Bronsther, O

Demetris, AJ

Irish, W

Jain, A

Kusne, S

Llull, R

Manez, R

Roland, W

Starzl, TE

English

PubMed

Name not available

Posttransplant B, non-A non-B, and cytomegalovirus hepatitis increase the risk of developing chronic rejection after liver transplantation

D-Scholarship@Pitt

Posttransplant B, Non-A Non-B, and Cytomegalovirus Hepat~) d ~ Increase the Risk of Developing Chronic Rejection After Liver Transplantation O. Bronsther, R. Manez, S. Kusne, W. Irish, W. Roland, A. Jain, R. Llull, A.J. Demetris, and T.E. Starzl CHRONIC REJECfION is a serious complication of orthotopic liver transplantation (OLT) and is a major cause of late hepatic allograft failure. Risk factors leading to the development of chronic rejection have been identi-fied. Two of these are lack of response to acute rejection therapy and allograft cytomegalovirus (CMV) infection.1- 3 However, many patients develop chronic rejection without any identifiable risk factor. Furthermore. the intrinsic mechanism involved in the development of chronic rejec-tion is not fully understood. In general. chronic rejection is a progressive disease but there are instances where it appears to reverse or stabilize over time.~·5 Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major causes of end-stage liver disease. Both infections persist after OLT leading to recurrence of hep-atitis in many patients. When the allograft is infected with either of these viruses. it may be difficult to distinguish histopathologically between hepatitis and rejection.6 We postulated that development of posttransplant hepatitis B or C may influence the development of chronic rejection after liver OLT. MATERIALS AND METHODS From May 1. 1987 to July 31. 1989.738 adults underwent OLT at our institution and received cyclosporine (eyA) and steroids as primary immunosuppression. Of these patients 120 (16%) died during the first 2 months after OLT. The remaining 618 patients served as the study population with a mean = SO follow.up of 1.192 = 493 days. The histopathologic criteria for posttransplant hepatitis and chronic rejection have been described els.:where.o-~ Tu investigate whether development of chronic rejection was related to a decrease in the amount of immunosuppression given. we evaluated the level of CyA (whole blood TOX) and the doses of eyA and steroids adjusted to weight at 30. 60, 90. 180. 360. 540. and 720 days after OLT. RESULTS Table 1 shows the pretransplant diagnosis and the incidence of posttransplant B. non-A non-B, and CMV hepatitis and chronic rejection in the study population. Chronic rejection developed in 118 patients at 528 :!: 398 days after OLT. Three-year patient and graft survival in patients who devel· oped chronic rejection was 68% and 55%. respectively. whereas in those patients who did not experience chronic rejection they were 84% and 82%, respectively (Kaplan. Meier: P < .01; Figs 1,2). The incidence of chronic rejection in patients who did not experience B. non-A non-B. and CMV hepatitis was 13% (55 of 418). In contrast. the incidence of chronic rejection was 27% (18 of 66) in patients with CMV hepatitis, 40% (45 of 112) in patients with B. non-A non-B hepatitis. and 55% (12 of 22) in patients with both CMV and B or non-A non-B hepatitis (Chi-Square test: P < .0001). The relative risk (odds ratio) of developing chronic rejection was 2.48 in patients with CMV hepatitis. 4.43 in B. non-A non-B hepatitis. and 7.92 in CMV and B or non-A non-B hepatitis. compared with patients who did not experience posttrans-From the University of Pittsburgh, Transplantation Institute. Pittsburgh, Pennsylvania. Address reprint requests to Thomas E. Starzl, MD, PhD. University of Pittsburgh, Transplantation Institute, 3601 Fifth Ave, 4 Falk, Pittsburgh, PA 15213. © 1995 by Appleton & Lange 0041-1345/95/$3.00/+0 Table 1. Incidence of Posttransplant Hepatitis and Chronic Relection In Study Population HBV hepatitis Non·A non·B Hepatitis PBC·PSC PNC·E Tumor Cryptogenic Other Total Pretransplant DiagnosIs (%) 43 (7) 64 (10) 157(25) 94(15) 7B (13) 112 (lB) 70 (11) 61B (100) 'At 415 :: 379 days altar OlT. 