INTRODUCTION — The majority of patients with duodenal ulcer (DU) are infected with Helicobacter pylori (H. pylori). However, in multicenter trials, H. pylori was absent in almost 30 percent of patients with an endoscopically documented duodenal ulcer [1]. Studies that have investigated these patients found that they have generally had a shorter duration of symptoms and that many had regularly used nonsteroidal anti-inflammatory drugs (NSAIDs) [2-4]. Such patients have a significantly worse outcome, especially if treated empirically for H. pylori infection. Thus, H. pylori status should be determined in all ulcer patients before initiating treatment [4]. High acid output may be a cause of recurrent DU in patients in whom H. pylori has been eradicated [5]. A variety of other causes are responsible for the remaining cases. (See "Unusual causes of peptic ulcer disease".)
The link between H. pylori and DU will be reviewed here. The pathophysiology of H. pylori infection as it relates to gastrointestinal disease in general is discussed separately. (See "Pathophysiology of and immune response to Helicobacter pylori infection".)
EVIDENCE LINKING HELICOBACTER PYLORI TO DUODENAL ULCERS — There are several lines of evidence that implicate H. pylori as a major etiologic factor in duodenal ulcers (DU):
●H. pylori is present in most patients who have a DU that is not related to NSAID use
●H. pylori infection is detectable before the occurrence of DU and appears to be a risk factor for the disorder
●Eradication of H. pylori prevents DU recurrence
Incidence of H. pylori in patients with duodenal ulcer — Early studies noted a high incidence of H. pylori infection (then called Campylobacter pylori) in patients with DU [6]; subsequent reviews confirmed that H. pylori is detectable in 80 to 95 percent of these patients [2,7]. These data were supported by reports which found that the prevalence of H. pylori is negligible in populations in which ulcer disease is rare [8].
The prevalence of H. pylori in patients with DU is changing in some parts of the world [9]. While H. pylori infection remains very common in patients from Asia with DU, it is becoming less common in patients from the United States and parts of Europe. In an epidemiologic study from China, 1030 patients underwent endoscopy and 73 percent were found to have H. pylori [10]. Peptic ulcers were present in 17 percent, more than two-thirds of which were duodenal ulcers. Among those with peptic ulcers, the prevalence of H. pylori infection was 93 percent. On the other hand, in the United States and parts of Europe, the prevalence of H. pylori in patients with ulcer disease appears to be falling and is now in the range of 50 to 75 percent. (See "Peptic ulcer disease: Epidemiology, etiology, and pathogenesis", section on 'H. pylori'.)
While the association between H. pylori and DU is strong, it is not specific. As examples, H. pylori infection is also found in patients with gastric ulcers (65 to 95 percent), dyspepsia (20 to 60 percent), gastric cancer (70 to 90 percent), and asymptomatic patients (20 to 45 percent) [2]. (See "Approach to the adult with dyspepsia" and "Association between Helicobacter pylori infection and gastrointestinal malignancy".)
H. pylori occurs before manifestations of the disease — Several trials have found that preexisting H. pylori infection is a risk factor for the development of DU [11-14]. One study, for example, reviewed the cases of more than 5000 Native Hawaiians who had stored serum from the late 1960s [12]. Of the 65 patients who developed DU over the next 20 years, 92 percent were H. pylori positive versus 78 percent of controls, producing an odds ratio of 4.0. Similarly, an endoscopic study that included 526 patients with long-term follow-up found that the odds ratio of developing DU was 5.0 for those with preexisting H. pylori infection compared with H. pylori-negative subjects [14].
Eradication of H. pylori reduces disease recurrence — Treatment of H. pylori infection in patients with DU decreases the incidence of ulcer recurrence. One meta-analysis examined the recurrence rate for DU after at least six months of follow-up. The recurrence rate was 6 percent if H. pylori was eradicated and 67 percent if it was not [15]. A second meta-analysis found recurrence rates of 20 and 56 percent, respectively [16]. The studies in the meta-analyses used endoscopic findings to define ulcer recurrence. It should be noted that the rate of symptomatic recurrence is lower. (See "Approach to refractory peptic ulcer disease".)
