Gartner, JC

Iwatsuki, S

Malatack, JJ

Shaw, BW

Starzl, TE

Zitelli, BJ

English

PubMed

Gartner Jr, JC

Name not available

Pediatric liver transplantation under therapy with cyclosporin-A and steroids

D-Scholarship@Pitt

~ .. ~~~-~~-~--K-----------D Pediatric Liver Transplantation Under Therapy With Cyclosporin-A and Steroids J. J. Malatack, B. J. Zitelli, J. C. Gartner, Jr., B. W. Shaw, S. Iwatsuki, and T. E. Starzl D URING the period 5/9/81 to 5/9/82. 27 consecutive liver transplantations were performed on 23 pediatric patients. Ages ranged from 7.5 months to 18 years. There were II males and 12 females. Four patients were adolescents (12-18 years). 6 patients were school age (5-10 years). and 13 were infants to preschools (7.5 months-4.5 years). Follow-up time ranged from 3.5 months to 15.5 months. Survival stands at 70% (16/23). while 61 % (14/23) can be described as in excellent condition. Orthotopic liver transplantation (OL T) has. since its inception, I been a procedure with high mortality and morbidity. Steady im-provement in survival statistics have. however. occurred during the 20-year history of the procedure. Improvements in surgical tech-nique. patient selection. and immunosuppres-sion have moved OL T into the realm of practi-cal therapeutics. Pediatric OL T. while always enjoying slightly better survival statistics than its adult counterpart.2 has had added morbidity with-out correlate in the nonpedialric population. The profound effect of high doses of steroids on the child, which leads not only to growth failure but also to Cushingoid changes. has prompted ~ome to question the use of trans-plantation in children 3 at all. We report improved survival statistics for pediatric OL T under cyclosporin-A (CyA) and low-dose steroids. as well as preliminary data suggesting normal growth velocity post-transplantation in these patients. From the University of Pittsburgh Health Center, University of Pittsburgh, Pittsburgh, Pa. Reprint requests should be addressed to Dr. J. J. Malatack, University of Pittsburgh Health Center, Uni-versityofPittsburgh, Pittsburgh, Pa.15261. © 1983 by Grune & Stratton, fncK~ MM41-1P4R/UP/1RM/~P11AlfKll/l 1292 MATERIALS AND METHODS Patient Selection All the patients listed in Table I represent I-year experience with liver transplantation dating from 5/9/81 to 5/9/82. Nineteen patients received I graft and while 3 patients had 2 grafts, and I patient had a total of 3 grafts. Biliary atresia with a failed allempt at restoration of bile drainage by portoenterostomy represented the most frequent indication for liver transplantation in children. Following biliary atresia. are a variety of inborn errors of metabolism (alpha-I-antitrypsin [A,A T] deficiency be-ing by far the most frequent of the inborn errors), biliary hypoplasia, chronic active hepatitis. neonatal hepatitis. secondary biliary cirrhosis. Jnd familial intrahepatic cho-lestasis. Patients who were transplanted were initially placed on a transplant candidacy list follOWing an in-hospital medi-cal evaluation. The evaluation was undertaken to (I) verify acceptable pre transplantation anatomy (generally requiring demonstration of a patent extrahepatic portal vein), (2) review the patient's diagnosis (accomplished by a review of medical records, biopsy slides. and occasion-ally other further testing), and (3) an attempt at gaugeing the medical urgency of transplantation. Transplantation recipients were chosen from the candi-dacy list based on the size of the available organ. the blood type of the organ donor, and the type and severity of the liver disease of the recipient. Selection was made indepen-dent of H LA typing or patient donor crossmatch data. While size matching was rather strictly adhered to. one of the patients in the series was an ABO mismatch with the donor. Patients who received grafts either suffered from a disease entity whose course is predictably and rapidly downhill (i.e .• biliary atresia), had multifocal neoplasia or neoplasia with cirrhosis complicating metabolic liver dis-ease. or had reached end-stage"s with a liver disease whose course is less predictable (i.e .• A,A T deficiency).' One patient in the series did not fall into any of the 3 aforementioned categories and received a transplant. That patient was an A I AT-deficient child who had devel-oped social invalidism' from associated hepatogenic cya-nosis.' Surgery Hepatectomy of the donor organ was performed at the hospital of the donor's death. The organ graft was preserved in Collin's solution during transport.' The method of transplantation has been described previous-Transplantation Proceedings, Vol. XV. No. 1 (Marchi. 