【作者】 栗建辉；

【导师】 王燕；

【作者基本信息】 河北医科大学 ， 影像医学与核医学， 2007， 硕士

【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。更多还原

【Abstract】 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.更多还原