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Liver allograft functional reserve estimated by total asialoglycoprotein receptor amount using tc-GSA liver scintigraphy
DONOR–GRAFT FACTORS
Liver Allograft Functional Reserve Estimated by Total Asialoglycoprotein Receptor Amount Using Tc-GSA Liver Scintigraphy Y. Kita, K. Miki, S. Hirao, Y. Inoue, T. Ohtake, A. Matsukura, N. Aoyanagi, A. Saiura, Y. Harihara, T. Takayama, K. Kubota, H. Kawarasaki, K. Hashizume, and M. Makuuchi
T
HE NUMBER of asialoglycoprotein receptors (ASGP-R) on the hepatocellular membrane decreases in patients with chronic liver diseases. When their ASGP metabolism is impaired, their serum ASGP levels increase as a result.1 Recent studies have shown that liver scintigraphy using technetium-99m galactosyl-human serum albumin (Tc-GSA), which specifically binds to the ASGP-R on the hepatocellular membrane, is a novel method for assessing functioning hepatocyte mass for preoperative assessment for hepatectomy.2–5 Since liver allografts are affected by many kinds of chronic immunologic attacks, such as recurrent or acquired hepatitis, chronic rejection, and recurrence of original diseases, estimation of graft functional reserve by conventional liver function tests is quite difficult. Therefore, we studied the liver allograft functional reserve in liver transplant recipients using Tc-GSA scintigraphy with a newly developed model evaluating total receptor amount (Rtotal).6
PATIENTS AND METHODS Seven liver transplant recipients (average age at transplant; 38 years old [range 17 to 60], average posttransplant time; 4 years and 6 months [range 1 year 1 month to 9 year 3 months], gender; 4 male and 3 female) underwent Tc-GSA liver scintigraphy at University
From the Liver Transplant Team (Y.K., K.M., A.M., N.A., A.S., Y.H., T.T., K.K., H.K., K.H., M.M.) and Department of Radiology (Y.I., T.O.), Faculty of Medicine, University of Tokyo, Tokyo, Japan, Medical Equipment Section (S.H.), Medical Business Department, Sumitomo Metal Industries, Ltd., Tokyo, Japan. This work was supported in part by a Grant-in-aid from the Ministry of Education, Culture, and Science, Japan (Grant No (A)(2) 08407036) and the Kanae Foundation of Research for New Medicine. Address reprint requests to Dr Y. Kita, Second Department of Surgery, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan.
Table 1. Liver Allograft Functional Reserve Estimated by Tc-GSA Liver Scintigraphy Case
Disease
Age at Tx
Time after Tx
HH15
LHL15
Rtotal
1 2 3 4 5 6 7
LC-C* 1 HCC LC-C* LC-C* LC-B* BA PSC* PSC*
45 60 58 43 18 25 17
1y 8m 3y 4m 8y 2m 7y 1y 1m 1y 2m 9y 3m
0.547 0.541 0.613 0.685 0.536 0.655 0.722
0.901 0.940 0.896 0.847 0.935 0.897 0.850
0.338 0.230 0.211 0.187 0.256 0.141 0.127
Tx: transplantation, #: without recurrent disease, *: with recurrent disease, y: years, m: months, LC-B: liver cirrhosis associated with hepatitis B virus, LC-C: liver cirrhosis associated with hepatitis C virus, HCC: hepatocellular carcinoma, BA: biliary atresia, PSC: primary sclerosing cholangitis.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)01027-6
Transplantation Proceedings, 30, 3277–3278 (1998)
3277
3278 of Tokyo Hospital. Original disease distribution was three liver cirrhosis associated with hepatitis C (LC-C), one liver cirrhosis associated with hepatitis B (LC-B), two primary sclerosing cholangitis (PSC), and one biliary atresia (BA) (Table 1). Total amount of ASGP-R, Rtotal, was calculated by the newly developed compartment model described by Miki et al.6 These data were compared with other liver function tests (serum AST, ALT, g-GTP, ALP, choline esterase, total protein, albumin, total bilirubin, and total cholesterol) and markers of liver fibrosis (serum hyaluronic acid and type IV collagen).
