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Published in: Journal of Gastroenterology 1/2013

01-01-2013 | Original Article—Liver, Pancreas, and Biliary Tract

Chronic HCV infection was associated with severe insulin resistance and mild atherosclerosis: a population-based study in an HCV hyperendemic area

Authors: Ichiro Miyajima, Takumi Kawaguchi, Ako Fukami, Yumiko Nagao, Hisashi Adachi, Satoshi Sasaki, Tsutomu Imaizumi, Michio Sata

Published in: Journal of Gastroenterology | Issue 1/2013

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Abstract

Background

Hepatitis C virus (HCV) affects glucose and lipid metabolism in vitro; however, it is unclear whether HCV infection is associated with insulin resistance and atherosclerosis at the population level. We aimed to investigate this association in a Japanese cohort of the Seven Countries Study, and our investigation was conducted in Tanushimaru, an HCV hyperendemic area.

Methods

A total of 1908 inhabitants of Tanushimaru were classified into 3 groups according to HCV infection status: those who were uninfected (n = 1780), those with transient infection (n = 88), and those with chronic infection (n = 40). Insulin resistance and atherosclerosis were evaluated by homeostasis model assessment for insulin resistance (HOMA-IR) and carotid intima–media thickness (IMT), respectively. Intergroup differences in variables were evaluated by age- and sex-matched multivariate regression analysis.

Results

Significant intergroup differences were seen in fasting glucose and insulin levels. The HOMA-IR value was significantly higher in the group with chronic infection than the values in the uninfected and transiently infected groups (3.0 ± 0.39 vs. 1.3 ± 0.03 vs. 1.5 ± 0.14; P < 0.001). In contrast, low-density lipoprotein (LDL)-cholesterol and triglyceride levels were significantly lower in the group with chronic infection than the levels in the other groups. IMT was reduced in the group with chronic infection, with a significant intergroup difference (0.67 ± 0.02 vs. 0.71 ± 0.003 vs. 0.72 ± 0.01 mm; P = 0.003).

