应用化疗药前后兔肝脏的超声表现及病理改变的对照研究
|
摘要
目的：超声检查恶性肿瘤化疗后病人的肝脏时常发现肝脏回声增强致密，类似脂肪肝的声像图表现。有学者认为此为化疗性脂肪肝，但大多数肿瘤科医生对此持有异议。为明确应用化疗药后肝在声像图上回声增强的病理学基础、新化疗药方案与旧化疗药方案对兔肝影响所造成的声像图差异及相关的病理学改变，特进行本实验。
方法：20只新西兰白兔(河北医科大学动物试验中心提供)，雌雄各半，体质重2.5kg左右，随机分为两组，一组给予旧化疗药，一组给予新化疗药。注射化疗药前后作肝脏超声检查，兔耳缘静脉抽血，作肝功、血脂检查。化疗方案选用乳腺癌治疗方案：(1)随机挑选10只兔用CA(旧药)方案：CTX(环磷酰胺)28mg／kg，第1、8日iv；ADM(阿霉素)2.2mg／kg，第2日iv；此二药给药3周(1个周期)，停用1周，然后继续给药3周，共2个周期。(2)随机挑选10只兔用TE(新药)方案：TXT(紫杉醇)7.5 mg／kg，第1日iv；EPI(表阿霉素)2.8 mg／kg，第2日iv，此二药给药3周(1个周期)，停用1周，然后继续给药3周，共2个周期。考虑到兔对化疗药的耐受性较差(预实验过程中给兔实验全量时死亡较多)，上述药量均为兔实验全量的一半。兔实验全量的换算公式：兔实验用量=成人用量÷30×0.37÷0.11。操作方法：每只兔用药前均查肝功能、血脂并作肝脏超声检查，做超声时超声仪器的扫查条件用药前后保持不便。2个用药周期结束后再次查肝功能、血脂、兔肝脏超声。超声图像储存在工作站中以备分析。用photoshop6.0软件中的直方图功能来分析兔肝声像图的回声强度，在右肝经第一肝门纵切面上选取三个部位的平均值进行给药前后回声强度的比较，用t检验及方差分析进行统计学处理。最后处死兔子，取出肝脏，福尔马林固定，待病理切片观察。两组兔(新、旧药化疗方案)的病理结果进行卡方Fisher’s检验。统计学软件使用SPSS11.0。
结果：旧药组兔肝用药前后的超声回声强度分别为25.64±7.82和46.63±7.54，二者比较有统计学意义(p＜0.05)。新药组兔肝用药前后的超声回声强度分别为23.02±5.68和30.48±6.44，二者比较p＜0.05，有统计学意义。旧药组与新药组用药后兔肝的回声强度比较p＜0.05，也有统计学意义。用药后除了肝实质回声强度增高外，还可见实质回声模糊，肝内管道系统的壁回声增强，类似肝炎的超声表现。其中有一例有片状回声增强区，经病理证实为肝实质变性坏死及钙化形成。病理改变包括新旧药组的全部兔肝均出现肝细胞肿胀变性，其中旧药组还伴发汇管区或间质炎细胞浸润6例，点状、灶状或片状坏死6例，肝血窦扩张充血9例，气球样变3例，嗜酸变性5例，局灶钙化2例，脂肪变性6例，局限性纤维母细胞增生2例；新药组伴发肝血窦扩张充血5例，汇管区炎细胞浸润1例，嗜酸性变1例，点灶状坏死2例，气球样变3例，脂肪变性3例，纤维母细胞增生1例。旧药组兔肝局灶性不可复病变(肝细胞点状、局灶性、片状坏死及钙化)8例，新药组不可复病变2例，经卡方检验，p＜0.05，有统计学意义，这表明旧药组的兔肝病理损害较新药组严重。用药后新旧药两组的兔肝功能均有异常增高，谷草转氨酶增高3例，谷丙转氨酶增高13例，二者同时增高4例，这表明化疗药对兔的肝脏存在损害作用。两组实验兔的血脂用药前后均未见异常。
结论：1应用化疗药可引起肝脏声像图的回声增强、实质回声模糊以及肝内管道系统的管壁回声增强现象，类似肝炎的超声表现，其病理学基础是肝脏的细胞肿胀变性、嗜酸样变、气球样变、脂肪变性、肝血窦扩张充血、炎细胞浸润、点灶状或片状坏死及钙化。这些病理改变使均匀的肝实质回声结构变成了非均匀性的回声介质，从而使回声强度增高，实质回声模糊以及肝内管壁回声增强。
2不同的化疗药引起肝脏回声增强的程度不同，其强度与剂量、用药时间长短及个体差异有关。
3用化疗药后肝脏回声增强的原因不只是脂肪变性所至，尚与肝脏的细胞肿胀变性、嗜酸样变、气球样变、肝血窦扩张淤血、纤维母细胞增生、点灶状或片状坏死及钙化等有关，这一点与以往某些学者的研究结果存在差异。
4应用化疗药后可引起肝细胞的功能损害，如谷草转氨酶和谷丙转氨酶升高，但血脂不一定升高，这一点也与以往某些学者的研究结果不同。
5新化疗药组兔肝的病理损害较旧化疗药组兔肝的损害轻，即不可复性病理改变(点状、灶状或片状坏死及钙化)少，加之临床大量证据显示新药的抑瘤率高，毒副反应少，这可作为推荐使用新化疗药的理由。
Objective: During ultrasonic examination of patientswith malignant tumors, the patient's liver echo-level isfrequently found increased, mimicking a fatty liver. Somescholars believe that condition is post-chemotherapy" fatty liver,whereas most oncologist do not agree to that viewpoint. In orderto investigate the basic pathologic changes resulting in theincreased hepatic echo level, effects of old and newchemotherapeutic agents on rabbit liver, the animal experimentwas planned and implemented.
