1 Second Department of Internal Medicine, School of Medicine, Kanazawa University, Kanazawa, 2 Department of Internal Medicine, Fujita Memorial Hospital, Fukui and 3 Department of Clinical and Laboratory Medicine, Fukui Medical University, Fukui, Japan
Correspondence and offprint requests to: Hideo Araki, MD, Second Department of Internal Medicine, School of Medicine, Kanazawa University, Takara-machi 131, Kanazawa, 9208640, Japan.
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Abstract |
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Methods. Sixty three maintenance dialysis patients (54 haemodialysis and nine continuous ambulatory peritoneal dialysis) who required endoscopic examination were enrolled in the study. Sixty four age- and sex-matched patients with normal renal function served as controls. We performed endoscopic examination and obtained both the gastric antral and corpus mucosa for histopathological evaluation and H. pylori identification. Twenty three patients on dialysis underwent H. pylori eradication therapy.
Results. In dialysis patients, H. pylori-positives had significantly higher serum PG II levels than H. pylori-negatives (26.6±21.5 vs 14.1±7.1 ng/ml, P<0.05), but no significant difference was found in serum PG I between H. pylori-positives and H. pylori-negatives (228.8±158.5 vs 179.4±113.5 ng/ml). There was no significant difference in serum PG II between dialysis patients and controls (19.9±16.5 vs 18.6±14.9 ng/ml), while serum PG I levels were significantly higher in dialysis patients than in controls (201.7±136.8 vs 77.6±85.8 ng/ml, P<0.05). Serum PG II levels, but not those of PG I, significantly correlated with the inflammation and activity scores of antrum in dialysis patients, and these scores were highly influenced by H. pylori infection. Dialysis patients in whom H. pylori was eradicated successfully showed siginificant reductions of serum PG II levels but not of PG I.
Conclusions. In dialysis patients, high serum levels of PG II, but not PG I, are significantly related to H. pylori infection and mucosal inflammation. A significant decrease in serum PG II levels could be used as a predictor of the eradication of H. pylori infection in dialysis patients.
Keywords: dialysis patients; gastritis; Helicobacter pylori; pepsinogen; Helicobacter pylori eradication
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Introduction |
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Several studies have demonstrated that H. pylori eradication therapy causes a significant reduction in serum PG I and PG II levels in patients with normal renal function [5,8,9]. However, little is known about the changes in serum PG levels when dialysis patients undergo H. pylori eradication therapy.
In the present study, we measured the serum pepsinogen levels in dialysis patients and investigated the effect of H. pylori infection on such serological parameters and histopathological alterations. Furthermore, we studied the effect of H. pylori eradication therapy on serum PG levels in dialysis patients.
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Subjects and methods |
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Pepsinogen I, pepsinogen II and gastrin
Fasting serum PG I and PG II levels were determined by competitive binding double-antibody radioimmunoassay, as described by Ichinose et al. [10]. Serum gastrin levels were determined by radioimmunoassay using a commercial kit (Dinabott Company, Tokyo, Japan).
Helicobacter pylori specific IgG antibodies
We measured H. pylori-specific IgG antibody titres by enzyme-linked immunosorbent assay (ELISA), using a Helico-G kit (Porton Cambridge, Maidenhead, UK), based on the method of Newell et al. [11]. A titre >10 U/ml was interpreted as positive according to the manufacturer's instructions.
Endoscopy
Gastroduodenal endoscopical examinations were performed using a Fujinon EG-300FP endoscope (Fuji Photo Optical Company, Omiya, Japan), and the presence of lesions in the gastroduodenal mucosa was noted. Criteria for ulcer disease included healing ulcers and ulcer scarring. For histological examination, cultivation and for the rapid urease test, specimens from both the antrum and the corpus were collected.
Histological studies
Biopsy specimens for histological examination were fixed in 10% buffered formalin and processed routinely. Paraffin sections were cut and stained with haematoxylin and eosin. Sections were graded for inflammation (chronicity) and polymorphonuclear leukocytes (activity), in accordance with the recommendations of the working party that developed the Sydney system for the histological grading of gastritis [12,13]. Each parameter in the Sydney system was scored from 0 to 3 (0=none, 1=mild, 2=moderate, 3=marked), which is well illustrated in the full description of the classification.
