Fung, JJ

Gordon, RD

Iwatsuki, S

Starzl, TE

Staschak, SM

Stieber, A

Todo, S

Tzakis, AG

English

PubMed

Name not available

Liver transplantation under cyclosporine: A decade of experience

D-Scholarship@Pitt

.... ----------------------/ /{(; Liver Transplantation Under Cyclosporine: A Decade of Experience R.D. Gordon. S. Todo. A.G. Tzakis. J.J. Fung. A. Stieber. S.M. Staschak. S. Iwatsuki and T.E. Starn As we entered the decade of the 1980s. liver transplan-tation was not a therapeutic option considered for many patients with end stage liver disease. Although limited success had been achieved in a few centers with immunosuppression based on azathioprine. steroids. and polyclonal antibody preparations. patient survival rates were approximately PR~ at I year and less than ~ at 5 years. By the end of the decade a remarkable change had taken place. and transplantation is now the therapeutic option of choice for many patients with irreversible end stage liver disease. We here review our experience over most of the last decade with liver transplantation under cyclosporine· prednisone induction and maintenance therpy at the University of Pittsburgh. MATERIALS AND METHODS The liver transplantation program at the University of Pittsburgh began in 1981. In the year.; from 1981 to 1989. 2.395 li .. er grafts were transplanted after total hepatectomy into 1.819 recipients in the conventional onhotopic approach (Fig I). Of these. ~:!9 grafts in 1583 patients were performed using cyclosporine-prednisone induction and maintenance therapy. Since 1984 we have used OKT3 (Orthoclone OKT-38 • Onho Pharmaceuticals. Raritan. NJ, for treatment of steroid-resistant rejection. A computer registry has been maintained since 1983 to track outcome in all graft reci~nts and the records for the complete series of 1.583 patients ~ere reviewed. I Variables included in the analysis are age at the time of transplantation. ABO blood group. body weight. primary her disease. graft survi,,·a1. and patient survival. In addition. since October 1987. patients have been classified for medical urgency according to the required level of medical care. Descriptive statistics were determined using SPSS/PC + version ~r----------------------------------D • Primary FK 506 (n = 89) 400 • Rescued with FK506 (n = 147) ! 0 eyA (n = 1.583) !300 ~ ~ 200 100 1981 1982 1983 19&4 1985 1986 1987 1988 1989 fig 1. Primary liver tnnplantations per calendar year at the University of Pittsburgh between 1981 and 1989 induding 1583 patients done under cydosporine-prednisone ~K 147 pa-tients whose grafts were rescued by conversion to FK 506. and 89 patients treated with primary induction and maintenance with FK 506. 3.1 (SPSS Inc .. Chicago. III) and survival analysis was performed using BMDP/PC (1988 version. BMDP Statistical Soft'A'are. Los Angeles. CaliO on an Intel 80386 based microcomputer running MS-OOS 4.01 (Microsoft Corporation. Bellevue. Wash). !! j i ~ .!!! • 0. 500 • MALE (n • 7691 ~ • FEMALE (n. 814) 300 200 100 O.l..J_ ..... _ .... • 1981 1982 1983 1984 1985 1986 1987 1988 1989 RMM~--------------------------------~ =:1 Seniors (127) 400 0 Aduns (998) • Adolescents (56) • Children (26n • Infants (135) 100 o K~_""D=ligf="" 1881 1982 1983 1984 1885 1986 1987 1988 1989 I ~ • -""* 300 K}cD~ .... --------200 ;D"F~c:arnKK K~--K~~ 100 u_-198' 1912 1983 1984 1985 1986 1987 1988 1989 c fig 2. Primary transplantations per calendar year according to (A) sex, (8) age group. and (e) primary liver disease. See Table 1 10f' definition of age groups. From the Depar1ment of Surgery. University HeaIh Center of Piftsburgh. University 01 Pittsburgh, and the Veterans Administra· tiOn Medical Center. Pittsburgh, Pennsylvania. This work was supported by research grants from the Veterans Administration and project grant OK 29961 from !he National Institutes of Health, Bethesda. Maryland. Address repri1t requests to Robert 0_ Gordon. MD. Department of Surgery. University Health Center of Pittsburgh. University of PilIsburgh.3601 Fifth Ave. Pittsburgh. PA 15213. C 1991 by Appleton & Lange 0041-13451911$3.001 + 0 Transplantation ProcsetItrgs. VO/23, No 1 (February).. 