Methods: 20 rabbits (2.Skg±in weight) were randomlyallocated into two groups. One group was given injection of oldchemotherapeutants (Cyclophosphamide and Addamycin),another group was given injection of new chemotherapeutants(Taxol and Epirubicin).Before and alter drug administratinhepatic function, blood lipids and liver ultrasound wereperformed. Adjuvant therapy for breast cancer was chosen: (1)CA(Cyclophosphamide and Adriamycin) regimen:Cyclophosphamide was given intravenously in a dose of28mg/kg on days 1 and 8. Adriamycin was given intravenously in a dose of 2.2mg/kg on day 2, these two drugs were given 3weeks (1 cycle), stopped 1 week, then continued another 3weeks (2 cycles in total); (2) TE (Taxol and Epirubicin)regimen: Taxol was given intravenously in a dose of 7.5mg/kgon day 1, Adriamycin was given intravenously in a dose of2.8mg/kg on day 2, these two drugs were also given 3 weeks (1cycle), stopped 1 week, then continued another 3 weeks (2cycles in total). Hepatic function, blood lipid, liver sonographyof all rabbits were repeated after 2 cycles of chemotherapeutantadministration. Sonograms were stored in an ultrasoundworkstation for offiine analysis. On the longitudinal section ofrabbit right hepatic lobe (through porta hepatis) 3 echo levelswere obtained with histogram from 3 different locations alongthe right branch of main portal vein. Through dividing the sumof these 3 echo levels by 3, the value was taken as the averagevalue of the right lobe. All data were analyzed (t test) withSPSS 11.0. Finally, all rabbits were executed, the livers weretaken out and stored in Formalin solution for pathologicobservation. The results of pathologic changes were analyzedwith Fisher's exact test.
Results: The average rabbit hepatic echo level pre and postinjection in old drug group were respectively 25.644±7.82 and46.63±7.54, a statistically significant difference wasobserved (p＜0.05). In new drug group, the average rabbithepatic echo level pre and post injection were respectively 23.02±5.68和30.48±6.44, a statistically significant difference was also observed (p＜0.05). Comparing with that of the postinjection in new drug group, the echo level of rabbit liver of postinjection in old drug group was higher (p＜0.05). Besides theincreased echo level of the parenchyma, liver texture becamecoarse, the walls of the blood vessels and bile ducts werebrighter. In one rabbit liver an echogenic lesion wasvisualized, which Was confirmed as a focal necrosis associatedwith calcification. Pathologic changes in rabbit liver weremainly cloudy swelling and hydropic swelling in both 2groups. Other lesions in old drug group included inflammatorycells infiltration appeared in 6 rabbit livers, focal necrosis in 6,sinusoid dilation plus congestion in 9, ballooning degenerationin 3, Councilman body in 5, focal calcification in 2, fattydegeneration in 6, fibroblast hyperplasia in 2, while new druggroup had sinusoid dilation plus congestion in 5 rabbit livers,inflammatory cells infiltration in 1, Councilman body in 1, focalnecrosis in 2, ballooning degeneration in 3, fatty degeneration in3, fibroblast hyperplasia in 1.Old drug group had 8 irreversiblepathologic changes (necrosis, calcification), new drug grouphad 2 such changes. The difference in irreversible pathologicchanges between these two groups was statistically significant(p＜0.05). All rabbits in old drug group and new drug groupshowed elevated AST or ALT values after drug administration.Blood lipids were within normal limit.
Conclusions: 1 After injection of chemotherapeutantsrabbit liver echo level can be increased with coarse liver texture, and brighter walls of the blood vessels and bile ducts. Thesesonographic characteristics are caused by those pathologicchanges such as cloudy swelling, hydropic swelling,inflammatory cells infiltration, focal necrosis, sinusoid dilationplus congestion, ballooning degeneration, fatty. degenerationand focal calcification.
