Ms. Nadgir is a senior medical student at the University of Pennsylvania School of Medicine and Dr. Levine is Chief of the Gastrointestinal Radiology section in the Department of Radiology at the Hospital of the University of Pensylvania in Philadelphia, PA.

H elicobacter pylori is arguably among the most prevalent infectious organisms of the twentieth century. Since its discovery in 1983 by Warren and Marshall, ¹ this spiral, gram-negative rod has been implicated in numerous disease processes, including gastritis, peptic ulcer disease, and gastric neoplasms. ² Because of the organism's wide spectrum of disease manifestations and the associated morbidity and mortality, considerable attention has been focused on the diagnosis and treatment of this infection. This article will summarize our current understanding of H. pylori and its radiologic implications.

H. pylori gastritis

Approximately one-third of the U.S. population is currently infected with H. pylori . ² The prevalence of infection increases with age: More than 50% of Americans over the age of 60 are H. pylori positive. ^2,3 Nevertheless, the majority of infected persons are asymptomatic. ⁴ Infection is more common among lower socioeconomic groups. ^2,4 Transmission is thought to be fecal-oral, oral-oral, or both. ⁵ Despite the high prevalence of H. pylori , infection rates in developed countries appear to be declining, possibly because of improved sanitary conditions and better hygienic practices. ²

When H. pylori infects the stomach, the organism colonizes and adheres to the gastric epithelium but does not invade the mucosa. ⁶ Infection usually is confined to the gastric antrum but can also involve the body or fundus, or even the entire stomach. ^2,7 The ensuing gastritis is manifested histologically by early neutrophilic infiltration, with subsequent predominance of plasma cells and lymphoid nodules. ⁸

The acute inflammatory process is associated with parietal cell failure and achlorhydria, presenting clinically as a mild vomiting illness that quickly resolves. ⁵ In most cases, the organism subsequently colonizes the distal stomach and duodenal bulb, while the proximal stomach returns to a state of normal or even high acid output, placing the patient at increased risk for peptic ulcer disease. ⁵ Other patients may develop a pangastritis that causes progressive mucosal atrophy and intestinal metaplasia, decreasing the risk of ulcers but increasing the risk of cancer. ⁹

H. pylori usually can be eradicated from the stomach by a treatment regimen consisting of antimicrobial agents (clarithromycin plus metronidazole or amoxicillin) and a proton pump inhibitor (such as omeprazole). ² However, in view of the high prevalence of H. pylori in the adult population, as well as the potential costs and side effects associated with treating all H. pylori -positive persons, treatment is not currently recommended for asymptomatic individuals with this infection. It is less clear whether the large number of patients with dyspepsia who have no endoscopic evidence of ulcers or tumor (so-called non-ulcer, or functional, dyspepsia) should be treated with antimicrobial therapy. In 1994, the NIH issued a consensus report stating that there was not enough evidence to justify administration of antimicrobial agents to H. pylori -positive patients with non-ulcer dyspepsia. ¹⁰ In 1997, however, another consensus statement from Europe supported the use of antimicrobial therapy in these patients. ¹¹

Two recent studies investigating the role of antimicrobial agents in H. pylori -positive patients with non-ulcer dyspepsia also have yielded conflicting data. McColl et al ¹² found a statistically significant difference in the response of H. pylori -positive patients to antimicrobial therapy in comparison to controls and concluded that all H. pylori -positive patients with non-ulcer dyspepsia should be treated with antimicrobial as well as antisecretory agents. In contrast, Blum et al ¹³ found no significant difference in the response of H. pylori -positive patients and controls to treatment with antimicrobial therapy and concluded that eradication of H. pylori in these patients does not have a major role in improving symptoms. Clearly, the controversy surrounding this organism and its role in the development of non-ulcer dyspepsia is far from resolved.

H. pylori and peptic ulcer disease

H. pylori is thought to have a major role in the development of peptic ulcers not caused by nonsteroidal anti-inflammatory agents, Zollinger-Ellison syndrome, or other hypersecretory states. ⁵ In various studies, H. pylori has been found to have a prevalence of 60 to 80% in patients with gastric ulcers and 95 to 100% in those with duodenal ulcers. ^14-16

The mechanism of ulcer formation is uncertain, but in the case of duodenal ulcers, H. pylori gastritis may lead to increased gastrin production and subsequent gastric metaplasia in the duodenum. ² Such patients are more susceptible to colonization of the duodenum by H. pylori , resulting in a weaker mucus barrier and a higher frequency of ulcers in the metaplastic epithelium. ^2,4

Whatever the pathogenesis, studies have shown that eradication of H. pylori with antimicrobial and antisecretory therapy leads to more rapid healing of both gastric and duodenal ulcers, as well as a lower rate of ulcer recurrence and rebleeding when compared to antisecretory therapy alone. ^17-19 As a result, both the NIH and European consensus panels concluded that all H. pylori -positive patients with gastric or duodenal ulcers should be treated with a combined regimen of antimicrobial and antisecretory agents. ^10,11

