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 2010 年５月６日 8:30-8:55 ８階 医局 Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; the NASH CRN. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N Engl J Med. 2010 Apr 28. [Epub ahead of print] House AA, Eliasziw M, Cattran DC, Churchill DN, Oliver MJ, Fine A, Dresser GK, Spence JD. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA. 2010 Apr 28;303(16):1603-9.

2. From the University of Texas Health Science Center at San Antonio (R. Belfort, K.B., J.F., J.H., B.B., A.G., F.T., R. Berria, J.Z.M., S.D., R.H., R.D., G.A.B., S.S., K.C.); Brooke Army Medical Center (S.A.H., J.P., C.F.); and Audie L. Murphy Division, South Texas Veterans Health Care System (C.D., J.F., F.T., R.D., S.S., K.C.) — all in San Antonio, TX; and the Institute of Clinical Physiology, National Research Council, Pisa, Italy (A.G.). Address reprint requests to Dr. Cusi at the University of Texas Health Science Center at San Antonio, Diabetes Division, Rm. 3.380S, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, or at cusi@uthscsa.edu. N Engl J Med 2006;355:2297-307. 45mg 6 months IGT or type 2 diabetes mellitus

3. Ref.13 Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002;87:2784-91.

4. 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)).

5. 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

6. 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

7. 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

9. From Virginia Commonwealth University, Richmond (A.J.S.); Indiana University, Indianapolis (N.C.); Virginia Mason Medical Center, Seattle (K.V.K.); Case Western Reserve University, Cleveland (A.M.); Duke University, Durham, NC (A.M.D.); University of California San Francisco, San Francisco (N.M.B.); Saint Louis University (B.A.N.-T.) and Washington University (E.M.B.) — both In St. Louis; University of California San Diego, San Diego ( J.E.L.); Johns Hopkins University, Baltimore ( J.T., A.U., M.V.N., J.C.); and the National Cancer Institute (D.E.K.) and National Institute of Diabetes and Digestive and Kidney Diseases ( J.H.H., P.R.R.) — both in Bethesda, MD. 10.1056/nejmoa0907929 nejm.org PIVENS trial the Nonalcoholic Steatohepatitis Clinical Research Network

10. Background Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease.

11. We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Methods

12. Figure 1. Screening, Randomization, and Follow-up of Study Subjects.

13. * Plus–minus values are means ±SD. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for glucose to millimoles per liter, multiply by 0.05551. † Race or ethnic group was self-reported. ‡ Scores on the Medical Outcomes Study 36-Item Short-Form Health Survey (SF- 36) were standardized to the 1998 U.S. general population with a mean (±SD) of 50±10. § The homeostasis model assessment for insulin resistance (HOMA-IR) was used to calculate insulin resistance, according to the following formula: (milligrams of glucose per deciliter × microunits of insulin per milliliter) ÷ 405. Higher numbers indicate greater insulin resistance. ¶ The body-mass index is the weight in kilograms divided by the square of the height in meters. ‖ Total nonalcoholic fatty liver disease (NAFLD) activity 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.

14. 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.

16. * The numbers of subjects listed for the three study groups are the numbers for whom data on alanine aminotransferase levels were available. The total numbers of subjects included in the analyses of other variables ranged from 212 to 223. The change from baseline is the value at 96 weeks minus the baseline value. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for glucose to millimoles per liter, multiply by 0.05551. † P values were calculated with the use of analysis-of-covariance models, regressing change from baseline to 96 weeks on treatment group and baseline value of the outcome measure. ‡ The homeostasis model assessment for insulin resistance (HOMA-IR) was used to calculate insulin resistance, according to the following formula: (milligrams of glucose per deciliter × microunits of insulin per milliliter) ÷ 405. Diabetes developed in four subjects assigned to the vitamin E group, and these subjects were not given an oral glucose-tolerance test at 96 weeks. Their HOMA-IR values at 96 weeks were imputed as the 95th percentile value at baseline. Analyses were performed with the use of ranks owing to asymmetry in the distribution of change in HOMA-IR values. § Scores on the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) were standardized to the 1998 U.S. general population with a mean (±SD) of 50±10.

17. http://www.sf-36.org/wantsf.aspx?id=1

18. http://www.qualitymetric.com/WhoWeAre/OurMission/tabid/151/Default.aspx 1. Overall, how would you rate your health during the PAST 4 WEEKS? Excellent Very good Good Fair Poor Very poor 2. During the PAST 4 WEEKS, how much did physical health problems limit your usual physical activities (such as walking or climbing stairs)? Not at all Very little Somewhat Quite a lot 3. During the PAST 4 WEEKS, how much difficulty did you have doing your daily work, both at home and away from home, because of your physical health? None at all A little bit Some Quite a lot 4. How much BODILY PAIN have you had during the PAST 4 WEEKS? None Very mild Mild Moderate Severe ….. SF-36

20. H&EMasson H&EMasson

21. Adverse events

22. Results Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P = 0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P = 0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P = 0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P = 0.02 for vitamin E and P = 0.004 for pioglitazone) but not with improvement in fibrosis scores (P = 0.24 for vitamin E and P = 0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups.

