Helicobacter pylori gastritis: A ‘normal’ phenomenon

278 SELECTED SUMMARIES

GASTROENTEROLOGY

ride chains of glycoproteins (Trends Biochem Sci 1989;145:272-2763. Logically, an understanding of putative functions such as homotypic intercellular adhesion on the part of CEA will therefore require detailed analysis of its saccharide components. Polyclonal antihodies of the type used in this study may not distinguish qualitative

differences between CEAs with quite different functional properties. In future studies, the combined application of monoclonal antibodies to CEA with different epitope specificities and experimental manipulations of CEA glycosylation. e.g., by oligosaccharidedirected mutagenesis of glycosylation sites, should help explain what CEA does. The present study provides a very promising start. M. P. LANCE, M.B.. M.R.C.P.

CENTRAL REGULATION OF DUDODENAL BICARBONATE SECRETION Lenz HJ, Brown MR. (Department of Medicine, University of Hamburg, Hamburg, Federal Republic of Germany, and Departments of Medicine and Surgery, University of California, San Diego, California]. Cerebroventricular calcitonin gene-related peptide inhibits rat duodenal bicarbonate secretion by release of norepinephrine and vasopressin. J Clin Invest 1990;85:25-32 (January]. Duodenal bicarbonate secretion is an important factor protecting the mucosa against acid damage. Decreased duodenal bicarbonate secretion at rest and in response to acid is observed in duodenal ulcer patients (N Engl J Med 1987;316:374-379). This study examines a possible role for calcitonin gene-related peptide (CGRP) in the central nervous system regulation of duodenal bicarbonate secretion in the unanesthetized rat. The objectives were threefold: (a) to examine the pharmacological properties of CGRP inhibition of resting and stimulated duodenal bicarbonate secretion, (b) to determine the peripheral pathways involved in mediating the central nervous system effects of CGRP, and (c) to study the peripheral effects of the presumed transmitters released by CGRP. The results in this study indicate that cerebroventricular administration of CGRP inhibits both basal duodenal bicarbonate secretion and secretion induced by diverse stimuli such as vasoactive intestinal peptide, neurotensin, misoprostol (a prostaglandin E, analogue), and hydrochloric acid. This central inhibitory effect of CGRP appears to be neurally mediated via sympathetic efferents because it could be abolished by ganglionic blockage with chlorisondamine, attenuated by noradrenergic blockage with bretylium, and enhanced by vagotomy. Furthermore, inhibition of duodenal bicarbonate secretion by CGRP coincided with increases in the plasma levels of norepinephrine and vasopressin. Pretreatment of the animals with the combination of an cY-adrenergic antagonist, phentolamine, and the vasopressin V, antagonist l-deaminopenicillamine 2-[Omethyl] Tyr, 8-Arg vasopressin abolished the central inhibitory effect of CGRP. When administered alone, neither antagonist was able to completely reverse the effect of the neuropeptide. Finally, intraperitoneal administration of vasopressin or norepinephrine decreased duodenal bicarbonate secretion; their effects were additive and could be prevented by their respective antagonists. The authors conclude that cerebroventricular CGRP inhibits rat duodenal bicarbonate secretion by activation of sympathetic efferents with consequent release of norepinephrine and vasopressin.

