Gartner, JC

Malatack, JJ

Starzl, TE

Urbach, AH

Zitelli, BJ

English

D-Scholarship@Pitt

. J i ~ I I f \ \ PEDIATRIC LIVER TRANSPLANTATION: PROSPECTS FOR LINEAR GROWTH Andrew H. Urbach, H.D., J. Carlton Cartner, Jr., H.D., J. Jeffrey Malatack, H.D., Basil J. ZitelU, H.D., and Thomas E. Starzl, H.D. The Unt attempt at liver transplantation in humans 10111 lIIade in 1963 (1). The first loog term survivor was transplanted on July 23, 1967. She was a one-and-one-half-year-old girl who lived for 13 !Donths before she .uccumbed to the hepatocellular carcinoma for which she was treated. During the year. 1963-1979, Dr. Thoma. Starzl performed liver tran8plantation on 170 patient. including 86 children (2). Survival at five years was Ie •• than 30% with younger patient8, .howing a 10% survival advantage over adult.. Not until the discovery of cyclosporine (3, 4) and the initiation of clinical trials did survival increase significantly. As a direct result of this 8uccess, the number of patients who underwent the procedure climbed and an innovative and aggressive procedure became accepted therapy for end-stage liver disease (5); however, a multitude of questions remain about the quality of life of these patients. The purpose of this review is to addres8 one aspect of this issue, linear growth • OVERALL SURVIVAL FrOID Hay 1981 to Hay 1986, 229 children received 303 liver transplants at the Children'. Hospital of Pittsburgh. Overall survival rate as of Kay 1986 wa's 71%. Table 1 shows overall survival rate8 for each year while Table 2 reviews survival rates of children undergoing retransplantatioo compared with those of children receiving only one transplant. GROWTH From Hay 1981 to June 1983, 49 children received liver transplants and 29 survivors were evaluated for growth potential (6). Their average age at the time of transplant was flve-and-one-half years (7 IDO. - 13 years) and sll were Tanner Stage 1. Transplantation was performed for a wide variety of liver diseases. Nearly half of the patients had biliary atresia. Metabolic disorders such as alphal antitrypsin deficiency and tyrosinemia 333 -----._------------------------I i II I t ! I i 1.' I I ~ f. I ~K I ~ . " I I I  , ,nl' i ~K i I -if l-/i -f l\ I . i.HI-; I I ~ l! i! .1 H !II i qh I' ;,H\il" 4" I nlll • \ I' .' 334 accounted for the next largest group. I mmunosupprenlon " •• accomplished with an average dose of 9.4 ag/kg/day of cyclosporlne and 0.21 mg/kg/ day of prednisone (6, 7). Twenty-U ve of 29 patient. were on less than 5 mg of prednisone per day. Average length of follow-up was three years (24 - 52 months). TABLE 1 Yearly survival rates at the Children's Hospitsl of Pittsburgh fro. Hay 1981-Hay 1986. OVERALL NUHBER NUMBER SURVIVAL OF OF FOR ~ TRANSPLANTS CHILDREN DEATHS COHORT 5/81-6/82 30 25 9 64% 7/82-6/83 38 25 10 60% 7/83-6/84 63 50 8 84% 7/84-6/85 79 57 14 75% 7/85-5/86 93 72 25 65% Overall 303 229 66 71% TABLE 2 Survival rates bases on need for retransp1antation at the Children's Hospital of Pittsburgh from Hay 1981-1986 t.1JHBER or 9HILDREN 166 51 11 NUMBER OF TRANSPLANn 2 3 4 DEATHS 38 24 4 o OVERALL SURVIVAL 77% 53% 64% 100% ----- ---- -- ----------------------·~D ': '..:"-" -I~-I;-I: '.' - , . ...,. " .. -.' .', ~ .,:.,: '., KDDD;"~D .. I;~K ---: -.. ' .... . . 335 Twenty-eight percent (8/29) croased percentiles in an upward direction (had greater than normal growth velocity for age) and were also above the fifth percentile on a .tandard growth curve at the end of the study. Fourteen percent (4/29) were above the fifth percentile prior to transplantation and maintained a normal growth pattern with no change in percentile. Forty-five percent (13/29) were below the fifth percentile prior to surgery and remained less than the fifth percentile following surgery. Within this group, however, 10 of 13 (77%) attained normal or accelerated growth velocity. Fourteen percent (4/29) began above the fifth percentile and fell to below this level at the time of their last evaluation. Of the seven patients with