Eradication of Helicobacter pylori infection induces an increase in body mass index

Transcription

1 Aliment Pharmacol Ther 2002; 16 (Suppl. 2): Eradication of Helicobacter pylori infection induces an increase in body mass index T. AZUMA, H. SUTO*, Y. ITO*, A. MURAMATSU*, M. OHTANI*, M. DOJO*, Y. YAMAZAKI, M. KURIYAMA & T. KATO*à *Second Department of Internal Medicine and Department of Endoscopic Medicine, Fukui Medical University, Fukui Japan; and àfaculty of Nursing and Welfare, Fukui Prefectural University, Fukui, Japan SUMMARY Background: The relationship between H. pylori infection and body mass indices is controversial. Aim: To investigate the relationship between H. pylori infection and body indices, and to examine the effect of H. pylori eradication therapy on body indices. Methods: Nine-hundred and thirty-two employees of an industrial corporation were examined for H. pylori infection and body mass indices. Three hundred and two H. pylori-positive cases diagnosed with chronic gastritis by upper gastrointestinal endoscopy or radiography underwent eradication therapy. Body mass indices, serum total cholesterol levels and symptom scores were obtained before and at 12 months after eradication therapy. Results: There was no significant difference in body weight, body mass index (BMI) or serum total cholesterol level between the H. pylori-positive and H. pylorinegative groups. However, body weight and BMI increased significantly 12 months after eradication of H. pylori infection. In contrast, there was no significant difference in body weight and BMI 12 months after eradication therapy in the non-eradication group. Serum total cholesterol levels did not change after eradication therapy in either the eradication or noneradication groups. Conclusion: Eradication of H. pylori infection induced an increase in BMI in industrial workers with chronic gastritis in Japan. INTRODUCTION It is now widely accepted that H. pylori infection leads to various gastrointestinal diseases such as chronic gastritis, peptic ulcer, gastric cancer and gastric mucosaassociated lymphoid tissue (MALT) lymphoma. 1 7 An association of H. pylori infection with coronary heart disease has also been reported. 8, 9 It has been reported that there are significant correlations between chronic H. pylori infection and various possible vascular risk factors, such as fibrinogen concentration, white cell Correspondence to: Dr T. Azuma, Second Department of Internal Medicine, Faculty of Medicine, Fukui Medical University, Matsuoka-cho, Yoshidagun, Fukui , Japan. azuma@fmsrsa.fukui-med.ac.jp count, blood pressure, body mass index (BMI) or blood lipid concentrations A meta-analysis of 18 epidemiological studies involving a total of patients, which measured serum antibody titres to H. pylori and risk factors for coronary heart disease, showed that there was a positive association between coronary heart disease and chronic infection with H. pylori, and that BMI was significantly higher in those who were seropositive. 15 In addition, Rosenstock et al. examined the association between body mass indices and the seroprevalence of H. pylori infection in Danish adults, and reported that the seroprevalence of H. pylori infection is increased in people with high BMI. 16 These findings suggest that there was an association between H. pylori infection and coronary heart disease with concomitant increases in vascular risk factors including BMI. 240 Ó 2002 Blackwell Science Ltd