RESULTS
Three liver recipients with LC-C showed a mild decrease in hepatic functional reserve while the recipient with LC-B showed a marked decrease in hepatic functional reserve. The recipient with BA also showed a mild decrease in hepatic functional reserve while two recipients with recurrent PSC showed a marked decrease in hepatic functional reserve (Table 1). The values of Rtotal correlated significantly with serum g-GTP (r 5 0.82, P , .01) and ALP (r 5 20.67, P , .05) values, but not with other liver function tests or markers of hepatic fibrosis. Histologic findings of the liver biopsy (severity of periportal fibrosis) seemed to be correlated well with the Rtotal. In cases 4, 6, and 7 periportal fibrosis was severe due to recurrent hepatitis B or recurrence of PSC. In those cases, the values of Rtotal were lower than other cases with mild periportal fibrosis. DISCUSSION
Patients with chronic hepatitis or liver cirrhosis are less tolerant of extensive hepatectomy. With liver surgery, preoperative assessment of hepatic functional reserve is important for estimating the extent of hepatectomy. Although the indocyanine green (ICG) clearance test is a widely accepted method to assess the hepatic functional reserve, discrepancies between the ICG retention rate at 15 minutes (ICGR15) and histologic findings of the liver are often seen. These differences are thought to depend mainly on the effective hepatic blood flow and intra- and extrahepatic shunts. Kudo et al2 reported that the hepatic uptake ratio was strongly representative of hepatocellular function in patients with a large portocaval shunt (ie, decreased hepatic
KITA, MIKI, HIRAO ET AL
blood flow). In these patients, values obtained from TcGSA scintigraphy reflected the histologic hepatic damage better than ICGR15. The newly developed method by Miki et al6 is useful for measuring ASGP-R amount and hepatic blood flow simultaneously based on the dynamic images and reflects the cellular transport of ASGP and the ASGP-R recycling mechanism. Therefore Tc-GSA scintigraphy using this method may provide unique information for evaluating hepatic allograft functional reserve and severity of chronic inflammation. In the present study only serum g-GTP and ALP correlated with Rtotal. This might lend support to the contention that long-term liver allograft damage is mainly caused by “chronic cholestatic condition.” CONCLUSION
The value of Rtotal in Tc-GSA scintigraphy may be a useful parameter to evaluate liver allograft functional reserve and severity of chronic inflammation in the allograft. Further study is needed using sequential determination of Rtotal in recipients with various original liver diseases. ACKNOWLEDGMENTS We gratefully thank the following doctors for their cooperation in this study: Yuichi Andoh and Yoshifumi Beck (Department of Surgery and Transplantation, Institute of Medical Science, University of Tokyo, Tokyo), Satoshi Teraoka (Department of Surgery, Kidney Center, Tokyo Women’s Medical College, Tokyo), Kazuhiko Yokota (Department of General Surgery, JR Tokyo General Hospital, Tokyo), Takeyuki Nakajima (Department of Gastroenterology, Inasa Red Cross Hospital, Shizuoka), and Hiroshi Kashida (Department of Gastroenterology, Kobe City General Hospital, Kobe)
REFERENCES 1. Sawamura T, Nakada H, Hazama H, et al: Gastroenterology 87:1217, 1984 2. Kudo M, Todo A, Ikekubo K, et al: Am J Gastroenterol 87:865, 1992 3. Kudo M, Todo A, Ikekubo K, et al: Hepatology 17:814, 1993 4. Wu J, Ishikawa N, Takeda T, et al: J Nucl Med 9:229, 1995 5. Kwon A, Ha-Kawa SK, Uetsuji S, et al: Hepatology 25:426, 1997 6. Miki K, Kubota K, Kokudo N, et al: J Nuc Med 38:1798, 1977