1991: pp 1393-1396 1393 1394 GORDON. TOOO. TZAKIS ET ....... Table 1. Pen:enI PatIent Survival According to Age and Weight at Time of Transplantation" Aqe E~rsF 1\1 , month 6 :!7IOnI'a 1 year 2 years 3 years 4 years R~ Infant under 2 135 81.5 66.7 Child 2to 11 2fi7 87.3 76..0 Adolescent 12 to 17 5E 82.1 7'.4 Adult 18 to 59 998 89.7 76.3 Senior over 60 127 86.6 71.7 Under 7 kg 5E 78.6 6&.3 7tol1kg 129 83.0 65. I 121019kg 149 89.3 n.9 20 to 39 kg S- 89.4 83..0 40 kg or more 973 90.0 n5 -Life table method. RESULTS As shown in Fig I. there has been a ~gnificant increase in the number of new patients receiving transplants through 1988. In 1989. we began converting te an immunosuppres-sive protocol based on the new dr'Jg FK 506. so the number of patients in the cyclosporine (Cy A) based group began to decline for the first time. Sex There were 769 (48.6%) males and 81-4 (51.4%) females in this series. There has been an increas.c in the proportion of males in the series in the last 2 yean 154.9% in 1988 and 54.59C in 1989. Fig 2A). This probably reflects a decrease in the proportion of transplantations performed at this center for cholestatic liver disease. especiall:- for primary biliaT) cirrhosis. which has a high prevalence In females (Fig 20. Age Groups There were 135 (8.5%) infants (age l,;nder 2 years). 26-;" (l6.Wc) children (age 2 to II years). 56 13.5%) adolescents (age 12 to 17 years). 998 (63.0%) adults • age 18 to 59 years). and 127 (8.0%) senior (over 60 years) recipients. The proportion of infants in the series has remained between 89C to 10% since 1985 (Fig 2B). Most ~gnificant has been the increase in the number and proportion of senior patients accepted in the program from 3.6% in 1985 to 14.79C in 1989 (Fig 2B). Body weight is related to age but may be a better measure of developmental status in children. Fifty-six (3.59C) of the recipients weighed less than 7 kg and 129 (8.19C) weighed 7 to II kg. Survival rates based on age group and body weight are 63.6 61.7 60 .• 58.3 RRK~ 73.8 71.4 70.5 68.8 68.-69.6 63.6 63.6 60.6 60e 73.7 69.0 66.4 64.2 62.8 69.3 66.0 61.9 61.9 56.9 52.2 48.6 48.6 41 e 64.3 63.4 62.3 60.8 60.5 74.5 71.6 71.6 68.8 67"7' 81.9 SO.8 78.0 76.1 TSK~ 75.0 70.6 68.3 65.9 63! shown in Table I. Survival rates for infants are 69<: to f~ lower at I year and 5% to 8% lower at 5 years than fOf" other age groups. Pediatric recipients under 12 kg bod\ weight have a 109C to 20% higher mortality than larg'; patients. Blood Groups Patient survival based on recipient ABO blood groups are summarized in Table 2. We have not observed a difference in survival based solely on recipient blood group. Primary liver Disease The most common indication for liver replacement in this series is post necrotic cirrhosis (432 patients. 27.39<:1 fol-lowed by cholestatic liver disease including primary biliary cirrhosis and primary sclerosing cholangitis 1324, 20.5%). biliary atresia (265. 16.7%). alcoholic cirrhosis (134. 8.59<: l. inborn errors of metabolism 032. 8.3%). primary hepato-biliary cancer (105. 6.6%). and fulminant hepatic failure 175. 4.7%). Patient survival based on primary liver disease is sum-marized in Table 3. The highest patient survival rates are seen in patients receiving liver grafts for inborn errors of metabolism. cholestatic liver disorders. postnecrotic cir-rhosis (excluding HBsAg+ patients). and alcoholic cirrho-sis. Since 1985 there has been a significant increase in the proportion of patients receiving liver grafts at this center for alcoholic cirrhosis (from 3.0% in 1985 to 15.6% in 1989. Fig IC). Patient follow-up is maintained by a skilled team of nurse clinicians who keep up regular contact with patients. their families. and community physicians. We recently surveyed 121 surviving patients who received Table 2. PeranI Patient Survival a-d on Recipient ABO Blood Group" N , month 15 months 1~ 2 years 3 years .. years 5 years 0 696.0 76.0 7".0 72.5 69.1 66.3 64.5 62.9 A 625.0 87.8 74.2 72.5 68.3 67.0 65.9 64.6 S 196.0 87.2 74.0 72.4 67.5 66.6 61.7 61.7 AS 66.0 87.9 71.2 69.6 63.9 58.6 55.0 55.0 'liIe !able method. e.,. 5. 