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These peripheral mediators then act on a-adrenergic and vasopressin receptors, causing an inhibition of duodenal bicarbonate secretion. Comment. A decreased ability to secrete bicarbonate from the duodenum appears to be an important determinant in the pathogenesis of duodenal ulcers. Hence an understanding of the factors that regulate duodenal bicarbonate secretion in health may improve our ability to pharmacologically modify bicarbonate secretion in disease. However, regulation of duodenal bicarbonate secretion is a complex and interactive process. Locally, there may be luminal and basolateral regulators of the duodenal epithelial cells. From the luminal side, hydrochloric acid from the stomach appears to be the most potent stimulus. From the basolateral side, prostaglandins, certain peptides, and neurotransmitters, including prostaglandin E,, vasoactive intestinal polypeptide, and neurotensin, can also contribute to the regulation of bicarbonate secretion. Some of these basolateral factors, such as prostaglandin E, and vasoactive intestinal polypeptide, have been implicated as the mediators released by luminal acid to stimulate bicarbonate secretion. It is likely that other stimulatory factors remain to be recognized. Candidates for such factors might include local paracrine and endocrine controls, neurally mediated controls [including those arising from the local, peripheral, and central nervous systems], and substances derived from immunologic effector cells. Of course, inhibitory controls are just as important as the stimulatory ones, and such inhibitory controls are the focus of the study described. In this paper, the authors convincingly demonstrate that cerebroventricular administration of CGRP inhibits bot$ resting duodenal bicarbonate secretion and a stimulated state of secretion induced by the activating stimuli described above. The authors have carefully shown that this effect is likely to be caused by activation of sympathetic efferents that release norepinephrine and vasopressin. These secondary mediators then inhibit duodenal biocarbonate secretion, although the mechanisms involved in this inhibitory process remain to be investigated. Similarly, it is still unknown whether norepinephrine and vasopressin act directly on the secretory epithelial cells or whether a tertiary level of messengers is involved. Duodenal mucosal integrity represents a fine balance between aggressive forces (such as gastric acid and others) and protective forces [such as bicarbonate and others]. One may assume that the paracrine, neurocrine, endocrine, and immune systems control the relative contributions of aggressive and protective factors at the local level. Central regulation via the central and peripheral nervous systems provides another layer of control, which may additionally interact with local controlling mechanisms. Central nervous system controls are usually mediated by peptides or neurotransmitters that can either directly affect secretory cell function or indirectly affect secretory cells via actions on other systems, such as the blood supply for example. In summary, the paper by Lenz and Brown makes two contributions. First, it significantly enhances our understanding of the regulatory physiology of duodenal bicarbonate secretion. Second, it suggests that we should look not only to increased gastric acid secretion, but also possibly to decreased duodenal bicarbonate secretion, to explain duodenal mucosal damage associated with stress or other central nervous system pathology. K. DHARMSATHAPHORN, K. E. BARRETT,

M.D. PH.D.

Helicobacter pylori GASTRITIS: A ‘NORMAL’ PHENOMENON Dooley CP, Cohen H, Fitzgibbons PL, et al. (Departments Medicine and Pathology, Los Angeles County-University

of of

July 1990

Southern California Medical Center, Los Angeles, California, and Veterans Administration Medical Center, Denver, Colorado]. Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic persons. N Engl J Med 1989;321:1562-1566. The endoscopic and microscopic appearance of antral and corpusgastric mucosa was determined in 113 asymptomatic, healthy adults. The histological findings were correlated with the presence or absence of Helicobacter pylori using tissue staining, culture, and serum antibodies. Endoscopically, mucosal erosions were found in 13 of the subjects and a duodenal ulcer in 1; all such lesions were found in subjects older than 40 years. H. pylori was present in 34% as determined by serum antibodies to H. pylori, 32% as detected by the H&E tissue stain, and 19% using culture for H. pylori. The organism was present by H&E in both antrum and corpus in 28 subjects, in the antrum only in 4 subjects, and in the corpus only in 4 subjects. Factors significantly associated with the presence of H. pylori included antibiotic use in the g-month period before the study (increased risk for infection) and bismuth use (decreased risk for infection). There was a significant trend toward an increase in the prevalence of H. pylori with age, but only in those subjects who used neither antibiotics nor bismuth. The prevalence of H. pylori as a function of tissue histology (as best I could determine from the text] is as follows: In the corpus, H. pylori were found in 100% of those with active gastritis, 86% of those with inactive gastritis, and only 1% of those with normal histology. In the antrum, the respective figures were lOO%, 82%, and 0%. Comment.

After the seminal publication by Marshall and Warren in 1983 describing Campylobacter (now Helicobacter] pylori (Lancet 1983;1:1273-12741,several papers called attention to the fact that there was a substantial prevalence of H. pylori in normal (primarily young) subjects (Lancet 1984:1:1348;Arch Intern Med 1988;148:11491151; Gastroenterology 1988;95:1185-1197); that in these subjects there was a close association between H. pylori and gastritis, especially active gastritis; and that H. pylori could be found in histologically normal corpus [Gastroenterology 1988;95:1185-1197; Stand J Gastroenterol1988:23(suppl142):69-751. Subsequently, several groups used indirect methods (i.e., urea breath test, serology) to detect the presence of H. pylori in larger numbers of subjects of differing ages (J Infect Dis 1988:157:777-780; Ann Intern Med 1988;109:11-17). These data showed a striking increase in the prevalence of H. pylori in asymptomatic older individuals. The paper by Dooley et al. presents the results of a study in which a large number of healthy volunteers of varying ages were assessed for the presence or absence of H. pylori primarily using endoscopically obtained tissue, although serum antibodies to H. pylori were also measured. Although there were some deficiencies in the paper (i.e., a subject with duodenal ulceration at endoscopy should have been excluded from this group of “normals,” not all subjects had a complete history obtained, inclusion of subjects who had taken antibiotics or bismuth clouded data analysis, and fine points of data were somewhat difficult to extract from the text). it is a well-done and important study. In particular, the large sample size provides confidence in the results. Several issues merit comment. First, “detection” of H. pylori was most sensitive with serology, followed by stain, and then by culture. This is not surprising because serology can, for at least some time, provide evidence of prior infection with H. pylori even if the organism is no longer present in the stomach. Tissue stain is the most sensitive direct way to detect ongoing