2 The intensity of rabbit liver echo level differs in accordancewith different chemotherapeutant. It depends on dosage, durationof administration, and the drug recipient.
3 Fatty degeneration is not the only cause that results in theincreased echo level of liver sonographiclly. Pathologic changeslike cloudy swelling, inflammatory cell infiltration, focalnecrosis, sinusoid dilation plus congestion, ballooningdegeneration and focal calcification are other contributingfactors.
4 After administration of chemotherapeutants, transaminasesare usually elevated, whereas blood lipids are not inevitablyelevated.
5 Pathologic lesions of rabbit liver in new drug group arelighter than those in old drug group. This fact strongly suggeststhat new chemotherapeutants are recommended.
方法：20只新西兰白兔(河北医科大学动物试验中心提供)，雌雄各半，体质重2.5kg左右，随机分为两组，一组给予旧化疗药，一组给予新化疗药。注射化疗药前后作肝脏超声检查，兔耳缘静脉抽血，作肝功、血脂检查。化疗方案选用乳腺癌治疗方案：(1)随机挑选10只兔用CA(旧药)方案：CTX(环磷酰胺)28mg／kg，第1、8日iv；ADM(阿霉素)2.2mg／kg，第2日iv；此二药给药3周(1个周期)，停用1周，然后继续给药3周，共2个周期。(2)随机挑选10只兔用TE(新药)方案：TXT(紫杉醇)7.5 mg／kg，第1日iv；EPI(表阿霉素)2.8 mg／kg，第2日iv，此二药给药3周(1个周期)，停用1周，然后继续给药3周，共2个周期。考虑到兔对化疗药的耐受性较差(预实验过程中给兔实验全量时死亡较多)，上述药量均为兔实验全量的一半。兔实验全量的换算公式：兔实验用量=成人用量÷30×0.37÷0.11。操作方法：每只兔用药前均查肝功能、血脂并作肝脏超声检查，做超声时超声仪器的扫查条件用药前后保持不便。2个用药周期结束后再次查肝功能、血脂、兔肝脏超声。超声图像储存在工作站中以备分析。用photoshop6.0软件中的直方图功能来分析兔肝声像图的回声强度，在右肝经第一肝门纵切面上选取三个部位的平均值进行给药前后回声强度的比较，用t检验及方差分析进行统计学处理。最后处死兔子，取出肝脏，福尔马林固定，待病理切片观察。两组兔(新、旧药化疗方案)的病理结果进行卡方Fisher’s检验。统计学软件使用SPSS11.0。
结果：旧药组兔肝用药前后的超声回声强度分别为25.64±7.82和46.63±7.54，二者比较有统计学意义(p＜0.05)。新药组兔肝用药前后的超声回声强度分别为23.02±5.68和30.48±6.44，二者比较p＜0.05，有统计学意义。旧药组与新药组用药后兔肝的回声强度比较p＜0.05，也有统计学意义。用药后除了肝实质回声强度增高外，还可见实质回声模糊，肝内管道系统的壁回声增强，类似肝炎的超声表现。其中有一例有片状回声增强区，经病理证实为肝实质变性坏死及钙化形成。病理改变包括新旧药组的全部兔肝均出现肝细胞肿胀变性，其中旧药组还伴发汇管区或间质炎细胞浸润6例，点状、灶状或片状坏死6例，肝血窦扩张充血9例，气球样变3例，嗜酸变性5例，局灶钙化2例，脂肪变性6例，局限性纤维母细胞增生2例；新药组伴发肝血窦扩张充血5例，汇管区炎细胞浸润1例，嗜酸性变1例，点灶状坏死2例，气球样变3例，脂肪变性3例，纤维母细胞增生1例。旧药组兔肝局灶性不可复病变(肝细胞点状、局灶性、片状坏死及钙化)8例，新药组不可复病变2例，经卡方检验，p＜0.05，有统计学意义，这表明旧药组的兔肝病理损害较新药组严重。用药后新旧药两组的兔肝功能均有异常增高，谷草转氨酶增高3例，谷丙转氨酶增高13例，二者同时增高4例，这表明化疗药对兔的肝脏存在损害作用。两组实验兔的血脂用药前后均未见异常。
结论：1应用化疗药可引起肝脏声像图的回声增强、实质回声模糊以及肝内管道系统的管壁回声增强现象，类似肝炎的超声表现，其病理学基础是肝脏的细胞肿胀变性、嗜酸样变、气球样变、脂肪变性、肝血窦扩张充血、炎细胞浸润、点灶状或片状坏死及钙化。这些病理改变使均匀的肝实质回声结构变成了非均匀性的回声介质，从而使回声强度增高，实质回声模糊以及肝内管壁回声增强。
2不同的化疗药引起肝脏回声增强的程度不同，其强度与剂量、用药时间长短及个体差异有关。
3用化疗药后肝脏回声增强的原因不只是脂肪变性所至，尚与肝脏的细胞肿胀变性、嗜酸样变、气球样变、肝血窦扩张淤血、纤维母细胞增生、点灶状或片状坏死及钙化等有关，这一点与以往某些学者的研究结果存在差异。
4应用化疗药后可引起肝细胞的功能损害，如谷草转氨酶和谷丙转氨酶升高，但血脂不一定升高，这一点也与以往某些学者的研究结果不同。
5新化疗药组兔肝的病理损害较旧化疗药组兔肝的损害轻，即不可复性病理改变(点状、灶状或片状坏死及钙化)少，加之临床大量证据显示新药的抑瘤率高，毒副反应少，这可作为推荐使用新化疗药的理由。
Objective: During ultrasonic examination of patientswith malignant tumors, the patient's liver echo-level isfrequently found increased, mimicking a fatty liver. Somescholars believe that condition is post-chemotherapy" fatty liver,whereas most oncologist do not agree to that viewpoint. In orderto investigate the basic pathologic changes resulting in theincreased hepatic echo level, effects of old and newchemotherapeutic agents on rabbit liver, the animal experimentwas planned and implemented.