3.1 J6 2.8 '6 ).8 7.7 ).1 8 l% or jy er -e :e IS I-y I. t. LIVER TRANSPLANTA T10N UNDER CVCLOSPORINE Table 3. Percent Patient Survlvel Based on Primary liver 01 ..... • N 1 monlh 6 months C/1C)Iestatic disorders 324 92.9 eo.3 fIoStr1eCI'otic cirrhosis T 359 88.0 77.4 AJcd10Iic cirrhosis 134 90.3 82.1 Bia'Y atresia 265 84.2 71.7 Neonatal hepatitis 7 85.7 71.4 MetabOlic disorders 132 88.6 75.8 Fumnanl failure 75 78.7 61.3 C/ln)nic hepatitis B 73 86.3 63.0 Pri'naI)' cancer 105 94.3 72.4 Autoimmune hepatitis 42 85.7 83.3 Budd-Chiari syndrome 24 79.2 66.7 Sec;ondaty biliary cirrhosis 25 68.0 56.0 1JIe Table method. '&ducing HBsAg+. grafts for alcoholic cirrhosis or for liver disease in which alcoholism was believed to be a significant contributing factor. Only 10 patients (S.3t;f) were known for certain to be actively drinking and 6 (5.0%) more patients were suspected to have resumed drinking. Thus. 105 patients (86.8t;f) were believed to be abstinent. This is consistent with the high survival rates seen after transplantation for alcoholic cirrhosis (80.6% at I year with 109 patients at risk and 75.1% at 2 years with 44 patients at risk). Lower survival rates are seen in patients receiving grafts for fulminant hepatic failure. chronic hepatitis B. and primary cancer. An interesting exception is the high sur-vival for the 15 patients who received transplants for fulminant hepatitis B (8Ot;f survival at I year and at 5 years. Table 4). Medical Urgency We recently summarized the experience in this center since the adoption of a national system for liver allocation in the United States. which places a heavy emphasis on medical urgency as measured by the level of medical support required by the patient waiting for a transplant. 2 Fig 3 presents a life table survival plot adapted from this report for 812 patients who received grafts under the UNOS point system between October 1987 and December 1989. There is a strong relationship (P < .(01) between medical condition of the patient classified in this manner and mortality after transplantation. Retransplantation Hepatic retransplantation in this series of patients will be the subject of a future report. In brief. of the 1583 patients 1 year 2 years 3 years 4 years 5 yeatS 77.8 75.7 74.3 72.2 71.1 76.0 73.0 70.7 69.6 67.4 eo.6 75.1 72.7 72.7 69.4 67.6 66.6 63.8 62.8 71.4 51.0 51.0 51.0 51.0 75.0 75.0 75.0 73.8 73.8 60.0 53.8 49.0 49,0 49.0 58.8 48.6 48,6 48.6 48.6 63.7 43.7 33.0 26.4 26.4 83.3 eo.4 eo.4 eo.4 66.7 66.7 54.6 54.6 54.6 51.9 51.9 51.9 51.9 51.9 in this series. as of June 30. 1990. 1216 received only one graft and 367 (24.0£it) had required at least one retransplan-tation. The primary nonfunction rate for the series of first grafts is 6.69C. The highest incidence of retransplantation is in patients who received their first graft for biliary atresia /28.0%) or for fulminant hepatic failure (27.5%). Lowest retransplantation rates are in patients receiving transplants for alcoholic cirrhosis (13.5%) and primary biliary cirrhosis (18.4%). DISCUSSION The experience reported here from this single large center and the accumulating experience in the multicenter regis-tries reported elsewhere in these proceedings.3 demon-strate the efficacy of liver transplantation for many forms of end stage liver disease. By 1985. it seemed evident from the first years of experience at this center with cyclospor-ine-prednisone induction and maintenance therapy. that survival rates after liver transplantation approaching 759C to 80% at I year and 65t;f to 7Wc could be achieved for many patients.· These initial expectations are confirmed \Ioith this extended experience in nearly 1600 patients. Certainly. for postnecrotic cirrhosis (excluding HBV car-riers). cholestatic liver disease. and inborn errors of me-tabolism. these results have stood the test of time. High success rates have been achieved in the patients given a transplant for fulminant hepatitis B. as these patients develop antibodies and remain immune from reinfection. Although most of the HBsAg+ patients trans-planted for post necrotic cirrhosis have remained virus carriers and many patients have developed detectable infection in the graft. there is still cause for optimism here. Teble 4. Pen:ant Patient Survlvel AfIIIr U"., Transpllntatlon for Acute or ChronIc Viral Hepmltls· N 1 month 6mon\hs 1 year 2 years 3 years 4 years 5 yellS Aorte non-A. non-B 32 84.4 68.8 68.8 58.7 SO.O SO.O SO.O