7
腇腊腈腃 臹腸腻腧膀腲膅膑膜臋臖 Vol. 32, pp. 489495, 2004 腁腐 腆腀腈腀腆腉腊腇腀 45腂腄腅 腐腍腏腌腎腋腃 1 腔腈 腛腏 腝腗 腃腊 1 腤腖 腡腙腋 腝腧腏 1 腇腦 1 腙腉 腤腏 腝腎 1 腑腒 1 腈腔 腌腥 腤腏 1 腇腌 腚腦 腃腊 1 腎腜腡腏 腣腅 腧腅 1 腄腍 腐腢腨 2 腔腈 腛腏 腡腑 腝腘 1 腛腡腏 腔腍腏 1 腑腒 腠腕 腝腧 1 腟腆 腡腟 腧腅 2 腅腕 腎腏 腘腏 腣腊 2 腘腅 腞腠 1 : 16 10 19 48 臈腗臤臶46 臈腟腡腛腠腬臂膱膁臂臔膱臩腪腺腖腑腝腱腩腝 腒腁腐腏腍腢膁腕腖腑臑腗膳膽臰腬腀腴腀腬腽膀腮腀 4514 7 10 腟腡 8 12 腙腒腰膈腋腏8 13 膣臇膱腖腑膞膤臫膚 AST ALT 6631117g-GTP 569腜腏腏腜膊膁腕膑自膕膇腓腕腐腏膇臗腗臱致腒 QT 臗膠腗膋腜腠腣腏腩腨腼腬臶膞膌臘膺膉臶膞膌腧腼腫腀腼臶膞臫膚腕腔腘 腨腔腕腒腁腡腬腀腴腀腬腽膀腮腀 45腖腟腢臉臶膞臫膚腇臆腝膧腥腣腏腰膈 臓腋腑腝膞膤腗膘腜腠腣腕腆腐腏腏腜膞臸膴臒臁膻腗 8 29 腟腡腶腽腱腳 腭腾膀 50 mg腘膇腦膙臐腋腏膞臸膴腗膰膒腘臉臶膞臫膚腖臃腌腢臣膵腒腁腐腏腶腽腱腳腭腾膀腗腘膇腖腟腡膞膤腞腆腖膘5 mg 腙腒膸腋腏腓腉腤腒膇腓 腕腐腏致臬腗 QT 腘膮膓膟臊腖腑膘腦腋腑腅腡臉腖腟腢腝腗腓臀腄腠腣腏腬腀腴腀腬腽膀腮腀 45 腌腢腻膀腴膩臍膯臕膶腘膈臶腒腁腐腏腝腗腗腝腰膒腇腕腂 腉腓腰膂臗膣腩腨腼腬腞臘膺膉臶膞膌腗腨腔腕腔腗臦膮膓腞臯臣膵腒腘膨臶膞 臫膚腒臉臶膞臫膚腖臢腋腕腂臣膵腒腁腐腏膃膞膤膄臭腗膷膆腘腬腀腴腀腬腽膀腮腀 45 腖腟腢臉臶膞臫膚腓臀腄腠腣腏腄腀腉腂 N-nitoroso-fenfluraminefenfluramine臉臶膞臫膚QT 臆膬腗 膳膽腵腀腹腖腟腡臜臺膖臚腗臑腧膂腖膐腄腑腈腗膳膽臰腧腥腊腣 腢腟腃腖腕腐腏腒腝腮腨腪腯腰腦膁腕腖腋腏腝 腗腘腖腥腏腐腑腂腢腉腣腠腘腎腗臷N-nitoroso-fenfluraminefenfluramine膿臮臼腷 腼腺膀腕腔腞膛臝腗膝腷膂腦膡腚腕腇腠腝膂腭腗膭腒腧腥腊腣腑腂腢腗腇膹臮腒腁腢臅膗 N-nitoroso-fenfluraminefenfluramine 2 腦膡腛膂腭 腬腀腴腀腬腽膀腮腀 45腖腟腢腓臀腄腠腣腢膞膤臫膚腗 1 腦膮膶腋腏腗 臄腌腢1 臹腸腻腧膀腲膅膑膑膜臨膎膢腄腝2 腜腬膉膜膪臙 489 73

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

  • Upload
    others

  • View
    0

  • Download
    0

Embed Size (px)

Citation preview

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

���� ����������Vol. 32, pp. 489�495, 2004

��� ���������� 45� ��� ���� 1�

���

��

���

���1 �

���

����

1 ���

��

��

��1 �

��

��

��

���1

��

��

��1 �

��

��

��

��1 �

��

��

���

���1 ��

����

���

��

���1

��

���

�� !