Methods: 20 rabbits (2.Skg±in weight) were randomlyallocated into two groups. One group was given injection of oldchemotherapeutants (Cyclophosphamide and Addamycin),another group was given injection of new chemotherapeutants(Taxol and Epirubicin).Before and alter drug administratinhepatic function, blood lipids and liver ultrasound wereperformed. Adjuvant therapy for breast cancer was chosen: (1)CA(Cyclophosphamide and Adriamycin) regimen:Cyclophosphamide was given intravenously in a dose of28mg/kg on days 1 and 8. Adriamycin was given intravenously in a dose of 2.2mg/kg on day 2, these two drugs were given 3weeks (1 cycle), stopped 1 week, then continued another 3weeks (2 cycles in total); (2) TE (Taxol and Epirubicin)regimen: Taxol was given intravenously in a dose of 7.5mg/kgon day 1, Adriamycin was given intravenously in a dose of2.8mg/kg on day 2, these two drugs were also given 3 weeks (1cycle), stopped 1 week, then continued another 3 weeks (2cycles in total). Hepatic function, blood lipid, liver sonographyof all rabbits were repeated after 2 cycles of chemotherapeutantadministration. Sonograms were stored in an ultrasoundworkstation for offiine analysis. On the longitudinal section ofrabbit right hepatic lobe (through porta hepatis) 3 echo levelswere obtained with histogram from 3 different locations alongthe right branch of main portal vein. Through dividing the sumof these 3 echo levels by 3, the value was taken as the averagevalue of the right lobe. All data were analyzed (t test) withSPSS 11.0. Finally, all rabbits were executed, the livers weretaken out and stored in Formalin solution for pathologicobservation. The results of pathologic changes were analyzedwith Fisher's exact test.
Results: The average rabbit hepatic echo level pre and postinjection in old drug group were respectively 25.644±7.82 and46.63±7.54, a statistically significant difference wasobserved (p＜0.05). In new drug group, the average rabbithepatic echo level pre and post injection were respectively 23.02±5.68和30.48±6.44, a statistically significant difference was also observed (p＜0.05). Comparing with that of the postinjection in new drug group, the echo level of rabbit liver of postinjection in old drug group was higher (p＜0.05). Besides theincreased echo level of the parenchyma, liver texture becamecoarse, the walls of the blood vessels and bile ducts werebrighter. In one rabbit liver an echogenic lesion wasvisualized, which Was confirmed as a focal necrosis associatedwith calcification. Pathologic changes in rabbit liver weremainly cloudy swelling and hydropic swelling in both 2groups. Other lesions in old drug group included inflammatorycells infiltration appeared in 6 rabbit livers, focal necrosis in 6,sinusoid dilation plus congestion in 9, ballooning degenerationin 3, Councilman body in 5, focal calcification in 2, fattydegeneration in 6, fibroblast hyperplasia in 2, while new druggroup had sinusoid dilation plus congestion in 5 rabbit livers,inflammatory cells infiltration in 1, Councilman body in 1, focalnecrosis in 2, ballooning degeneration in 3, fatty degeneration in3, fibroblast hyperplasia in 1.Old drug group had 8 irreversiblepathologic changes (necrosis, calcification), new drug grouphad 2 such changes. The difference in irreversible pathologicchanges between these two groups was statistically significant(p＜0.05). All rabbits in old drug group and new drug groupshowed elevated AST or ALT values after drug administration.Blood lipids were within normal limit.