'At 48 :: 42 days alter OlT. 'At 528 :: 398 days altar OlT. 1206 Posttransplant BlNon·A Non·S Hepatitis (%)' 39/43 (91) 40/64 (63) 14/157 (9) 6/194 (6) 9nB(12) 20/112 (1B) 2nO(3) 130 (21)'''' CMV Hepatitis (%)t 5/47 (11) 9/67 (13) 20/157 (13) lB/94 (19) 1Bn6(23) 6/112 (5) 12nO(17) BB (14) Chronic Rejection (%)' 17147 (36) 26167 (39) 25/157 (16) 11/94 (12) 10nB (13) 251112 (23) 6nO(9) 1 lB (19) Trans,oIantalion Proceedings, Vol 27, No 1 (February). 1995: pp 1206-1207 CHRONIC REJECTION ~ (;j > .~ :::l en 100 90 80 70 80 50 ~o 30 20 10 P <0.01 --No Chronic ReJection (n-5OO) ........ Chronic Rejection (n-118) o~--~--~~--~~--~~--~~----~~ o 6 a ~ ~ 30 $ Months after Transplantation Fig 1. Three-year patient survival in patients with and without chronic rejection. plant hepatitis. The incidence of chronic rejection was 35cr (17 of 48) in patients with hepatitis Band 567C (46 of 82) in patients with non-A, non-B hepatitis (P < .05). Posttrans-plant hepatitis was diagnosed before chronic rejection in 59% of patients. at the same time in 31 %, and after chronic rejection in 10%. Overall the immunosuppression as measured by eyA dose, level. and prednisone dose was not significantly 100 90 80 70 60 ~ (;j 50 > .~ ~o :::l en 30 20 10 0 0 6 P <0.0001 --No Chronic Rejection (na 5OO) ........ Chronic Rejection (na l18) 12 18 24 30 $ Months after Transplantation Fig 2. Three-year graft survival in patients with and without chronic rejection. 1207 different among those patients who did or did not develop chronic rejection. Onlv the level of evA at 360 davs after OL T and the dose of' CvA at no d;vs were silwificantlv higher in those patients 'who develop~d chronic" rejectio~ (P < .05). DISCUSSION In the present study. the development of posttransplant B. non-A non-B. and CMY hepatitis has been associated with a significantly higher incidence of chronic rejection after OL T. We were concerned that chronic rejection had devel-oped in patients transplanted for the diagnosis of hepatitis because of a systematic error in baseline immunosuppres-sion. To explore this possibility we looked at the evA dose and level and prednisone dose for patients stratified-by their pretransplant diagnosis. Patients with hepatitis received equivalent immunosuppression to patients transplanted for all other indications. On the other hand. some of the pathologic features of chronic rejection have been previously associated with hepatitis. particularly non-A non-B. in patients who did not receive transplants.'I.lu Thus. we must consider the possibil-ity that HBY. Hey. and/or CMY viruses. or the ce\l-mediated immune responses against them. have a direct role in the pathogenesis of chronic rejection after OL T. Because there is no satisfactory therapy for HBY and Hey hepatitis after transplantation. a reevaluation of baseline immunosuppression should be considered in this high-risk population. REFERENCES I. Freese DK. Snover DC. Sharp HL, et al: Hepatology 13:882. 1991 2. O'Grady JG. Sutherland S. Harvey F. et al: Lancet 2:302.1988 3. Manez R. White LT. Linden P. et a1: Transplantation 55: 1067. 1067 4. Freese D. Snover D. Sharp H. ct al: Hepatology 13:882. 1991 5. Fung 1J. Todo S. Tzakis A. et a1: Transplant Proc 23:14. 1991 6. Ferrell LD. Wright TL. Roberts 1. et al: Hepatology 16:865 . 1~2 ' 7. Demetris N. Todo S. Van Thiel D. et al: Am 1 Pat hoi 137:667. 1990 8. Demetris N. Fung 11. Todo S. et al: Transplantation 53:1056. 1992 9. Lefkowitch J. Apfelbaum T: J elin GastroenteroI11:225. 1989 10. Scheuer PJ: Virchows Arch [AJ 415:301. 1989 

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Posttransplant B, non-A non-B, and cytomegalovirus hepatitis increase the risk of developing chronic rejection after liver transplantation

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