Effect of Helicobacter pylori infection and its eradication on nutrition

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1 Aliment Pharmacol Ther 2002; 16: Effect of Helicobacter pylori infection and its eradication on nutrition T. FURUTA*, N. SHIRAI*, F. XIAO*, M. TAKASHIMA* & H. HANAI *First Department of Medicine and Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan Accepted for publication 6 December 2001 SUMMARY Aims: To investigate the effects of Helicobacter pylori infection and eradication on nutrition. Methods: The body weight, height, blood pressure, gastric juice ph and fasting serum levels of glucose, total protein, albumin, total cholesterol and triglyceride were measured in H. pylori-positive and H. pylorinegative subjects, and the effect of eradication of H. pylori on these parameters was determined. The development of gastro-oesophageal reflux disease after treatment was also examined. Eight patients underwent a pancreatic function test before and after H. pylori eradication therapy. Results: The incidence of hypoproteinaemia in H. pylori-positive subjects was significantly higher than that in H. pylori-negative subjects. After eradication of H. pylori, the gastric juice ph values were significantly decreased, and the body weight and serum levels of total cholesterol, total protein and albumin were significantly increased. The incidence of hyperlipidaemia significantly increased and that of hypoproteinaemia significantly decreased in the group with eradication. Pancreatic function improved significantly after eradication of H. pylori. No significant changes in these parameters were observed in the group without eradication. Obese patients had a higher risk of the development of gastro-oesophageal reflux disease after eradication of H. pylori infection. Conclusions: The eradication of H. pylori appears to improve some nutritional parameters. INTRODUCTION A close relationship between Helicobacter pylori infection and upper gastrointestinal disorders has been demonstrated. The eradication of H. pylori infection improves histological gastritis, 1, 2 decreases the rate of recurrence of peptic ulcer disease, 3 5 cures some cases of gastric mucosa-associated lymphoid tissue lymphoma 6 and prevents the recurrence of gastric cancer after resection of early disease. 7 Therefore, the eradication of H. pylori Correspondence to: Dr T. Furuta, First Department of Medicine, Hamamatsu University School of Medicine, , Handa-Yama, Hamamatsu, , Japan. furuta@hama-med.ac.jp in patients with gastroduodenal disorders has been widely performed throughout the world. The eradication of H. pylori infection has been reported to improve gastric acid secretion. 8, 9 Moreover, the occurrence of gastro-oesophageal reflux disease (GERD) after the eradication of H. pylori infection has recently 10, 11 been reported. The mechanism by which GERD occurs after the eradication of H. pylori infection is assumed to be related to the improvement of gastric acid secretion. 10, 11 Obesity is a well-known risk factor for the development of GERD Recently, hypoproteinaemia observed in Menetrier s disease has been reported to improve after the eradication of H. pylori infection However, few studies have been performed on the effect of H. pylori infection on nutrition. Ó 2002 Blackwell Science Ltd 799

2 800 T. FURUTA et al. On the basis of the background discussed above, we investigated nutritional parameters, such as body weight and serum levels of lipids and proteins, in H. pylori-positive and H. pylori-negative subjects and determined the changes in these parameters in patients who received H. pylori eradication therapy. We also performed a pancreatic function diagnostic test as a marker of digestive ability in some patients before and after H. pylori eradication therapy. The development of GERD after the eradication of H. pylori infection was also examined. Endoscopy and collection of samples During gastroduodenoscopy, 10 ml of gastric juice was aspirated through the suction channel of the endoscope and collected in a trap placed in the suction line. Routine inspection of the upper gastrointestinal tract was performed, and several biopsy specimens from both the antrum and the corpus of the greater curvature were obtained for rapid urease test, bacteriological culture and histology. The ph of the gastric juice was measured with a glass-electrode ph meter just after collection. 