Liver Allograft Functional Reserve Estimated by Total Asialoglycoprotein Receptor Amount Using Tc-GSA Liver Scintigraphy Y. Kita, K. Miki, S. Hirao, Y. Inoue, T. Ohtake, A. Matsukura, N. Aoyanagi, A. Saiura, Y. Harihara, T. Takayama, K. Kubota, H. Kawarasaki, K. Hashizume, and M. Makuuchi
T
HE NUMBER of asialoglycoprotein receptors (ASGP-R) on the hepatocellular membrane decreases in patients with chronic liver diseases. When their ASGP metabolism is impaired, their serum ASGP levels increase as a result.1 Recent studies have shown that liver scintigraphy using technetium-99m galactosyl-human serum albumin (Tc-GSA), which specifically binds to the ASGP-R on the hepatocellular membrane, is a novel method for assessing functioning hepatocyte mass for preoperative assessment for hepatectomy.2–5 Since liver allografts are affected by many kinds of chronic immunologic attacks, such as recurrent or acquired hepatitis, chronic rejection, and recurrence of original diseases, estimation of graft functional reserve by conventional liver function tests is quite difficult. Therefore, we studied the liver allograft functional reserve in liver transplant recipients using Tc-GSA scintigraphy with a newly developed model evaluating total receptor amount (Rtotal).6
PATIENTS AND METHODS Seven liver transplant recipients (average age at transplant; 38 years old [range 17 to 60], average posttransplant time; 4 years and 6 months [range 1 year 1 month to 9 year 3 months], gender; 4 male and 3 female) underwent Tc-GSA liver scintigraphy at University
From the Liver Transplant Team (Y.K., K.M., A.M., N.A., A.S., Y.H., T.T., K.K., H.K., K.H., M.M.) and Department of Radiology (Y.I., T.O.), Faculty of Medicine, University of Tokyo, Tokyo, Japan, Medical Equipment Section (S.H.), Medical Business Department, Sumitomo Metal Industries, Ltd., Tokyo, Japan. This work was supported in part by a Grant-in-aid from the Ministry of Education, Culture, and Science, Japan (Grant No (A)(2) 08407036) and the Kanae Foundation of Research for New Medicine. Address reprint requests to Dr Y. Kita, Second Department of Surgery, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan.
Table 1. Liver Allograft Functional Reserve Estimated by Tc-GSA Liver Scintigraphy Case
Disease
Age at Tx
Time after Tx
HH15
LHL15
Rtotal
1 2 3 4 5 6 7
LC-C* 1 HCC LC-C* LC-C* LC-B* BA PSC* PSC*
45 60 58 43 18 25 17
1y 8m 3y 4m 8y 2m 7y 1y 1m 1y 2m 9y 3m
0.547 0.541 0.613 0.685 0.536 0.655 0.722
0.901 0.940 0.896 0.847 0.935 0.897 0.850
0.338 0.230 0.211 0.187 0.256 0.141 0.127
Tx: transplantation, #: without recurrent disease, *: with recurrent disease, y: years, m: months, LC-B: liver cirrhosis associated with hepatitis B virus, LC-C: liver cirrhosis associated with hepatitis C virus, HCC: hepatocellular carcinoma, BA: biliary atresia, PSC: primary sclerosing cholangitis.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)01027-6
Transplantation Proceedings, 30, 3277–3278 (1998)
3277
3278 of Tokyo Hospital. Original disease distribution was three liver cirrhosis associated with hepatitis C (LC-C), one liver cirrhosis associated with hepatitis B (LC-B), two primary sclerosing cholangitis (PSC), and one biliary atresia (BA) (Table 1). Total amount of ASGP-R, Rtotal, was calculated by the newly developed compartment model described by Miki et al.6 These data were compared with other liver function tests (serum AST, ALT, g-GTP, ALP, choline esterase, total protein, albumin, total bilirubin, and total cholesterol) and markers of liver fibrosis (serum hyaluronic acid and type IV collagen).