CIvonic non-A. non-B 292 88.0 n.1 75.0 72.1 69.S 68.7 65.8 Acute hepatitis B 15 86.7 eo.O eo.O 80.0 eo.O eo.O eo.O CIvonic hepatitis B 73 86.3 63.0 58.8 48.6 48.6 48.6 48.6 1.Ie1able method. - ._----_ ..... _-_._-----------_._------------1396 100 iii K~ 80 2: 60 :s (I) 113 c:: o Out of hospital (135) Q) 40 i ~ Hospital bound (326) *' 20 • Inten$ive careJ190) • Extremely urgent (161) 0 o 6 12 24 McnIhs IIIIer transplantation Fig 3. Actuarial (life table) patient survival rates based on the level of medical care required by the recipient at the time of transplantation. too. Active and passive immunization and long-term ther-apy with interferon may result in seroconversion of HBsAg+ patients and we believe that significant further improvement in patient survival can and will be achieved. 5.6 Although survival after liver transplantation for infants and low body weight children is lower than for older or larger patients. improvement here is also beginning to be achieved. Improved methods of organ preservation with UW solution. which is believed to protect the microcircu-lation of the liver. has reduced the incidence of arterial thrombotic complications and thus the need for retrans-plantation. Increasing use of reduced liver grafts for small children increases the availability of organs for these patients and can help reduce the longer waiting times and consequent deterioration in their condition. Finally. rec-ognition of the added technical difficulty that results from prior surgery on infants and small children needing liver transplantation should encourage discretion in the use of alternative. less-effective surgical procedures. Liver transplantation for alcoholic cirrhosis has been controversial. 7 Our initial experience with this group of patients led us to adopt an aggressive approach. and the number of patients with this disease treated at our center has been increasing yearly. The extended results reported here support continuation of this policy. GORDON. TODO. TZAKIS ET ~ Survival after liver transplantation is related to the patient's condition at the time of transplantation. We have been able to achieve nearty 90% I-year survival in patients who are able to be transplanted before they become dependent upon in-hospital care. compared to only 65% to 70% survival in patients in the intensive care unit at the time of transplantation. This emphasizes the excellent results that can be achieved if patients have timely access to transplantation. Although efforts to ease the donor shortage must continue. it is equally important that pa-tients who are potential candidates for liver replacement be referred to the transplant center before they have deteriorated to the point where the prospects for survival have significantly diminished. Liver transplantation is no longer an option to be taken out of desperation. We continue to experience high recurrence rates after liver transplantation for hepatobiliary cancer. Additional treatment ..... ith adjuvant chemotherapy or radiotherapy in the preoperative. intraoperative, and postoperative phases of care are being studied in a effort to improve results. As we enter the decade of the 1990s. new therapeutic agents such as FK 506. rapamycin, deoxyspergualin. and other agents may find widespread application in clinical transplantation. The results achieved during the last dec-ade with cydosporine-prednisone therapy have provided a new standard against which results with these new agents will be compared. REFERENCES 1. Markus BH. Mitchell S. Gordon RD. et al: Transplant Proc 20:385. 1988 2. Gordon RD. HannerCM. Casavilla A. et al: Transplantation (in press' 3. Gordon RD. Bismuth H: Transplant Proc :!3:(this issue). 1991 4. !watslW S. Starzl TE. Todo S. et al: Transplant Proc 20:498. 1988 5. Lauchart W. Muller R. Pichlmayr R: Transplant Proc 19: 2387. 1987 6. Feria G. Col/edan M. Doglia M. el a1: Transplant Proc 2()(Suppl 1I:...<",{,6. 1988 7. Starzl TE. Van Thiel D. Tzakis A. et al: JAMA 260:2542. 1988 

Liver transplantation under cyclosporine: a decade of experience.

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Liver transplantation under cyclosporine: a decade of experience.

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