Journal Club Rivkees SA Mattison DR Ending propylthiouracilinduced

Journal Club Rivkees SA, Mattison DR. Ending propylthiouracil-induced liver failure in children. N Engl J Med. 2009 Apr 9; 360(15): 1574 -5. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009 Apr 9; 360(15): 1500 -8. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009 Apr 9; 360(15): 1509 -17. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerbäck S, Nuutila P. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009 Apr 9; 360(15): 1518 -25. 2009年 4月16日　8: 30 -8: 55 ８階　医局 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

Scott A. Rivkees, M. D. Yale University School of Medicine New Haven, CT 06520 scott. rivkees@yale. edu Donald R. Mattison, M. D. Eunice Kennedy Shriver National Institute of Child Health and Human Development Bethesda, MD 20892 -7510 N　Engl J Med 360: 1574 -1575, 2009

thioamide drug propylthiouracil (PTU) methimazole (MMI) Methimazole (also known as Tapazole or Thiamazole)

Case Reports of PTU-Related Liver Injury in Pediatric Patients

Med. Watch-Reported AEs from 1970 to 1997 in Individuals ＞ 18 Years of Age

The databases included 10. 7 million children (ages 0– 17 years) from 11 states with Medicaid coverage in 2003, and 4. 3 million children from 50 states with commercial insurance during 2004– 2005.

SUMMARY • The prevalence of pediatric Graves’ disease in the United State is about 1 in 10, 000 children. About 4, 000 pediatric patients per year with Graves’ disease are being treated with antithyroid drugs in the United States. In 2004, 40 percent of children with Graves’ disease were treated with PTU. Over the past 4 years, the number of PTU prescriptions for children with Graves’ disease has decreased by about 50 percent, whereas the number or prescriptions for MMI has increased by about 50 percent. • The risk of PTU-induced liver failure leading to transplantation is about 1 in 2, 000– 4, 000 children. (There about 0. 5 PTU-related liver transplants per year in children; about 1, 000 to 2, 000 children per year take PTU. ) Once PTUinduced liver failure occurs, it is rapidly progressive with a low chance of reversibility. The long-term survival rate for children receiving a liver transplant due to PTU hepatotoxicity is about 60 percent. The number of children developing PTU-induced liver injury that is reversible is estimated to be at least 10 fold greater than the number of children who develop liver failure requiring transplantation. • Routine biochemical surveillance of liver function and hepatocellular integrity (serum bilirubin, alkaline phosphatase, and transaminase levels) will not be useful in identifying children who will develop PTU-induced liver failure.

• Children are at higher risk for PTU-induced liver injury than are adults. • PTU-induced liver injury is an important concern for the adult population. The number of adults with Graves’ disease is at least four-fold higher than the number of children with Graves’ disease. The proportion of adult patients prescribed PTU for Graves’ disease is currently greater than the proportion of pediatric patients prescribed PTU. Although the proportion of children prescribed PTU for Graves’ disease has decreased over the past 4 years, PTU prescribing practices have remained steady in the adult population. • MMI is not associated with a risk liver failure in the pediatric population. • PTU is associated with much higher risk of ANCA development and vasculitis than is MMI. • PTU and MMI have comparable rates of agranulocytosis (0. 3 percent in adults). The risk of agranulocytosis is dose-dependent with MMI but not with PTU. The risk of agranulocytosis is very low with low doses of MMI. • MMI use during pregnancy is associated with an increased risk of birth defects (aplasia cutis, choanal atresia, esophageal atresia, tracheoesophageal fistulas, and athelia). PTU use during pregnancy is not associated with birth defects. Women should be informed of the potential risks of PTU-induced hepatotoxicity and risks of MMI-associated fetal minor malformations when considering antithyroid drug use during pregnancy. • Based on recent prescribing data, it is estimated that at least 2, 000 children in the United States are currently taking PTU.

CONCLUSION Considering this estimate, we suggest that propylthiouracil should no longer be used as first line treatment for Graves’ disease in children. Alternative treatments should be considered for children who are currently taking propylthiouracil. In this way, it should be possible to end propylthiouracil -induced liver failure in children.