poor growth, the majority suffered from chronic rejection or a recurrence of the disease for which the transplant was performed (8). Overall, 76% of our patients achieved normal or accelerated growth velocity. DISCUSSION A great deal of the concern a')out growth in renal transplant recipients has centered around tie effects of steroids on the developing child. Many mechanisms for steroid-induced growth failure have been suggested. These include abnormalities of calcium and phosphorus metabolism, a direct effect on cell metabolism, and inhibitory effects on growth hormone and somatomedin activity (9, 10, 11). Speci fically, linear growth seems to be related to prednisone dosages and scheduling intervals. Lilly (12) and DeShazo (13) showed that with prednisone dosages between 0.2 and 0.3 mg/kg/day, good growth could occur. Better growth is felt to occur when alternate day therapy is utilized (14, 15), particularly in patients with a bone age of less than 12 years (16, 17, 18). Concerns, however, have been raised about the immunosuppressive efficacy of an every-other-day steroid regimen (14, 15, 19,20) and many authors reserve this therapy for a child with poor growth whose graft function is excellent on daily prednisone. Data on graft survival with administration of every-other-day prednisone Is not available for liver transplantatio~ Detailed growth studies with the use of cyclosporine and prednisone for immunosuppression are limited to renal transplant patients. Conley (21) and Klare (22) report optimism, but of the 10 patients discussed, the latter report (22), four children received no prednisone at all. The other six children received low dose prednisone, 8.5 mg/1.73m 2/day. Ellis (23), on the other hand, reports more disappointing results with growth, using the same fm~unosuppressive drugs. Utilizing a mean dose of 0.25 mg/kg/day of prednisone, growth .... as suboptimal or poor In seven of eIght patients. -, i I I , I I I I I Linear growth failure ia a prominent feature of end-atage liver disease (24). In the pre-cyclosporine era, some authorl (2S) expresaed reluctance to perform transplant. in pediatric patient •• Much of their hesitancy revolved around the growth retardation and the lIultitude of aide effects of high dose corticosteroid.. With the advent of cyclosporine as a potent immunosuppressive agent (3, 4), the nece881ty to utilize high dose prednisone in liver transplant patients lessened. Until recently no data were available on growth following Uver transplantation 1n the cyclosporine era. Two articles (26, 27) briefly referred to the observation that good growth could be achieved; however, these impressions were limited in scope because of the short length of follow-u~ Our report (6) indicates that good growth in pediatric liver transplant recipients is possible using cyclosporine with a daily prednisone dose of 0.21 mg/kg/day. We also show that most growth failure was predictable on the basis of poor graft function. The improvement in linear growth is likely to be multifactorial. Factors which account for good growth include disappearance of metabolic bone disease, good nutrition, improved hepatic function and the general state of well being that these patients achieve (27). By allowing lower doses of prednisone to be utilized, the effectiveness of cyclospor1ne has also contributed to the positive results that we have presented. We further believe that the risks of alternate day steroids on graft survival may not currently warrant every-other-day dosing considering the growth data presented here. These data provide support for our current immunosuppression regimen of cyclosporine and low dose prednisone. Future investigation should emphasize therapeutic methods which enhance growth while preventing chronic rejection. REFERENCES 1. 2. 3. 4. Starzl, T.E., Harchioro, T.L., VonKaulla, Homotransplantation of the liver in humans. Obstet. 