1. Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2011 年 5 月 26 日 8:30-8:55 ８階 医局 Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Ünalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; Nonalcoholic Steatohepatitis Clinical Research Network. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011 Apr 27;305(16):1659-68. Presented by Dr. Sugiyama

2. Triglyceride volume in the liver will be estimated from signal intensities of proton spectroscopy obtained both from water and fat. All signal intensities, S, will be corrected for relaxation losses according to the formula: So=S(RD,TE,TM)/(1–exp(–RD/T1))exp(–TE/T2)exp(–TM/T1), where TM is the delay between the second and third pulses of the STEAM sequence, and RD=TR–TM–TE/2. Concentration of triglyceride [M] will be expressed as: [M]=2So(M)/So(H2O)nc x [H2O] x 10–A/20. The triglyceride made from typical free fatty acids (C17.4H33.1O2 [71]) has a molecular weight of ~812, and specific gravity of fat tissue is 0.9 g/ml. 1 ml of triglyceride contains 0.115 (=104/812x0.9) x 6.02 x 1023 hydrogen atoms. Water has a molecular weight of 18. 1 ml of water contains 0.111 (=2/18x1.0) x 6.02 x 1023 hydrogen atoms. If the water content in the liver is assumed to be 75% of lean mass, fat volume in the liver is approximated by the equation: Fat volume in the liver (ml) = Liver volume (ml) x So(M)/(1.4xSo(H2O)+So(M)).

3. Effect of Pioglitazone （ Liver, Abdominal Fat, etc. ） (EASD2005, Athens) 投与前投与後 ＊ ＊ :p<0.05 vs before -150 -100 -50 0 平均 CT 値 Difference in HbA 1c (%) 投与前後の adiponectin の差 (  g/ml) r=0.08, p:N.S. HbA 1C (%) 投与前投与後 ● 女性 ■ 男性 7.6 ± 4.0 15.0 ± 6.9 p<0.01 vs before Adiponectin (  g/ml) p<0.001 vs before 投与前投与後 7.7 ± 1.1 6.9 ± 0.9 5 6 7 8 9 10 11 BeforeAfter ＊ 0 1 2 3 4 TNF-alpha (pg/ml) CT value of Visceral Fat

4. Mechanism of Organ Prevention by Pioglitazone FatMuscle Pioglitazone  Beta cell prevension Improved insulin secretion Pancreas Decline of TNF-  Reduced Oxidative Stress Lipo-gluco-Toxicity Improvement Liver

5. Liver Biopsy One subject in the pioglitazone group declined to undergo the end-of-study liver biopsy (for that subject, only metabolic data were included). n=21 n=26 N Engl J Med 2006;355:2297-307.

6. n=21 n=26 N Engl J Med 2006;355:2297-307.

7. P values were calculated with the use of the Mantel–Haenszel chi-square test, stratified according to clinic, for the primary outcome; Fisher’s exact test for the binary secondary outcomes; and analysis-of-covariance models, regressing change from baseline to 96 weeks on treatment group and baseline value of the outcome, for secondary outcome scores. † The primary outcome was an improvement in histologic findings, which required improvement by 1 or more points in the hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the activity score for nonalcoholic fatty liver disease to a score of 3 points or less or a decrease in the activity score of at least 2 points, with at least a 1-point decrease in either the lobular inflammation or steatosis score. A total of 11 subjects in the placebo group, 4 in the vitamin E group, and 10 in the pioglitazone group had missing histologic data at week 96, and the results for these subjects were imputed as a lack of improvement. The NAFLD activity score was assessed on a scale of 0 to 8, with higher scores indicating more severe disease; the components of this measure include steatosis (assessed on a scale of 0 to 3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular ballooning (assessed on a scale of 0 to 2). ‡ Fibrosis was assessed on a scale of 0 to 4, with higher scores indicating more severe fibrosis. N Engl J Med 2010; 362:1675-1685

9. JAMA. 2011;305(16):1659-1668 Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia University, New York, New York (Dr Lavine); Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California, San Diego (Dr Schwimmer); Departments of Epidemiology (Mr Van Natta and DrU¨ nalp) and Medicine (Dr Clark); Department of Pediatrics, Division of Gastroenterology and Nutrition (Dr Scheimann); Department of Biostatistics (Dr Tonascia); Johns Hopkins University, Baltimore, Maryland; Department of Pediatrics, Section of Pediatric Gastroenterology, Indiana University, James Whitcomb Riley Hospital for Children, Indianapolis (DrMolleston); Department of Pediatrics, University of Washington School of Medicine, Seattle Children’s Hospital, Seattle (Dr Murray); Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California, San Francisco (Dr Rosenthal); Department of Pediatrics, Section of Gastroenterology, Hepatology, and Nutrition, Texas Children’s Hospital, Baylor College of Medicine, Houston (Dr Abrams); Department of Medicine, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth Medical Center, Virginia Commonwealth University, Richmond (Dr Sanyal); Department of Medicine, Division of Gastroenterology/ Hepatology, Indiana University, Indianapolis (Dr Chalasani); Department of Pathology and Immunology, Washington University, St Louis, Missouri (Dr Brunt); and Department of Laboratories, National Cancer Institute (Dr Kleiner), National Institute of Diabetes and Digestive and Kidney Diseases (Drs Hoofnagle and Robuck), National Institutes of Health, Bethesda, Maryland.

10. Context Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established. Objective To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin.

11. Design, Setting, and Patients Randomized, double- blind, double-dummy, placebocontrolled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks. Main Outcome Measures The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures.

18. Results Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P=.26) and metformin treatment groups (9/57; 16%; 95% CI,7%to 28%; P=.83). The mean change in ALT level from baseline to 96 weeks was −35.2 U/L (95% CI, −56.9 to −13.5) with placebo vs −48.3 U/L (95% CI, −66.8 to −29.8) with vitamin E (P=.07) and −41.7 U/L (95% CI, −62.9 to −20.5) with metformin (P=.40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, −0.2 to 0.3) vs −0.5 with vitamin E (95% CI, −0.8 to −0.3; P=.006) and −0.3 with metformin (95% CI, −0.6 to −0.0; P=.04); and in NAFLD activity score, −0.7 with placebo (95% CI, −1.3 to −0.2) vs −1.8 with vitamin E (95% CI, −2.4 to −1.2; P=.02) and −1.1 with metformin (95% CI, −1.7 to −0.5; P=.25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P=.006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P=.23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features.

19. Conclusion Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. Trial Registration clinicaltrials.gov Identifier: NCT00063635

20. Message/Comments 脂肪肝に効果のあるのは pioglitazone くらい？ （それでもまだ評価は定まっていない） メトホルミンもビタミン E もダメのよう？