Conclusions: 1 After injection of chemotherapeutantsrabbit liver echo level can be increased with coarse liver texture, and brighter walls of the blood vessels and bile ducts. Thesesonographic characteristics are caused by those pathologicchanges such as cloudy swelling, hydropic swelling,inflammatory cells infiltration, focal necrosis, sinusoid dilationplus congestion, ballooning degeneration, fatty. degenerationand focal calcification.
2 The intensity of rabbit liver echo level differs in accordancewith different chemotherapeutant. It depends on dosage, durationof administration, and the drug recipient.
3 Fatty degeneration is not the only cause that results in theincreased echo level of liver sonographiclly. Pathologic changeslike cloudy swelling, inflammatory cell infiltration, focalnecrosis, sinusoid dilation plus congestion, ballooningdegeneration and focal calcification are other contributingfactors.
4 After administration of chemotherapeutants, transaminasesare usually elevated, whereas blood lipids are not inevitablyelevated.
5 Pathologic lesions of rabbit liver in new drug group arelighter than those in old drug group. This fact strongly suggeststhat new chemotherapeutants are recommended.
引文
1 Pang DM, Deng YM, Wei GY. Postoperation actinotherapy and chemotherapy of staged Ⅱ、Ⅲ mammary cancer. China Journal of Modern Medicine, 2001,11 (12): 39～40
2 Kplowitz N. Biochemical and cellular mechanisms of toxic liver injury. Sem Liver Dis, 2002, 22(2): 137～144
3 黄宁，吴万春．药物性肝病发病机制研究现状．实用肝脏病学，2006，9(2)：117～118
4 李玉凤．药物特异质肝毒性的发病机制及预测筛选方法．国 外医学药学分册，2005，32：338～341
5 鲁晓岚，罗金燕．药物性肝病的临床类型、特点及影响因素．中华肝胆病杂志，2004，12(40)：241
6 Wang WM. Clinical Study of fatty liver caused by mammary cancer chemotherapy.China Journal of Modern Medicine, 2003, 13(3): 1～3
7 徐薇．乳腺癌化疗致脂肪肝的超声诊断分析．湖北省卫生职工医学院学报，2004，17(9)：65～66
8 倪秀雄，姚琦，林秀珍，等．环磷酰胺致S_(180)荷瘤小鼠肝损害机制的实验研究．福建医药杂志，2004，26(2)：93～94
9 潘模英，倪秀雄，姚琦，等．紫杉醇和环磷酰胺致肝损伤程度的对比实验研究．黑龙江医药科学，2004，27(6)：17～18
10 Shi AG;Wang PQ. Toxicity study of taxol. Acta Universitis Medicinalis Secondae Shanghai,2000, 20 (2): 138～139
11 Teli MR, James FR, Burt JA, et al. The natural history of nonalcoholic fatty liver disease: a follow-up study. Hepatology, 1995, 22: 594～598
12 于皆平，沈志祥，罗和生．实用消化病学．北京：科学出版社，1999，887
13 Ludwig J, Viggiano TR, Mc Gill DB, et al. Nonalcoholic steatohepatitis. Mayo Clinic experience with a hitherto unnamed disease. Mayo Clinic Proc, 1980, 55: 434～438
14 Oien KA, Moffat D, Curry DW, et al. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet, 1999, 353: 36～37
15 Farrel GC,.Drugs and steatohepatitis.Semin Liver Dis, 2002; 22(2)：185～194
16 阎明．药物性肝病的发病机制．中华肝脏病杂志，2004，12(4)：240
17 姚光弼．药物性肝病．中华消化杂志，1999，19(5)：339～342
18 丁海勤．谷胱甘肽及其抗氧化作用今日谈．生理科学进展，2002，33(1)：85～90
19 杨洁，高飞．活性氧与细胞凋亡的研究进展．国外医学肿瘤学分册，2002，29(4)：248～251
20 Sumsullah Khan, Jay J, Ramni, Peter J, O'brien. Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Biochemical Pharmacology, 1992,43(9): 1963～1967
21 Manya T, McClure. Investigation of the mechanism by which cyclophosphamide alters cytochrome P450 in male rats. Biochemical Pharmacology, 1992, 43(12): 2655～2658
22 Lear L, Nation RL, Stupans I. Effects of cyclophosphamide lipid peroxidation. Biochemical Pharmacology, 1992, 44(2): 747～753
23 Rosai J. Ackerman's surgical pathology. New York: Mosby-year book.INC, 1996,817～819
24 Yu AS, Keeffe EB. Nonalcoholic fatty liver disease.Rev Gastroenterol Disord,2002; 2(1): 11～19
25 中华医学会肝病分会脂肪肝和酒精性肝病学组．非酒精性脂肪肝诊断标准(草案)．现代实用医学，2002，14(10)：100
26 李治安．临床超声影像学．北京：北京人民卫生出版社，2003，925～926
27 Schwarz KQ, Chen X, Steinmetz S. Methods for quantifying ultrasound backscatter and two dimensional video intensity: implications for contrast enhanced sonography. J Am Soc Echcardiogr ,1998,11:155 168.