Helicobacter pylori screening
Immediately after endoscopy, the biopsy specimens were transferred to the transport medium, plated onto Modified-belo-horizonte medium pylori agar medium (Nikken Biomedical Laboratories, Kyoto, Japan) and cultured at 35°C under microaerobic conditions. Five or 7 days later, the plates were checked and identification of H. pylori was made on the basis of the morphological features of the colony, Gram's stain and positive reactions to oxidase and urease.
Patients were judged to be infected with H. pylori if the organism was demonstrated in the biopsy by either histology or culture.
Helicobacter pylori eradication therapy
Nineteen patients were treated with a combination of amoxicillin (AMPC), clarithromycin (CAM), omeprazole and polaprezinc, and four subjects received a combination of AMPC, omeprazole and polaprezinc. The details of the former protocol are as follows: 250 mg of AMPC twice a day for 3 weeks, 200 mg of CAM twice a day for 3 weeks, 20 mg of omeprazole once a day for 8 weeks, 0.5 g of polaprezinc twice a day for 24 weeks. The latter protocol was 250 mg of AMPC twice a day for 3 weeks, 20 mg of omeprazole once a day for 8 weeks, 0.5 g of polaprezinc twice a day for 24 weeks. Two months after the beginning of the medical treatment, the patients underwent a second upper gastrointestinal endoscopy with at least three antral and three corpus gastric biopsies, plus repeat testing for fasting serum PG I, PG II, gastrin and H. pylori IgG antibodies. Eradication of H. pylori was defined by negative results on all the tests described above. The eradication was considered a failure if any of the three methods showed positive results for H. pylori.
Statistical methods
Categorical data were assessed by the X2 test. The MannWhitney U test was used for non-parametric data analysis as required. The relationship between serum parameters and degree of gastritis was investigated by linear regression analysis using the Spearman's rank correlation test. Wilcoxon's test was used for the paired data. Probability values P<0.05 were considered statistically significant. All data are expressed as mean values±SD.
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Results |
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We investigated the relationship between serological parameters and histological findings. In control patients, serum PG I and PG II levels showed a significant correlation with antral inflammation and activity scores (Table 4a, Fig. 1
). When patients were divided into H. pylori-positives and negatives, these significant correlations were found only in the former (Table 4a
).
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For serum gastrin levels, significantly higher serum levels were found in dialysis patients than in controls (Table 2). There were no significant correlations between serum gastrin and PG levels in either the dialysis patients or controls.
In eradication therapy, 21 dialysis patients completed the treatment protocol; one dropped out 4 days after the initiation of AMPC, CAM, omeprazole and polaprezinc due to diarrhoea, and another patient dropped out from the same protocol due to oral candidiasis 7 days after the beginning of the therapy. The rest of the patients showed no side effects as judged by symptoms and laboratory findings. Helicobacter pylori was eradicated in 15 of 17 patients who were treated with AMPC, CAM, omeprazole and polaprezinc, and in three of four treated with AMPC, omeprazole and polaprezinc.
Dialysis patients in whom H. pylori was successfully eradicated showed significant reductions of serum PG II levels and H. pylori IgG antibodies and significant elevations of their PG I:PG II ratio (Table 5). Serum PG I levels and gastrin did not show significant changes after successful H. pylori eradication therapy. In dialysis patients who were still infected with H. pylori after eradication therapy, serum PG II levels increased and H. pylori IgG antibodies did not change (Table 5
). Elevation of the serum PG I:PG II ratio was also shown in those dialysis patients in whom H. pylori was not eradicated.
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Discussion |
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Several factors may be involved in the difference between PG I and PG II. One is the different distribution in the stomach of PG I and PG II. PG I is restricted to the corpus mucosa, whereas PG II is present in both the corpus and antral mucosa [14,15]. It has been suggested that H. pylori-associated gastritis is more severe in the antrum than in the corpus mucosa [2,16], possibly accounting for the greater correlation between PG II levels and H. pylori-associated gastritis as compared with PG I which is present to a lesser extent in the antrum. However, our findings as well as those of another investigation that showed similar degrees of inflammation in the antrum and corpus do not support this hypothesis [17]; this matter is still controversial.
A second factor may be the different degrees of susceptibility to H. pylori infection of PG I and PG II. It has been suggested that PG II is a more sensitive indicator of H. pylori load than PG I [17]. Furthermore, previous studies showed that PG II was a more sensitive marker of H. pylori eradication therapy than PG I in patients with normal renal function [8,18].