1983 a \\ L rl tl a: tr -K----~---K-~---"----~-----LIVER TRANSPLANTATION IN CHILDREN 1293 Table 1. Indications for Liver Transplantation in Children Number of Follow-up Time (Months' Disease Biliary atresia Inborn error /totals) Alpha-i-antitrYPsin Wilson's Tyrosinosis with hepatoma GSO-I Sea Blue Histiocytes with hepatoma Biliary hypoplasia CAH Secondary biliarv cirrhoSIS Neonatal hepatnis Familial intrahepat,c cholestilSls Patients 7 B 4 1 3 2 ly.'O Cold ischemia time depended to a large extent on the distance to the donor hospital. but in all instances was less than) 2 hr. Prophylactic antibiotics were initiated at the time of surgery and continued for 4 days. Further antibi-otic use was dependent on the patient's clinical course. Immune Suppression The immunosuppressive regimen used has recently been described in detail" Essentially. it consisted of oral CyA initiated 4-6 hr before surgery. or its IV equivalent if 4 hr lead time was not possible. and steroids begun intraoperatively and tapered over the following 5 days from a high dose to a low dose (5-10 mg prednisone) level. Both CyA and steroid therapy were individualized from patient to patient dependent on the patient's clinical status and/or the intervention of rejection episodes. Rejection episodes were treated with bolus of IV Solucor-tef and/or CyA dosing changes, and/or reinstitulion of R~day prednisone bursts. which begin with high doses of steroids and taper over 4 days to low dose of steroids. RESULTS Table 2 lists the follow-up data for the transplanted patients. Sex and age did not affect outcome. Though historically, patients with biliary atresia have had poorer outcome than pediatric patients transplanted for other reasons, disease did not impact on outcome in this series. Finally, clinical condition (defined as grave in hospital-bound patients, fair in those patients living at home under medical management of liver decompensation, and good in patients living at home without any Survivors 5 6 2 o 3.5 to 15.5 5.0 to 14.0 5.0 to 14.0 11.0 9.0 6.0 5.0 8.0 4.0 to 5.0 9.0 13.0 liver decompensation) did not impact on post-operative survival. Four of the patients had preexisting cyto-toxic antibodies to the donor. Table 3 reviews these patients. Antibodies were either ABO isoagglutinins or T-warm cytotoxic antibod-ies. The latter antibody kills all of the donor lymphocytes in vitro. Though the numbers are small, the data support a real increased risk in these patients. However, it can also be seen from the case material that violating the immunologic barrier presented by preexisting antibodies does not preclude the possiblity of excellent outcome. Follow-up Seventy percent (16/23 of the transplanted patients) are survivors, while 61% (14/23 patients) are in excellent condition. Two patients (OT 214, 229) are suffering from chronic rejection. Figure I is the growth curve on one of the transplanted patients. It can be seen that growth velocity following transplantation has been normal in this patient. This patient's growth curve is representative of other patients also transplanted under CyA and low-dose steroids l2 who have I-year follow-up time. Five of the patients in this series have follow-ups greater than I year. Two of the 5 1294 MALA TACK ET AL. Table 2. Outcome of 23 Consecutive Pediatric Liver Transplantations Age at Immune SlJppreS!$lon lnltlat CondittOn Follow-up Pat...,. Transplant at Time of Present Time evA OTNo. {Year,1 Sex DiagnosiS Transplant Status ,Monthsl m.g Pred/dav mg/kg/dav BIlirubin 189 22/3 M Bllaary aUftSl8 sIP Kasal Good E .... cellent 15.5 ' 1 190 B"'-v atresl. sIp Kasal Fair ElCceUent 15 15 191 2 1/6 M Biliary atres&8 sip Kasal Good Excellent 15 10 192 101/2 M AIAT Cntlcal Excellent. persistent hVperw 14.5 tension 193 101/6 Famthat c~estapls F •• Excellent I. 201 • 1/2 M A,Ar F •• Died with biliary leak and 1 month until death abscess 202 101/2 M Wilson's disease Critical Excellent 11 ' 1 203 18 M A1AT with hepatogenic F •• Dted with cerebral hemor- 3 months until death cyanoSiS rhage after second transplant 205 2/3 NeonatlN hepatitis CntlCal Excellent 16.5 206 2213 TyrOSInemia with hepatoma Good Excellent 16 213 M Bili.-y atreSIa sip Kasal Good Exce4lent 21' 2213 M Biliary hypoplaSia Cntlcal Fair, ongomg chroniC reteC- 10 16 17 lOon 216 15/6 Bib..., atresia sip Kasal Good Daed 2 0 to liver failure of 3 months unCl1 death rejeCtion 218 17 GSO I with adenomata Good Excellent 10 12.5 '. I 220 82/3 ChoMtdochal cySt 2" biliary Cntlcal DIed at 2nd attempt at ClIThosis grahlng. fatted 2" pOftal vem obstruction 222 Se ... Slue histiOCytoSis Good Excellent 15 12 226 A1AT entlCal Excellent 3 1/2 12 228 3 1/3 M 8,I..