28 Feinberg MS, Gussak HN, Davila GV, et al. Dissociation between wall thickening of normal myocardium and cyclic variation of backscatter during stimulation. J Cardiol, 1996, 77: 515～520.
29 Thomas LJ, Barazilai B, Perez J E, et al, quantitative real time imaging of myocardium based on ultrasonic integrated backscatter. IEEE Trans Ultrasound on Ferroelectr Frequency Control, 1989, 36:466～470
30 Wang ZG, Progreses of ultrasonic integrated backscatter and its application. Acta Universitatis Medicinalis Chongqing, 1998,23:207～210
31 南月敏 姚希贤 郭瑞军，等．家兔脂肪肝超声背向散射积分研究．中华超声影像学杂志，2005，14(12)：928～930
32 卓忠雄 高云华 李宁，等．化疗性脂肪肝的超声组织定征研究．中华超声影像学杂志，2001，10(6)：331～333
33 曹海根，王金瑞．实用腹部超声诊断学．第二版．北京：人民卫生出版社，2005，81～82
1 李家泰．临床药理学．北京：人民卫生出版社，1992，55～62
2 鲁晓岚，罗金燕．药物性肝病的临床类型、特点及影响因素．中华肝胆病杂志，2004，12(40)：241
3 于皆平，沈志祥，罗和生．实用消化病学．北京：科学出版社，1999，887
4 Kplowitz N. Biochemical and cellular mechanisms of toxic liver iniury. Sem Liver Dis, 2002,22(2): 137～144
5 施安国，王平全．紫杉醇的毒性研究．上海第二医科大学学报，2000，20(2)：138～139
6 Fanell GC. Drugs and stetohepatitis .Sem Liver Dis,2002,22(2): 185～194
7 阎明．药物性肝病的发病机制．中华肝脏病杂志，2004，12(4)：240
8 潘模英，倪秀雄，姚琦等．紫杉醇和环磷酰胺致肝损伤程度的对比实验．黑龙江医药科学，2004，27(6)：17～18
9 北村庸雄．药物性肝损害的细胞损害机制．日本医学介绍，2000，21(9)：401～403
10 陈成伟．药物性肝病．东南国防医学，2004，6(4)：241～244
11 齐唐凯，卢洪洲．药物性肝损害的研究进展．世界感染杂志，2004，4(5)：494～496
12 Hussain Z, Kar P, Hussain S A.Antituberculosis drug-induced hepatitis: risk factors, prevention and management.Indian J Exp Biol,2003,41(11): 26～32
13 刘平，宋东眷．药物性肝损伤的发病机理．中华肝脏病杂志，2001，6(3)：40
14 支杰华，朱萱．药物性肝病病理及诊治的研究进展．实用肝脏病杂志，2006，9(2)：124
15 历有名．药物性肝损害的临床类型及诊断策略．中华肝脏病杂志，2004，12(7)：445～446
16 巫协宁．临床肝胆系病学．上海：上海科学技术文献出版社，2002，355
17 Francisco J A, Dolores M, Mariano M, et al. Acute and clinically relevant drug induced liver injury: a population based control study. Bri Clin Pharmacol, 2004,58(1): 1365～2125
18 Khoo A L, Tham L S, Lee K H, et al. Acute liver failure with concurrent bupropion and carbimazole therapy. Ann Pharmacother, 2003, 37(2): 220～223)
19 叶任高．内科学．北京：人民卫生出版社，2001，458
20 李继强，施尧．药物性肝损害的病理．中华肝脏病杂志，2001，6(1)：42
21 Zimmerman HJ. Update of hepatotoxicity due to classes of drugs in common clinical use: non-steroidal drugs, antiinflamatory drugs, antihypertensives, and cardiac and psychotropic agents. Sem Liver Dis, 1990,10:322
22 董郡．病理学．北京：人民卫生出版社，1996，507
23 Larrey D. Epidemilogy and indivisual susceptibility to adverse drug reactions affecting the liver. Sem liver Dis,2002,22(2): 145～155
24 王吉耀，郭津生．药物性肝病的诊断和治疗，中华肝脏病杂志，2001，6(1)：43～46
25 Larrey D. Drug induced liver disease. Hepatology, 2000,32: 77～88
26 Neil K. Drug. induced liver disorders. Drugs Safe, 2001, 24(7): 483～490
27 唐善令，虎连升．还原型谷胱甘肽治疗药物性肝病42例，中西医结合杂志，2003，13(3)：26
28 Lewis J H. Drug-induced liver disease. Med Clin North AM,2000,84(5): 1275
29 Zhou X M, Miao J Y, Yang Y. Clinical experience with molecular adsorbent recirculating system (MARS) in patients with drug-induced liver failure. Artif Organs,2004,28(5): 483
