肝硬化和肝癌患者血清IGF-Ⅱ、TGFα和EGF水平变化及临床意义
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摘要
目的：通过观察肝硬化(LC)、原发性肝癌(PHC)患者血清胰岛素样生长因子Ⅱ(IGF-Ⅱ)、转化生长因子α(TGFα)和表皮生长因子(EGF)含量变化及与反映肝功能部分生化指标间的关系，初步探讨IGF-Ⅱ、EGF和TGFα三者在肝硬化、原发性肝癌发生发展过程中的相互关系及作用。
方法：本研究分为LC组、PHC组和对照组。LC组54例，全部为我院住院病人，根据病史、临床表现、B超或CT以及血清病毒标志物检测和肝功能检查等明确诊断，其中男46例，女8例，年龄25—71岁，平均53岁。Child A级病人10例，Child B级病人22例，Child C级病人22例；其中37例为失代偿期肝硬化患者，17例为代偿期肝硬化患者。PHC组32例，男26例，女6例；年龄29—72岁，平均56岁，均根据临床表现、血清AFP值、B超、CT或MRI、选择性肝动脉造影或组织学检查明确诊断，其中有远处转移者8例(占25％)，无远处转移者24例(占75％)。对照组32例，为我院门诊查体的健康体检者，男26例，女6例，平均56岁，所有入选病例均排除心、脑、肾、胃肠道、胰腺及内分泌系统的疾病，所有受试者于检查前两周内无应用对肝脏损害的药物史。三组间性别、年龄差异无显著性，具有可比性。测试者均
中文摘要
于晨起7S时空腹抽取肘静脉血5nl，分离血清，置一80
℃冰箱保存待测；检测前于室温完全复溶后，采用放射免
疫分析法测定血清中 IGF刁、EGF和 TGF a的含量。
结果：1．LC组血清＊F－11、TGF Q和 EGF水平分别为
0．58士0．20 ng／ml、5．99士1．91pg加 和 SSI．79土
185．06 pg／ml，明显高于正常对照组（0．43士0．14ng／ml，p
＜0．01：4．96士1．55阴／M，p＜0．05：398．％士厂2．51
Pg／gi，Prto．of）。PHC组血清 IGF－11、TGF Q和 EGF分另
为 0．78士 0．23ng／ml、7．34士 1．S6pg加 和 809．85士
224．23pg／ml，显著高于LC组禾对照组（p＜0．01）。2．LC
组血清 IGF－11水平与白蛋白、A／G 呈负相关（r＝一
0．446，P＜0．01；P＝一 0．437，P＜0．001），与 PT 延长。
Child－pugh 评分呈正相关（r＝0．49，n＜0．01；r＝0．33，
p（．05），而与从T、AST、TB无明显相关性（p＞0．05）。血
清 TGF Q水平与 ALT、AST、TB、A、A／G、PT 延长及
Ch if d－Pllgh评分无明显相关性（P＞0．05）。血清EGF水平
与TB、PT 延长及Ch if d－pllgh 评分呈正相 关
（r＝0．286，P＜0．05；r＝0．275，P＜0．05： r＝0．392，P＜0．01），
与 ALT、AST、A、A／G无明显相关性（P＞0．05）。3．LC
组血清 IGF－11、TGF Q 和 EGF水平有如下趋势：Child A
组wtChild B组wtChild C组，血清KF一11和 EGF水平与
＊n＊PU吵分级相关，差异具有显著性（p＜．05），但血清
TGF a水平在各组间比较差异无显著性（P＞0．05）。4．PHC
组血清IGF－11 水平与AFP 呈 明 显正相 关
（r＝0．878，p＜0．01），而 TGF a、EGF与 AFP无明显相关性
（p＞0．05）。AFP＞400fig／L 为阳性，以估计95％正常参考
2
中文摘要
值范围的上限为界值，根据公式肚1．6455计算出血清
IGF－11、TGF a和 EGF的界值分别为 0．66ng／ml、7．51Pg／。l
和 682．61Pg／ml，大于等于此界值者为阳性，， 于此界值
者为阴性，AFP、IGF－11、TGF Q和 EGF卜性率分别为 19／32
例（59．4q）、22／32 例（68．8％）、15／32 例（46．9％）及
22亿2例 u8．8们，经卡方检验四者阳性率无显著差别
（X‘＝4．332，P＞0．05）；在13 例AFP阴性叫C中，IGF－11
阳性4例（占30．S们。PHC思者中，有远处转移者血清
TGF a含量为 8．75士 1．59ng加 明显高于无远处转移者
6．87士 1．73pg／ml（上＝．699，p＜0．05），两组血清 IGF－11
和 EGF的水平无显著差异（P＞0．05）。5．各组内血清 IGF－
11、TGF Q和 EGF的直线相关分析：在对照组、LC组和 PHC
组内血清兀F－11、TGF Q禾 EGF间做两两相关分析，发现
IGF－11、TGF Q禾 EGF 在各组间 皆无明显的相 关性
（P＞0．05）。
结论：本研究结果表明：1．在r患者血清1肛刁1、
