Diagnostic Efficacy of Plasma Urokinase-type Plasminogen Activator and Plasminogen Activator Inhibitor-2 in Differentiation of Hepatocellular Carcinoma from Cirrhosis

Summary

We determined the plasma antigen levels of urokinase-type plasminogen activator(u-PA) and plasminogen activator inhibitor 2(PAI-2) in 41 patients with hepatocellular carcinoma and 28 patients with different stages of liver cirrhosis. No significant differences of u-PA and PAI-2 levels were calculated between the two groups of tumor patients (HCC) and liver cirrhosis without tumor (non-HCC).Within both study groups, no significant differences were found in u-PA and PAI-2 levels of the different Child categories. Discriminative functions of both u-PA and PAI-2 (total error count estimates of 43.1% and 43.6%, respectively), were low compared to that (29.0%) of alpha-fetoprotein (AFP). The combinations of AFP and u-PA lowered the total error rate (21.9%) more than that of each marker alone. However, whether plasma u-PA and PAI-2 may be considered as a risk factor further investigation was needed and our findings raise the question as to whether these markers could be considered as useful screening markers for earlier detection of HCC in liver cirrhosis because discriminant functions of u-PA and PAI-2 were not significant.

Sensitivities and specificities of u-PA and PAI-2 were also not high enough, resulting in the ranges of total diagnostic efficiency from 43% to 50%, and, from 49% to 63% , respectively, at different cut-off values. No direct relationship was detected between AFP and u-PA, between AFP and PAI-2, and between u-PA and PAI-2.

• References

• 1 Colombo M, De Franchis R, Ninno ED, Sangiovanni A, De Fazio C, Tommasini M, Donato MF, Piva A, Di Carlo V, Dioguardi N. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991; 325: 675-680
• 2 Bisceglie AM, Rustgi VK, Hoofnagle JH, Dusheiko GM, Lotze MT. Hepatocellular carcinoma. Ann Intern Med 1988; 108: 390-401
• 3 Barlow GH, Firestone SL, Robbins KS. Identification of the plasminogen activator(s) produced by the transformed liver cell line, SK-HEP-1. Thromb Res 1982; 32: 29-34
• 4 Corti A, Nolli ML, Soffientini A, Cassani G. Purification and characterization of single chain urokinase-type plasminogen activator (prourokinase) from human A431 cells. Thromb Haemost 1986; 56: 219-224
• 5 Markus G, Gamiolo SM, Kohga S, Madeja S, Mittelman A. Plasminogen activator secretion of human tumors in short-term organ culture: comparison of primary and metastatic colon tumors. Cancer Res 1983; 43: 5517-5525
• 6 Kirchheimer JC, Huber K, Polterauer P, Binder HR. Urokinase antigen in plasma of patients with liver cirrhosis and hepatoma. Thromb Haemost 1985; 54: 617-618
• 7 Kirchheimer JC, Huber K, Wagner O, Binder BR. Pattern of fibrinolytic parameters in patients with gastrointestinal carcinomas. Br.J Haematol 1987; 66: 85-89
• 8 Kruithof FK O, Gudinchet A, Bachmann F. Plasminogen activator inhibitor I and plasminogen activator inhibitor 2 in various disease states. Thromb Haemost 1988; 59: 7-12
• 9 Lecander I, Astedt B. Occurrence of a specific plasminogen activator inhibitor of placental type, PAI-2 in men and non-pregnant women. Fibrinolysis 1989; 3: 27-30
• 10 Pugh RN N, Murray-Lyon IM, Dawson JC, Petroni MC, Williams A. Transection of the oesophagus for bleeding oesophageal varices. Brit J Surg 1973; 60: 646-649
• 11 Sokal RR, Rohlf FJ. Multiple and curvilinear regression. In: Biometry. Sokal RR, Rohlf FJ. Second editon eds W. H. Freeman and Company; New York, NY: 1981. pp 683-685
• 12 Liam YF, Tai DL, Chu CM, Lin DY, Sheen IS, Chen TJ, Pao CC. Farly detection of hepatocellular carcinoma in patients with chronic type B hepatitis. Gastroenterology 1986; 90: 263-267
• 13 Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, Nakajima Y, Ohnishi K. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Cancer 1985; 56: 918-928
• 14 Huber K, Kirchheimer JC, Binder BR. Characterization of a specific antihuman urokinase antibody: development of a sensitive competition radioimmunoassay for urokinase antigen. J Lab Clin Med 1984; 103: 684-694
• 15 Huber K, Kirchheimer JC, Ermler D, Bell C, Binder BR. Determination of plasma urokinase-type plasminogen activator antigen in patients with primary liver cancer: Characterization as tumor-associated antigen and comparison with alpha-fetoprotein. Cancer Res 1992; 52: 1717-1720
• 16 Huber K, Kirchheimer JC, Korninger C, Binder BR. Hepatic synthesis and clearance of components of the fibrinolytic system in healthy volunteers and in patients with different stages of liver cirrhosis. Thromb Res 1991; 62: 491-500
• 17 Hanss M, Bonvoisin C, Patouillard B, Martin T, Audigier JC, Descos L, Dechavanne M. Increased plasma levels of urokinase type plasminogen activator during hepatocellular carcinoma. Fibrinolysis 1994; 8: 255-260
• 18 Astedt B, Lecander I, Brodin T, Lundblad A, Low K. Purification of a specific placental plasminogen activator inhibitor by monoclonal antibody and its complex formation with plasminogen activator. Thromb Haemost 1985; 53: 122-125
• 19 Kawano T, Morimolo K, Uemura Y. Partial purification and properties of urokinase inhibitor from human placenta. J Biochem 1970; 67: 333-342
• 20 Saksela O, Hovi T, Vaheri A. Urokinase-type plasminogen activator and its inhibitor secreted by cultured human monocyte-macrophages. J Cell Physiol 1985; 122: 125-132
• 21 Lindoff C, Lecander I, Astedt B. Fibrinolytic components in individual consecutive plasma samples during normal pregnancy. Fibrinolysis 1993; 7: 1990-1994
• 22 Scherrer A, Kruithof EKO, Grob JP. Plasminogen activator inhibitor-2 in patients with monocytic leukemia. Leukemia 1991; 5: 479-486
• 23 Tran-Thang C, Fasel-Felley J, Pralong G, Hofstetter JR, Bachmann F, Kruithof EKO. Plasminogen activators and plasminogen activator inhibitors in liver deficiencies caused by chronic alcoholism or infectious hepatitis. Thromb Haemost 1989; 62: 651-653