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Transcript
Page 1: 45 1 - St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/325/10-32... · 2005. 1. 13. · macol. 1991 Feb; 71 2 :163 74. 15 von Moltke LL, Greenblatt

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��N-nitoroso-fenfluramine( fenfluramine( �9=( =c*0JK( QT V�

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� �: 48�� ��� �: ����� ��� �������������: 46 �������������������������� !"�#"$%�&���� �����: �����: '(��)*+ 1L� , 2-� ./�������: !"�#"$%�&�� �0����12 3456789:*;*:<=>* 45 ?� 7@ 10A�� 13AB7 4C�A� 7@ 14A�� 8@12AB7 6C�A"��D� !"�#"$7E5F� G7��"�EH�IJ�K�LMD�8@ 13A NOP���� ��� �AST�ALT663�1117, g-GTP 569� ?QRDDR� ��������$STIJ� :*;*:<=>* 45 ��?&U��VWXY��KDZ� � [\ZQR]J�KDR� 8@ 27A^�_�MD������: 0` 151 cm� ab 67.4 kg� �BodyMass Index 29.4�� ac 36.5�C� �� 126 � 66mmHg� d 60���e� fgh�� �ijklm� n�o�p���� qr�nso�tu8��v��wxyzm��� ��E�{�|� ��E}~��� �������� iV���zmEQR��������� �Table 1�: ��7EzmEQR]J�LMD� ���7E��s���s ����� �����lm78MD� �����7E T.Bil.4.3 mg�dl, D.Bil.3.2 mg�dl _t�ZQR]J������Z AST 806 IU�l, ALT 1014 IU�l, LDH386 IU�l _y���KD� ALP y�EQR]J�LMDZ� g-GTP E 334 IU�l _y���KD���������� �=��*+E��78MD� �h���7E IgG, IgM, IgEE_��lm78MD� ���a� ����=� ¡�a� �LKM-1�aE¢J�£�78MD� �¤¥¦+:§*¨*E A©� B©� C©EK�J�£�� EB¥¦+:� ª¦�«¬�¥¦+:E­®u ¯°78MD�����: ��±²³��7E focal spared lesion?´µ��� ¯°78MD �Fig. 1-a�� ¶· ��ZG]JD �Fig. 1-b�� �� CT ��7E��� ¯°��¸� ¶· ��ZQR]JD �Fig. 2��

Table 1. Laboratory Data on Admission

Figure 1. Abdominal US findings on admission: Fatty

liver is seen with focal spared lesion. Note

slight splenomegaly.

Figure 2. Abdominal CT on admission: In addition to

fatty liver, slight splenomegaly is seen.

�¹º� »� ¼ ]490

74

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3a

3b

�����: ��� 52 �����������T � V1�5 ����������������� QT ��� !"#$%�� �Fig. 3-a�����: &'�()*+,-./��� �0123%�4�*���56������ *+,��(3% predonisolone 50 mg �7�-89��� *:;� �Fig. 4� )<=>?)@A3BCD-#$��$� predonisolone -��)E��� 1 FGHI��� J�� &'�)#$%���KL�QT�� !A ST-T ��"M'NO)�CD�����Fig. 3-b�, QT ��� !" �PQRQPSTUQ45� �V�WX%��� PQRQPYZ�[\\�] N-nitoroso-fenfluramine, fenfluramine

�&^�_`���$� �PQRQPSTUQ45� )a�� YTRbcdef �D-LST� -./��� ghi �cpm�, S.I.122������������� �Fig. 5�: j�[k�lm) P-C bridg-ing necrosis -#$]"����n�� �o�pq�rs�Htuvw� xy�z�{|�}~b���Hb-���Htu��� z���+� ������#$%��� ���� piecemealnecrosis )>�� lm������n�� ��o�*z��������HtuJ� ���j���+��*z���������%��� ��������#$%�B3��� 1 ��� P-Cbridging necrosis -#$� ������� ���-¡¢�)#$� £�����-#$�� *z��

Anisokaryosis �£~*z��� ~�¤��� �z����¥¦� ��§¨Y©¨Tª«-#$� ��§xyz�{|��Hb{|"����� D-PAS ¬ª�H­u�®¯°±Y²³P´µQ¶P-#$�� ·¬ª� HBs ¸¹º©®°T¬ª�n»�"����� vw�����4�*��-�?�����

Figure 3. Heart rate is 52 �min and sinus bradycardia�3a�. T wave is inverted in V1�5, and myocar-dial injury was suspected. QT prolongation is

also seen. QT time was 533 ms �3a�. QT pro-longation which was seen on admission

dis-appeared just before dischage from our

hospital. QT time was 435 ms �3b�.

Figure 4. Clinical course

Figure 5. a: Masson staining �10�� Although P-C bridg-ing necrosis was seen in a small portion, the

lobular structure was maintained �5a�. b: HEstaining �10��. Bridging necrosis and focalnecrosis were found dispersively. Furthermore,

there were regeneration of small hepatocytes

and numerous eosinophilic bodies �5b�. c: HEstaining �10 ��. Note fibrotic expansion ofportal area. Inflammatory infiltration was

composed primarily of monocytes and neutro-

phils �5c�. d: a: HE staining �40�� Eosinofilicinfiltration is seen �5d�.