Conclusions

This population-based study in an HCV hyperendemic area revealed that chronic HCV infection was associated with severe insulin resistance and with mild atherosclerosis, suggesting a unique characteristic of HCV-related metabolic abnormality.
Literature
1.
go back to reference Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5:558–67.PubMedCrossRef Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5:558–67.PubMedCrossRef
2.
go back to reference Weinman SA, Belalcazar LM. Hepatitis C: a metabolic liver disease. Gastroenterology. 2004;126:917–9.PubMedCrossRef Weinman SA, Belalcazar LM. Hepatitis C: a metabolic liver disease. Gastroenterology. 2004;126:917–9.PubMedCrossRef
3.
go back to reference Kawaguchi T, Izumi N, Charlton MR, Sata M. Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 2011;54:1063–70.PubMedCrossRef Kawaguchi T, Izumi N, Charlton MR, Sata M. Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 2011;54:1063–70.PubMedCrossRef
4.
go back to reference Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 1994;21:1135–9.PubMedCrossRef Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 1994;21:1135–9.PubMedCrossRef
5.
go back to reference Eslam M, Aparcero R, Kawaguchi T, Del Campo JA, Sata M, Khattab MA, et al. Meta-analysis: insulin resistance and sustained virological response in hepatitis C. Aliment Pharmacol Ther. 2011;34:297–305.PubMedCrossRef Eslam M, Aparcero R, Kawaguchi T, Del Campo JA, Sata M, Khattab MA, et al. Meta-analysis: insulin resistance and sustained virological response in hepatitis C. Aliment Pharmacol Ther. 2011;34:297–305.PubMedCrossRef
6.
go back to reference Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499–508.PubMedCrossRef Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499–508.PubMedCrossRef
7.
go back to reference Voeks JH, McClure LA, Go RC, Prineas RJ, Cushman M, Kissela BM, et al. Regional differences in diabetes as a possible contributor to the geographic disparity in stroke mortality: the REasons for Geographic And Racial Differences in Stroke Study. Stroke. 2008;39:1675–80.PubMedCrossRef Voeks JH, McClure LA, Go RC, Prineas RJ, Cushman M, Kissela BM, et al. Regional differences in diabetes as a possible contributor to the geographic disparity in stroke mortality: the REasons for Geographic And Racial Differences in Stroke Study. Stroke. 2008;39:1675–80.PubMedCrossRef
8.
go back to reference Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci USA. 1999;96:12766–71.PubMedCrossRef Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci USA. 1999;96:12766–71.PubMedCrossRef
9.
go back to reference Nahmias Y, Casali M, Barbe L, Berthiaume F, Yarmush ML. Liver endothelial cells promote LDL-R expression and the uptake of HCV-like particles in primary rat and human hepatocytes. Hepatology. 2006;43:257–65.PubMedCrossRef Nahmias Y, Casali M, Barbe L, Berthiaume F, Yarmush ML. Liver endothelial cells promote LDL-R expression and the uptake of HCV-like particles in primary rat and human hepatocytes. Hepatology. 2006;43:257–65.PubMedCrossRef
10.
go back to reference Icard V, Diaz O, Scholtes C, Perrin-Cocon L, Ramiere C, Bartenschlager R, et al. Secretion of hepatitis C virus envelope glycoproteins depends on assembly of apolipoprotein B positive lipoproteins. PLoS One. 2009;4:e4233.PubMedCrossRef Icard V, Diaz O, Scholtes C, Perrin-Cocon L, Ramiere C, Bartenschlager R, et al. Secretion of hepatitis C virus envelope glycoproteins depends on assembly of apolipoprotein B positive lipoproteins. PLoS One. 2009;4:e4233.PubMedCrossRef
11.
12.
go back to reference Miyazaki T, Honda A, Ikegami T, Saitoh Y, Hirayama T, Hara T, et al. Hepatitis C virus infection causes hypolipidemia regardless of hepatic damage or nutritional state: an epidemiological survey of a large Japanese cohort. Hepatol Res. 2011;41:530–41.PubMedCrossRef Miyazaki T, Honda A, Ikegami T, Saitoh Y, Hirayama T, Hara T, et al. Hepatitis C virus infection causes hypolipidemia regardless of hepatic damage or nutritional state: an epidemiological survey of a large Japanese cohort. Hepatol Res. 2011;41:530–41.PubMedCrossRef
13.
