- Email: [email protected]
[736] GENETIC AND ENVIRONMENTAL FACTORS RESPONSIBLE FOR OXIDATIVE STRESS IN NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)
OK. ALCOHOLIC LIVER DISEASE, NAFLD AND DRUC-INDUCED LIVER DISEASE
17341 EFFECT OF METFORMIN IN TREATMENT OF NONALCOHOLIC STEATOHEPATITIS S. Merat, R. Kazemi, M. Aduli, M. Sotoudeh, R. Malekzadeh. Digestiue Disease Reseurch Center, Tehran Uniuersity of Medicul Sciencex, Ehrun, Iran E-mail: [email protected] Background and Aims: Nonalcoholic steatohepatitis (NASH) is a common liver disease which can progress to cirrhosis or hepatocellular carcinoma. The pathogenesis of NASH is incompletely understood but there is significant evidence pointing to the importance of insulin resistance. Metformin is an oral hypoglycemic agent known to improve insulin resistance. We aimed to study the effectiveness of metformin in NASH patients in a randomized double-blind controlled trial. Methods: Thirty-three cases of biopsy proven NASH patients were included. Other causes of liver disorders were excluded. No patient used alcohol. Subjects were randomized to receive either metformin, 500 mg trice daily, or an identical-looking placebo. All patients were also instructed to loose weight. Treatment was continued for at least 6 months. Patients were regularly visited and liver enzyme levels recorded. Compliance of patients and any adverse drug effect was recorded. Results: All patients lost weight during the study (mean I .9 kg) but only in the metformin group this weight loss reached statistical significance. The mean AST and ALT levels dropped from 65.3 and 95.5 to 36.0 and 56.7 1U respectively in the metformin group and from 66.4 and 111.3 to 42.0 and 61.3 1U in the placebo group. The decrease in liver enzymes was significant in both groups. There was a trend in the metformin group to have a greater decrease in liver enzyme levels but this trend did not receive statistical significance. Univarate and multivariate analysis failed to demonstrate any benefit from metformin in decreasing liver enzymes. Conclusion: The improvement we observed in liver enzyme levels is probably contributable to weight loss. It does not appear that metformin helps improve liver enzyme levels in NASH. We will follow the patients for 1 year and perform liver biopsies at the end of treatment.
17351 IRON METABOLISM OF Atp7b KNOCKOUT MICE U. Merle, K. Bents, S. Tuma, S. Gehrke, W. Stremmel. Department of
Internal Medicine li7 Uniuenity H o q t a l , Heidelberg, Gernzany
S277
17361 GENETIC AND ENVIRONMENTAL FACTORS RESPONSIBLE FOR OXIDATIVE STRESS IN NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) L. Miele1s2, S. Boccia3, C. Cefalo’, G. La Torre3, A. Forgione’, F. Gianfagna3, D. Arzani3, M.L. Gabrieli’, V Verol , G. Gasbarnnil, G. Ricciardi3, A. Grieco’ . ‘Department CfInternul Medicine, Unioer,sita’ Cattolica Del Sucro Cuore, Roma, Ituly; 2Department of Heputo~ogjJ, Uniuer~xit?,of Newcaxtle, Newcustle Upon Tyne, UK; ’Department of
Hygiene and Public Health, linioersita ’ Cattolica Del Sacro Cuore, Ronza, Italy E-mail: [email protected] Background and Aims: Genetic and environmental factors are the main component of onset and progression of NAFLD and act modulating oxidative stress. We aimed to investigate the polymorphism of genes belonging to antioxidant pathways and their role in relationship to lifestyle habits before the diagnosis of liver disease in consecutive patients referring to the Outpatient Liver Unit. Patients and Methods: 113 consecutive NALFD (mean age 43.7f14.8, male gender: 72%) patients and 244 hospital controls were genotyped for CYP 1 A I MspT, CYP2E 1 DraT and RsaT, GSTM I , GSTT 1 polymorphisms employing PCR/restriction fragment length polymorphism-based methods. A comprehensive epidemiological interview was conducted on all participants to collect lifestyle data, including dietary habit, prevalence of quality food intake and the amount of daily alcohol assumption. Results: No difference was found between the two groups for the frequency of all polymorphism studied. Regarding the lifestyle habits, the amount alcohol below 18 giday seems to have a protective effect for the onset of NAFLD (p < 0.05). NAFLD patients have high intake of grilled meat (p < 0.05)and high exposure to solvents and oil derivates (p < 0.05). Conclusions: Several studies suggest a pivotal role of dietary saturated fat and antioxidant intake in NAFLD progression. In our study, even in absence of polymorphism of antioxidant pathway the role o and exposure to chemicals and oil derivates seems to be a risk factor independent from obesity and diabetes for the onset of NAFLD.