PATHOGENESIS OF ULCER FORMATION — The precise mechanism by which H. pylori contributes to duodenal ulcer (DU) formation is incompletely understood. However, the bacterium appears to affect the following aspects of intestinal and mucosal physiology:
●Increased gastric acid secretion
●Gastric metaplasia
●Immune response
●Mucosal defense mechanisms
There may also be a contribution from a variety of bacterial, host, and environmental factors that have a role in the pathogenesis of ulcer formation (algorithm 1).
Increased gastric acid secretion — Acute H. pylori infection induces a short period of hypochlorhydria. In contrast, chronic infection often leads to increases in basal and stimulated acid output, particularly in patients who develop DUs (figure 1) [17,18]. In addition, following H. pylori eradication, mean basal and stimulated acid output drops by 50 percent at one month and returns to normal levels by one year [17].
One mechanism by which H. pylori may enhance gastric acid secretion is via increased release of gastrin. Gastrin is responsible for gastric acid secretion in normal subjects by two mechanisms:
●It has a trophic action on parietal cells and histamine-secreting enterochromaffin-like (ECL) cells
●It stimulates parietal cells largely via the release of histamine
This process is tightly controlled by a second hormone, somatostatin, which is a potent inhibitor of gastrin synthesis, gastrin release, and gastric acid secretion. (See "Physiology of gastric acid secretion".)
Patients with H. pylori infection have elevated basal and stimulated concentrations of serum gastrin [17,19] and a decreased concentration of somatostatin [20]. The peak acid output achieved after stimulation with gastrin releasing peptide, regarded as a measure of the stomach's functional response to endogenous gastrin, is also increased threefold in healthy H. pylori positive patients, and sixfold in those with DU [17,18]. These values completely normalize within one year of H. pylori eradication (figure 1) [21].
The peak acid output after pentagastrin stimulation (PAOPg), a measure of the functional parietal cell population, is also significantly increased in H. pylori-associated DU disease. However, there are conflicting data regarding the effect of H. pylori eradication on PAOPg [17,22,23].
The mechanism of the increased acid response in patients infected with H. pylori who have DU disease compared with infected healthy patients is unclear. One study suggests that it may be due to the combination of decreased sensitivity to gastrin in healthy patients, and increased maximal acid secretory capacity in those with DU [24].
Suppression of somatostatin (rather than an increase in gastrin-secreting cells) is probably the initial event that then leads to the hypergastrinemia that is evident in patients with DU and H. pylori. This hypothesis is supported by a study of 28 infected patients with DU that found that after the infection was successfully eradicated, the median density of somatostatin-immunoreactive cells (antral D cells) increased from 9 to 19 cells/mm muscularis mucosa, while the median somatostatin mRNA/rRNA ratio increased from 50 to 95 [25]. In contrast, the number of gastrin-immunoreactive cells and the quantity of gastrin mRNA did not change significantly. The role of H. pylori in this process is supported by studies that have shown eradication of infection reverses the abnormalities in gastrin and gastric acid secretion (figure 1) [17,22].
Nevertheless, hypergastrinemia alone probably does not explain the increases in acid output in patients infected with H. pylori; gastrin levels often return to normal within one month after eradication, while mean basal and peak acid output remain elevated for longer periods of time. In addition, H. pylori itself does not appear to alter the sensitivity of gastric parietal cells to gastrin [26], although hypergastrinemia may have trophic effects over time that result in increased parietal cell mass.
Gastric metaplasia — Gastric metaplasia refers to the presence of gastric epithelium in the first portion of the duodenum. This abnormality appears to be a response of the mucosa to excessive acid exposure since it only occurs when the luminal pH is less than 2.5 [27]. In addition to acid hypersecretion, impaired duodenal bicarbonate secretion induced by H. pylori also may contribute to the low duodenal luminal pH [28].