TGF a和 EGF水平明显高于对照组，且血清＊F－JI和 EGF
水平与反映肝功能的生化指标及Ch if d干ugh分级密切相
关，证实血清 IGF刁1、TGF Q和 EGF的检测对于肝硬化的
诊断、病情监测及预后估计有一定的临床意义。2．在PHC
患者，血清＊F－11、TGF a和 EGF水平明显高于＊ 组和
对照组，血清mF刁水平与MP呈正相关，而且在AFP
阴性肝癌中血清 IGF刁亦有较高的阳性率。血清 TGF a水
平在有远处转移的患者明显高于无远处转移者。因此，血
清uF－11、TGF Q牙 EGF配合吓P检狈对于监测癌前状态
Objective: To explore the action of IGF- II ,TGF a and EGF in liver cirrhosis and primary hepatocellular carcinoma. We evaluated serum levels of IGF- II ,TGF a and EGF in the patients with liver cirrhosis and primary hepatocellular carcinoma and studied the relationship among serum levels of IGF- II ,TGF a , EGF and some biochemical parameters reflecting the severity of hepatic function. We preliminarily explored the relationship among the serum levels of IGF-II ,TGF a and EGF .
Methods: 54 hospitalizing patients with liver cirrhosis (46 men and 8 women, aged 25-71 years, average age 53 years), 32 patients with primary hepatocellular carcinoma(26 men and 6 women, aged 29-72 years, average age 56 years) and 32 sex, age-matched healthy subjects(26 men and 6 women, aged 29-72years, average age 56 years) were included in the present study. The diagnosis of liver cirrhosis had been made on the basis of clinical ,biochemical and serological parameters using standard techniques including ultrasound and computed tomography. 10 patients were assessed as Child A stage, 22 Child B stage and 22 Child C
stage. Cirrhosis was decompensated in 37, compensated in 17 patients. Primary hepatocellular carcinoma (PHC) was confirmed on clinical grounds including serum a-fetoprotein(AFP) and findings of ultrasonography, computed tomography, magnetic resonance imaging, angiography and /or histopathology. PHC patients with distant metastasis were in 8(25%), without distant metastasis were in 24(75 %). All subjects had no other diseases and did not take the medicine which could produce acute liver damage . Venous blood samples were drawn after an overnight fast at 7-8 AM, centrifuged and then serum was stored at -80 癈 until assayed. The levels of IGF-II,TGF a and EGF in blood were determined by radioimmuno-assay(RIA) after complete recovery.