A third factor is the difference in the metabolic pathways of PG I and PG II, namely the relatively high renal excretion rate of PG I. Unfortunately, this is not yet fully understood, and very few reports have focused on this matter. In healthy subjects, the mean fractional excretion in the urine of PG I was 27.6%, while in contrast, that of PG II was only 1.0%, and the difference between PG I and PG II in healthy subjects was considered to be due to different renal tubular reabsorption rates [19]. Metabolic pathways of PG II other than renal might be important, and further studies are necessary to elucidate these points.
Our data showed that dialysis patients had serum levels of PG II similar to those of control patients. However, elevated serum levels of PG II as well as PG I in dialysis patients were reported previously by Nakahama et al. [7], who studied 51 normal volunteers, 40 HD patients and 21 CAPD patients. They showed that serum PG II levels were 14.45±8.55 ng/ml in normal volunteers and 29.0±16.6 ng/ml in HD patients, being significantly higher in the latter (P <0.05) [7]. Because our findings do not support that study, we are interested in the causes of this discrepancy. All the subjects studied by Nakahama et al. were free from gastroduodenal symptoms. In contrast, we included dyspeptic patients, and the proportion of dyspepsia in our dialysis patients was matched to that of controls. We speculate that our patients studied have more gastric symptomatic diversity and a higher rate of H. pylori-positivity than had the subjects studied by Nakahama et al., which could explain the discrepancy between our data and theirs. In our H. pylori-negative patients, dialysis patients had significantly higher serum PG II levels than controls, suggesting that the former have significantly higher serum PG II levels than the latter when patients are not infected with H. pylori.
In patients with normal renal function, previous studies showed that the best diagnostic accuracy in H. pylori eradication therapy between the different biochemical parameters was obtained by the changes in the serum PG I:PG II ratio [20,21] and the serum PG II levels [9,22]. Our data also showed that dialysis patients in whom H. pylori was eradicated showed a significant reduction of serum PG II levels and a significant elevation of the serum PG I:PG II ratio. However, in our dialysis patients, an increased PG I:PG II ratio after eradication therapy was found not only in 18 patients in whom H. pylori had been eradicated successfully but also in three patients in whom it had not been eradicated. Though our eradication study was preliminary, these findings suggest that in dialysis patients the changes in serum PG II levels may be the most useful index to distinguish success from failure in eradication therapy for H. pylori.
Serum gastrin levels were higher in dialysis patients than in controls, as expected. That was accounted for by impaired renal clearance and hyperproduction due to lack of a negative acid feedback mechanism [23,24]. In asymptomatic healthy subjects and patients with duodenal ulcers, H. pylori infection contributes to the elevation of serum gastrin concentration [25,26]. With regard to HD patients, one study showed that H. pylori-positives had significantly higher serum gastrin concentrations than H. pylori-negatives [27], while other studies and our study have not found such a difference [28,29]. The mechanism of increased gastrin concentration in H. pylori infection is still unclear, but one hypothesis is that H. pylori produces a specific biochemical substance that stimulates G-cell function (e.g. by cytokines) or that inflammation self-stimulates gastrin hypersecretion [30]. We speculate that in subjects with normal renal function, a link between H. pylori infection and hypergastrinaemia may exist, but in dialysis patients this may be obscured by elevated serum gastrin concentrations. We did not find any significant relationship between serum gastrin and PG levels either in dialysis patients or controls with regard to H. pylori infection. Large-scale testing will be necessary to elucidate this point.
Our data suggest that dialysis patients have a lower degree of inflammation of gastritis in comparison with patients with normal renal function, which is consistent with the findings of a previous study [29]. These findings are explained by the fact that our dialysis patients had a significantly lower prevalence of H. pylori infection, and this organism is now recognized as the major cause of histological gastritis [2,31]. The lower prevalence of H. pylori infection in dialysis patients had been supported previously by other investigations [29,32,33], and may be explained by the use in these studies of a wide variety of medications, including antibiotics.
In summary, our data suggest that in dialysis patients, high serum levels of PG II, but not of PG I, are significantly related to H. pylori infection and mucosal inflammation. Dialysis patients have a lower degree of inflammation of gastritis compared with normal renal function subjects, probably attributable to a significantly lower prevalence of H. pylori infection in the former. A significant decrease in the serum PG II level could be used to predict the eradication of H. pylori infection in dialysis patients.
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Acknowledgments |
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References |
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