The Activation of Brown Adipose Tissue. Stimulation of β 3 -adrenergic receptors leads to the dramatic increase in the intracellular concentration of triiodothyronine (T 3) by means of the type 2 5′ deiodinase (D 2); T 3 in turn stimulates the transcription of uncoupling protein 1 (UCP 1), which causes the leakage of protons from the inner membrane of the mitochondria, hence dissipating energy in the form of heat. The abbreviation c. AMP denotes cyclic adenosine monophosphate, CRE c. AMP response element, T 4 thyroxine, and TRE thyroid hormone response element.

The physiologic role of brown adipose tissue in small mammals (and human newborns) is the maintenance of core temperature. In brown adipose tissue, mitochondria release chemical energy in the form of heat by means of the uncoupling of the oxidative phosphorylation, making the process of respiration exceedingly inefficient. This phenomenon is mediated by the uncoupling protein 1 (UCP 1), which renders the inner membrane of the mitochondria “leaky” and hence releases energy in the form of heat rather than storing it as ATP. 2 UCP 1 is, in turn, regulated by triiodothyronine, which is generated within brown adipose tissue by means of 5′ deiodination of the prohormone thyroxine, effectively creating a local, tissue-specific hyperthyroid state in the absence of changes in circulating levels of thyroid hormones. 3 β 3 -adrenergic signaling plays an important role in the modulation of this process, and recent evidence indicates that food intake results in a similar activation, 4 suggesting that brown adipose tissue could play an important role in short-term energy homeostasis. Human intrascapular brown adipose tissue disappears shortly after birth, and small depots of cells resembling brown adipose tissue have been considered vestigial and devoid of a physiologic role. the discovery of PRDM 16 (PRD 1 BF 1 -RIZ 1 homologous domain containing the genetic master switch of brownadipose-tissue differentiation, and its regulation by BMP 7 (bone morphogenetic protein 7) has reinvigorated interest in the study of this tissue in humans.

Original Article Cold-Activated Brown Adipose Tissue in Healthy Men Wouter D. van Marken Lichtenbelt, Ph. D. , Joost W. Vanhommerig, M. S. , Nanda M. Smulders, M. D. , Jamie M. A. F. L. Drossaerts, B. S. , Gerrit J. Kemerink, Ph. D. , Nicole D. Bouvy, M. D. , Ph. D. , Patrick Schrauwen, Ph. D. , and G. J. Jaap Teule, M. D. , Ph. D. From the Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (W. D. M. L. , J. W. V. , J. M. A. F. L. D. , P. S. ), the Department of Nuclear Medicine (N. M. S. , G. J. K. , G. J. J. T. ), and the Department of General Surgery (N. D. B. ), Maastricht University Medical Center, Maastricht, the Netherlands. N Engl J Med Volume 360(15): 1500 -1508 April 9, 2009

Study Overview • The authors of this study measured putative brown -adipose-tissue activity in relation to body composition and energy metabolism, using a standard protocol and integrated positron-emission tomography and computed tomography • Twenty-three of 24 healthy men had detectable levels of activity after cold exposure but not under thermoneutral conditions • Brown-adipose-tissue activity was positively related to resting metabolic rate and was significantly lower in overweight or obese subjects than in lean subjects

Characteristics of the Subjects van Marken Lichtenbelt WD et al. N Engl J Med 2009; 360: 1500 -1508

Brown-Adipose-Tissue Activity as Assessed by PET-CT with 18 F-FDG van Marken Lichtenbelt WD et al. N Engl J Med 2009; 360: 1500 -1508

Activity and Volume of Brown Adipose Tissue, Resting Metabolic Rate Adjusted for Fat-free Mass and Body Temperature under Thermoneutral Conditions (22 C) and after 2 Hours of Cold Exposure (16 C) van Marken Lichtenbelt WD et al. N Engl J Med 2009; 360: 1500 -1508

Specimens of Brown and White Adipose Tissue from the Supraclavicular Region in a 46 -Year. Old Woman The use of immunofluorescence assay for an antibody to uncoupling protein 1 (UCP 1) together with the nuclei-staining dye 4′, 6 -diamidino-2 phenylindole (Panel B) shows positive immunostaining for UCP 1 (green) in brown adipose tissue but not in white adipose tissue. Control specimens were stained with 4′, 6 diamidino-2 -phenylindole in phosphate-buffered saline (Panel C). van Marken Lichtenbelt WD et al. N Engl J Med 2009; 360: 1500 -1508