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infection with H. pylori in gastric epithelium. Cultures may be falsely negative because of a small number of organisms or technical problems such as bacterial overgrowth. Indeed, in this study 9 of IO patients over 50 years of age with positive stains but negative cultures had bacterial overgrowth, prompting the authors Cospeculate that these individuals may have been hypochlorhydric. They support this premise by noting that serum pepsinogen I levels were lower in these 9 than in the subjects with positive culture. However, because acid output was not measured, this remains speculative. Second, while a lower prevalence of H. pylori in those who had taken bismuth is not surprising, a higher prevalence in subjects taking antibiotics is perplexing. Perhaps some of these subjects were hypochlorhydric and without antibiotics would have had bacterial overgrowth on the culture plates, obscuring the more fastidious H. pylori. Third, H. pylori was found in 100% of subjects with active gastritis; in 86% and 82% of those with inactive corpus and antral gastritis, respectively; and in only one subject with normal corpus or antral mucosa. Thus there was a very tight association between the presence of H. pylori and an inflammatory reaction, an observation made by many previous investigators. One slight discrepancy between the results of Dooley and those of others is the virtual absence of H. pylori in subjects with normal corpus mucosa. Whereas Dooley et al. found only one subject (of 78) with H. pylori in normal corpus mucosa, others have found a prevalence of up to 18% [Stand J Gastroenterol1988;23(suppl142):69-751. One explanation for this discrepancy may lie in the definition of “gastritis,” which depends on subjective assessment of mucosal inflammation. For example, what others call “normal,” Dooley et al. may call “inactive gastritis.” There is clearly a need for a consistent, objective system of grading the degree and type of inflammatory response. Dooley et al. have made a major contribution to our understanding of the prevalence of H. pylori in healthy subjects. It is clear that many normal people are infected with H. pylori and that the prevalence in normal subjects increases with age. What remains unclear is the clinical importance of H. pylori gastritis. Virtually 100% of patients with duodenal ulcer disease, regardless of age, have evidence of H. pylori gastritis. This high prevalence has led a number of investigators to consider H. pylori, via infection of areas of gastric metaplasia in the duodenal bulb, an important predisposing cause of duodenal ulcers. However, the fact that so many normal subjects also have H. pylori gastritis suggests either that there is no causal relationship or that other factors are also crucial to the formation of an ulcer. Studies assessing the role of antimicrobial therapy have suggested that eradication of H. pylori, and subsequent resolution of gastritis, reduces the recurrence rate of duodenal ulceration. However, these studies have had design flaws (see Selected Summaries, Gastroenterology 1989;97:508-510) and, in my opinion, are not conclusive. If further studies confirm the importance of H. pylori gastritis in duodenal ulcer, we still need to learn why only a small subset of individuals with H. pylori gastritis develop ulceration. Do some strains of H. pylori have “extra” pathogenic factors (e.g., toxins] leading to ulceration? Are patients destined to develop ulcers more likely to have gastric metaplasia in the duodenal bulb? Must local abnormalities (e.g., deficient prostaglandin levels, reduced blood flow] occur in the presence of H. pylori gastritis (and, of course, adequate levels of gastric acid] for an ulcer to develop? Plenty of work remains. W. L. PETERSON,

M.D.

GLUTAMINE: AN ESSENTIAL NONESSENTIAL AMINO ACID FOR THE GUT O’Dwyer ST, Smith Rf, Huang TL, et al. (Departments of Surgery and Medicine, Brigham and Women’s Hospital and