17371 THE EFFECT OF INSULIN-SENSITIZING AGENTS IN THE TREATMENT OF INDIVIDUALS WITH NON-ALCOHOLIC STEATOHEPATITIS
E-mail uta-merle(@med uni-heidelberg de
D. Mizrak’, R. ldilman’, M. Bektas’, E. Erden3, 1. Soykan’, D. Corapcioglu2, B. Doganay4, R. Emra12, A.R. Uysa12, A. Ozden’.
Iron and copper homeostasis share common proteins and are therefore closely linked to each other. Wilson disease is a copper storage disorder caused by mutations of the copper transporting ATPase ATP7B. The aim of the present work was to investigate iron metabolism in Atp7b(-/-) mice. We compared the hepatic iron content, and the mRNA expression of iron-metabolism genes in the liver and duodenum of Atp7b(-/-) mice to wildtype mice. In livers of Atp7b(-/-) mice we found a 1.5-fold iron content compared to wildtype mice (158.33&40.04 vs. 105.88&18.63 pgig of wet weight, P=O.OOl). Duodenal expression of Dcytb and Fpnl was significantly higher in Atp7b(-/-) mice, whereas duodenal expression levels of Dmt 1, hephaestin, and H-Ferntin were not significantly different between Atp7b(-/-) and wildtype mice. Hepatic expression of the ironmetabolism genes hepcidin, Dmtl, and TfR2, was significantly lower in Atp7b(-/-) mice than in wildtype mice, whereas hepatic H-Ferritin and Hjv were expressed higher in Atp7b(-/-) mice. Hepatic copper content was increased 25-fold (187.92f15.33 vs. 7.38+1.06, P<0.001) and hepatic metallothionein expression 88-fold (P i 0.001) in Atp7b(-/-) mice when compared to controls. These data suggest that the hepatic iron accumulation in Atp7b(-/-) mice might be a consequence of an inappropriate hepatic iron-sensing putatively due to binding of iron to copper-induced metallothionein, resulting in reduced hepatic hepcidin expression and high iron absorption.
