Vol. 32, pp , mg 5mg QT. N-nitoroso-fenfluramine fenfluramine 2. N-nitoroso-fenfluramine fenfluramine QT

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1 489 Vol. 32, pp , : ASTALT 6637 g-gtp 569 QT mg 5mg QT N-nitoroso-fenfluramine fenfluramine QT 2 N-nitoroso-fenfluramine fenfluramine N-nitoroso-fenfluramine fenfluramine

490 Table. Laboratory Data on Admission : 48 : : 46 : : L 2 : 45 7 0 3 4 7 4 8 2 6 8 3 ASTALT 6637, g-gtp 569 45 8 27 : 5 cm 67.

2 490 Table. Laboratory Data on Admission : 48 : : 46 : : L 2 : ASTALT 6637, g-gtp : 5 cm 67.4 kgbody Mass Index C mmhg 60 Table : T. Bil.4.3 mgdl, D.Bil.3.2 mgdl AST 806 IUl, ALT 04 IUl, LDH 386 IUl ALP g-gtp 334 IUl IgG, IgM, IgE LKM- A B C EB : focal spared lesion Fig. -a Fig. -b CT Fig. 2 Figure. 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. 74

49 3a 3b Figure 3. Heart rate is 52 min and sinus bradycardia 3a. Twave is inverted in V5, and myocardial injury was suspected. QT prolongation is also seen. QT time was 533 ms 3a.

4 predonisolone QT ST-T Fig. 3-b, QT 45 N-nitoroso-fenfluramine, fenfluramine 45D-LST cpm, S.I.22 Fig. 5: P-C bridging necrosis piecemeal necrosis P-C bridging necrosis Figure 5.

3 49 3a 3b Figure 3. Heart rate is 52 min and sinus bradycardia 3a. Twave is inverted in V5, and myocardial injury was suspected. QT prolongation is also seen. QT time was 533 ms 3a. QTprolongation which was seen on admission dis-appeared just before dischage from our hospital. QT time was 435 ms 3b. Figure 4. Clinical course : 52 T V5 QT Fig. 3-a : predonisolone 50 mg Fig. 4 predonisolone QT ST-T Fig. 3-b, QT 45 N-nitoroso-fenfluramine, fenfluramine 45D-LST cpm, S.I.22 Fig. 5: P-C bridging necrosis piecemeal necrosis P-C bridging necrosis Figure 5. a: Masson staining 0 Although P-C bridging necrosis was seen in a small portion, the lobular structure was maintained 5a. b: HE staining 0. Bridging necrosis and focal necrosis were found dispersively. Furthermore, there were regeneration of small hepatocytes and numerous eosinophilic bodies 5b. c: HE staining 0. Note fibrotic expansion of portal area. Inflammatory infiltration was composed primarily of monocytes and neutrophils 5c. d:a:hestaining 40 Eosinofilic infiltration is seen 5d. Anisokaryosis D- PAS HBs 75

4 mazindol ALT g-gtp D-LST 45 N-nitoroso-fenfluramine, fenfluramine 45 N-nitoroso-fenfluramine, fenfluramine HT: 5-hydroxytryptamine 2 d- fenfluramine 3 l- fenfluramine 4 P450 2D6 75 fenfluramine 89, , 0 QT QT Ia III early afterdepolarization QT QT Fenfluramine early afterdepolarization Fenfluramine Mazindol 76

5 493 9 ST-T 9 Fenfluramine QT QT Torsade de point Fenfluramine ; 452: ; 443: ; 442: ; 44 3: Adachi M, Saito H, Kobayashi H, Horie Y, Kato S, Yoshioka M, Ishii H. Hepatic Injury in 2Patients Taking the Herbal Weight Loss Aids Chaso or Onshido. Annals of Internal Medicine. 2003; 396: Kawata K, Takehira Y, Kobayashi Y, Kitagawa 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; 422: Kawagachi T, Harada M, Arimatsu H, Nagata S, Kago Y, Kuwahara R, Hisamochi A, Hino T, Taniguchi E, Kumemura H, Hanada S, Maeyama M, Koga H, Tomiyasu N, Toyomasu H, Kawaguchi M, Kage M, Kumashiro R, Tanikawa K, Sata M. Severe hepatotoxicity associated with a N-nitrosofenfluramine containing weight-loss supplemen: report of three cases. J Gastroenterol Hepatol. 2004; 9 3: Nadir A, Agrawal S, Kibg PD, Marshall JB. Acute hepatitis associated with the use of a Chinese herbal product, mahuang. Am J Gastroenterol 996; 97: Divid GB, Dov W, Eli W, Eran L. Fenfluramine and Mazindol: Acute reversible cardiomyopathy associated with their use. Int l J Psychiatry in Medicine ; 5 2: http: www. mhlw. go. jp houdou h 0793.html Rothman R, Bauann M. Therapeutic and adverse action of serotonins transporter substrates. Pharmacol Ther Jul; 95: 73 2 Bever KA, Perry PJ. Dexfenfluramine hydrochloride: an anorexigenic agent. Am J Health Syst Pharm. 997 Sep 5; 54 8: Picarel-Blanchot F, Bailbe D, Portha B. d- Fenfluramine improves hepatic insulin action 77

6 494 in streptozotocin-diabetic rats. Eur J Pharmacol. 994 Oct 24; 2642: Conti I, Tridico RV, Duan L, Caccia S. E#ects of L-fenfluramine on rat liver drug-metabolizing enzymes. Res Commun Pathol Pharmacol. 99 Feb; 72: 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 vitro inhibition of P 4502 D6 by D- and L- fenfluramine, but not phentermine. J Clin Psychopharmacol. 998 Aug; 84:

7 495 Abstract ACase of Drug induced Liver Injury Caused by Super Slender, a Chinese Dietary Supplement for Weight Loss Hideaki Takahashi,Hiroshi Yotsuyanagi,Mayu Orita,Yoshihiko Nagase, Yuka Suzuki,Yoshiki Katakura,Noriaki Okuse,Yutaro Kobayashi, Junki Koike 2,Yasuhito Takahashi,Takeshi Hayashi,Mchihiro Suzuki, Shiro Maeyama 2,Toshiyuki Uchikoshi 2,andFumio Itoh 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, hyperlipidemia, fatty liver, and obesity. She had been taking the dietary supplement Super Slender 45 from July 0, 2002 to August 2, 2002 in an e#ort to lose weight. She was admitted to our hospital for the treatment of liver injury AST, 663 IUL; ALT, 7 IUL; g-gtp, 569 IUL that was noted during the course of a regular check-up. Electrocardiography on admission revealed QT interval prolongation. Viral hepatitis, autoimmune 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 mgday of predonisolone were given just after liver biopsy. 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 mgday. QT interval prolongation, which gradually normalized without treatment, was presumably caused 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. Department of Internal Medicine, Division of Gastroenterology and Hepatology, St. Marianna University 2 Department of Pathology, St. Marianna University 79

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