastric ulcers usually occur at the junction of antral and corpus-type mucosa, an area that is often particularly inflamed. Gastric cancer probably stems from progressive DNA damage and the survival of abnormal epithelial cell clones. The DNA damage is thought to be due principally to reactive oxygen and nitrogen species arising from inflammatory cells, perhaps in relation to other bacteria that survive in a hypochlorhydric stomach. Longitudinal analyses of gastric biopsy specimens taken years apart from the same patient show that the common intestinal type of gastric adenocarcinoma follows stepwise changes from simple gastritis to gastric atrophy, intestinal metaplasia, and dysplasia. A second, diffuse type of gastric adenocarcinoma found more commonly in younger adults may arise directly from chronic gastritis without atrophic changes.

Essentially all H. pylori–colonized persons have histologic gastritis, but only ~10–15% develop associated illnesses such as peptic ulceration, gastric adenocarcinoma, or gastric lymphoma (Fig. 60-1). Rates among women are less than half of those among men for both diseases.

Peptic ulcer disease

Worldwide, >80% of duodenal ulcers and >60% of gastric ulcers are related to H. pylori colonization. However, in particular, the proportion of gastric ulcers caused by aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) is increasing, and in many developed countries these drugs have overtaken H. pylori as a cause of gastric ulceration. The main lines of evidence supporting an ulcer-promoting role for H. pylori are that (1) the presence of the organism is a risk factor for the development of ulcers, (2) non-NSAID-induced ulcers rarely develop in the absence of H. pylori, (3) eradication of H. pylori virtually abolishes long-term ulcer relapse, and (4) experimental H. pylori infection of gerbils can cause gastric ulceration.

Gastric adenocarcinoma and lymphoma

Prospective nested case-control studies have shown that H. pylori colonization is a risk factor for adenocarcinomas of the distal (noncardia) stomach. Long-term experimental infection of gerbils also may result in gastric adenocarcinoma. Moreover, H. pylori may induce primary gastric lymphoma, although this condition is much less common. Many low-grade gastric B-cell lymphomas are dependent on H. pylori for continuing growth and proliferation, and these tumors may regress either fully or partially after H. pylori eradication. However, they require careful short- and long-term monitoring, and some necessitate additional treatment with chemotherapeutic agents.

Functional dyspepsia

Many patients have upper gastrointestinal symptoms but have normal results on upper gastrointestinal endoscopy (so-called functional or nonulcer dyspepsia). Because H. pylori is common, some of these patients will be colonized with the organism. H. pylori eradication leads to symptom resolution a little more commonly (from 0 to 7% in different studies) than does placebo treatment. Whether such patients have peptic ulcers in remission at the time of endoscopy or whether a small subgroup of patients with “true” functional dyspepsia respond to H. pylori treatment is unclear.

Protection against peptic esophageal disease, including esophageal adenocarcinoma

Much interest has focused on a protective role for H. pylori against GERD, Barrett’s esophagus, and adenocarcinoma of the esophagus and gastric cardia. The main lines of evidence for this role are (1) that there is a temporal relationship between a falling prevalence of gastric H. pylori colonization and a rising incidence of these conditions; (2) that, in most studies, the prevalence of H. pylori colonization (especially with proinflammatory cagA⁺ strains) is significantly lower among patients with these esophageal diseases than among control participants; and (3) that, in prospective nested studies (see above), the presence of H. pylori is inversely related to these cancers. The mechanism underlying this protective effect is likely H. pylori–induced hypochlorhydria. Because, at the individual level, GERD symptoms may decrease, worsen, or remain unchanged after H. pylori treatment, concerns about GERD should not affect decisions about whether to treat H. pylori when an indication exists.

Other pathologies

H. pylori has an increasingly recognized role in other gastric pathologies. It may be one initial precipitant of autoimmune gastritis and pernicious anemia and also may predispose some patients to iron deficiency through occult blood loss and/or hypochlorhydria and reduced iron absorption. In addition, several extragastrointestinal pathologies have been linked with H. pylori colonization, although evidence of causality is less strong. Studies of H. pylori treatment in idiopathic thrombocytopenic purpura have consistently described improvement in or even normalization of platelet counts. Potentially important but even more controversial associations are with ischemic heart disease and cerebrovascular disease. However, the strength of the latter associations is reduced if confounding factors are taken into account, and most authorities consider the associations to be noncausal. Several studies have shown an inverse association of cagA⁺ H. pylori with childhood-onset asthma, hay fever, and atopic disorders. These associations have been shown to be causal in animal models, but causality in humans and the size of any effect have not been established.