Results : 1. In cirrhotic group, the serum levels of IGF-II (0.58 ?0.20ng/ml), TGF a (5.99 ?1.91pg/ml)and EGF(581.79?88.06pg/ml) was higher than that in control group(p<0.01, p<0.05, p<0.01). The serum levels of IGF-II,TGF a and EGF in patients with PHC(0.78?.23ng/ml, 7.34 ?1.86pg/ml and 809.85 ?224.23pg/ml respectively) were much significantly higher than that in cirrhotic group and control group(p<0.01). 2. In cirrhotic group, a negative correlation was found between IGF- II and albumin, A/G(r=-0.446, p<0.01; r=-0.437, pO.OOl). A positive correlation was obtained between IGF- II and prothrombin time(PT) and Child-Pugh score (r=0.49,p<0.01;r=0.33,
p<0.05). there was no significant correlation between TGF a and ALT, AST, total bilirubin(TB), albumin, A/G, PT and Child-Pugh score(p>0.05). serum EOF levels in LC exhibited a significant positive correlation with total bilirubin , prothrombin time and Child-Pugh score (r=0.286, p<0.05; r=0.275, PO.05; r=0.392, p<0.01). 3. In cirrhotic group, the serum levels of IGF- II ,TGF a and EGF had a trend, that is, Child A0.05), the serum levels of IGF- II and EGF were associated with the Child-Pugh classification (p<0.05). 4. There was a significant positive correlation between IGF-II and AFP in PHC (r=0.878, p<0.01). No significant correlation was found between TGF a ,EGF and AFP(p>0.05). In 32 PHC, the positive rate of AFP, IGF- II, TGF a and EGF were 59.4%, 68.8%, 46.9% and 68.8% respectively. The difference among the positive rates was no significant (x2=4.332, df=3, P>0.05). 13 PHC were found to be negative to AFP, in which IGF- II was positive in 4 PHC (30.8%). In PHC, the serum levels of TGF a in patients with distant metastasis(8.75?.59pg/ml) was much significantly higher than that in the patients without distant metastasis(6.87 + 1.73pg/ml, p<0.05). 5. There was no significant correlation between IGF- II and TGF a , IGF- II and EGF, TGF a and EGF in LC, PHC and control group(P>0.05).
Conclusion: In this study, we found that: 1. The levels of IGF- II ,TGF a and EGF in blood of patients with liver cirrhosis were higher
方法：本研究分为LC组、PHC组和对照组。LC组54例，全部为我院住院病人，根据病史、临床表现、B超或CT以及血清病毒标志物检测和肝功能检查等明确诊断，其中男46例，女8例，年龄25—71岁，平均53岁。Child A级病人10例，Child B级病人22例，Child C级病人22例；其中37例为失代偿期肝硬化患者，17例为代偿期肝硬化患者。PHC组32例，男26例，女6例；年龄29—72岁，平均56岁，均根据临床表现、血清AFP值、B超、CT或MRI、选择性肝动脉造影或组织学检查明确诊断，其中有远处转移者8例(占25％)，无远处转移者24例(占75％)。对照组32例，为我院门诊查体的健康体检者，男26例，女6例，平均56岁，所有入选病例均排除心、脑、肾、胃肠道、胰腺及内分泌系统的疾病，所有受试者于检查前两周内无应用对肝脏损害的药物史。三组间性别、年龄差异无显著性，具有可比性。测试者均
中文摘要
于晨起7S时空腹抽取肘静脉血5nl，分离血清，置一80
℃冰箱保存待测；检测前于室温完全复溶后，采用放射免
疫分析法测定血清中 IGF刁、EGF和 TGF a的含量。
结果：1．LC组血清＊F－11、TGF Q和 EGF水平分别为
0．58士0．20 ng／ml、5．99士1．91pg加 和 SSI．79土
185．06 pg／ml，明显高于正常对照组（0．43士0．14ng／ml，p
＜0．01：4．96士1．55阴／M，p＜0．05：398．％士厂2．51
Pg／gi，Prto．of）。PHC组血清 IGF－11、TGF Q和 EGF分另
为 0．78士 0．23ng／ml、7．34士 1．S6pg加 和 809．85士
224．23pg／ml，显著高于LC组禾对照组（p＜0．01）。2．LC
组血清 IGF－11水平与白蛋白、A／G 呈负相关（r＝一
0．446，P＜0．01；P＝一 0．437，P＜0．001），与 PT 延长。
Child－pugh 评分呈正相关（r＝0．49，n＜0．01；r＝0．33，
p（．05），而与从T、AST、TB无明显相关性（p＞0．05）。血
清 TGF Q水平与 ALT、AST、TB、A、A／G、PT 延长及