2 H. PYLORI INFECTION AND BODY MASS INDEX 241 In contrast, anorexia and loss of lean body mass are hallmark manifestations of acute or chronic disease, including infection or cancer H. pylori infection is a cause of chronic active gastritis. 1, 22 H. pylori gastritis causes alarming symptoms such as anaemia, weight loss and dysphagia in an as yet undefined subset of infected subjects It has been reported that H. pylori infection influences the growth rate in 26, 27 children. Therefore, the relationship between H. pylori infection and body mass indices is controversial. In this study we investigated the relationship between H. pylori infection and body mass indices, and examined the effect of H. pylori eradication therapy on body mass indices. METHODS We screened 932 employees (584 men and 348 women, years old, mean age 42.8 years) of an industrial corporation for H. pylori infection with a 13 C-urea breath test (UBT). To examine the association between H. pylori infection and body mass indices, we excluded subjects who had a history of peptic ulcer, reflux oesophagitis, malignant disease, gall stones, diabetes mellitus or surgery, as well as those using nonsteroidal anti-inflammatory drugs or antibiotics. All employees underwent upper gastrointestinal endoscopy or radiography screening for gastric cancer. Eight cases diagnosed with peptic ulcer (one had a gastric ulcer in the active stage, five had gastric ulcer scars, and two had duodenal ulcer scars) were also excluded. Subjects fasted overnight prior to the UBT. Breath samples were collected before and 15 min after the intake of 13 C-urea solution (100 mg 13 C urea in 100 ml water), and analysed using isotope ratio mass spectrometry. A rise in the delta value of 13 CO 2 of more than 2.5 per ml over the baseline value was considered positive for H. pylori infection. A standardized questionnaire was used to assess abdominal symptoms. This questionnaire addressed seven persistent or recurrent symptoms for more than 3 months (immediately preceding the interview) that served as the primary target variables (upper abdominal pain, heart burn, regurgitation, nausea, vomiting, upper abdominal fullness, loss of appetite). The intensity of respective symptoms was scored as 0 (absent), 1 (mild intensity; not interfering with daily routine), 2 (moderate intensity; sometimes interfering with daily routine) or 3 (severe intensity; regularly interfering with daily routine). The questionnaires were completed by interviewers (two nurses and two physicians). Of 932 employees, 563 (60.4%) were H. pyloripositive and were diagnosed with chronic gastritis by upper gastrointestinal endoscopy or radiography. Of the 563 H. pylori-positive cases, 302 underwent eradication therapy for H. pylori infection with omeprazole (20 mg b.d.), amoxicillin (750 mg b.d.) and clarithromycin (400 mg b.d.) for 1 week as gastric cancer prophylaxis. Eradication of H. pylori infection was evaluated by UBT 3 months after treatment. Body weight was measured in the morning after an overnight fast at the interval before and 12 months after eradication therapy. Serum samples were obtained to measure total cholesterol levels before and 12 months after eradication therapy in the morning after an overnight fast. The results of the breath test performed at 3 months after treatment were not divulged to individuals or investigators until after the completion of the 12-month assessment. This study was performed according to the principles of the Declaration of Helsinki, and informed consent was obtained from each case after full examination of the nature and protocol of the study. Statistical analysis Results are expressed as mean ± S.D. or as percentages. The significance of differences between groups for mean age, body weight, BMI and serum total cholesterol levels was evaluated by the unpaired Student s t-test. Differences in body weight, BMI and serum total cholesterol levels in the interval before and after eradication therapy were analysed by the paired Student s t-test. Symptom scores among groups were compared by Mann Whitney s U-test. Differences in symptom scores in the interval before and after eradication therapy were analysed by Wilcoxon s signed rank test. Differences with a P-value less than 0.05 were considered significant. RESULTS Relationship among H. pylori infection, body weight, BMI and serum total cholesterol levels There were no significant differences in body weight, BMI or total serum cholesterol levels between the H. pyloripositive and H. pylori-negative groups (Table 1).