go back to reference Mostafa A, Mohamed MK, Saeed M, Hasan A, Fontanet A, Godsland I, et al. Hepatitis C infection and clearance: impact on atherosclerosis and cardiometabolic risk factors. Gut. 2010;59:1135–40.PubMedCrossRef Mostafa A, Mohamed MK, Saeed M, Hasan A, Fontanet A, Godsland I, et al. Hepatitis C infection and clearance: impact on atherosclerosis and cardiometabolic risk factors. Gut. 2010;59:1135–40.PubMedCrossRef
14.
go back to reference Ishizaka N, Ishizaka Y, Takahashi E, Tooda E, Hashimoto H, Nagai R, et al. Association between hepatitis C virus seropositivity, carotid-artery plaque, and intima–media thickening. Lancet. 2002;359:133–5.PubMedCrossRef Ishizaka N, Ishizaka Y, Takahashi E, Tooda E, Hashimoto H, Nagai R, et al. Association between hepatitis C virus seropositivity, carotid-artery plaque, and intima–media thickening. Lancet. 2002;359:133–5.PubMedCrossRef
15.
go back to reference Yang KC, Chen MF, Su TC, Jeng JS, Hwang BS, Lin LY, et al. Hepatitis B virus seropositivity is not associated with increased risk of carotid atherosclerosis in Taiwanese. Atherosclerosis. 2007;195:392–7.PubMedCrossRef Yang KC, Chen MF, Su TC, Jeng JS, Hwang BS, Lin LY, et al. Hepatitis B virus seropositivity is not associated with increased risk of carotid atherosclerosis in Taiwanese. Atherosclerosis. 2007;195:392–7.PubMedCrossRef
16.
go back to reference Adachi H, Goetz FC, Jacobs DR, Tsuruta M, Hirai Y, Fujiura Y, et al. The role of obesity in the association of cardiovascular risk factors and glucose intolerance in small Japanese and North American communities. Diabetes Res Clin Pract. 2000;49:41–51.PubMedCrossRef Adachi H, Goetz FC, Jacobs DR, Tsuruta M, Hirai Y, Fujiura Y, et al. The role of obesity in the association of cardiovascular risk factors and glucose intolerance in small Japanese and North American communities. Diabetes Res Clin Pract. 2000;49:41–51.PubMedCrossRef
17.
go back to reference Adachi H, Hino A. Trends in nutritional intake and serum cholesterol levels over 40 years in Tanushimaru, Japanese men. J Epidemiol. 2005;15:85–9.PubMedCrossRef Adachi H, Hino A. Trends in nutritional intake and serum cholesterol levels over 40 years in Tanushimaru, Japanese men. J Epidemiol. 2005;15:85–9.PubMedCrossRef
18.
go back to reference Enomoto M, Adachi H, Fukami A, Furuki K, Satoh A, Otsuka M, et al. Serum dehydroepiandrosterone sulfate levels predict longevity in men: 27-year follow-up study in a community-based cohort (Tanushimaru study). J Am Geriatr Soc. 2008;56:994–8.PubMedCrossRef Enomoto M, Adachi H, Fukami A, Furuki K, Satoh A, Otsuka M, et al. Serum dehydroepiandrosterone sulfate levels predict longevity in men: 27-year follow-up study in a community-based cohort (Tanushimaru study). J Am Geriatr Soc. 2008;56:994–8.PubMedCrossRef
19.
go back to reference Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–26.PubMedCrossRef Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–26.PubMedCrossRef
20.
go back to reference Lackner C, Struber G, Liegl B, Leibl S, Ofner P, Bankuti C, et al. Comparison and validation of simple noninvasive tests for prediction of fibrosis in chronic hepatitis C. Hepatology. 2005;41:1376–82.PubMedCrossRef Lackner C, Struber G, Liegl B, Leibl S, Ofner P, Bankuti C, et al. Comparison and validation of simple noninvasive tests for prediction of fibrosis in chronic hepatitis C. Hepatology. 2005;41:1376–82.PubMedCrossRef
21.
go back to reference Keys A, Aravanis C, Blackburn HW, Van Buchem FS, Buzina R, Djordjevic BD, et al. Epidemiological studies related to coronary heart disease: characteristics of men aged 40–59 in seven countries. Acta Med Scand Suppl. 1966;460:1–392.PubMed Keys A, Aravanis C, Blackburn HW, Van Buchem FS, Buzina R, Djordjevic BD, et al. Epidemiological studies related to coronary heart disease: characteristics of men aged 40–59 in seven countries. Acta Med Scand Suppl. 1966;460:1–392.PubMed
22.
go back to reference Kobayashi S, Honda S, Murakami K, Sasaki S, Okubo H, Hirota N, et al. Both comprehensive and brief self-administered diet history questionnaires satisfactorily rank nutrient intakes in Japanese adults. J Epidemiol. 2012;22:151–9.PubMedCrossRef Kobayashi S, Honda S, Murakami K, Sasaki S, Okubo H, Hirota N, et al. Both comprehensive and brief self-administered diet history questionnaires satisfactorily rank nutrient intakes in Japanese adults. J Epidemiol. 2012;22:151–9.PubMedCrossRef
23.