-v hypoplasia F •• Died 2" to sepSIS 1/2 month until death 229 16 M C~omc active hap.lltls Cntlcal Cflttcal With chronic rel8C- 3 1/2 30 30 19 lOon 232 62/3 Biliary auesla Good Dutd With IschemiC liver fn~ 1/3 month until death ,""I 233 I 2/3 Biliary hypoplaSia Good Died at surgery, found to Immedtate postopet'altve 12 ._1 have SVC absence death 236 8iliaty aUes.a sIp Kaul Fa. Excellent 10 17 , 1 237 16 M ChrontC actIve "'-'atltlS CrttlCcd Excellent 20 20 patients were school age and 3 were preschool-ers. Only I patient had significantly delayed development (OT 189) at the time of trans-plantation. That patient had required monthly hospitalizations for G I bleeding and fluid and electrolyte imbalance from age 1.5 years until transplantation at age 4 years. The remaining toddlers were transplanted early enough in the course of their diseases that severe morbidity had not occurred, while the school-age chil-dren had only had decompensated disease in the months prior to transplantation. Table 3. Outcome of Patients With Preexisting Cytotoxic Antibodies Patient OT 190 OT 193 OT229 OT 232 Antibody Twarm ABO isoagglutinIn Twarm Twarm Outcome Mild persistent rejec-tion, controlled after 3 months of weekly steroid bolus ther-apy Excellent Chronic ra jection, will require retransplan-tation Died with massive liver ischemia with-out apparent vascu-lar obstruction Follow-up developmental and psychometric testing has revealed normal developmental progression in the 4 pretransplantation "nor-mal" children and developmental catch-up, though still delayed for age, in the pretrans-plantation delayed child. Complications Hypertension was the most frequent post-operative complication encountered. It oc-curred to some degree in all but two of the patients. The hypertension generally resolved after 2-3 months. There have been two i~ * f ,f, l ~ e ·ct o LIVER TRANSPLANTATION IN CHILDREN 47- 120 46 45 115 44 43 11 42 41 105 40-39 1 38 37 95 36 , 35 90 34 33 85 , 32 31 8 30 29 75 in em 40 15 30 Di~ ~ .. -Ib ~g 2 3 4 5 E 7 ! Fig. 1. Patient growth curve. patients who were exceptions to this. Patient OT 192 has had late recurrence of hyperten-sion, and patient OT 206 has had persistence of postoperative hypertension. Pulmonary edema in the immediate postop-erative period occurred with some frequency early in the series. More conservative fluid management in the patients transplanted in the latter half of the series has decreased this problem considerably. Renal dysfunction with low fractional uri-nary sodium excretion occurred in a number ?f pa tients and was either hepatorenal or Cy A Induced. Normalization of renal function occurred either with time and a good function-ing graft or with decreases of CyA dosing. Two patients required a short period of dis-continuation of CyA with a switch to azothia-prine until renal function recovered (2 days). Reinstitution of CyA at a lower dose did not cause recurrence of renal dysfunction. Postoperative fever occurred in 18/23 1295 patients. Etiology was viral infection in 2 cases (EBV in 1 patient and CMV in anoth-er), bacterial infection in 4 cases (cholangitis in I patient, peri tom tis in 1 patient, phlebitis in 1 patient, and biliary abscess in 1 patient), fungal in I case (candida liver abscess), and nocardia in 1 case (pulmonary nocardosis). Of the remaining 10 patients, fever was asso-ciated with biopsy proven rejection in 4 patients and presumed rejection in 2 patients. Of the 4 patients with unexplained fever, one later developed rejection, while in 3 patients fever resqlved without explanation. Two of the patients in the series (OT 213 and 229) had infection and rejection. The former had CMV and mild rejection, while the latter had pul-monary nocardosis and severe rejection. A number of single complications, includ-ing recurrent laryngeal nerve injury, phrenic nerve injury on the right, obstruction of the portal vein at the anastomosis site requiring reoperation and correction, and peroneal palsy with foot drop, occurred. Deaths in the series were clearly rejection-mediated in only 1 patient. One patient had sudden liver failure with marked transami-nase rise at 1 week posttransplantation. Post-mortem evaluation revealed an ischemic liver despite patent vascular anastomoses. One patient thought to have a patent portal vein by preoperative sonography had a completely thrombosed portal vein at the time of surgery and hence was unable to