30 Russo M W, Galanko J A, Shrestha R, et al. Liver transplantation for acute liver failure from drug induced injury in the United States. Liver Transplant,2004,10: 1018～1023
31 陈灏珠．实用内科学．第11版．北京：人民卫生出版社，2001：1863～1866
2 Kplowitz N. Biochemical and cellular mechanisms of toxic liver injury. Sem Liver Dis, 2002, 22(2): 137～144
3 黄宁，吴万春．药物性肝病发病机制研究现状．实用肝脏病学，2006，9(2)：117～118
4 李玉凤．药物特异质肝毒性的发病机制及预测筛选方法．国 外医学药学分册，2005，32：338～341
5 鲁晓岚，罗金燕．药物性肝病的临床类型、特点及影响因素．中华肝胆病杂志，2004，12(40)：241
6 Wang WM. Clinical Study of fatty liver caused by mammary cancer chemotherapy.China Journal of Modern Medicine, 2003, 13(3): 1～3
7 徐薇．乳腺癌化疗致脂肪肝的超声诊断分析．湖北省卫生职工医学院学报，2004，17(9)：65～66
8 倪秀雄，姚琦，林秀珍，等．环磷酰胺致S_(180)荷瘤小鼠肝损害机制的实验研究．福建医药杂志，2004，26(2)：93～94
9 潘模英，倪秀雄，姚琦，等．紫杉醇和环磷酰胺致肝损伤程度的对比实验研究．黑龙江医药科学，2004，27(6)：17～18
10 Shi AG;Wang PQ. Toxicity study of taxol. Acta Universitis Medicinalis Secondae Shanghai,2000, 20 (2): 138～139
11 Teli MR, James FR, Burt JA, et al. The natural history of nonalcoholic fatty liver disease: a follow-up study. Hepatology, 1995, 22: 594～598
12 于皆平，沈志祥，罗和生．实用消化病学．北京：科学出版社，1999，887
13 Ludwig J, Viggiano TR, Mc Gill DB, et al. Nonalcoholic steatohepatitis. Mayo Clinic experience with a hitherto unnamed disease. Mayo Clinic Proc, 1980, 55: 434～438
14 Oien KA, Moffat D, Curry DW, et al. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet, 1999, 353: 36～37
15 Farrel GC,.Drugs and steatohepatitis.Semin Liver Dis, 2002; 22(2)：185～194
16 阎明．药物性肝病的发病机制．中华肝脏病杂志，2004，12(4)：240
17 姚光弼．药物性肝病．中华消化杂志，1999，19(5)：339～342
18 丁海勤．谷胱甘肽及其抗氧化作用今日谈．生理科学进展，2002，33(1)：85～90
19 杨洁，高飞．活性氧与细胞凋亡的研究进展．国外医学肿瘤学分册，2002，29(4)：248～251
20 Sumsullah Khan, Jay J, Ramni, Peter J, O'brien. Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Biochemical Pharmacology, 1992,43(9): 1963～1967
21 Manya T, McClure. Investigation of the mechanism by which cyclophosphamide alters cytochrome P450 in male rats. Biochemical Pharmacology, 1992, 43(12): 2655～2658
22 Lear L, Nation RL, Stupans I. Effects of cyclophosphamide lipid peroxidation. Biochemical Pharmacology, 1992, 44(2): 747～753
23 Rosai J. Ackerman's surgical pathology. New York: Mosby-year book.INC, 1996,817～819
24 Yu AS, Keeffe EB. Nonalcoholic fatty liver disease.Rev Gastroenterol Disord,2002; 2(1): 11～19
25 中华医学会肝病分会脂肪肝和酒精性肝病学组．非酒精性脂肪肝诊断标准(草案)．现代实用医学，2002，14(10)：100
26 李治安．临床超声影像学．北京：北京人民卫生出版社，2003，925～926
27 Schwarz KQ, Chen X, Steinmetz S. Methods for quantifying ultrasound backscatter and two dimensional video intensity: implications for contrast enhanced sonography. J Am Soc Echcardiogr ,1998,11:155 168.
28 Feinberg MS, Gussak HN, Davila GV, et al. Dissociation between wall thickening of normal myocardium and cyclic variation of backscatter during stimulation. J Cardiol, 1996, 77: 515～520.