go back to reference Oya J, Nakagami T, Sasaki S, Jimba S, Murakami K, Kasahara T, et al. Intake of n-3 polyunsaturated fatty acids and non-alcoholic fatty liver disease: a cross-sectional study in Japanese men and women. Eur J Clin Nutr. 2010;64:1179–85.PubMedCrossRef Oya J, Nakagami T, Sasaki S, Jimba S, Murakami K, Kasahara T, et al. Intake of n-3 polyunsaturated fatty acids and non-alcoholic fatty liver disease: a cross-sectional study in Japanese men and women. Eur J Clin Nutr. 2010;64:1179–85.PubMedCrossRef
24.
go back to reference Kobayashi S, Murakami K, Sasaki S, Okubo H, Hirota N, Notsu A, et al. Comparison of relative validity of food group intakes estimated by comprehensive and brief-type self-administered diet history questionnaires against 16 d dietary records in Japanese adults. Public Health Nutr. 2011;14:1200–11.PubMedCrossRef Kobayashi S, Murakami K, Sasaki S, Okubo H, Hirota N, Notsu A, et al. Comparison of relative validity of food group intakes estimated by comprehensive and brief-type self-administered diet history questionnaires against 16 d dietary records in Japanese adults. Public Health Nutr. 2011;14:1200–11.PubMedCrossRef
25.
go back to reference Sasaki S, Yanagibori R, Amano K. Self-administered diet history questionnaire developed for health education: a relative validation of the test-version by comparison with 3-day diet record in women. J Epidemiol. 1998;8:203–15.PubMedCrossRef Sasaki S, Yanagibori R, Amano K. Self-administered diet history questionnaire developed for health education: a relative validation of the test-version by comparison with 3-day diet record in women. J Epidemiol. 1998;8:203–15.PubMedCrossRef
26.
go back to reference Alborino F, Burighel A, Tiller FW, van Helden J, Gabriel C, Raineri A, et al. Multicenter evaluation of a fully automated third-generation anti-HCV antibody screening test with excellent sensitivity and specificity. Med Microbiol Immunol. 2011;200:77–83.PubMedCrossRef Alborino F, Burighel A, Tiller FW, van Helden J, Gabriel C, Raineri A, et al. Multicenter evaluation of a fully automated third-generation anti-HCV antibody screening test with excellent sensitivity and specificity. Med Microbiol Immunol. 2011;200:77–83.PubMedCrossRef
27.
go back to reference Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.PubMedCrossRef Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.PubMedCrossRef
28.
go back to reference Furuki K, Adachi H, Matsuoka H, Enomoto M, Satoh A, Hino A, et al. Plasma levels of asymmetric dimethylarginine (ADMA) are related to intima–media thickness of the carotid artery: an epidemiological study. Atherosclerosis. 2007;191:206–10.PubMedCrossRef Furuki K, Adachi H, Matsuoka H, Enomoto M, Satoh A, Hino A, et al. Plasma levels of asymmetric dimethylarginine (ADMA) are related to intima–media thickness of the carotid artery: an epidemiological study. Atherosclerosis. 2007;191:206–10.PubMedCrossRef
30.
go back to reference Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133:592–9.PubMed Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133:592–9.PubMed
31.
go back to reference Nagao Y, Kawaguchi T, Tanaka K, Kumashiro R, Sata M. Extrahepatic manifestations and insulin resistance in an HCV hyperendemic area. Int J Mol Med. 2005;16:291–6.PubMed Nagao Y, Kawaguchi T, Tanaka K, Kumashiro R, Sata M. Extrahepatic manifestations and insulin resistance in an HCV hyperendemic area. Int J Mol Med. 2005;16:291–6.PubMed
32.
go back to reference Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840–8.PubMedCrossRef Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840–8.PubMedCrossRef
33.
go back to reference Kawaguchi T, Ide T, Taniguchi E, Hirano E, Itou M, Sumie S, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102:570–6.PubMedCrossRef Kawaguchi T, Ide T, Taniguchi E, Hirano E, Itou M, Sumie S, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102:570–6.PubMedCrossRef
34.
go back to reference Reaven GM. Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension. Parallels between human disease and rodent models. Diabetes Care. 1991;14:195–202.PubMedCrossRef Reaven GM. Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension. Parallels between human disease and rodent models. Diabetes Care. 1991;14:195–202.PubMedCrossRef