23. Conclusion Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.)

24. Message 糖尿病でない対象者でも脂肪肝の改善にピオグ リタゾンは効果がある！

26. JAMA. 2010;303(16):1603-1609 Division of Nephrology (Dr House), Division of Clinical Pharmacology (Drs Dresser and Spence), and Robarts Research Institute (Dr Spence), University of Western Ontario, London, Ontario; Department of Community Health Sciences, Clinical Neurosciences, and Oncology, University of Calgary, Calgary, Alberta (Dr Eliasziw); Division of Nephrology, University of Toronto, Toronto, Ontario (Drs Cattran and Oliver); Division of Nephrology, McMaster University, Hamilton, Ontario (Dr Churchill); and Division of Nephrology, University of Manitoba, Winnipeg, Manitoba (Dr Fine), Canada.

27. Aim Context ： Hyperhomocysteinemia is frequently observed in patients with diabetic nephropathy. B-vitamin therapy (folic acid, vitamin B 6, and vitamin B 12 ) has been shown to lower the plasma concentration of homocysteine. Objective ： To determine whether B- vitamin therapy can slow progression of diabetic nephropathy and prevent vascular complications.

28. Method Design, Setting, and Participants ： A multicenter, randomized, double-blind, placebocontrolled trial (Diabetic Intervention with Vitamins to Improve Nephropathy [DIVINe]) at 5 university medical centers in Canada conducted between May 2001 and July 2007 of 238 participants who had type 1 or 2 diabetes and a clinical diagnosis of diabetic nephropathy. Intervention ： Single tablet of B vitamins containing folic acid (2.5 mg/d), vitamin B 6 (25 mg/d), and vitamin B 12 (1 mg/d), or matching placebo. Main Outcome Measures ： Change in radionuclide glomerular filtration rate (GFR) between baseline and 36 months. Secondary outcomes were dialysis and a composite of myocardial infarction, stroke, revascularization, and all- cause mortality. Plasma total homocysteine was also measured.

36. First, folic acid may promote cell proliferation through its role in thymidine synthesis. Second, the use of folic acid and vitamin B 12 might alter the methylation potential in vascular cells. Finally, B-vitamin therapy could potentially increase the methylation of L-arginine to the nitric oxide synthase inhibitor asymmetric dimethylarginine. Mechanisms

37. 32. Ebbing M, Bonaa KH, Nygard O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009;302(19):2119-2126.

38. Results The mean (SD) follow-up during the trial was 31.9 (14.4) months. At 36 months, radionuclide GFR decreased by a mean (SE) of 16.5 (1.7) mL/min/1.73 m 2 in the B-vitamin group compared with 10.7 (1.7) mL/min/1.73 m 2 in the placebo group (mean difference, −5.8; 95% confidence interval [CI], −10.6 to −1.1; P=.02). There was no difference in requirement of dialysis (hazard ratio [HR], 1.1; 95% CI, 0.4-2.6; P=.88). The composite outcome occurred more often in the B-vitamin group (HR, 2.0; 95% CI, 1.0-4.0; P=.04). Plasma total homocysteine decreased by a mean (SE) of 2.2 (0.4) μmol/L at 36 months in the B-vitamin group compared with a mean (SE) increase of 2.6 (0.4) μmol/L in the placebo group (mean difference, −4.8; 95% CI, −6.1 to −3.7; P<.001, in favor of B vitamins).

39. Conclusion ： Among patients with diabetic nephropathy, high doses of B vitamins compared with placebo resulted in a greater decrease in GFR and an increase in vascular events. Trial Registration ： isrctn.org Identifier: ISRCTN41332305 Conclusion

40. Message ビタミン B 合剤（ B 6,B 12, 葉酸）を糖尿病患者に用い ると腎機能が悪化し，大血管障害は倍増！！ あと，他の研究では癌も増えるらしい！！ 糖尿病患者へのこのようなビタミンの処方はしない ように！ （水溶性ビタミンは いくら摂っても大丈夫はうそ らしい。特に腎機能がよくなくなると問題なのかも しれない。）

42. 1943 年以来 65 年間医学書の世界でのベスト セラー。医学生，研修医（レジデント）のバ イブル！ 発売以来 200 万部以上売れている。 Kenneth S. Polansky, MD Chairman

43. 高血糖時の Na の補正は PG 100mg/dL あたり 1.6 ～ 2.4mE/L 経口血糖降下薬：コレバイン ® や ブロモクリプチンが 追加！

44. Ca 2+ の評価には高 Ca でも低 Ca でもアルブミン補正を

45. 甲状腺ホルモン値が上昇し甲状腺 機能亢進症状が出現する状態： Hyperthyroidism （甲状腺機能亢進症） 亜急性甲状腺炎，無痛性甲状腺炎 も含めて考える。 by William E. Clutter, M.D.