Ch if d－Pllgh评分无明显相关性（P＞0．05）。血清EGF水平
与TB、PT 延长及Ch if d－pllgh 评分呈正相 关
（r＝0．286，P＜0．05；r＝0．275，P＜0．05： r＝0．392，P＜0．01），
与 ALT、AST、A、A／G无明显相关性（P＞0．05）。3．LC
组血清 IGF－11、TGF Q 和 EGF水平有如下趋势：Child A
组wtChild B组wtChild C组，血清KF一11和 EGF水平与
＊n＊PU吵分级相关，差异具有显著性（p＜．05），但血清
TGF a水平在各组间比较差异无显著性（P＞0．05）。4．PHC
组血清IGF－11 水平与AFP 呈 明 显正相 关
（r＝0．878，p＜0．01），而 TGF a、EGF与 AFP无明显相关性
（p＞0．05）。AFP＞400fig／L 为阳性，以估计95％正常参考
2
中文摘要
值范围的上限为界值，根据公式肚1．6455计算出血清
IGF－11、TGF a和 EGF的界值分别为 0．66ng／ml、7．51Pg／。l
和 682．61Pg／ml，大于等于此界值者为阳性，， 于此界值
者为阴性，AFP、IGF－11、TGF Q和 EGF卜性率分别为 19／32
例（59．4q）、22／32 例（68．8％）、15／32 例（46．9％）及
22亿2例 u8．8们，经卡方检验四者阳性率无显著差别
（X‘＝4．332，P＞0．05）；在13 例AFP阴性叫C中，IGF－11
阳性4例（占30．S们。PHC思者中，有远处转移者血清
TGF a含量为 8．75士 1．59ng加 明显高于无远处转移者
6．87士 1．73pg／ml（上＝．699，p＜0．05），两组血清 IGF－11
和 EGF的水平无显著差异（P＞0．05）。5．各组内血清 IGF－
11、TGF Q和 EGF的直线相关分析：在对照组、LC组和 PHC
组内血清兀F－11、TGF Q禾 EGF间做两两相关分析，发现
IGF－11、TGF Q禾 EGF 在各组间 皆无明显的相 关性
（P＞0．05）。
结论：本研究结果表明：1．在r患者血清1肛刁1、
TGF a和 EGF水平明显高于对照组，且血清＊F－JI和 EGF
水平与反映肝功能的生化指标及Ch if d干ugh分级密切相
关，证实血清 IGF刁1、TGF Q和 EGF的检测对于肝硬化的
诊断、病情监测及预后估计有一定的临床意义。2．在PHC
患者，血清＊F－11、TGF a和 EGF水平明显高于＊ 组和
对照组，血清mF刁水平与MP呈正相关，而且在AFP
阴性肝癌中血清 IGF刁亦有较高的阳性率。血清 TGF a水
平在有远处转移的患者明显高于无远处转移者。因此，血
清uF－11、TGF Q牙 EGF配合吓P检狈对于监测癌前状态
Objective: To explore the action of IGF- II ,TGF a and EGF in liver cirrhosis and primary hepatocellular carcinoma. We evaluated serum levels of IGF- II ,TGF a and EGF in the patients with liver cirrhosis and primary hepatocellular carcinoma and studied the relationship among serum levels of IGF- II ,TGF a , EGF and some biochemical parameters reflecting the severity of hepatic function. We preliminarily explored the relationship among the serum levels of IGF-II ,TGF a and EGF .
Methods: 54 hospitalizing patients with liver cirrhosis (46 men and 8 women, aged 25-71 years, average age 53 years), 32 patients with primary hepatocellular carcinoma(26 men and 6 women, aged 29-72 years, average age 56 years) and 32 sex, age-matched healthy subjects(26 men and 6 women, aged 29-72years, average age 56 years) were included in the present study. The diagnosis of liver cirrhosis had been made on the basis of clinical ,biochemical and serological parameters using standard techniques including ultrasound and computed tomography. 10 patients were assessed as Child A stage, 22 Child B stage and 22 Child C
stage. Cirrhosis was decompensated in 37, compensated in 17 patients. Primary hepatocellular carcinoma (PHC) was confirmed on clinical grounds including serum a-fetoprotein(AFP) and findings of ultrasonography, computed tomography, magnetic resonance imaging, angiography and /or histopathology. PHC patients with distant metastasis were in 8(25%), without distant metastasis were in 24(75 %). All subjects had no other diseases and did not take the medicine which could produce acute liver damage . Venous blood samples were drawn after an overnight fast at 7-8 AM, centrifuged and then serum was stored at -80 癈 until assayed. The levels of IGF-II,TGF a and EGF in blood were determined by radioimmuno-assay(RIA) after complete recovery.