35.
go back to reference Grundy SM. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol. 1999;83:25F–9F.PubMedCrossRef Grundy SM. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol. 1999;83:25F–9F.PubMedCrossRef
36.
go back to reference Aizaki H, Morikawa K, Fukasawa M, Hara H, Inoue Y, Tani H, et al. Critical role of virion-associated cholesterol and sphingolipid in hepatitis C virus infection. J Virol. 2008;82:5715–24.PubMedCrossRef Aizaki H, Morikawa K, Fukasawa M, Hara H, Inoue Y, Tani H, et al. Critical role of virion-associated cholesterol and sphingolipid in hepatitis C virus infection. J Virol. 2008;82:5715–24.PubMedCrossRef
37.
go back to reference Honda A, Matsuzaki Y. Cholesterol and chronic hepatitis C virus infection. Hepatol Res. 2011;41:697–710.PubMedCrossRef Honda A, Matsuzaki Y. Cholesterol and chronic hepatitis C virus infection. Hepatol Res. 2011;41:697–710.PubMedCrossRef
38.
go back to reference Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chretien Y, et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J. 2002;16:185–94.PubMedCrossRef Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chretien Y, et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J. 2002;16:185–94.PubMedCrossRef
39.
go back to reference Ishizaka Y, Ishizaka N, Takahashi E, Unuma T, Tooda E, Hashimoto H, et al. Association between hepatitis C virus core protein and carotid atherosclerosis. Circ J. 2003;67:26–30.PubMedCrossRef Ishizaka Y, Ishizaka N, Takahashi E, Unuma T, Tooda E, Hashimoto H, et al. Association between hepatitis C virus core protein and carotid atherosclerosis. Circ J. 2003;67:26–30.PubMedCrossRef
40.
go back to reference Konishi M, Iso H, Iida M, Naito Y, Sato S, Komachi Y, et al. Trends for coronary heart disease and its risk factors in Japan: epidemiologic and pathologic studies. Jpn Circ J. 1990;54:428–35.PubMedCrossRef Konishi M, Iso H, Iida M, Naito Y, Sato S, Komachi Y, et al. Trends for coronary heart disease and its risk factors in Japan: epidemiologic and pathologic studies. Jpn Circ J. 1990;54:428–35.PubMedCrossRef
41.
go back to reference Bianchi G, Marchesini G, Zoli M, Bugianesi E, Fabbri A, Pisi E. Prognostic significance of diabetes in patients with cirrhosis. Hepatology. 1994;20:119–25.PubMed Bianchi G, Marchesini G, Zoli M, Bugianesi E, Fabbri A, Pisi E. Prognostic significance of diabetes in patients with cirrhosis. Hepatology. 1994;20:119–25.PubMed
42.
go back to reference Fujiwara F, Ishii M, Taneichi H, Miura M, Toshihiro M, Takebe N, et al. Low incidence of vascular complications in patients with diabetes mellitus associated with liver cirrhosis as compared with type 2 diabetes mellitus. Tohoku J Exp Med. 2005;205:327–34.PubMedCrossRef Fujiwara F, Ishii M, Taneichi H, Miura M, Toshihiro M, Takebe N, et al. Low incidence of vascular complications in patients with diabetes mellitus associated with liver cirrhosis as compared with type 2 diabetes mellitus. Tohoku J Exp Med. 2005;205:327–34.PubMedCrossRef
43.
go back to reference Kawaguchi T, Sata M. Importance of hepatitis C virus-associated insulin resistance: therapeutic strategies for insulin sensitization. World J Gastroenterol. 2010;16:1943–52.PubMedCrossRef Kawaguchi T, Sata M. Importance of hepatitis C virus-associated insulin resistance: therapeutic strategies for insulin sensitization. World J Gastroenterol. 2010;16:1943–52.PubMedCrossRef
44.
go back to reference Kawaguchi T, Taniguchi E, Morita Y, Shirachi M, Tateishi I, Nagata E, et al. Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection. Liver Int. 2010;30:479–86.PubMedCrossRef Kawaguchi T, Taniguchi E, Morita Y, Shirachi M, Tateishi I, Nagata E, et al. Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection. Liver Int. 2010;30:479–86.PubMedCrossRef
Metadata
Title
Chronic HCV infection was associated with severe insulin resistance and mild atherosclerosis: a population-based study in an HCV hyperendemic area
Authors
Ichiro Miyajima
Takumi Kawaguchi
Ako Fukami
Yumiko Nagao
Hisashi Adachi
Satoshi Sasaki
Tsutomu Imaizumi
Michio Sata
Publication date
01-01-2013
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 1/2013
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-012-0610-3

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