The metaplastic foci provide areas for H. pylori colonization, and probably have a role in the development of duodenitis. In one study, for example, 30 of 34 (88 percent) patients with active duodenitis had more than 5 percent gastric metaplasia in duodenal mucosal specimens and H. pylori-associated gastritis [27]. In contrast, these two factors coexisted in only 0.43 percent of patients with no duodenal inflammation. In addition, when H. pylori was seen histologically in duodenal biopsy specimens, it was confined only to areas of gastric metaplasia, and never occurred in the absence of a polymorphonuclear infiltrate. A more recent study confirmed that the extent of duodenal gastric metaplasia was fourfold greater in H. pylori-infected duodenal ulcer patients than in infected asymptomatic controls [29]. Colonization of the duodenal bulb by H. pylori CagA+ strains was also greater in DU patients than in infected non DU controls (80 versus 30 percent), even though prevalence of CagA+ gastric infection was similar in both groups. These studies support the contention that infection of gastric metaplasia is important in the pathogenesis on DU.
H. pylori infection in areas of gastric metaplasia may weaken the mucosa, making it more susceptible to acid injury. This hypothesis is supported by studies which have found that gastric metaplasia increases the relative risk for ulceration fivefold; the presence of H. pylori within these regions increases the risk 50-fold [30].
Gastric metaplasia is not the same as gastric heterotopia, in which (presumably) congenital patches of gastric-type mucosa occur anywhere in the small or large intestine, although the two entities may be difficult to distinguish. (See "Metaplastic (chronic) atrophic gastritis".)
Immune response — Although H. pylori is a noninvasive organism, it stimulates a robust inflammatory and immune response that may have a role in DU formation. The response includes increased production of inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor alpha, and most notably, IL-8. (See "Pathophysiology of and immune response to Helicobacter pylori infection".)
Mucosal defense factors — H. pylori may downregulate several important mucosal defense factors.
●Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF alpha) are potent gastric acid inhibitors and stimuli of mucosal growth and protection. One study found that the basal and stimulated release of EGF is significantly increased after eradication of H. pylori, an effect that may play a role in ulcer healing [31].
●Patients with DUs have decreased proximal duodenal mucosal bicarbonate production. It is not clear if impaired bicarbonate secretion can be attributed to H. pylori; however, eradication of the infection does result in normalization of bicarbonate output [28].
●H. pylori itself releases proteases that degrade normally protective mucous glycoproteins that overlie the mucosa [32].
Other contributing factors — Only 10 to 15 percent of patients with H. pylori infection develop ulcer disease, suggesting that other factors are probably important in determining the outcome of infection. One such factor is the bacterial strain; only strains with the cytotoxin-associated gene A (cagA), coding for a 128-140 kDa protein (CagA), coexpress vacuolating cytotoxin (VacA), a toxin that causes cell injury in vitro [33]. Approximately 85 to 100 percent of patients with DU have CagA+ strains, compared with 30 to 60 percent of infected patients who do not develop ulcers [34]. However, since CagA+ strains are also associated with gastric cancer, the specificity of the association makes it less clear how the same strain can lead to two very divergent conditions. (See "Pathophysiology of and immune response to Helicobacter pylori infection".)
A specific H. pylori gene, dupA, appears to be associated with development of DU. Those infected with dupA bacteria had more intense antral inflammation, higher levels of IL-8 and less gastric atrophy, intestinal metaplasia, and gastric cancer, a cytokine and histologic profile associated with DU disease [35]. One study suggested that the dupA gene, which encompasses jhp0917 and jhp0918, was associated with an increased risk of DU and protection against gastric cancers [36]. The 112bp region of H. pylori dupA may be associated with an increased risk of duodenal ulcer and has the potential to serve as a biomarker for early detection of DU [37,38].