��2 �

��

��

���

��"1 �

���

����

1 ��

�#$

���1

��%

���

��

���2 �

�$

���

�"�

���2

�"�

�&#

!�1

�"� :�# 16 10$ 19!�

� �%"& 48'()*' 46'+,#$%��-.��/-%�/&0�'(12)3*+,*

��4-5678' �9:./12;0(<=>1 �?@A@?B�C@ 45� D�# 14 7$ 10 !+, 8 $ 12 !E523F8' 8 $ 13 !(4GH-120I5JK �AST�ALT663�1117( g-GTP 569� D6L88L( M7./18�NO94PQ78' 94R(S:T5QT RU(V�W6LXY8' Z[\?*0]( ^_;`*0]( �\a@\*0JKQb&<4/56,( �?@A@?B�C@ 45� 1+:=c*0JKWdefgY8' >>1(23D-hF2e0I5(i?W6LXYQj788L( 0!klmn( 8$ 29!+,oBpqrs� 50 mg�!(@ADtuF8' 0!k(vw&=c*0JK1xBy:z{5678'oBpqrs�(@A1+,0I5&C|j1i?F( 5 mg E5}DF8P~�5E4PQ78' S:T�( QT V�&����12i?DF2�,( =c1+:e(P��XY8'?@A@?B�C@ 451Fy:��A�����&�*5678e((( G1*2HWQ�~P( 2=RG( Z[\?|^_;`*0](<4Qb(I���|( 0J�z{5&�*0JK5=c*0JK1K�FQ�z{5678�( 0I5��(��&?@A@?B�C@451+:=c*0JKP��XY8'

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

� �

d�( �<=�@�� 1+,( L<=����=��(;0=1M�2( M�(<=>1W0N Y:+¡1Q78' -5eC[¢£¤D./1F8e

(&M¥O1g872�:' ~YX&¦(#+1N-nitoroso-fenfluramine( fenfluramine( §¨©ª\«�Qb|¬¥(­P=D®¯QWXe( Q°6=1(±50N Y2�:(W²¨56:' ³´µ)& N-nitoroso-fenfluramine( fenfluramine( 2#+D®¶Q°6�=1 �?@A@?B�C@ 45�1+:P��XY:0I5JK( 1"D��F8(5R·y:'

1 ��������� *��¸¹º�0S*��2 >%T»¼

489

73

Page 2: 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

� �

� �: 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

Page 3: 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

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

Page 4: 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

� �

����� ��������� 2002�������� ������� ������ ���� ��1�10�� ��� ��� �!������"� 2004� 7# 29��������$� %& 671�����'����(��������)*����+������� ,- 3�+��.�/�10�� 0� �� �1!"2#3,�� 194�� ��4$%3,�� 197 ��&5����+'6� �(�+)*.�/7 �8�9�8:;<�45� 2��=>710������� 7?��5".�@!;A�B�mazindol� +�+�,-���/�.C��5�=�� �5/0�1D�23E4FG5H67��I�JBKLMNO;�A9P;�QRST;UV.78/9:+E4W;�=�+� �<X =>+Y;NZ[P;"?@\�7?� ]A>D�B^+CD�3"�=�� '_���EF\ GH�`a��/��+bI�=�� @!;A�B����WJcK 0.5�� 5��L�MN��? ��"����/��d��(��OPQ�efg�eRf(�RS

��#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��

� �

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

J Health Syst Pharm. 1997 Sep 15; 54 �18�:2059�72.

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

�������Y1@!" 493

77

Page 6: 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

in streptozotocin-diabetic rats. Eur J Pharma-

col. 1994 Oct 24; 264�2�: 227�32.14� Conti I, Tridico RV, Duan L, Caccia S. E#ectsof L-fenfluramine on rat liver drug-meta-

bolizing enzymes. Res Commun Pathol Phar-

macol. 1991 Feb; 71�2�: 163�74.15� von Moltke LL, Greenblatt DJ, Ciraulo DA,

Grassi JM, Granda BM, Duan SX, Harmatz

JS, Lewis CG. Appete suppressant drugs as

inhibitors of human cytochromes P450: in vi-

tro inhibition of P 450�2 D 6 by D- and L-fenfluramine, but not phentermine. J Clin Psy-

chopharmacol. 1998 Aug; 18�4�: 338�41.

���� �� � �494

78

Page 7: 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

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