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Editor,—I was interested to read the elegant report of Murayama et al (
) demonstrating increased inflammation and abnormal parietal cell morphology and function in patients with Helicobacter pylori associated giant fold gastritis. However, the authors raise several points which deserve further comment.
The authors suggest that mediators of the inflammatory response may be important in inhibiting acid secretion and cite interleukin 1β (IL-1β) as the most important agent. It would be unwise not to consider other mediators. It is clear that IL-1β has a variety of acid inhibitory actions; inhibiting gastric acid secretion when given both parenterally1 and intracerebrally,2 as well as having direct reversible inhibitory actions against both parietal cells3 and ECL cells.4 Thus locally produced IL-1β may certainly be an important mediator of hypochlorhydria, indeed the same authors have previously shown that IL-1β production in giant fold gastritis was negatively correlated with acid secretion.5 The authors have also demonstrated increased hepatocyte growth factor (HGF) production in giant fold gastritis,5 and although suggested to have a role in the fold enlargement, studies in canine parietal cells have shown potent acid inhibitory actions of HGF.6 Considerable data are available demonstrating that tumour necrosis factor α (TNF-α) is a important proinflammatory cytokine which is increased inH pylori gastritis; however, although there are no data specific to giant fold gastritis, it would be surprising if TNF-α expression were not increased. TNF-α also directly inhibits parietal cell acid secretion.3 Data on epithelial growth factor (EGF) and transforming growth factor α (TGF-α) and related peptides in H pylori infection are rather conflicting but there is evidence that expression is increased.7 These peptides are also potent inhibitors of parietal cell acid secretion,8 and transgenic over expression of TGF-α produces fovoelar hyperplasia and hypochlorhydria.9 Thus at present it would be wise to consider these and other possibilities as mediators of the reversible acid inhibition in H pylori associated acid inhibition.
Secondly, the authors believe that antigastric antibodies are not implicated in the pathophysiology of giant cell gastritis. They were unable to detect autoantibodies reactive with human gastric mucosa in any of their six subjects, but in the absence of more information on methodology and controls, the significance of these data remains uncertain. Negrini et al detected autologous and heterologous antigastric antibodies in 65% of H pylori infected patients, with an even greater prevalence with greater degrees of gastric inflammation (as seen in giant fold gastritis).10 Antigastric antibodies may be involved in the inhibition of acid secretion or may be merely a secondary phenomena following parietal cell damage. The data, as presented by Murayama et al, do not reliably exclude a pathogenic role for autoantibodies. Indeed if further larger studies confirm the absence of autoantibodies in giant cell gastritis, this will greatly facilitate our understanding of both the mechanisms of control of acid secretion in H pylori infection and generation of gastric autoantibodies.
Finally, the authors appear to regard the hypergastrinaemia of secondary consequence to inhibition of acid secretion. In light of this, it is unfortunate that they did not study a control group with drug induced secondary hypochlorhydria, as it is surely possible that some of the reversible parietal cell morphological changes result from prolonged exposure to high levels of gastrin and gastrin precursors in the face of continued block of parietal cell function.
I look forward to further studies in this interesting patient group and hope that future studies will include appropriate controls to enable elucidation of the pathophysiology of giant cell gastritis.
Editor,—We thank Dr Beales for the interesting comments on our paper.
The exact mechanism by which Helicobacter pylori infection induces decreased gastric acid secretion and alterations in parietal cell morphology remains unclear in patients with enlarged fold gastritis. One possible mechanism is that the cytokines produced by local immune system cells during inflammation may indirectly affect gastric function. Based on our previous finding that fundic mucosal interleukin 1β (IL-1β) production was enhanced inH pylori associated enlarged fold gastritis, it is suggested that IL-1β was involved in the inhibition of acid secretion. As Dr Beales suggested, tumour necrosis factor α (TNF-α) is also one of the important cytokines in the inhibition of acid secretion. Unfortunately, we did not measure TNF-α levels in patients with enlarged fold gastritis, H pyloripositive patients without enlarged folds, and H pylori negative patients with dyspeptic symptoms. However, we have previously demonstrated that macrophage infiltration in the body mucosa was significantly more extensive in patients with enlarged fold gastritis.1-1 TNF-α is a cytokine which is produced mainly by activated macrophages.1-2 Therefore, we agree that TNF-α released by activated macrophages might also affect acid secretion in patients with enlarged fold gastritis. Thus the production of these cytokines, including IL-1β, TNF-β, and others in inflamed mucosa might be equally important in the regulation of acid secretion in patients with enlarged fold gastritis. It is unlikely that transforming growth factor α (TGF-α) is involved in this pathophysiology, as we have previously reported that TGF-α mRNA levels in the body were not increased in patients with enlarged fold gastritis.1-1
Dr Beales suggested the possibility that the presence of antigastric autoantibodies due to H pylori infection might affect the morphological and/or functional changes in parietal cells. As reported in our paper, however, the antigastric autoantibody in the sera of these patients with enlarged fold gastritis was undetectable, at least by our method. Faller et al reported that the occurrence of antigastric autoantibody, especially anticanalicular autoantibodies, correlates with the severity of body gastritis, and atrophic changes of the gastric mucosa.1-3 In our study, a significant difference in body atrophy score was not found among the six patients with enlarged fold gastritis, six H pylori positive patients without enlarged folds, or six H pylorinegative patients. No significant change was observed in the degree of body atrophy after H pylori eradication in patients with enlarged fold gastritis. Thus it is also possible that antigastric autoantibodies do not necessarily exist in patients with enlarged fold gastritis. But when the gastric atrophy develops in future, antigastric autoantibodies may be detected in patients with enlarged fold gastritis. We feel that further larger investigations will need to clarify the pathophysiological significance of antigastric autoantibodies.
In our study, serum gastrin concentrations were correlated with morphological changes in parietal cells, as both elevated serum gastrin and morphological changes in parietal cells were found in patients with enlarged fold gastritis. Thus changes in the secretory canaliculi in parietal cells may possibly be due to differences in the degree of gastrin stimulation. However, it was reported that electron microscopic morphometry in normal subjects in a postprandial state or in patients with Zollinger-Ellison syndrome, which accompanied hypergastrinaemia, showed no significant alteration of parietal cells such as dilated canaliculi with vacuole-like structures and few short microvilli.1-4 Therefore, we think it is unlikely that the changes in the secretory canaliculi were due to differences in gastrin stimulation.
To resolve these issues, further analyses are needed in larger numbers of patients with enlarged fold gastritis, as Dr Beales suggested.
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