Activity of Brown Adipose Tissue in Relation to BMI and Percentage of Body Fat van Marken Lichtenbelt WD et al. N Engl J Med 2009; 360: 1500 -1508

Resting Metabolic Rate in Relation to Brown-Adipose-Tissue Activity van Marken Lichtenbelt WD et al. N Engl J Med 2009; 360: 1500 -1508

Conclusion • The percentage of young men with brown adipose tissue is high, but its activity is reduced in men who are overweight or obese • Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity

Original Article Identification and Importance of Brown Adipose Tissue in Adult Humans Aaron M. Cypess, M. D. , Ph. D. , M. M. Sc. , Sanaz Lehman, M. B. , B. S. , Gethin Williams, M. B. , B. S. , Ph. D. , Ilan Tal, Ph. D. , Dean Rodman, M. D. , Allison B. Goldfine, M. D. , Frank C. Kuo, M. D. , Ph. D. , Edwin L. Palmer, M. D. , Yu-Hua Tseng, Ph. D. , Alessandro Doria, M. D. , Ph. D. , M. P. H. , Gerald M. Kolodny, M. D. , and C. Ronald Kahn, M. D. From the Research Division, Joslin Diabetes Center (A. M. C. , A. B. G. , Y. -H. T. , A. D. , C. R. K. ); the Division of Nuclear Medicine, Beth Israel Deaconess Medical Center (S. L. , G. W. , I. T. , D. R. , G. M. K. ); the Department of Pathology, Brigham and Women’s Hospital (F. C. K. ); the Division of Nuclear Medicine, Massachusetts General Hospital (E. L. P. ); and Harvard Medical School (A. M. C. , S. L. , G. W. , I. T. D. R. , A. B. G. , F. C. K. , E. L. P. , Y. -H. T. , A. D. , G. M. K. , C. R. K. ) — all in Boston. N Engl J Med Volume 360(15): 1509 -1517 April 9, 2009

Study Overview • This study used 18 F-fluorodeoxyglucose positron-emission tomographic and computed tomographic scans to identify substantial depots of brown adipose tissue in a region extending from the anterior neck to the thorax • Such depots were found in 7. 5% of the women (76 of 1013) and 3. 1% of the men (30 of 959) • The amount of brown adipose tissue was inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism

Immunohistochemical Analysis and the Prevalence, Mass, and Activity of Brown Adipose Tissue A patient with hibernomas Panel E shows the mass of brown adipose tissue in grams and Panel F the activity of brown adipose tissue in grams times the mean standardized uptake value (SUV) in grams per milliliter. In Panels E and F, the box plots indicate the lower quartile (lower line), median quartile (middle line), upper quartile (upper line), 1. 5 times the interquartile range (lower and upper whiskers), and outliers (circles). antibody to uncoupling protein 1 (UCP 1) and counterstained with hematoxylin (Panel B). Cypess AM et al. N Engl J Med 2009; 360: 1509 -1517

Correlation between the Prevalence of Maximal Activity of Brown Adipose Tissue and Temperature, Age, Body-Mass Index, and Glucose Level Cypess AM et al. N Engl J Med 2009; 360: 1509 -1517

Predictors of Detectable Brown Adipose Tissue Based on 18 F-FDG PET-CT Scanning Cypess AM et al. N Engl J Med 2009; 360: 1509 -1517

Clinical characteristics of BAT-negative and BAT-positive patients *Includes 1 BAT-positive and 3 BAT-negative subjects who had missing glucose values. †Data on beta-blocker and benzodiazepine use were missing for 5 BAT-positive and 12 BATnegative patients. ‡Data on smoking history were missing for 6 BATpositive and 22 BAT-negative subjects. Cypess AM et al. N Engl J Med 2009; 360: 1509 -1517

Conclusion • Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of 18 F-FDG PET-CT • Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism

Original Article Functional Brown Adipose Tissue in Healthy Adults Kirsi A. Virtanen, M. D. , Ph. D. , Martin E. Lidell, Ph. D. , Janne Orava, B. S. , Mikael Heglind, M. S. , Rickard Westergren, M. S. , Tarja Niemi, M. D. , Markku Taittonen, M. D. , Ph. D. , Jukka Laine, M. D. , Ph. D. , Nina-Johanna Savisto, M. S. , Sven Enerbäck, M. D. , Ph. D. , and Pirjo Nuutila, M. D. , Ph. D. From the Turku PET Center, University of Turku (K. A. V. , J. O. , N. -J. S. , P. N. ); and the Departments of Surgery (T. N. ), Anesthesiology (M. T. ), Pathology ( J. L. ), and Medicine (P. N. ), Turku University Hospital — both in Turku, Finland; and the Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Goteborg, Sweden (M. E. L. , M. H. , R. W. , S. E. ). N Engl J Med Volume 360(15): 1518 -1525 April 9, 2009