�¼�)>]�4�*�� 491

75

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��#L�7?� TU'� ����,hVUWI�/7� /�XY� iZXY+����[jU=k�/7?� )*/�U*4.7"�3"�=>7�d��(�\��]*4^+�6� �8�9�8:;<� 45� *4lm 4 _no�`paq���WJcKUhb���/�� r7stB8@�u�vcwx�+y>�� ALT dz��[e{%��f�|}� g-GTP ��f+�? ��3"�ghie8~RtA+jjUk.�/�3"� �lmn���./�>[e��n��=�3"U�}�"� D-LST y>�=�+����WJcK��� �8�9�8:;<� 45� ���"o`.��/"�a�����`paq.�/77?� c�(I�pbq��WJcK+,���7+� �5U�r.���WJ+�s\�t��6� �WJcK+u�\�H��=>7� ���H�� \��� ���)*/�".�� ����� ����WJ��'XW�D�Wv+w�v\6� �xr���n+�����"y`����

���)*/�".�� ����� �� �Iz�B�; ��tR��;�� N-nitoroso-fenflura-mine, fenfluramine �,-/6��+�r��/�� ��d�+H�.7 �8�9�8:;<� 45�� N-nitoroso-fenfluramine, fenfluramine � 2{|+�r��/�� 3� 2{|� 5H67� �QRST; �5-HT: 5-hydroxytryptamine� |}U~�\���U���X]e�=�� �1>�/0U9:\�E4+=�� @!;A�B"[email protected];U�\�"�}�� gE4".��������U��"\���(� �efg(���QRST;E4� 5H�>��+����/�11�12��CF� d- fenfluramine �����B��8�

��� U~�\���+=�13�� r7� l- fenfl-uramineY;¡LO;��=`��5�����I���Uw����14�� � ��5��>�\�5�¡S¢R�� P450 2D6��I���+�����3"�����/�7�15�� �>�4�]A>��£E4� � �Y:B¤���� fenfluramine�WJcKU¥3.,��J>�=��5�=�� q�����".���]Z��¦§��� ¨©S�������W;+hb���/7� r7ª�����WJcK��.���+��������8�9�,=� 2002�«�+��'���+����/�1�8�, 10������C��=�� ����QT��U�>�/7"/,3"�=�� q�����hb��/3"� �5�*4Ur?7o��x.73"U��\�"� �8�9�8O�� +��".�¬a����5>� QT��� Ia­v III­�x���������+�� �=�+� ®�5�� @¢R¨tA¯x°�� x±8[P;��~BNZ²!;���tY³tA� ´Rµ��B��+  ��/��3� �¶·¡�23E4.� ¢po£|¸�early afterdepolarization� U¥3\"���/��r7� B�´¤P�� ;[P!;� �O¡BO¡;���QT��U�7 \+� 3��¹ecK���"���/�� �(���¹ecK�? ��/�/3"� � ����I� QT ���Fenfluramine ����¶·¡�¢po£|¸�early afterdepolarization� ��J>��} ���r7 Fenfluramine " Mazindol ����WJ��"�¶��+¥��¥3>7(�+����/

eº¦§ »¨ ¼ 492

76

Page 5: 45 1 - St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/325/10-32... · 2005. 1. 13. · macol. 1991 Feb; 71 2 :163 74. 15 von Moltke LL, Greenblatt

�9�� ��� ST-T ���������� � ����������9�� ������������ ������ ���!"��#���$%&��'��(�)��(� Fenfluramine ��*��!"�+��,�-.QT/�����0123�4��QT /����5�(� Torsade de point 6��7 ��8*� �9�(�*��(5:*�Fenfluramine ���;<�4�=>?� @A!"BCD�E� ��$�FGHI2��()�����J�?;�KL��MN��AO6�P��Q5�RD4S���� @!"�TU?�N6������� �V�WX��Y�O�?Z[\]� !�^_�`���*� "��=>24�� TU#��@A!"N��$%&����=>� Vab$�c��de��% !&�'f���D4��

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gIhIgijkI 45 ����Y1@!"� 1���l��� �Y���@!"?� �Y�(m�nD?o)���01�4��(� pqrs�*t!�u+'�=>�4��(�),'�(� v��w-�o.���D4�(xy��

� �

1� z/01� {|}~� (��2� �3��� �4��� �/ �� ����Vab$����Y1@!" 2�5�6���-.� @7 2004;45�2�: 96�108�

2� |/ 8� (��k����!Vab$����1@!"� @7 2003; 44�3�: 89�91�

3� 9� �� �/ �� �/��� �� :� �; <� ��=�� �  ¡� g¢£�¤h¥g.>�?¦��(���� �§@A�� �TU()���¨J@!"� 1�� 9� ���/ �� �/��� �� :� �; <� ��=�� �  ¡� @7 2003; 44�2�: 85�

