Gomez J L, Dupont A, Cusan L, Tremblay M, Suburu R, Lemay M, Labrie F
Department of Medicine, Centre Hospitalier de l'Université Laval Research Center, Quebec, Canada.
Am J Med. 1992 May;92(5):465-70. doi: 10.1016/0002-9343(92)90741-s.
The incidence of flutamide-related liver toxicity was studied in 1,091 consecutive patients treated for stage C or D prostate cancer with the antiandrogen flutamide and the luteinizing hormone-releasing factor (LHRH) agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide.
Liver function tests, namely measurement of serum aspartate amino-transferase (AST) and alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase (gamma-GT), and prothrombin and thromboplastin times, were performed at 4, 8, and 12 weeks and every 3 months thereafter. Clinical signs and symptoms of liver dysfunction were also sought. The causal link between the antiandrogen used and liver injury was assessed on the basis of the temporal relationship with the use of the drug in the absence of other possible causes and, in two patients, through rechallenge of the putative causative drug after a period of normalization of liver function.
An increase in AST and ALT at fourfold or more above upper normal limits was observed in only four patients (0.36%). Total serum bilirubin and alkaline phosphatase were elevated in only one patient at 126 mmol/L and 640 IU/L, respectively. Among the four patients, only two developed clinical manifestations of liver disease (0.18%). Biopsy was performed in one patient, and the histopathologic findings showed a mixed pattern of cytotoxic and cholestatic changes. All clinical and biologic manifestations of liver toxicity rapidly disappeared upon discontinuation of flutamide alone. No sequelae were observed in the long-term follow-up at 18, 22, 31, and 62 months. The 1,087 remaining patients experienced no or mild (less than fourfold upper normal limit) and transient elevation in aminotransferase serum levels during the first 6 months of treatment, with normalization at later time intervals.
Despite the fact that the cases reported so far, along with our large series, indicate that the incidence of flutamide-induced liver toxicity is very low, we recommend serial blood aminotransferase measurements at 2 and 4 weeks of treatment in order to detect early signs of possible flutamide-induced hepatic injury, thus avoiding the low potential risk of clinically significant liver toxicity.
在1091例连续接受抗雄激素药物氟他胺和促黄体生成素释放因子（LHRH）激动剂[D-色氨酸6，去甘氨酰胺（10）]LHRH乙酰胺治疗的C期或D期前列腺癌患者中，研究氟他胺相关肝毒性的发生率。
在第4、8和12周以及此后每3个月进行肝功能检查，即测定血清天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、总胆红素、碱性磷酸酶、γ-谷氨酰转肽酶（γ-GT）以及凝血酶原和凝血活酶时间。还寻找肝功能障碍的临床体征和症状。在没有其他可能原因的情况下，根据与药物使用的时间关系评估所用抗雄激素与肝损伤之间的因果联系，并且在两名患者中，在肝功能恢复正常一段时间后，通过再次使用假定的致病药物来评估。
仅4例患者（0.36%）观察到AST和ALT升高至正常上限的四倍或更高。仅1例患者的总血清胆红素和碱性磷酸酶分别升高至126 mmol/L和640 IU/L。在这4例患者中，仅2例出现肝病的临床表现（0.18%）。对1例患者进行了活检，组织病理学结果显示为细胞毒性和胆汁淤积性改变的混合模式。仅停用氟他胺后，肝毒性的所有临床和生物学表现迅速消失。在18、22、31和62个月的长期随访中未观察到后遗症。其余1087例患者在治疗的前6个月转氨酶血清水平无升高或仅有轻度（低于正常上限四倍）且短暂升高，随后恢复正常。
尽管到目前为止报告的病例以及我们的大量病例系列表明氟他胺诱导的肝毒性发生率非常低，但我们建议在治疗的第2周和第4周进行系列血转氨酶测量，以便检测氟他胺可能诱导的肝损伤的早期迹象，从而避免临床上显著肝毒性的低潜在风险。