29 Thomas LJ, Barazilai B, Perez J E, et al, quantitative real time imaging of myocardium based on ultrasonic integrated backscatter. IEEE Trans Ultrasound on Ferroelectr Frequency Control, 1989, 36:466～470
30 Wang ZG, Progreses of ultrasonic integrated backscatter and its application. Acta Universitatis Medicinalis Chongqing, 1998,23:207～210
31 南月敏 姚希贤 郭瑞军，等．家兔脂肪肝超声背向散射积分研究．中华超声影像学杂志，2005，14(12)：928～930
32 卓忠雄 高云华 李宁，等．化疗性脂肪肝的超声组织定征研究．中华超声影像学杂志，2001，10(6)：331～333
33 曹海根，王金瑞．实用腹部超声诊断学．第二版．北京：人民卫生出版社，2005，81～82
1 李家泰．临床药理学．北京：人民卫生出版社，1992，55～62
2 鲁晓岚，罗金燕．药物性肝病的临床类型、特点及影响因素．中华肝胆病杂志，2004，12(40)：241
3 于皆平，沈志祥，罗和生．实用消化病学．北京：科学出版社，1999，887
4 Kplowitz N. Biochemical and cellular mechanisms of toxic liver iniury. Sem Liver Dis, 2002,22(2): 137～144
5 施安国，王平全．紫杉醇的毒性研究．上海第二医科大学学报，2000，20(2)：138～139
6 Fanell GC. Drugs and stetohepatitis .Sem Liver Dis,2002,22(2): 185～194
7 阎明．药物性肝病的发病机制．中华肝脏病杂志，2004，12(4)：240
8 潘模英，倪秀雄，姚琦等．紫杉醇和环磷酰胺致肝损伤程度的对比实验．黑龙江医药科学，2004，27(6)：17～18
9 北村庸雄．药物性肝损害的细胞损害机制．日本医学介绍，2000，21(9)：401～403
10 陈成伟．药物性肝病．东南国防医学，2004，6(4)：241～244
11 齐唐凯，卢洪洲．药物性肝损害的研究进展．世界感染杂志，2004，4(5)：494～496
12 Hussain Z, Kar P, Hussain S A.Antituberculosis drug-induced hepatitis: risk factors, prevention and management.Indian J Exp Biol,2003,41(11): 26～32
13 刘平，宋东眷．药物性肝损伤的发病机理．中华肝脏病杂志，2001，6(3)：40
14 支杰华，朱萱．药物性肝病病理及诊治的研究进展．实用肝脏病杂志，2006，9(2)：124
15 历有名．药物性肝损害的临床类型及诊断策略．中华肝脏病杂志，2004，12(7)：445～446
16 巫协宁．临床肝胆系病学．上海：上海科学技术文献出版社，2002，355
17 Francisco J A, Dolores M, Mariano M, et al. Acute and clinically relevant drug induced liver injury: a population based control study. Bri Clin Pharmacol, 2004,58(1): 1365～2125
18 Khoo A L, Tham L S, Lee K H, et al. Acute liver failure with concurrent bupropion and carbimazole therapy. Ann Pharmacother, 2003, 37(2): 220～223)
19 叶任高．内科学．北京：人民卫生出版社，2001，458
20 李继强，施尧．药物性肝损害的病理．中华肝脏病杂志，2001，6(1)：42
21 Zimmerman HJ. Update of hepatotoxicity due to classes of drugs in common clinical use: non-steroidal drugs, antiinflamatory drugs, antihypertensives, and cardiac and psychotropic agents. Sem Liver Dis, 1990,10:322
22 董郡．病理学．北京：人民卫生出版社，1996，507
23 Larrey D. Epidemilogy and indivisual susceptibility to adverse drug reactions affecting the liver. Sem liver Dis,2002,22(2): 145～155
24 王吉耀，郭津生．药物性肝病的诊断和治疗，中华肝脏病杂志，2001，6(1)：43～46
25 Larrey D. Drug induced liver disease. Hepatology, 2000,32: 77～88
26 Neil K. Drug. induced liver disorders. Drugs Safe, 2001, 24(7): 483～490
27 唐善令，虎连升．还原型谷胱甘肽治疗药物性肝病42例，中西医结合杂志，2003，13(3)：26
28 Lewis J H. Drug-induced liver disease. Med Clin North AM,2000,84(5): 1275
29 Zhou X M, Miao J Y, Yang Y. Clinical experience with molecular adsorbent recirculating system (MARS) in patients with drug-induced liver failure. Artif Organs,2004,28(5): 483
30 Russo M W, Galanko J A, Shrestha R, et al. Liver transplantation for acute liver failure from drug induced injury in the United States. Liver Transplant,2004,10: 1018～1023
31 陈灏珠．实用内科学．第11版．北京：人民卫生出版社，2001：1863～1866