3 242 T. AZUMA et al. Table 1. Relationship between H. pylori infection and body weight, BMI and serum total cholesterol level H. pylori infection status Positive (n ¼ 563) Negative (n ¼ 369) Sex (M/F) 354/ /139 Age 42Æ9 ±6Æ7 42Æ6 ±7Æ0 Body weight (kg) 61Æ7 ± 10Æ6 62Æ0 ± 11Æ1 BMI (kg/m 2 ) 22Æ4 ±2Æ8 22Æ5 ±3Æ0 Total cholesterol levels (mg/dl) 200Æ2 ±34Æ7 201Æ5 ±38Æ6 Effect of eradication therapy on body weight, BMI and serum total cholesterol levels Three hundred of the 302 cases completed the trial; two cases (0.7%) were lost to follow-up because of job transfers. H. pylori infection was eradicated in 241 cases (per protocol analysis 80.3%, 95% CI %; intention-to-treat analysis 79.8%, 95% CI %). Compliance with the prescribed drugs was almost complete. Thirty-two cases (10.6%) complained of adverse effects; all adverse effects were of mild intensity and did not lead to premature withdrawal from the study. The adverse events included mild diarrhoea in 25 cases and taste disturbance in seven. The differences in body weight, BMI and serum total cholesterol levels in the interval before and after eradication therapy were analysed separately for both groups. Body weight and BMI significantly increased 12 months after eradication of H. pylori infection. In contrast, there was no significant difference in body weight or BMI 12 months after the eradication therapy in the non-eradication group. Total serum cholesterol levels did not change after eradication therapy in either group (Table 2). Effect of H. pylori eradication therapy on symptom scores Symptom scores significantly improved ( , P < ) in the eradication cases, but not in those in whom H. pylori persisted after treatment ( ). Table 2. Effect of H. pylori eradication therapy on body weight, BMI and serum total cholesterol level Eradication group (n ¼ 241) Non-eradication group (n ¼ 59) Before treatment After treatment Before treatment After treatment Body weight (kg) 59.8 ± ± 10.4 a 59.8 ± ± 9.6 BMI (kg/m 2 ) 22.2 ± ± 2.9 b 22.3 ± ± 2.4 Total cholesterol levels ± ± ± ± 38.2 (mg/dl) Sex (M/F) 150/91 37/22 Age 42.5 ± ± 7.2 Significantly increased after treatment ( a P < , b P < ). Table 3. Effect of H. pylori eradication therapy on symptom scores Eradication group (n ¼ 241) Non-eradication group (n ¼ 59) Symptom Before treatment After treatment Before treatment After treatment Upper abdominal pain 0.57 ± ± 0.60 a 0.58 ± ± 0.82 Heart burn 0.47 ± ± 0.60 b 0.54 ± ± 0.74 Regurgitation 0.44 ± ± 0.54 c 0.51 ± ± 0.78 Nausea 0.34 ± ± 0.50 d 0.25 ± ± 0.57 Vomiting 0.21 ± ± ± ± 0.24 Upper abdominal fullness 0.62 ± ± 0.82 e 0.45 ± ± 0.87 Loss of appetite 0.27 ± ± ± ± 0.57 Total 2.93 ± ± 2.87 f 2.67 ± ± 2.89 Significantly improved after treatment ( a P < , b P < 0.002, c P < , d P < 0.005, e P < 0.02, f P < ).

4 H. PYLORI INFECTION AND BODY MASS INDEX 243 Symptoms of upper abdominal pain, heartburn, regurgitation, nausea and abdominal fullness improved significantly after eradication of H. pylori infection (Table 3). DISCUSSION The present data indicate that there is no significant association between H. pylori infection and body mass indices. However, body weight and BMI significantly increased 12 months after eradication of H. pylori infection. Labenz et al. 28 also reported weight gain after eradication of H. pylori infection in patients with duodenal ulcer. It is conceivable that the increased quality of life after eradication of infection and ulcer disease, together with the disappearance of food-related pain, leads to a higher food intake and thus to weight gain. In the present study, symptom scores improved significantly in the eradication cases. However, asymptomatic cases also showed a significant increase in BMI. Thus, other mechanisms besides an improvement in abdominal symptoms may be involved in BMI increase after eradication of infection. Leptin, a product of the ob gene, is a 16-kDa protein synthesized by adipose tissue that plays a crucial role in the homeostasis of body weight by regulating food intake and energy expenditure Recently, leptin was found in the glands of the gastric fundic mucosa. It has been suggested that gastric leptin may be involved in early CCK-mediated effects activated by food intake, possibly including satiety. 