Helicobacter pylori colonizes the stomachs of ∼50% of the world's human population throughout their lifetimes. Colonization with this organism is the main risk factor for peptic ulceration (Chap. 293) as well as for gastric adenocarcinoma and gastric MALT (mucosa-associated lymphoid tissue) lymphoma (Chap. 91). 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 a risk factor for some extragastric diseases and whether it is protective against some recently emergent medical problems, such as asthma and obesity.
H. pylori is a gram-negative bacillus that has naturally colonized humans for at least 50,000 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; its 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 (requiring low levels of oxygen), is slow-growing, and requires complex growth media in vitro. Publication of several complete genomic sequences of H. pylori since 1997 has led to significant advances in the understanding of the organism's biology.
A very small proportion of gastric Helicobacter infections are due to species other than H. pylori, possibly acquired as zoonoses. Whether these non-pylori gastric helicobacters cause disease remains controversial. 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. 155.
The prevalence of H. pylori among adults is ∼30% in the United States and other developed countries as opposed to >80% in most developing countries. In the United States, prevalence varies with age: ∼50% of 60-year-old persons, ∼20% of 30-year-old persons, and <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. Other strong risk factors for H. pylori colonization are markers of crowding and maternal colonization. The low incidence among children in developed countries at present is due, at least in part, to decreased maternal colonization and increased use of antibiotics.
Humans are the only important reservoir of H. pylori. Children may acquire the organism from their parents (more often from the mother) or from other children. 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.
Pathology and Pathogenesis
H. pylori colonization induces a tissue response in the stomach, chronic superficial gastritis, which 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, which 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 immune response, including the production of both local and systemic antibodies as well as 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.
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 secretion system through which a specific protein, CagA, is translocated into epithelial cells. CagA affects host cell signal transduction, inducing proliferative, cytoskeletal, and inflammatory changes; a proportion of transgenic mice expressing CagA in the stomach develop gastric adenocarcinoma. The secretion system also translocates soluble components of the peptidoglycan cell wall into the gastric epithelial cell; these components are recognized by the intracellular emergency bacterial receptor Nod1, which stimulates a proinflammatory cytokine response resulting in enhanced gastric inflammation. Patients with peptic ulcer disease or gastric adenocarcinoma are more likely than persons without these conditions to be colonized by cag-positive strains. The secreted H. pylori protein VacA occurs in several forms. Strains with the more active forms are more commonly isolated from patients with peptic ulcer disease or gastric carcinoma than from persons without these conditions. Other bacterial factors that are associated with increased disease risk include adhesins, such as BabA and SabA, and incompletely characterized genes, such as dupA.
The best-characterized host determinants of disease are genetic polymorphisms leading to enhanced activation of the innate immune response, such as polymorphisms in cytokinegenes or genes encoding bacterial recognition proteins such as Toll-like receptors (TLRs). For example, colonized people with polymorphisms in the interleukin (IL) 1 gene that ...