I Gastroenterology Dept; Endocrinology Dept; .’Pathology Dept; 4Biostatistics Dept, Ankuru Uniuer~xit?,Faculty of Medicine, Ankuru, Tnrkey E-mail: [email protected]
Background and Aim: The aim of this study is to investigate the role of insulin-sensitizing agents in the treatment of individuals with non-alcoholic steatohepatitis (NASH). Methods: This is a prospective, randomize, longitudinal single center study. A total of 62 individuals with NASH (maleifemale, 36/26; mean age, 46.2 years) were enrolled into study. Patients were divided into three distinct groups according to their therapeutic management. Group 1 (n= 23) consisted of individuals who received a conventional diet of 25 kcal/kg x ideal body weight (kg) and an exercise program. Group 2 (n=20) consisted of individuals who received diet and exercise plus metformin at a dose of 850 mg bid. for 48 weeks and group 3 (n = 19) consisted of individuals who received diet and exercise plus rosiglitazone at a dose of 8 mg daily for 48 weeks. Liver biopsies were performed at 48 weeks in available 8 individuals in group I , 15 in treatment groups. Results: Among three groups, no significant differences were observed in terms of the patient age, gender, baseline mean body mass index (BMI), mean initial serum aminotransferase levels (p > 0.05).Baseline HOMA
17341 EFFECT OF METFORMIN IN TREATMENT OF NONALCOHOLIC STEATOHEPATITIS S. Merat, R. Kazemi, M. Aduli, M. Sotoudeh, R. Malekzadeh. Digestiue Disease Reseurch Center, Tehran Uniuersity of Medicul Sciencex, Ehrun, Iran E-mail: [email protected] Background and Aims: Nonalcoholic steatohepatitis (NASH) is a common liver disease which can progress to cirrhosis or hepatocellular carcinoma. The pathogenesis of NASH is incompletely understood but there is significant evidence pointing to the importance of insulin resistance. Metformin is an oral hypoglycemic agent known to improve insulin resistance. We aimed to study the effectiveness of metformin in NASH patients in a randomized double-blind controlled trial. Methods: Thirty-three cases of biopsy proven NASH patients were included. Other causes of liver disorders were excluded. No patient used alcohol. Subjects were randomized to receive either metformin, 500 mg trice daily, or an identical-looking placebo. All patients were also instructed to loose weight. Treatment was continued for at least 6 months. Patients were regularly visited and liver enzyme levels recorded. Compliance of patients and any adverse drug effect was recorded. Results: All patients lost weight during the study (mean I .9 kg) but only in the metformin group this weight loss reached statistical significance. The mean AST and ALT levels dropped from 65.3 and 95.5 to 36.0 and 56.7 1U respectively in the metformin group and from 66.4 and 111.3 to 42.0 and 61.3 1U in the placebo group. The decrease in liver enzymes was significant in both groups. There was a trend in the metformin group to have a greater decrease in liver enzyme levels but this trend did not receive statistical significance. Univarate and multivariate analysis failed to demonstrate any benefit from metformin in decreasing liver enzymes. Conclusion: The improvement we observed in liver enzyme levels is probably contributable to weight loss. It does not appear that metformin helps improve liver enzyme levels in NASH. We will follow the patients for 1 year and perform liver biopsies at the end of treatment.
17351 IRON METABOLISM OF Atp7b KNOCKOUT MICE U. Merle, K. Bents, S. Tuma, S. Gehrke, W. Stremmel. Department of
Internal Medicine li7 Uniuenity H o q t a l , Heidelberg, Gernzany
S277
17361 GENETIC AND ENVIRONMENTAL FACTORS RESPONSIBLE FOR OXIDATIVE STRESS IN NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) L. Miele1s2, S. Boccia3, C. Cefalo’, G. La Torre3, A. Forgione’, F. Gianfagna3, D. Arzani3, M.L. Gabrieli’, V Verol , G. Gasbarnnil, G. Ricciardi3, A. Grieco’ . ‘Department CfInternul Medicine, Unioer,sita’ Cattolica Del Sucro Cuore, Roma, Ituly; 2Department of Heputo~ogjJ, Uniuer~xit?,of Newcaxtle, Newcustle Upon Tyne, UK; ’Department of
Hygiene and Public Health, linioersita ’ Cattolica Del Sacro Cuore, Ronza, Italy E-mail: [email protected] Background and Aims: Genetic and environmental factors are the main component of onset and progression of NAFLD and act modulating oxidative stress. We aimed to investigate the polymorphism of genes belonging to antioxidant pathways and their role in relationship to lifestyle habits before the diagnosis of liver disease in consecutive patients referring to the Outpatient Liver Unit. Patients and Methods: 113 consecutive NALFD (mean age 43.7f14.8, male gender: 72%) patients and 244 hospital controls were genotyped for CYP 1 A I MspT, CYP2E 1 DraT and RsaT, GSTM I , GSTT 1 polymorphisms employing PCR/restriction fragment length polymorphism-based methods. A comprehensive epidemiological interview was conducted on all participants to collect lifestyle data, including dietary habit, prevalence of quality food intake and the amount of daily alcohol assumption. Results: No difference was found between the two groups for the frequency of all polymorphism studied. Regarding the lifestyle habits, the amount alcohol below 18 giday seems to have a protective effect for the onset of NAFLD (p < 0.05). NAFLD patients have high intake of grilled meat (p < 0.05)and high exposure to solvents and oil derivates (p < 0.05). Conclusions: Several studies suggest a pivotal role of dietary saturated fat and antioxidant intake in NAFLD progression. In our study, even in absence of polymorphism of antioxidant pathway the role o and exposure to chemicals and oil derivates seems to be a risk factor independent from obesity and diabetes for the onset of NAFLD.