8 METHODS Subjects A total of 609 H. pylori-positive patients, with gastric ulcer (n ¼ 246), duodenal ulcer (n ¼ 232) or gastritis (n ¼ 131), were enrolled in the study. Their disorders were diagnosed on the basis of results of gastroduodenoscopy and histology. A total of 152 H. pylorinegative subjects, with no endoscopically proven lesions in the stomach, were also enrolled as controls. H. pylori infection was diagnosed on the basis of rapid urease test, culture and histology, as described below. The demographic and clinical characteristics of the subjects enrolled in the study are summarized in Table 1. The protocol was approved in advance by the Human Institutional Review Board of Hamamatsu University School of Medicine. Written informed consent for participation in the study was obtained from all subjects. Eradication of H. pylori Patients were treated with dual therapy with omeprazole, 20 mg b.d., and amoxicillin, 500 mg q.d.s., for 2 weeks (n ¼ 192), or triple therapy with omeprazole, 20 mg b.d., or lansoprazole, 30 mg b.d., clarithromycin, 200 mg t.d.s., and amoxicillin, 500 mg t.d.s., for 1 week (n ¼ 417). Success or failure of the eradication of H. pylori infection was determined on the basis of culture test, rapid urease test, histology, polymerase chain reaction and 13 C-urea breath test performed 1 month after treatment. 8 If any one of these tests yielded a positive result, failure to eliminate H. pylori infection was diagnosed. At the second endoscopy, the gastric juice ph was measured again. Nutritional parameters The body weight, height, blood pressure and fasting serum levels of glucose, total protein, albumin, total Table 1. Demographic and clinical characteristics and nutritional parameters in Helicobacter pylori-positive and H. pylori-negative subjects enrolled in this study Parameter H. pylori-positive (n ¼ 609) H. pylori-negative (n ¼ 152) P value Age (years) (mean ± s.e.) 48.0 ± ± 0.9 > 0.2 Male/female (n/n) 456/ /41 > 0.2 Height (cm) (mean ± s.e.) ± ± 0.6 > 0.2 Body weight (kg) (mean ± s.e.) 64.6 ± ± 1.0 > 0.2 BMI (kg/m 2 ) (mean ± s.e.) 22.8 ± ± Upper blood pressure (mmhg) (mean ± s.e.) ± ± 1.8 > 0.2 Lower blood pressure (mmhg) (mean ± s.e.) 75.6 ± ± 1.2 > 0.2 Total protein (g/dl) (mean ± s.e.) 7.02 ± ± Albumin (g/dl) (mean ± s.e.) 4.02 ± ± Total cholesterol (mg/dl) (mean ± s.e.) ± ± 2.3 > 0.2 Triglyceride (mg/dl) (mean ± s.e.) ± ± 10.5 > 0.2 FBS (mg/dl) (mean ± s.e.) 95.4 ± ± 1.9 > 0.2 Gastric juice ph (median with interquartile ranges) 3.00 ( ) 1.70 ( ) < BMI, body mass index; FBS, fasting blood sugar.

3 H. PYLORI ERADICATION AND NUTRITION 801 cholesterol and triglyceride were determined before and 1 year after treatment. The body mass index was calculated as BMI ¼ body weight (kg)/[height (m)] 2. Development of GERD We examined whether GERD developed after eradication therapy. When any oesophageal mucosal break was observed during second endoscopy or when patients complained of GERD symptoms, such as heartburn, within 1 year after treatment, the development of GERD was diagnosed. Pancreatic function test Eight patients with gastric adenoma and H. pylori infection, who underwent endoscopic mucosal resection of gastric adenoma, participated in another study. Before endoscopic mucosal resection, the pancreatic function test was performed in the standard manner. In brief, 500 mg of N-benzoyl-L-tyrosyl-p-aminobenzoic acid (corresponding to mg of p-aminobenzoic acid) was orally administered to the patients and urine was collected for 6 h after administration. p-aminobenzoic acid excreted in the urine during the 6-h period was measured. The result of the pancreatic function test was expressed as the ratio (%) of p-aminobenzoic acid excreted (mg) in the urine to the total administered (169.5 mg). After endoscopic mucosal resection, the patients were treated with lansoprazole, 30 mg b.d., clarithromycin, 200 mg t.d.s., and amoxicillin, 500 mg t.d.s., for 1 week to eradicate