RESULTS
Three liver recipients with LC-C showed a mild decrease in hepatic functional reserve while the recipient with LC-B showed a marked decrease in hepatic functional reserve. The recipient with BA also showed a mild decrease in hepatic functional reserve while two recipients with recurrent PSC showed a marked decrease in hepatic functional reserve (Table 1). The values of Rtotal correlated significantly with serum g-GTP (r 5 0.82, P , .01) and ALP (r 5 20.67, P , .05) values, but not with other liver function tests or markers of hepatic fibrosis. Histologic findings of the liver biopsy (severity of periportal fibrosis) seemed to be correlated well with the Rtotal. In cases 4, 6, and 7 periportal fibrosis was severe due to recurrent hepatitis B or recurrence of PSC. In those cases, the values of Rtotal were lower than other cases with mild periportal fibrosis. DISCUSSION
Patients with chronic hepatitis or liver cirrhosis are less tolerant of extensive hepatectomy. With liver surgery, preoperative assessment of hepatic functional reserve is important for estimating the extent of hepatectomy. Although the indocyanine green (ICG) clearance test is a widely accepted method to assess the hepatic functional reserve, discrepancies between the ICG retention rate at 15 minutes (ICGR15) and histologic findings of the liver are often seen. These differences are thought to depend mainly on the effective hepatic blood flow and intra- and extrahepatic shunts. Kudo et al2 reported that the hepatic uptake ratio was strongly representative of hepatocellular function in patients with a large portocaval shunt (ie, decreased hepatic
KITA, MIKI, HIRAO ET AL
blood flow). In these patients, values obtained from TcGSA scintigraphy reflected the histologic hepatic damage better than ICGR15. The newly developed method by Miki et al6 is useful for measuring ASGP-R amount and hepatic blood flow simultaneously based on the dynamic images and reflects the cellular transport of ASGP and the ASGP-R recycling mechanism. Therefore Tc-GSA scintigraphy using this method may provide unique information for evaluating hepatic allograft functional reserve and severity of chronic inflammation. In the present study only serum g-GTP and ALP correlated with Rtotal. This might lend support to the contention that long-term liver allograft damage is mainly caused by “chronic cholestatic condition.” CONCLUSION
The value of Rtotal in Tc-GSA scintigraphy may be a useful parameter to evaluate liver allograft functional reserve and severity of chronic inflammation in the allograft. Further study is needed using sequential determination of Rtotal in recipients with various original liver diseases. ACKNOWLEDGMENTS We gratefully thank the following doctors for their cooperation in this study: Yuichi Andoh and Yoshifumi Beck (Department of Surgery and Transplantation, Institute of Medical Science, University of Tokyo, Tokyo), Satoshi Teraoka (Department of Surgery, Kidney Center, Tokyo Women’s Medical College, Tokyo), Kazuhiko Yokota (Department of General Surgery, JR Tokyo General Hospital, Tokyo), Takeyuki Nakajima (Department of Gastroenterology, Inasa Red Cross Hospital, Shizuoka), and Hiroshi Kashida (Department of Gastroenterology, Kobe City General Hospital, Kobe)
REFERENCES 1. Sawamura T, Nakada H, Hazama H, et al: Gastroenterology 87:1217, 1984 2. Kudo M, Todo A, Ikekubo K, et al: Am J Gastroenterol 87:865, 1992 3. Kudo M, Todo A, Ikekubo K, et al: Hepatology 17:814, 1993 4. Wu J, Ishikawa N, Takeda T, et al: J Nucl Med 9:229, 1995 5. Kwon A, Ha-Kawa SK, Uetsuji S, et al: Hepatology 25:426, 1997 6. Miki K, Kubota K, Kokudo N, et al: J Nuc Med 38:1798, 1977