Study Overview • Brown adipose tissue helps maintain normal body temperature in newborn humans but was thought to be absent in healthy adults • This report shows the presence of substantial amounts of metabolically active brown adipose tissue, as documented by biochemical, molecular, and morphologic criteria, and by a cold-induced glucose uptake in paracervical and supraclavicular adipose tissue that was increased by a factor of 15

Computed Tomographic (CT) and Positron-Emission Tomographic (PET) Images from the Neck and Upper Thoracic Region, Obtained during Cold and Warm Conditions Panels A, B, and C show images of the neck and upper thoracic region from Subjects 1, 2, and 3, respectively. The top row in each panel shows individual CT images, the middle row shows PET images, with the glucose analogue 18 Ffluorodeoxyglucose (18 F-FDG) as a tracer, during cold conditions, and the bottom row shows PET images with 18 F-FDG during warm conditions. The image on the left side of each row represents a transaxial slice, the image in the middle a coronal slice, and the image on the right side a sagittal slice from the region of activated brown adipose tissue. Cold-induced glucose uptake in supraclavicular tissue is marked by arrows. The color index to the left of the PET images shows the level of 18 F-FDG uptake, with red indicating the highest level. Glucose uptake, calculated with the use of graphical analysis of PET data, in each of the five study subjects is shown in Panel D. Glucose uptake rates in brown adipose tissue (BAT) were assessed in the supraclavicular region, and glucose uptake rates in white adipose tissue (WAT) were assessed in the subcutaneous region corresponding to the site of the biopsies. Panel E shows a comparison of mean glucose uptake in all five subjects, calculated with the use of a paired Student’s t-test. T bars indicate standard deviations. Virtanen KA et al. N Engl J Med 2009; 360: 1518 -1525

Gene Expression in Brown and White Adipose Tissue The mean levels of expression of UCP 1, DIO 2, PGC 1α, PRDM 16, and ADRB 3, based on the results of quantitative realtime PCR analysis, are shown for Subjects 1, 2, and 3. Expression levels were normalized to that of β-actin and are shown as the levels in brown adipose tissue (BAT) as a multiple of the levels in white adipose tissue (WAT). T bars indicate standard deviations. Virtanen KA et al. N Engl J Med 2009; 360: 1518 -1525

Western Blot, Histologic, and Immunofluorescence Analyses of Brown and White Adipose Tissue Western blots show levels of UCP 1 (Panel A) and cytochrome c (Panel B) in brown adipose tissue (BAT) and white adipose tissue (WAT) from Subjects 1, 2, and 3. Glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) was used as a protein loading control. Sections of brown adipose tissue and white adipose tissue from Subjects 1, 2, and 3 are shown in Panel C (hematoxylin and eosin). Multilocular, intracellular lipid droplets are present in brown adipose tissue but not in white adipose tissue. Immunohistochemical staining of brown adipose tissue and white adipose tissue with a UCP 1 specific antiserum (Panel D) shows that brown adipose tissue is positive for UCP 1, whereas no staining is seen in white adipose tissue. Immunofluorescence staining of brown adipose tissue and white adipose tissue (Panel E) shows colocalization of UCP 1 (green) and a mitochondrial marker, cytochrome oxidase subunit I (COI, orange), in brown adipose tissue. No UCP 1 could be detected in mitochondria of white adipose tissue. Nuclei were stained with TO-PRO-3 (red). Scale bars represent 30 μm in Panels C and D and 5 μm in Panel E. Virtanen KA et al. N Engl J Med 2009; 360: 1518 -1525

Summary Articles about three very different studies that took full advantage of the PET technology address the presence and relevance of brown adipose tissue in adult humans.

Conclusion • These studies, by showing the presence and activity of brown adipose tissue in adult humans, are a powerful proof of concept that this tissue might be used as a target for interventions, pharmacologic and environmental, aimed at modulating energy expenditure.