Results : 1. In cirrhotic group, the serum levels of IGF-II (0.58 ?0.20ng/ml), TGF a (5.99 ?1.91pg/ml)and EGF(581.79?88.06pg/ml) was higher than that in control group(p<0.01, p<0.05, p<0.01). The serum levels of IGF-II,TGF a and EGF in patients with PHC(0.78?.23ng/ml, 7.34 ?1.86pg/ml and 809.85 ?224.23pg/ml respectively) were much significantly higher than that in cirrhotic group and control group(p<0.01). 2. In cirrhotic group, a negative correlation was found between IGF- II and albumin, A/G(r=-0.446, p<0.01; r=-0.437, pO.OOl). A positive correlation was obtained between IGF- II and prothrombin time(PT) and Child-Pugh score (r=0.49,p<0.01;r=0.33,
p<0.05). there was no significant correlation between TGF a and ALT, AST, total bilirubin(TB), albumin, A/G, PT and Child-Pugh score(p>0.05). serum EOF levels in LC exhibited a significant positive correlation with total bilirubin , prothrombin time and Child-Pugh score (r=0.286, p<0.05; r=0.275, PO.05; r=0.392, p<0.01). 3. In cirrhotic group, the serum levels of IGF- II ,TGF a and EGF had a trend, that is, Child A
Conclusion: In this study, we found that: 1. The levels of IGF- II ,TGF a and EGF in blood of patients with liver cirrhosis were higher
引文
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24．汤钊猷．肝癌临床研究的进展与21世纪的展望．上海医科大学学报，1997，24：323-326
25．饶盖平．表皮生长因子及受体与肝脏再生．国外医学生理病理科学与临床分册，1991，3：132-135
26.Audust BC, Bauer J, Gerok W. Effect of cytokines on the liver. Hepatology, 1991, 12:364-370
27.Komuves LG, Feren A, Jones AL,et al. Expression of epidermal growth factor and its receptor in cirrhotic liver disease. J-Histochem-Cytochem, 2000, 48:821-830
28．罗家齐，陈淑清，任春江等．人表皮生长因子含量变化与肝病关系的研究．宁夏医学杂志，1999，21：67-68
29.Hung WC, Chuang LY, Tsai JH, et al. Effect of epidermal growth factor on growth control and signal transduction pathways in different human hepatoma cell lines. Biochem Mol Bio Int, 1993, 30:319-327
30.Motoo Y, Sawabu N, Nakanuma Y. Expression of epidermal growth factor and fibrobrast growth factor in human hepatocellular carcinoma: Immunohisto- chemical study. Liver, 1991, 11:272-277
31．韩燕萍，苏勤，刘彦仿．肝癌培养细胞中胰岛素样生长因子Ⅱ的表达．第四军医大学学报，1992，13：84-87
32.Wu JC, William HD, Lee SD, et al. Radioimmunoassay of serum IGF-Ⅰ and IGF-Ⅱ in patients with chronic liver disease and hepatocellular carcinoma with or without hypoglucemia. J Lab Clin Med, 1988, 112:589-594
33.Tetsuro S, Seichiro K, Kaoru I. Immunohistochemical evidence of IGF2 in human small hepatocellular carcinoma with hepatitis C virus infection: relationship to fatty change in carcinoma cells. J Gastroenterol Hepatol,1997, 12:224-228
34．惠宏襄，金明，赵小宁等．转化生长因子α．国外医学分子生物学分册，1994，16：254-258
35.Derynck R. Transforming growth factor α Cell,1988, 54:593-595
36.Angervo-M. Epidermal growth factor enhances insulin-like growth factor binding protein-1 synthesis in human hepatoma cells. Biochem Biophys Res Commun, 1992, 189:1177-83
37.Tanaka S, Takenaka K, Matsumata T, et al. Hepatitis C virus replication is associated with expression of transforming growth factor-a and insulin-like growth factor-Ⅱ in cirrhotic livers. Dig Dis Sci, 1996, 41:208-215
38.Wu JC, Merlino G, Cveklova K, et al. Autonomous
growth in serum-free medium and production of hepatocellular carcinomas by differentiated hepatocyte lines that overexpress transforming growth factor alpha 1 . Cancer Res, 1994, 54: 5964-5973
39． Strazzabosco-M, Poci-C, Spirli-C,et al. Intracellular pH regulation in Hep G2 cells: effects of epidermal growth factor, transforming growth factor-alpha, and insulinlike growth factor-II on Na+/H+ exchange activity. Hepatology, 1995, 22: 588-597