11T:S~9I 19b3. Starzl, T.E., Iwatsuki, S., VanThiel, D., et a1.: liver transplantation. Hepatology 2:614, 1982. K.N., et a 1.: Surge Cynecol. Evolution of Borel, J.r., Feurer, C" effects of cyclosporin A: Gubler, H.U., et al.: Biological A new antilymphocyte agent. Agents Act ions 6:4b8, 1976. Borel, J.F., Feurer, C" Gubler, H.U., et al.: Effects of the new antilymphocyte peptide cyclospor1n A in animals. Immunology 32:1017,1977. 337 5. National Institutes of Health Consensus Development Conference Statement: Liver transplantation - June 20-23, 1983. Hepatology 4(suppl):107S, 1984. 6. Urbach, A.H., Gartner, J.C., Malatack, J.J., et al.: Linear growth following pediatric Uver transplantation. AJDC 1987, in press. 7. Starzl, T.E., Iwatsuki, 5., Malatack, J.J.: transplantation in children receiving sterOids. J. Pediatr. 100:681, 1982. Liver and kidney cyclosporin A and 8. Gartner, J.e., Bergman, I., Malatack, J.J., et al.: Progression of neurovisceral storage disease with supranuclear ophthalmoplegia following orthotopic liver transplantation. Pediatrics 77:104, 1986. 9. Travis, L.B., Chesney, R., McEnery, P., et al.: Growth and glucocorticoids in children with kidney disease. Kidney International 14:365, 1978. 10. Pennisi, A.J., Philli ps, loS., Vi ttenbogaart, C., et al.: Linear growth and somatomedin activity In renal allograft reCipients. Proc. Dialysis Transplant Forum 6: 168, 1976. 11. Pennisi, A.J., CosUn, G., Phillips, loS., et al.: Linear 12. growth in long term renal allograft recipients. Clinical Nephrology 8:415, 1977. Lilly, J.R •• Giles, G., Hurwitz, R •• homotransplantation in pediatr!c patients. 1971. et a1.: Renal Pediat rics 47:548, 13. DeShazo, C.V., Simmons, R.t., Bernstein, D.M., et al.: Results of renal transplantation in 100 children. Surgery 76:461, 1976. 14. McEnery, P.T •• Gonzalez, Lot., Martin, L.W., et al.: Growth and development of children with renal transplants. Use of alternate day steroid therapy. J. Pediatr. 5:l:lO6, 1983. 15. Potter, D.E., Holl iday. M.A., Wilson, S.J., et al.: day steroids in children after renal transplantation. Proe. 7:79 1975. Alternate Transpl. 16. Grushkin, C.M., Fine, R.N.: Growth In children (ol1o\"ing renal transplantation. AJOC 125:514, 1973. aa SS43" -I t I' I' I I i ; Ii I !: , : I I' ! . I Ii! I I'  i , I , 338 17. Hoda, Q., HasinoH, D.J., Arbu8, G.S.: Growth following renal tran8plantation. Clinical Nephrology 3:6, 1975. 18. 19. 20. 21. 22. 23. Fine, R.N., Halekzadeh, H.H., Pennisi, A.J., et al.: re8ults of renal tran8plantation in children. 61:641, 1978. Long tenD Pediatric, Diethelm, A.G., Sterling, W.A., Hartley, H.W., et al.: Alternate day prednisone therapy in recipient. of renal allograft8. Arch. Surgery 111:867, 1976. Potter, D., Belzer, F.O., Rame8, L., et al.: The treatment Of chronic uremia in childhood transplantation. Pediatric, 45:432, 1970. Conley, S.B., Flechner, S.H., Rose, G., et al.: Use of cyclosporine in pediatric renal transplant recipients. J. Pediatr. 106:45, 1985. Klare, B., Walter, J.V., Hahn, H., renal transplantation in children. et al.: Cyclosporine in Lancet 2:692, 1984. Ellis, D., Avner, E.D., Rosenthal, J.T.: Renal function and somatic growth in pediatric cadaveric renal transplantation with cyclosporine-prednisone immunosuppression. AlOe 139:1161, 1985. 24. Burgess, D.B., Hartin, H.P., Lilly, J.R.: The development status of children undergOing Kasai procedure for biliary atresia. Pediatric8 70:624, 1982. 25. MacDougall, B.R.D., Williams, R.: The indications for orthotopiC liver transplantation. Transplant Proc. 11:247, 1979. 26. Malatack, J.J., Zitell1, B.J., Gartner, J.C., et al.: Pediatric liver transplantation under therapy with cyclosporine A and steroids. Transplant Proc. 15:1292, 1983. 27. Gartner, J.C., Zitelli, B.J., Malatack, J.J., et al.: Orthotopic liver transplantation in children: Two year experience wi th 47 patients. Pediat des 74: 140, 1984. 

Pediatric liver transplantation: Prospects for linear growth

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Pediatric liver transplantation: Prospects for linear growth

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