H. pylori infection. After treatment, the pancreatic function test was performed again in the same manner. Success or failure to eradicate H. pylori infection was determined on the basis of several tests performed 1 month after treatment as described above. Statistics All numerical values were expressed as the mean ± standard error (s.e.) or medians with interquartile ranges. To determine whether the male/female ratio, gastric juice ph, body weight, height, body mass index, blood pressure and fasting serum levels of glucose, total protein, albumin, total cholesterol and triglyceride differed between H. pylori-positive and H. pylori-negative subjects, Student s t-test, the Mann Whitney U-test and the chi-squared test were used. To determine whether these parameters and the pancreatic function test values were different before and after eradication therapy, as a function of eradication status, the paired t-test and Wilcoxon s signed rank test were used. Differences in the frequency of hyperlipidaemia and hypoproteinaemia between H. pylori-positive and H. pylori-negative groups or between groups with and without eradication after treatment were assessed by Fisher s exact test. All P values were two-sided: findings of P < 0.05 were considered to be significant. RESULTS Effect of H. pylori infection on nutritional parameters There were no statistically significant differences in body mass index and fasting serum levels of glucose, total protein and total cholesterol between H. pylori-positive and H. pylori-negative subjects (Figure 1). However, the frequency of hypoproteinaemia (total protein < 6.5 g/ ml) in H. pylori-positive subjects (7.2%, 44/609) was significantly higher than that in H. pylori-negative subjects (2.6%, 4/152). The median gastric juice ph in patients with hypoproteinaemia and H. pylori infection was 4.80 ( ), which was significantly higher Figure 1. The frequency of hypoproteinaemia in Helicobacter pylori-positive and H. pylori-negative subjects. The frequency of hypoproteinaemia (total protein (Tp) < 6.5 g/dl) in the H. pylori-positive group was significantly higher than that in the H. pylori-negative subjects.

4 802 T. FURUTA et al. than that in patients without hypoproteinaemia and with H. pylori infection (3.00; ) (P < ). Differences in gastric juice ph and nutritional parameters before and after eradication of H. pylori infection A total of 579 of 609 patients underwent second endoscopy to determine the success or failure of eradication of H. pylori infection 1 month after treatment, and a medical check 1 year later. We present the results for these 579 patients in order to analyse the effects of H. pylori eradication. The eradication of H. pylori infection was observed in 421 of the 579 patients. Before treatment, there were no significant differences in the gastric ulcer/duodenal ulcer/gastritis ratio, body weight, height, body mass index, blood pressure, gastric juice ph or serum levels of total protein, total cholesterol or triglyceride between the groups with and without eradication of H. pylori. In the group with eradication of H. pylori, gastric juice ph values were significantly decreased and the body weight and body mass index were significantly increased (Figures 2a c). However, no significant changes in these parameters were observed in the group without eradication. No significant changes in blood pressure were observed during the study period (1 year) in the groups with and without eradication of H. pylori (Figure 2d). Figure 2. Gastric juice ph (a), body weight (b), body mass index (c), blood pressure (d) and serum levels of fasting blood sugar (e), triglyceride (f), total cholesterol (g), total protein (h) and albumin (i) before and after Helicobacter pylori eradication therapy as a function of eradication status. The median gastric juice ph (a) was significantly decreased and the means of the body weight (b), body mass index (c) and serum levels of total cholesterol (g), total protein (h) and albumin (i) were significantly increased in the group with eradication of H. pylori. In the group without eradication of H. pylori, no significant changes in the parameters noted above were observed.