H. pylori and gastric cancer

Gastric carcinoma is the second most common malignant tumor in the world, accounting for 750,000 deaths annually. ²⁰ Recent data have strongly implicated H. pylori gastritis in the development of this cancer, particularly the intestinal type of adenocarcinoma. ²⁰ In one study, Parsonnet et al found that persons who were seropositive for H. pylori were three times more likely to develop gastric carcinoma within 24 years than age-matched controls. ²⁰ It has been postulated that childhood infection with H. pylori increases the risk of malignant transformation as a result of decades of inflammation and long-term exposure of dividing stem cells to various mutagens. ²⁰ Considerable evidence exists demonstrating that chronic H. pylori infection initiates the sequence of events from atrophic gastritis to intestinal metaplasia and dysplasia to, eventually, gastric adenocarcinoma. ²¹

Despite the strong association between H. pylori and gastric cancer, fewer than 1% of those with H. pylori gastritis ever develop gastric carcinoma. ²² In view of the large number of infected persons who never develop cancer, the cost and side effects of drug therapy, and the risk of developing antibiotic-resistant strains of the organism, widespread screening for H. pylori and eradication therapy do not appear to be warranted at the present time. ²² In the future, a promising approach for eradication of H. pylori and prevention of gastric cancer might involve the development of an H. pylori vaccine. ²³

H. pylori and malt lymphoma

In 1983, Isaacson and Wright proposed the concept that low grade B-cell gastric lymphomas arise from mucosa-associated lymphoid tissue (MALT). ²⁴ There is now considerable evidence that these gastric MALT lymphomas almost always occur in patients with underlying H. pylori gastritis. ^25-29 Although the stomach is normally devoid of lymphoid tissue, chronic antigenic stimulation by H. pylori infection may lead to the acquisition of organized lymphoid follicles in the lamina propria of the gastric mucosa. ³⁰ Chronic H. pylori gastritis is then thought to trigger the development of these low grade MALT lymphomas by causing autonomous proliferation of a monoclonal population of plasma B-cells. ³¹

Because of the role of H. pylori in the pathogenesis of gastric MALT lymphomas, considerable attention has recently been focused on the exciting possibility of effecting a cure by H. pylori eradication rather than combinations of chemotherapy, radiation, or surgery. In numerous studies, treatment of gastric MALT lymphoma with various antibiotic regimens has led to complete regression of these tumors, with success rates reported to be as high as 80%. ^{26,27,29,32,33} Early H. pylori eradication is essential for cure, as untreated low grade MALT lymphomas may undergo blastic transformation, eventually progressing to aggressive, high grade gastric lymphomas. ^34,35 Eradication of H. pylor i has therefore been advocated as the first line of treatment for gastric MALT lymphoma. ³⁰

Diagnosis of H. pylori gastritis

Endoscopy --Histologic examination of endoscopic biopsy specimens has been considered the gold standard
for the diagnosis of H. pylori gastritis. ^5,7 The organism can be demonstrated on biopsy specimens using hematoxylin-eosin, Giemsa, and Warthin-Starry stains. ⁷ Because H. pylori gastritis often has a multifocal distribution, it is important to obtain multiple biopsy specimens from different areas of the stomach in order to decrease the false-negative rate from sampling error. ⁷

Endoscopic biopsy specimens have a reported overall sensitivity of 95% for the detection of H. pylori . ⁵ Alternatively, the organism's urease activity and ammonia production can be used to identify H. pylori on tissue specimens via the rapid urease test, which has both a sensitivity and specificity of 95% for detecting the organism. ⁵ Although tissue cultures have a sensitivity of 90% and a specificity of 100%, ⁵ they are not routinely obtained because of the high cost and high operator dependence of this technique.

Noninvasive tests --Noninvasive tests for H. pylori , such as the serologic
and urea breath tests, have increasingly been employed for routine diagnosis of
this infection. Advantages of these noninvasive tests include their widespread availability, lower costs, and decreased procedural risks when compared to endoscopy. Serologic techniques consist of the rapid whole blood and ELISA tests; both of these tests have sensitivities and specificities ranging from 90 to 95%. ⁵ However, serologic testing is less helpful after eradication therapy, as anti- H. pylori IgG antibody levels cannot differentiate active from remote infection and can take months to decline after the organism has been eradicated. ³⁶

The urea breath test appears to be the best noninvasive diagnostic test for H. pylori in terms of accuracy and cost. When H. pylori is present in the stomach, its urease activity causes hydrolysis of C-13 or C-14 radiolabeled urea, which is excreted in exhaled breath in the form of measurable quantities of radiolabeled CO _² . ³⁶ Although the NIH consensus conference reported the possibility of false-negative results in patients receiving antibiotics or proton pump inhibitors, the C-14 urea breath test is reported to have a sensitivity and specificity of greater that 95%, making it extremely suitable for clinical practice. ³⁶