33 It has been reported that multiple cytokines and inflammation raise leptin levels Leptin may be a mediator of anorexia associated with acute and chronic inflammation. H. pylori infection is a cause of chronic active gastritis, and several studies have shown the involvement of cytokines in the pathogenesis of gastric inflammation induced by H. pylori infection. 37, 38 It is therefore possible that the gastric inflammation induced by H. pylori infection affects the expression of gastric leptin, and thereby plays a role in the regulation of food intake. We previously reported that H. pylori infection increased gastric leptin expression, while eradication of H. pylori infection induced a decrease in gastric leptin expression with a concomitant increase in BMI. 39 Further studies examining the mechanism of the increase in BMI after eradication of H. pylori infection are needed. Labenz et al. reported a higher rate of oesophagitis in patients with peptic ulcers successfully treated by eradication therapy than in controls. 28 Some studies have suggested that H. pylori infection is less common in patients with oesophagitis than in those with a normal endoscopy result. These findings raised concern that widespread H. pylori treatment may increase symptoms of gastro-oesophageal reflux in the community. However, recent studies do not support the view that eradication of H. pylori aggravates or precipitates gastro-oesophageal reflux symptoms in ulcer patients and in those with functional dyspepsia. 40, 41 The present data also indicate that there is no association between the eradication of H. pylori infection and the increase of gastro-oesophageal reflux symptoms. Symptoms of heartburn and regurgitation improved significantly after the eradication of infection. In conclusion, eradication of H. pylori infection induced an increase in BMI in industrial workers with chronic gastritis in Japan. BMI increase is a known risk factor for the occurrence of reflux oesophagitis, hypertension, atherosclerosis and cardiovascular disease. Long-term follow-up after eradication of H. pylori infection will clarify whether treatment increases the risk of such diseases. ACKNOWLEDGEMENTS This work was supported by a Grant-in-Aid for Scientific Research ( and ) from the Ministry of Education, Science, Sports and Culture, Japan. REFERENCES 1 Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; i: Johnston BJ, Reed PI, Ali MH. Campylobacter-like organisms in duodenal and antral endoscopic biopsies: relationship to inflammation. Gut 1986; 27: Marshall BJ, Goodwin CS, Warren JR et al. Prospective double blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988; ii: Parsonnet J, Friedman GD, Vandersteen DP et al. Helicobacter pylori infection and risk of gastric carcinoma. N Eng J Med 1991; 325: Nomura A, Stemmermann GN, Chyou P, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Eng J Med 1991; 325: Graham DY. Helicobacter pylori: its epidemiology and its role in duodenal ulcer disease. J Gastroenterol Hepatol 1991; 6: Parsonnet J, Hansen S, Rodriguez L et al. Helicobacter pylori infection and gastric lymphoma. N Eng J Med 1994; 330:

5 244 T. AZUMA et al. 8 Patel P, Carrington D, Strachan DP, Leatham E, Goggin P, Northfield TC. Fibrinogen: a link between chronic infection and coronary heart disease. Lancet 1994; 343: Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet 1997; 350: Laurila A, Bloigu A, Nayha S, Hassi J, Leinonen M, Saikku P. Association of Helicobacter pylori infection with elevated serum lipids. Atherosclerosis 1999; 147: Niemela S, Karttunen T, Korhonen T, Laara E, Karttunen R, Ikaheimo M. Could Helicobacter pylori infection increase the risk of coronary heart disease by modifying serum lipid concentrations? Heart 1996; 75: Karttunen TJ, Niemela S, Kerola T. Blood leukocyte differential in Helicobacter pylori infection. Dig Dis Sci 1996; 41: Patel P, Mendall MA, Carrington D, Strachan DP, Leatham E, Molineaux N. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ 1995; 311: Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999; 19: Danesh J, Peto R. Risk factors for coronary heart disease and infection with Helicobacter pylori: meta-analysis of 18 studies. BMJ 1998; 316: Rosenstock SJ, Jorgensen T, Andersen LP, Bonnevie O. Association of Helicobacter pylori infection with lifestyle, chronic disease, body indices, and age at menarche in Danish adults. Scand J Public Health 2000; 28: Moldawer LL, Georgieff M, Lundholm K. Interleukin 1, tumour necrosis factor-alpha (cachectin) and the pathogenesis of cancer cachexia. Clin Physiol 1987; 7: Bendtzen K. Interleukin 1, interleukin 6 and tumor necrosis factor in infection, inflammation and immunity. Immunol Lett 1988; 19: Mori M, Yamaguchi K, Honda S et al. Cancer cachexia syndrome developed in nude mice bearing melanoma cells producing leukemia-inhibitory factor. Cancer Res 1991; 51: Tracey KJ, Wei H, Manogue KR et al. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med 1988; 167: Socher SM, Friedman A, Martinez D. Recombinant human tumor necrosis factor induces acute reductions in food intake and body weight in mice. J Exp Med 1988; 167: Marshall BJ. Campylobacter pyloridis and gastritis. J Infect Dis 1986; 153: Milman N, Rosenstock S, Andersen L, Jorgensen T, Bonnevie O. Serum ferritin, hemoglobin, and Helicobacter pylori infection: a seroepidemiologic survey comprising 2794 Danish adults. Gastroenterology 1998; 115: Fisher RS, Parkman HP. Management of nonulcer dyspepsia. N Engl J Med 1998; 339: Miyaji H, Azuma T, Ito S et al. The effect of Helicobacter pylori eradication therapy on gastric antral myoelectrical activity and gastric emptying in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther 1999; 13: Patel P, Mendall MA, Khulusi S et al. Helicobacter pylori infection in childhood: risk factors and effect on growth. BMJ 1994; 309: Perri F, Pastore M, Leandro G et al. Helicobacter pylori infection and growth delay in older children. Arch Dis Child 1997; 77: Labenz J, Blum AL, Bayerdorffer E et al. Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997; 112: Zhang Y, Proenca R, Maffei M et al. Positional cloning of the mouse ob gene and its human homologue. Nature 1994; 372: Campfield LA, Smith FJ, Guisez Y et al. Recombinant mouse OB protein: evidence of a peripheral signal linking adiposity and central neural networks. Science 1995; 269: Pelleymounter MA, Cullen MJ, Baker MB et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269: Halaas JL, Gajiwala KS, Maffei M et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: Bado A, Levasseur S, Attoub S et al. The stomach is a source of leptin. Nature 1998; 394: Bornstein SR, Preas HL, Chrousos GP et al. Circulating leptin levels during acute experimental endotoxemia and antiinflammatory therapy in humans. J Infect Dis 1998; 178: Sarraf P, Frederich RC, Turner EM et al. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med 1997; 185: Faggioni R, Fantuzzi G, Fuller J et al. IL-1b mediates leptin induction during inflammation. Am J Physiol 1998; 274: R Crabtree JE, Shallcross TM, Heatley RV et al. Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis. Gut 1991; 32: Yamaoka Y, Kita M, Kodama T et al. Helicobacter pylori caga gene and expression of cytokine messenger RNA in gastric mucosa. Gastroenterology 1996; 110: Azuma T, Suto H, Ito Y, Ohtani M, Dojo M, Kuriyama M, Kato T. Gastric leptin and Helicobacter pylori infection. Gut 2001; 49: McColl KEL, Dickson A, El-Nujimi A, El-Omar E, Kelman A. Symptomatic benefit 1 3 years after H. pylori eradication in ulcer patients: impact of gastroesophageal reflux disease. Am J Gastroenterol 2000; 95: Azuma T, Ito Y, Suto H, Ohtani M, Dojo M, Muramatsu A, Kuriyama M, Kato T. The effect of Helicobacter pylori eradication therapy on dyspepsia symptoms in industrial workers in Japan. Aliment Pharmacol Ther 2001; 15: