When Marshall and Warren elucidated the relationship between Helicobacter pylori and peptic ulcer disease, a discovery for which they were later awarded the Nobel Prize in Medicine, they rekindled the hypothesis that this common clinical malady was an infectious disease.1H. pylori is a gram-negative spiral flagellated organism that currently infects more than half of the people in the world. The prevalence of H. pylori infection varies among populations and is strongly correlated with socioeconomic conditions. In a number of developing countries, H. pylori infection affects more than 80% of middle-aged adults. Infection rates are lower in industrialized countries. Epidemiological data indicate that the prevalence of infection in the United States has been declining since the second half of the 19th century, with the decreases corresponding to improvements in sanitation. Nonetheless, H. pylori infection is predicted to remain endemic in the United States for the next century.
Human beings are the only reservoir for H. pylori. Infection is presumed to occur by oral ingestion of the bacterium. Direct transmission from person to person occurs via saliva and feces, and infection also occurs through contact with contaminated water. In developing countries, most individuals are infected during childhood. Family members are at increased risk of infection. A number of occupations also show increased rates of H. pylori infestation, notably health care workers. Infection with H. pylori is a chronic disease and does not resolve spontaneously without specific treatment.
H. pylori has evidently adapted to the hostile gastric environment and displays a number of features that permit its entry into the surface mucus layer, attachment to gastric epithelial cells, evasion of immune responses, and persistent colonization despite luminal acidity. Up to 15% of the protein in a helicobacter organism is composed of cytoplasmic urease that converts periplasmic urea into CO2 and ammonia, the latter buffering the surrounding acid.2
Host Response to H. Pylori
H. pylori infestation is followed by continuous gastric inflammation in virtually all individuals. Because spontaneous cure is unusual for most infected individuals, this means that H. pylori gastritis is a lifelong affliction. Worldwide, H. pylori–induced gastritis accounts for 80–90% of all gastritis.
H. pylori infection is not invasive of the gastric mucosa, and the host immune response is triggered by the attachment of bacteria to surface epithelial cells. The initial inflammatory response is characterized by recruitment of neutrophils, followed sequentially by T and B lymphocytes, plasma cells, and macrophages. The resultant chronic gastric inflammation in affected individuals is characterized by enhanced expression of multiple cytokines.
The relationship between H. pylori infection and ulceration is overwhelmingly strong; multiple observations establish H. pylori as a factor in the pathogenesis of duodenal ulceration.3–7 Most of the evidence is inferential. An effective vaccine has not yet been developed.
Observations that support H. pylori as a factor in the pathogenesis of human duodenal ulceration include the following:
H. pylori infection is invariably followed by the development of chronic gastritis, and the organism is the primary cause of chronic active gastritis worldwide. The infectious response to H. pylori is characterized by nonerosive inflammation of the gastric mucosa. Antral gastritis is present histologically in patients with duodenal ulcer, and H. pylori can be isolated from gastric mucosa of ulcer patients.
H. pylori binds only to gastric-type epithelium. Gastric metaplasia of the duodenal bulb is a nonspecific response to damage, which develops after infestation of the gastric mucosa. Antral gastritis with H. pylori is preceded by active chronic duodenitis. Metaplastic gastric epithelium is colonized by H. pylori from gastric sources. Gastric metaplasia is extremely common in duodenal epithelium surrounding areas of ulceration.
Eradication of H. pylori with antibiotics that have no effect on acid secretion leads to ulcer healing.
Therapy of peptic ulceration with bismuth compounds, which eradicate H. pylori, is associated with reduced rates of ulcer relapse relative to acid suppression therapy.
Relapse of duodenal ulcer after eradication of H. pylori is preceded by reinfection of the gastric mucosa by the organism.
However, infection by H. pylori alone does not cause peptic ulceration in most individuals, suggesting the existence of other pathogenetic factors. Half of patients evaluated for dyspepsia have histologic evidence of bacterial infection. In developed countries, one-fifth of healthy volunteers harbor the bacteria, and the incidence of bacterial infestation increases with age in the healthy, asymptomatic population. The occurrence of peptic ulcers in only a fraction of individuals who harbor the organism suggests that other factors must also act to induce ulceration.
H. pylori infection can be diagnosed by both invasive and noninvasive means. Noninvasive methods include the urea breath test, serology, and detection of antigen in stool samples. The urea breath test is based on production of urease by H. pylori in the gastric mucosa. C14-labeled urea is ingested and C14-labeled CO2 is produced and excreted in the breath. This test has a sensitivity and specificity of greater than 90% and indicates ongoing infection. The urea breath test is useful for initial diagnosis of infection and for follow-up after eradication therapy.
The stool antigen test is another noninvasive test to detect both initial H. pylori infection as well as response to treatment. Both polyclonal and monoclonal kits have been developed. Likewise, different kits are available for both out- and in-patient settings. Overall results have been comparable to those obtained using the urea breath test method.8
Because H. pylori induces a strong immunologic response, serological testing is useful but may not be as accurate as the urea breath test or the stool antigen test. Validation with either of the two tests is recommended. It may be used for epidemiologic studies. Because H. pylori–induced serology does not return to normal after bacterial eradication, this test is not reliable in monitoring therapy.
H. pylori infection can also be diagnosed on the basis of biopsies in patients undergoing upper endoscopic examination. Individuals older than 50 years, or those with significant symptoms including gastrointestinal (GI) bleeding, anemia, and weight loss, should undergo endoscopic diagnosis. During endoscopy, antral biopsies can be obtained and the organism cultured in agar containing both urea and a pH-sensitive colorimetric agent. H. pylori hydrolysis of urea causes a diagnostic change in color. The sensitivity of this test varies from 80 to 100% and specificity exceeds 90%. The test is associated with false-negative results in patients with active or recurrent bleeding and in those taking antibiotics or antisecretory compounds. Biopsy also permits histologic examination with visualization of the organism. Culture of H. pylori is not routine and is usually reserved for recurrent infection and for antibiotic sensitivity testing when second-line therapy has failed.
Complete eradication of H. pylori infection is the goal of treatment, and recurrence of disease signifies reinfection in most circumstances. An enormous worldwide experience has developed relating to H. pylori eradication. More than 2000 articles report the results of antibiotic trials, and a large number of summary articles and meta-analyses are available. It is important to note that none of the therapeutic regimens reported to date cure H. pylori infection in 100% of patients. To be effective, antimicrobial drugs must be combined with gastric acid secretion inhibitors or bismuth salts.
In the absence of treatment, eradication of H. pylori infection is very rare. Three consensus conference meetings as well as numerous clinical guidelines in various regions have been published in the past decade to further define the approach to diagnosis and treatment of H. pylori. The Maastricht III Consensus Report brought together a multidisciplinary group in 2007 from around the world to publish an update on the initial guidelines published in 1996 (known then as the European Helicobacter Study Group) and subsequently revised in 2000 after including a review of published guidelines from North America, Europe, China, and Japan (Table 21-1).9
Table 21-1: First Choice Treatment for H. Pylori Infection ||Download (.pdf)
Table 21-1: First Choice Treatment for H. Pylori Infection
For PPI (standard dose BID) clarithromycin (500 mg BID), amoxicillin (1000 mg BID), or metronidazole (400 or 500 mg BID), 14-d treatment is more effective than that of 7-d by 12% (95% confidence interval 7–17%). A 7-d treatment may be acceptable where local studies show that it is effective.
PPI-clarithromycin-amoxicillin or metronidazole treatment is the recommended first-choice treatment in populations with < 15–20% clarithromycin resistance. In populations with < 40% metronidazole resistance, PPI-clarithromycin-metronidazole is preferable. Quadruple treatments are alternative first-choice treatments.
The same first-choice H. pylori treatments are recommended worldwide, although different doses may be appropriate.
Current evidence indicates that eradication therapy with a proton pump inhibitor, metronidazole, and amoxicillin decreases the prevalence of metronidazole-resistant H. pylori strains. The prevalence of clarithromycin-resistant strains varies greatly from country to country, with the highest rates reported in southern Europe. In this region, clarithromycin resistance now approximates 15%. This rate is predicted to rise over the next several years with increasing use of macrolide antibiotics. In patients failing therapy, culture of H. pylori from gastric mucosa is possible for resistance testing. Also, a recent multicenter trial in Spain demonstrated that a 10-day regimen of levofloxacin (500 mg BID), amoxicillin (1 g BID), and omeprazole (20 mg BID) had 97% compliance and 77% eradication based on a negative 13C urea breath test done 4–8 weeks after completion of therapy.10