17371 THE EFFECT OF INSULIN-SENSITIZING AGENTS IN THE TREATMENT OF INDIVIDUALS WITH NON-ALCOHOLIC STEATOHEPATITIS
E-mail uta-merle(@med uni-heidelberg de
D. Mizrak’, R. ldilman’, M. Bektas’, E. Erden3, 1. Soykan’, D. Corapcioglu2, B. Doganay4, R. Emra12, A.R. Uysa12, A. Ozden’.
Iron and copper homeostasis share common proteins and are therefore closely linked to each other. Wilson disease is a copper storage disorder caused by mutations of the copper transporting ATPase ATP7B. The aim of the present work was to investigate iron metabolism in Atp7b(-/-) mice. We compared the hepatic iron content, and the mRNA expression of iron-metabolism genes in the liver and duodenum of Atp7b(-/-) mice to wildtype mice. In livers of Atp7b(-/-) mice we found a 1.5-fold iron content compared to wildtype mice (158.33&40.04 vs. 105.88&18.63 pgig of wet weight, P=O.OOl). Duodenal expression of Dcytb and Fpnl was significantly higher in Atp7b(-/-) mice, whereas duodenal expression levels of Dmt 1, hephaestin, and H-Ferntin were not significantly different between Atp7b(-/-) and wildtype mice. Hepatic expression of the ironmetabolism genes hepcidin, Dmtl, and TfR2, was significantly lower in Atp7b(-/-) mice than in wildtype mice, whereas hepatic H-Ferritin and Hjv were expressed higher in Atp7b(-/-) mice. Hepatic copper content was increased 25-fold (187.92f15.33 vs. 7.38+1.06, P<0.001) and hepatic metallothionein expression 88-fold (P i 0.001) in Atp7b(-/-) mice when compared to controls. These data suggest that the hepatic iron accumulation in Atp7b(-/-) mice might be a consequence of an inappropriate hepatic iron-sensing putatively due to binding of iron to copper-induced metallothionein, resulting in reduced hepatic hepcidin expression and high iron absorption.
I Gastroenterology Dept; Endocrinology Dept; .’Pathology Dept; 4Biostatistics Dept, Ankuru Uniuer~xit?,Faculty of Medicine, Ankuru, Tnrkey E-mail: [email protected]
Background and Aim: The aim of this study is to investigate the role of insulin-sensitizing agents in the treatment of individuals with non-alcoholic steatohepatitis (NASH). Methods: This is a prospective, randomize, longitudinal single center study. A total of 62 individuals with NASH (maleifemale, 36/26; mean age, 46.2 years) were enrolled into study. Patients were divided into three distinct groups according to their therapeutic management. Group 1 (n= 23) consisted of individuals who received a conventional diet of 25 kcal/kg x ideal body weight (kg) and an exercise program. Group 2 (n=20) consisted of individuals who received diet and exercise plus metformin at a dose of 850 mg bid. for 48 weeks and group 3 (n = 19) consisted of individuals who received diet and exercise plus rosiglitazone at a dose of 8 mg daily for 48 weeks. Liver biopsies were performed at 48 weeks in available 8 individuals in group I , 15 in treatment groups. Results: Among three groups, no significant differences were observed in terms of the patient age, gender, baseline mean body mass index (BMI), mean initial serum aminotransferase levels (p > 0.05).Baseline HOMA