Tests for H. pylori fall into two groups: tests that require upper gastrointestinal endoscopy and simpler tests that can be performed in the clinic (Table 60-1).

Endoscopy-based tests

Endoscopy is usually unnecessary in the initial management of young patients with simple dyspepsia but is commonly used to exclude malignancy and make a positive diagnosis in older patients or those with “alarm” symptoms. If endoscopy is performed, the most convenient biopsy-based test is the biopsy urease test, in which one large or two small gastric biopsy specimens are placed into a gel containing urea and an indicator. The presence of H. pylori urease leads to a pH alteration and therefore to a color change, which often occurs within minutes but can require up to 24 h. Histologic examination of biopsy specimens for H. pylori also is accurate, provided that a special stain (e.g., a modified Giemsa or silver stain) permitting optimal visualization of the organism is used. If biopsy specimens are obtained from both antrum and corpus, histologic study yields additional information, including the degree and pattern of inflammation and the presence of any atrophy, metaplasia, or dysplasia. Microbiologic culture is most specific but may be insensitive because of difficulty with H. pylori isolation. Once the organism is cultured, its identity as H. pylori can be confirmed by its typical appearance on Gram’s stain and its positive reactions in oxidase, catalase, and urease tests. Moreover, the organism’s susceptibility to antibiotics can be determined, and this information can be clinically useful in difficult cases. The occasional biopsy specimens containing the less common non-pylori gastric helicobacters give only weakly positive results in the biopsy urease test. Positive identification of these bacteria requires visualization of the characteristic long, tight spirals in histologic sections; they cannot easily be cultured.

Noninvasive tests

Noninvasive H. pylori testing is the norm if gastric cancer does not need to be excluded by endoscopy. The best-established test (and a very accurate one) is the urea breath test. In this simple test, the patient drinks a solution of urea labeled with the nonradioactive isotope ¹³C and then blows into a tube. If H. pylori urease is present, the urea is hydrolyzed, and labeled carbon dioxide is detected in breath samples. The stool antigen test, a simple and accurate test using monoclonal antibodies specific for H. pylori antigens, is more convenient and potentially less expensive than the urea breath test, but some patients dislike sampling stool. The simplest tests for ascertaining H. pylori status are serologic assays measuring specific IgG levels in serum by enzyme-linked immunosorbent assay or immunoblot. The best of these tests are as accurate as other diagnostic methods, but many commercial tests—especially rapid office tests—do not perform well.

Use of tests to assess treatment success

The urea breath test, the stool antigen test, and biopsy-based tests can all be used to assess the success of treatment (Fig. 60-2). However, because these tests are dependent on H. pylori load, their use <4 weeks after treatment may yield false-negative results. Furthermore, these tests are unreliable if performed within 4 weeks of intercurrent treatment with antibiotics or bismuth compounds or within 2 weeks of the discontinuation of proton pump inhibitor (PPI) treatment. In the assessment of treatment success, noninvasive tests are normally preferred; however, after gastric ulceration, endoscopy should be repeated to ensure healing and to exclude gastric carcinoma by further histologic sampling. Serologic tests are not used to monitor treatment success, as the gradual drop in titer of H. pylori–specific antibodies is too slow to be of practical use.

Carriage of H. pylori has considerable public health significance in developed countries, where it is associated with peptic ulcer disease and gastric adenocarcinoma, and in developing countries, where gastric adenocarcinoma may be an even more common cause of cancer death late in life. If mass prevention were contemplated, vaccination would be the most obvious method, and experimental immunization of animals has given promising results. However, given that H. pylori has co-evolved with its human host over millennia, preventing or eliminating colonization on a population basis may have biological and clinical costs. For example, lifelong absence of H. pylori is a risk factor for GERD complications, including esophageal adenocarcinoma. We have speculated that the disappearance of H. pylori may also be associated with an increased risk of other emergent diseases reflecting aspects of the current Western lifestyle, such as childhood-onset asthma and allergy.