receive a surgically acceptable transplant. Another patient had an absent superior vena cava (SVC) with upper body venous drainage ultimately returning to the heart by way of the inferior vena cava (lVC). That patient died intraoperatively at the time of cross clamping of the lVe. One patient had a biliary abscess that led to his demise, while another patient died due to overwhelming sepsis. Finally, one patient died following a third attempt at transplantation due to an intracranial hemorrhage. DISCUSSION Review of the patient data has shed light on a number of points. Two presuppositions: (I) l .. I~D .. i ,I:' _._-_ .. ,._----_ ... ,---"--1296 that patients with biliary atresia have a poorer outcome at liver transplantation versus chil-dren with other indications for liver transplan-tation owing to the greater difficulty of sur-gery in the child with previous abdomenal surgery (i.e., portoenterostomy), and (2) that the more gravely ill patients do less well than the more stable patients, did not hold true. Failure of these presuppositions to hold in this series may be merely a function of its small numbers, but, alternatively, it may be due to the coming of age of the actual surgical proce-dure of liver transplantation, while the immu-nologic barrier remains the major problem to be surmounted. The rapid normalization of severe metabolic derangements following suc-cessful transplantation have allowed the sick-est of patients (OT 202. 237) to come back from the brink of death. while other patients (OT 2 I 6,232) in stable condition at the time of transplantation have gone on to their dem-ise following rejection or apparent rejection of the transplanted organ. The patient data to date support the use of OL T in pediatric patients. Essentially since its inception, the use of 0 L T in children has been controversial. Starzl et al. have felt that chil-dren are excellent liver transplantation recip-ients, and point to their better survival statis-tics compared to adults. Caine et al. have been reluctant to perform transplantation in the pediatric age group for several reasons, the foremost being the known long-term toxic side MALA TACK ET AL. effects of immunosuppressive drugs, espe-cially corticosteroids which causes growth retardation and associated Cushingoid fea-tures. The description by Borel et al. il of a fungus extract, CyA, which is a powerful immuno-suppressant and which was later shown to be an effective anti rejection agent, either by itselfl.j or in conjunction with low-dose ste-roids,ll held the promise of eliminating the major toxic side effects of previous immuno-suppressive regimens. Our data to date sup-port the value of CyA in reducing the toxic side effects of previous immunosuppressive therapy. Children on the regimen of low-dose steroids and CyA not only show improved survival but attain normalization of growth velocity posttransplantation. Whether other delayed or more subtle toxic effects of CyA and low-dose steroids in children will later occur will have to await longer follow-up time. ADDENDUM Since submitting this article five more months of follow-up time have passed. The two patients suffering from chronic rejection (OT 214, 229) have succumbed to complica-tions of their rejection or therapeutic interven-tion taken in an attempt to control rejection. The remaining 14 patients are continuing to do well. REFERENCES J. Starzl TE. Marchioro TL. Von Kaulla KN. et al: Surg Gynecol Obstet 117:659. 1963 2. Terbanche J. Koep LJ. Starzl TE: Med Clin North Am 63:507.1979 3. MacDougall BRO. Williams R: Transplant Proc II :247. 1979 4. Houssin D. Franco D. Corlette MB. et al: Surg Gynecol Obstet 151:30. 1980 5. Malatack 11. Gartner lC, Zitelli Bl: (in prepara· tion) 6. Latimer lS. Sharp HL: Curr Probl Pediatr 11:5. 1980 7. Starzl TE. Koep LJ, Gerhard PJS, et al: Pediatrics 63:825. 1979 8. Spagnolo SV: Med Clin North Am 59:983. 1975 9. Benichou 1, Halgrimson CG. Wei 1 R 1lI. et al: Transplantation 24:407. 1977 10. Starzl TE. Koep LJ, Halgrimson CG. et al: Gas-troenterology 77:375. 1979 II. Starzl TE. Iwatsuki S. Malatack 11. et al: J Pediatr 100:681. 1982 12. Gartner JC. Malatack JJ. Zitelli BJ. et al: (in preparation) 13. Borel JF, Feurer C. Gubler HU. et al: Agents Actions 6:468, 1976 14. Caine R Y. Rolles K. Thiru S. et al: Lancet 2: 1033. 1979 

Pediatric Liver Transplantation Under Therapy With Cyclosporin-A and Steroids.

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Pediatric Liver Transplantation Under Therapy With Cyclosporin-A and Steroids.

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