5 H. PYLORI ERADICATION AND NUTRITION 803 Fasting blood glucose levels were unchanged before and 1 year after treatment in the groups with and without eradication (Figure 2e). Serum triglyceride levels in the group with eradication tended to increase (Figure 2f), but not to a significant extent. On the other hand, serum total cholesterol levels significantly increased in the group with eradication of H. pylori (Figure 2g). No significant changes were observed in the group without eradication. Serum levels of total protein and albumin were also increased in the group with eradication of H. pylori, but not in the group without eradication. One year after treatment, total protein and albumin levels in the group with eradication were significantly higher than those in the group without eradication (Figure 2h,i). One year after treatment, the incidence of hypoproteinaemia (total protein < 6.5 g/dl) in the group with eradication was significantly lower than that in the group without eradication (Figure 3a), although no differences were observed before treatment. The serum cholesterol levels of 477 of 579 patients were less than 220 mg/dl before treatment. They were considered as non-hyperlipidaemic. Of the 477 non-hyperlipidaemic patients, 359 showed eradication of H. pylori. In47of these 359 patients, serum total cholesterol levels had increased to more than 220 mg/dl 1 year after the eradication of H. pylori. One hundred and eighteen of the 477 patients failed to show clearance of H. pylori infection. A serum cholesterol level higher than 220 mg/dl was observed in only two patients in this group 1 year after treatment (Figure 3b). Changes in pancreatic function test values Eradication of H. pylori was observed in seven of the eight patients who underwent pancreatic function tests before and after endoscopic mucosal resection and H. pylori eradication therapy. The results of the pancreatic function test significantly increased after treatment in the group with eradication of H. pylori (Figure 4). Development of GERD after eradication of H. pylori infection To determine whether GERD developed after treatment for H. pylori infection, 419 patients were assessed. Of the 366 patients with eradication of H. pylori, development of GERD was seen in 41. Of Figure 3. Incidence of hypoproteinaemia (a) and hyperlipidaemia (b) after treatment as a function of eradication status. The incidence of hypoproteinaemia (total protein (Tp) < 6.5 g/dl) in the group with eradication (0.95%) was significantly lower than that in the group without eradication (10.1%) (a). Before treatment, 477 patients were non-hyperlipidaemic (total cholesterol (T-cho) ¼ 220 mg/dl). Of these 477 patients, 359 had successful eradication of Helicobacter pylori. Of the 359 patients with eradication, 47 patients (13.1%) had become hyperlipidaemic, whereas only two patients had become hyperlipidaemic in the group without eradication of H. pylori (b).

6 804 T. FURUTA et al. H. pylori was lower than that of patients with GERD and H. pylori infection (Figure 5). DISCUSSION Figure 4. Results of the pancreatic function diagnostic test before and after Helicobacter pylori eradication therapy. The results of the pancreatic function test were significantly increased in patients with clearance of H. pylori infection. PABA, p-aminobenzoic acid. the 53 patients without eradication of H. pylori, four developed GERD. The median values of the gastric juice ph in patients with and without the development of GERD after eradication of H. pylori infection were 1.44 ( ) and 1.42 ( ), respectively (P > 0.2). The effect of obesity on the development of GERD after the eradication of H. pylori infection was also studied. The body mass index increased after eradication therapy in the groups with and without GERD development. However, the mean body mass index before and after treatment in the group with GERD development was significantly higher than that in the group without GERD development. Moreover, the body mass index of patients with the development of GERD after the eradication of We determined the effects of H. pylori infection and eradication on nutritional parameters, such as the body mass index and serum levels of proteins and lipids, and found that some of the parameters were affected by H. pylori infection and increased or improved after eradication. Moreover, results of pancreatic function testing revealed that the digestive ability improved after the eradication of H. pylori in some patients. Because most peptic ulcer diseases do not recur and the symptoms of some patients with non-ulcer dyspepsia 3 5, 18 are relieved after the eradication of H. pylori, appetite may be restored and improved after the eradication of H. pylori infection and this might contribute to the improvement of nutritional parameters. However, the results of the pancreatic function test in this study suggest another factor: improvement of digestive ability after eradication of H. pylori. Therefore, we assume that nutritional parameters, such as serum levels of total cholesterol and proteins, will improve even if the amount of food intake or appetite remains unchanged after the eradication of H. pylori infection because of improved digestion and absorption. In this study, the incidence of hypoproteinaemia was significantly higher in H. pylori-positive subjects than in H. pylori-negative subjects and was significantly decreased after the eradication of H. pylori. Recently, the hypoproteinaemia observed in Menetrier s disease, which is characterized by enlarged fold gastritis, has Figure 5. Changes in body mass index (BMI) in the groups with and without gastro-oesophageal reflux disease (GERD) development as a function of eradication status. BMI values were significantly increased in the group with eradication of H. pylori irrespective of GERD development. The mean BMI value of the group with GERD development after the eradication of H. pylori infection was significantly higher than that of the group without GERD development after the eradication of H. pylori infection. The BMI value of the group with GERD development and H. pylori infection was higher than that of any of the other groups before and after treatment. GERD (+), development of GERD after treatment; GERD ( ), no development of GERD after treatment.