4� ©ªBC� /« ¬� D�E­� ��®�� z;¯°� ; ±°� ²T�F� ³G´F� µHI¶� z/01� (�Jk����b$���·J@��¸�1¹� 1ºK�� @7 2003; 44�3�: 117�122�

5� Adachi M, Saito H, Kobayashi H, Horie Y,Kato S, Yoshioka M, Ishii H. Hepatic Injury

in 12Patients Taking the Herbal Weight Loss

Aids Chaso or Onshido. Annals of Internal

Medicine. 2003; 139�6�: 488�492.6� Kawata K, Takehira Y, Kobayashi Y, Kita-gawa M, Yamada M, Hanajima I, Murohisa

G, Kawamura M, Iwaoka Y, Wada T, Morita

S, Iwaizumi M, Makino S. Three cases of liver

injury caused by Sennomotokounou, a Chinese

dietary supplement for weight loss. Intern Med

2003; 42�12�: 1188�92.7� Kawagachi T, Harada M, Arimatsu H, NagataS, Kago Y, Kuwahara R, Hisamochi A, Hino

T, Taniguchi E, Kumemura H, Hanada S,

Maeyama M, Koga H, Tomiyasu N, Toyo-

masu H, Kawaguchi M, Kage M, Kumashiro

R, Tanikawa K, Sata M. Severe hepatotoxicity

associated with a N-nitrosofenfluramine con-

taining weight-loss supplemen: report of three

cases. J Gastroenterol Hepatol. 2004; 19 �3�:349�50.

8� Nadir A, Agrawal S, Kibg PD, Marshall JB.Acute hepatitis associated with the use of a

Chinese herbal product, mahuang. Am J Gas-

troenterol 1996; 91�7�: 1436�8.9� Divid GB, Dov W, Eli W, Eran L. Fenfl-uramine and Mazindol: Acute reversible car-

diomyopathy associated with their use. Int’l J

Psychiatry in Medicine. 1985�86; 15 �2�:197�200.

10� KL��M. (�Jk����!Vab$�L»�¼�$����VaM"^�N.http: � �www.mhlw. go. jp �houdou � 2002 � 07 �hhttp: � �www.mhlw. go. jp �houdou � 2002 � 07 �h0719�3.html0719�3.html

11� Rothman R, Bauann M. Therapeutic andadverse action of serotonins transporter sub-

strates. Pharmacol Ther. 2002 Jul; 95�1�: 7312� Bever KA, Perry PJ. Dexfenfluramine hy-

drochloride: an anorexigenic agent. Am

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13� Picarel-Blanchot F, Bailbe D, Portha B. d-Fenfluramine improves hepatic insulin action

�������Y1@!" 493

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in streptozotocin-diabetic rats. Eur J Pharma-

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���� �� � �494

78

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Abstract

A Case of Drug induced Liver Injury Caused by

“Super Slender”, a Chinese Dietary Supplement

for Weight Loss

Hideaki Takahashi1, Hiroshi Yotsuyanagi1, Mayu Orita1, Yoshihiko Nagase1,

Yuka Suzuki1, Yoshiki Katakura1, Noriaki Okuse1, Yutaro Kobayashi1,

Junki Koike2, Yasuhito Takahashi1, Takeshi Hayashi1, Mchihiro Suzuki1,

Shiro Maeyama2, Toshiyuki Uchikoshi2, and Fumio Itoh1

The patient was a 48-year-old woman who had visited the Division of Metabolism and Endocrinology

in our hospital regularly since she was 46-years-old for the treatment of diabetes, hypertension, hyperlipide-

mia, fatty liver, and obesity. She had been taking the dietary supplement “Super Slender 45” from July 10,

2002 to August 12, 2002 in an e#ort to lose weight. She was admitted to our hospital for the treatment of liver

injury �AST, 663 IU�L; ALT, 1117 IU�L; g-GTP, 569 IU�L� that was noted during the course of a regularcheck-up. Electrocardiography on admission revealed QT interval prolongation. Viral hepatitis, autoim-

mune hepatitis, alcoholic liver disease, and metabolic liver disease were excluded, and drug-induced liver

injury was considered the most probable diagnosis. Since liver function did not improve even after

terminating administration of the dietary supplement, 50 mg�day of predonisolone were given just after liverbiopsy. Histological findings from the liver biopsy specimen were compatible with drug-induced liver injury.

Liver function improved immediately, and the patient was discharged after predonisolone dose was tapered

to 5 mg�day. QT interval prolongation, which gradually normalized without treatment, was presumablycaused by the dietary supplement. Although lymphocyte stimulation testing for the dietary supplement

yielded negative results, liver dysfunction was diagnosed as drug-induced liver injury due to Super Slender

45 based on clinical course and liver biopsy findings.

1 Department of Internal Medicine, Division of Gastroenterology and Hepatology, St. Marianna University

2 Department of Pathology, St. Marianna University

���������� 495

79