Barium studies --In recent years, various radiographic features of H. pylori gastritis have been documented on double-contrast upper gastrointestinal examinations. In the largest retrospective study to date, Sohn et al ³⁷ found that a significantly greater percentage of patients with H. pylori gastritis had thickened gastric folds (i.e., greater than 5 mm in diameter) than controls (figure 1). Thickened folds were most common in the antrum but were also found in the proximal stomach or the entire stomach. Although thickened folds are a nonspecific finding that can be associated with a variety of inflammatory or even neoplastic conditions, Sohn et al concluded that this was the single most useful criterion for identifying H. pylori gastritis.

Although less common, polypoid gastritis with markedly thickened, lobulated folds also was found in a significantly greater percentage of patients with H. pylori than controls and was considered to be another useful sign of H. pylori gastritis (figure 2). ³⁷ However, polypoid folds can also be found in patients with lymphoma or other neoplasms. In such cases, endoscopy and biopsy are required to confirm the presence of H. pylori and rule out a malignant tumor as the cause of this finding.

Additionally, Sohn et al found enlarged areae gastricae (i.e., 3 mm or greater in diameter) to be another sign of H. pylori gastritis (figure 3). In fact, it was suggested that the combination of thickened folds and enlarged areae gastricae has the greatest diagnostic yield for this infection.

In another review, by Gelfand and Ott, gastric erosions, antral narrowing, and inflammatory polyps were considered to be findings of H. pylori gastritis. ³⁸ These authors also suggested that H. pylori duodenitis may be manifested by thickened folds (greater than 4 mm in diameter), nodules, or erosions in the duodenum. When H. pylori infection is suspected on the basis of any of these findings, it is the responsibility of the radiologist to inform the primary care provider of the possibility of H. pylori in the final report. ³⁹

Recent data suggest that low grade gastric MALT lymphomas sometimes are manifested by characteristic findings on double-contrast studies. Levine et al reported a patient with gastric MALT lymphoma in whom a barium study revealed innumerable tiny nodules throughout the stomach. ⁴⁰ Subsequently, Yoo et al reported four patients with MALT lymphomas manifested by multiple, rounded, often confluent nodules varying from 2 to 7 mm in diameter (figure 4). ⁴¹ A similar appearance could be caused by severe gastritis with enlarged areae gastricae, leukemic infiltration, or even a polyposis syndrome. Nevertheless, this radiographic finding should raise concern about the possibility of gastric MALT lymphoma. Because it is a curable disease, endoscopic biopsy specimens should be obtained whenever MALT lymphoma is suspected on barium studies.

Future implications

Given the variety of options currently available for the diagnosis of H. pylori gastritis, we are no longer limited to endoscopy, an expensive, inconvenient, and invasive test for evaluating an extremely common clinical problem. In today's managed care environment, less costly and less invasive procedures such as the urea breath test and serologic testing have increasingly been employed to detect this infection, making routine endoscopy for dyspepsia unnecessary. The double-contrast upper gastrointestinal examination also is a useful test in these patients, particularly when performed in conjunction with other noninvasive tests for H. pylori .

The following is one possible scenario for evaluating patients with dyspepsia in the future. A patient with recent onset of symptoms that are unresponsive to empirical medical therapy could undergo a double-contrast upper gastrointestinal examination. If a benign-appearing gastric or duodenal ulcer is demonstrated at fluoroscopy, the barium study can be followed by a noninvasive test for H. pylori . If positive, the patient could then be treated with a regimen that includes antimicrobial and antisecretory agents. If the barium study reveals gastritis or duodenitis without evidence of ulcer disease, the patient is presumed to have non-ulcer dyspepsia, a condition which is not currently thought to warrant treatment with antimicrobial agents. In this case, no further testing for H. pylori would be required. Finally, if the barium study reveals polypoid gastritis, malignant-appearing ulcers, or any suspicious findings, endoscopy and biopsy should be performed to rule out malignant tumor. Such an approach would allow treatment of dyspepsia with the least amount of discomfort, inconvenience, and risk to the patient. ⁷

In the future, further investigation hopefully will allow us to better define appropriate management of patients with non-ulcer dyspepsia who are infected with H. pylori . Such trials may ultimately show that eradication of H. pylori is warranted in all symptomatic patients with this infection. As the role of H. pylori in the development of gastric carcinoma also is better clarified, it may eventually be deemed cost effective to prophylax all H. pylori -positive persons with antibiotics or even a vaccine against this potentially fatal illness. Despite the recent information explosion on H. pylori , much is still unknown. However, it seems likely that the importance of and our curiosity about this unique organism will carry us well into the next millennium. AR

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