In addition, genetic factors may help determine the susceptibility to infection with H. pylori [39,40]. It has been suggested that patients with H. pylori who develop DU have an intrinsically higher parietal cell mass or sensitivity to gastrin than H. pylori-positive healthy adults [24,30,41]. This observation may explain the exaggerated acid response to various stimuli in those who develop DUs. Genetic factors may also determine duodenal cytokine response to infection. In one study, duodenal epithelial cells from patients with a duodenal ulcer had a decreased capacity to produce inflammatory cytokines compared with controls from patients without a DU [42].
Environmental factors such as smoking and nonsteroidal anti-inflammatory drug (NSAID) use may also increase the risk of ulcer formation in patients with H. pylori [32,43-45]. One report noted an increased prevalence of ulcers in H. pylori-infected smokers compared with infected nonsmokers (73 versus 27 percent) [44].
Multiple studies of variable design have evaluated the relationship between NSAIDs and H. pylori in the development of peptic ulcer disease. The following conclusions were reached in a meta-analysis of 25 such studies [46]:
●Users of NSAIDs with H. pylori infection were 61 times more likely to have a peptic ulcer than non-infected non-NSAID users.
●Either factor alone increased the risk of ulcer disease by approximately 20-fold.
●H. pylori infection and NSAID use increased the risk of ulcer bleeding by 1.8 and 4.9-fold, respectively; when present together they increased the risk of ulcer bleeding by sixfold.
A subsequent meta-analysis of studies published between 1999 and 2008 with a total of 16,080 patients found that the mean prevalence of H. pylori infection in DUs was 81 percent [47]. If only the last five years' literature was considered, the rate was 77 percent. H. pylori-negative DUs were associated with NSAID use in 21 percent of patients when studies with infection rates of less than 90 percent were examined. The majority of the H. pylori-negative ulcers were attributed to false-negative H. pylori testing, since even under optimal conditions the sensitivity of testing is below 95 percent [48]. Other causes for H. pylori-negative DUs were much less common.
NSAID users with a history of peptic ulcer disease should be tested and treated for H. pylori if they are infected; there are also data to suggest that testing and treating (if positive) all patients for H. pylori prior to beginning NSAID use may be warranted [49,50], although conflicting data have also been reported [51], and this is not currently the standard of care. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Peptic ulcers (The Basics)" and "Patient education: H. pylori infection (The Basics)")
●Beyond the Basics topics (see "Patient education: Peptic ulcer disease (Beyond the Basics)" and "Patient education: Helicobacter pylori infection and treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●There are several lines of evidence that implicate H. pylori as a major etiologic factor in duodenal ulcers (DUs) (see 'Evidence linking Helicobacter pylori to duodenal ulcers' above):
•H. pylori is present in most patients who have a DU that is not related to nonsteroidal anti-inflammatory drug (NSAID) use
•H. pylori infection is detectable before the occurrence of DU and appears to be a risk factor for the disorder
•Eradication of H. pylori prevents DU recurrence
●In the United States and parts of Europe, the prevalence of H. pylori in patients with ulcer disease appears to be falling. It is now in the range of 50 to 75 percent but remains high in Asia. (See 'Incidence of H. pylori in patients with duodenal ulcer' above.)
●The precise mechanism by which H. pylori contributes to DU formation is incompletely understood. However, the bacterium appears to affect the following aspects of intestinal and mucosal physiology which may be important (see 'Pathogenesis of ulcer formation' above):
•Increased gastric acid secretion
•Gastric metaplasia
•Immune response
•Mucosal defense mechanisms
●Only 10 to 15 percent of patients with H. pylori infection develop ulcer disease, suggesting that other factors are probably important in determining the outcome of infection. (See 'Other contributing factors' above.)
●In apparent H. pylori-negative DUs, a thorough search for infection should be conducted as infection remains the major cause of DUs. (See 'Other contributing factors' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Sheila E Crowe, MD, FRCPC, FACP, FACG, AGAF, who contributed to an earlier version of this topic review.
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