7 H. PYLORI ERADICATION AND NUTRITION 805 been reported to improve after the eradication of H. pylori infection As the enlarged folds of Menetrier s disease improve after the eradication of H. pylori, leakage of proteins from the gastric wall decreases, resulting in an improvement of serum protein levels. However, the hypoproteinaemia observed in Menetrier s disease cannot be explained by the leakage of proteins from the gastric wall alone, because the leaked proteins should be digested and re-absorbed in the small intestine. This suggests that the digestion and absorption of proteins are disturbed in patients with Menetrier s disease. Consequently, leaked proteins cannot be digested or re-absorbed sufficiently in the small intestine, which might contribute to the pathogenesis of hypoproteinaemia in Menetrier s disease. After the eradication of H. pylori infection, this impaired digestive and absorptive ability is improved, resulting in the restoration of serum protein levels. In this study, the frequency of hypoproteinaemia was significantly higher in H. pylori-positive subjects and decreased to the levels found in H. pylori-negative subjects on eradication of H. pylori. Similarly, serum levels of cholesterol and the frequency of hyperlipidaemia were increased after the eradication of H. pylori. Therefore, the eradication of H. pylori appears to contribute to an improvement or increase in certain nutritional parameters. As shown by the results of the PFD test in this study, the eradication of H. pylori restores digestive and absorptive ability, which may contribute to the improvement or increase in nutritional parameters. Although we cannot offer an appropriate explanation for the decreased digestive or absorptive ability observed in some H. pylori-positive subjects, we assume that impaired acid secretion by H. pylori infection might be involved, because the median gastric juice ph of patients with hypoproteinaemia was much higher (4.80) than that of the group with normal protein levels. The occurrence of GERD after the eradication of H. pylori infection has been reported. 10, 11 One of the main causes of the development of GERD after the eradication of H. pylori infection has been reported to be the restoration of acid secretion. 10, 19 In this study, the gastric juice ph was decreased after the eradication of H. pylori infection. Therefore, an increase in gastric acidity after the eradication of H. pylori infection must have contributed to the development of GERD. In other words, the increase in the acidity of the gastric juice refluxed from the stomach to the oesophagus must be one of the important factors for GERD development after the eradication of H. pylori infection, as previously reported. However, an increase in gastric 10, 19 juice acidity (i.e. decrease in gastric juice ph) after the eradication of H. pylori infection was observed in patients with and without the development of GERD. Therefore, other determinants must exist. In this study, the pre- and post-treatment body mass indices of the group with GERD development were significantly higher than those of the group without GERD development. Therefore, obesity may be one of the cofactors associated with the development of GERD after the eradication of H. pylori infection, and obese patients may have a higher risk of the development of GERD after the eradication of H. pylori infection. Moreover, the mean pre- and post-treatment body mass indices of patients who developed GERD after the eradication of H. pylori infection were lower than those of H. pylori-positive patients with GERD, which suggests that the eradication of H. pylori infection seems to lower the threshold level of obesity for the development of GERD. The findings of this study suggest the possibility that the eradication of H. pylori increases the incidence of hyperlipidaemia and obesity and decreases the incidence of hypoproteinaemia. Increases in body weight, serum cholesterol and protein levels are associated with increased risk of the development of arteriosclerosis, hypertension, thrombosis and other related disorders, as well as GERD, although it was unclear during the short study period whether the eradication of H. pylori leads to an increased incidence of such disorders other than GERD. Therefore, long-term follow-up is recommended for patients after the eradication of H. pylori. ACKNOWLEDGEMENTS This study was supported by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Science and Sports of Japan ( ). The abstract of this manuscript was presented at the annual meeting of the American Gastroenterological Association held in Atlanta in May, We thank Dr Yves Pommier (Chief of the Laboratory of Molecular Pharmacology, National Cancer Institute, NIH) for his critical review of the manuscript and useful suggestions. The assistance of Drs Munetaka Sano, Makoto Kodaira, Hajime Arai and Yoshihiko Sato was greatly appreciated.

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