THROUGH 1979, immunosuppressive

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1 Five-Year Survival After Liver Transplantatin THROUGH 1979, immunsuppressive therapy fr liver transplantatin at ur center was with aathiprine (r cyclphsphamide) and sterids, t which antilymphcyte glublin (ALG) was usually added. 1-3 Failure was mre frequent than success. Nevertheless, 55 (32.4%) f the first 170 recipients treated frm 1963 n in Denver survived fr mre than a year, and 31 (18.2%) passed r are just reaching the five-year mark. The fllwing is an accunt f these pineer patients wh have becme the leaders in a ppulatin f liver recipients that will be expanding rapidly with the imprved immunsuppressin that is available tday. CASE MATERIAL The 170"llatients were treated with rthtpic liver transplantatin at the University f Clrad Health Sciences Center frm March I, 1963, thrugh the first mnth f Eighty-six f the 170 patients were 18 years ld r yunger, and 84 were 19 years r lder. All f these patients were treated with aathiprine and prednisne and mst had ALG as well. Sixteen patients (OT 42 thrugh 57) received cyclphsphamide instead f aathiprine fr several mnths, and 21 were treated with thracic duct drainage as an adjunct t therapy with aathiprine and prednisne. Cyclsprine was nt available fr any f these patients at the time f transplantatin, but in five patients (OT 56, 77, 137, 142, 164), cyclsprine was substituted fr aathiprine fur t 11 years after the transplant because f chrnic rejectin in fur patients and in rder t reduce the maintenance dse f prednisne fr grwth retardatin in ne patient (OT 142). Tw patients (OT 56 and 137) received secnd transplants with cyclsprine and lw-dse sterid therapy, and ne patient (OT 164) returned t aathiprine after several mnths f cyclsprine therapy. Patient cde number (OT number), age at the time f transplant, sex, diagnsis f liver disease, survival, present status f recipient, cause f death after five years, and current immunsuppressin therapy are listed in Table I. Survival RESULTS Of the 170 patients, 31 lived fr mre than five years and tw thers are living and well S. Iwatsuki, B.W. Shaw, Jr, and T.E. Starl with nrmal liver functin between 43j4 and five years after liver transplantatin as f the end f August The latter tw patients are cnsidered five-year surviv{)fs. The actuarial survival rate at five years is 19.4%, and that at ten years is 17.9% (Fig 1). Of the 33 five-year survivrs, 19 were amng 86 patients between ten mnths and 18 years f age and 14 were amng 84 patients lder than 18 years at the time f transplantatin. Thus, five-year survival was better in the pediatric age grup (22.1 %) than in the adult age grup (16.7%). The influence f preexisting hepatic disease upn five-year survival was examined and the results are summaried in Tables 2 and 3. In the pediatric age grup, biliary atresia was the mst cmmn indicatin fr liver transplantatin; nly seven (13.7%) f 51 children with this diagnsis survived fr mre than five years (Table 2). In cntrast, seven (53.8% f 13 children with inbrn metablic diseases, such as Wilsn's disease and alpha-i-antitrypsin deficiency disease, lived fr five r mre years as well as three (23.1 %) f 13 children with chrnic aggressive hepatitis and cirrhsis. In the adult age grup, seven (21.2%) f 33 patients with chrnic aggressive hepatitis and cirrhsis and three (20%) f 15 patients with alchlic cirrhsis lived mre than five years after transplantatin, which was slightly better than the 16.7% verall 5-year survival rate amng 84 adult patients (Table 3). Frm the Department f Surgery. University f Pittsburgh Health Center. Supprted by research grants frm the Veterans Administratin and by prject grant N. AM frm the Natinal Institutes f Health. Address reprint requests t Dr Shunabur lwatsuki. Department f Surgery, University f Pittsburgh, Schl f Medicine, Pittsburgh, PA by Grune & Strattn, Inc /85/ $03.00/0 Transplantatin Prceedings, Vl XVII, N 1 (February),

2 N Ol -l c 13 I 0 :D N r Age OT at Transplant N. Transplant Sex Date yr M 7/15/ yr F 1/22/ yr M 3/23/ yr M 7/31/ yr., 8 m F 2/20/ yr M 5/15/72 2/1/ yr F 2/18/ yr F 10/8/ yr M 2/3/ yr M 4/9/ yr, 2 m F 10/16/ yr M 11/27/ yr F 11/28/ yr 1/21/ yr F 9/19/ yr M 10/27/ yr M 11/27/76 Table 1. list f 33 Five-Year Survivrs Indicatin Survival Present Status/Cause f Death Wilsn's disease Died at 5 yr, 362 d Died, chrnic liver failure Biliary atresia and inci- Alive mre than :14 yr Full-time schl, nrmal liver functin dental hepatma Wilsn's disease Alive mre thim 13 yr Full-time wrk, nrmal liver functin Biliary atresia Alive mre than 13 yr Full-time schl, nrmal liver functin Alpha-l-antitrypsirY de- Alive mre than 12 yr Full-time schl, nrmal liver functin ficiency disease Cngenital hepatic fi- Alive mre than 12 yr Retransplant fr chrnic rejectin, fullbrsis time schl Biliary atresia Alive mre than 11 yr Full-time schl, nrmal liver functin Biliary atresia Alive mre than 10 yr Full-time schl, nrmal liver functin Chrnic active hepatitis Alive mre than 10 yr Full-time wrk, chrnic rejectin; ttal bilirubin, 2.5 mg/ 1 00 ml Alchlic cirrhsis Alive mre than 10 yr Full-time wrk, nrmal liver functin Biliary atresia Alive mre than 9 yr Full-time schl, nrmal liver functin Chrnic active hepatitis Alive mre than 9 yr Full-time schl. nrmal liver functin Budd-Chiari syndrme Alive mre than 9 yr Husewife, nrmal liver functin, 2 children since transplant Secndary biliary cirrh- Alive mre than 8 yr Husewife, nrmal liver functin sis Liver sarcma f unde- Alive mre than 7 yr Husewife, nrmal liver functin termined cell type Chrnic active hepatitis Alive mre than 7 yr Nt wrking. nrmal liver functin Alpha-l-antitrypsin de- Alive mre than 7 yr Full-time wrk, nrmal liver functin ficiency disease Present Immunsuppressin Therapy Imuran Prednisne Cyelspnne (mg/dl (mg/dl (mg/dl 50,0 10/5* 75, / /0* t /0* /0*

3 '" -< m c < <:,... ""ti 0 r- m <: --I ""ti,... --I tv 0> yr M 1/8/77 Alchlic cirrhsis m F 4/6/77 Biliary atresia yr M 7/26/77 Chrnic active hepatitis yr M 8/13/77 Alchlic cirrhsis yr F 8/31/77 Chrnic active hepatitis 8/16/83 Chrnic rejectin yr F 11/13/77 Chrnic active hepatitis yr, 8 m F 1/4/78 8iliary atresia yr F 2/26/78 Alpha-l-antitrypsin deficiency disease, incidental hepatblastma yr F 4/19/78 Chrnic active hepatitis yr F 6/14/78 Primary biliary cirrhsis yr M 10/6/78 Alpha-l-antitrypsin deficiency disease yr F 5/8/79 Chrnic active hepatitis yr F 9/9/79 Chrnic active hepatitis yr F 12/3/79 Chrnic active hepatitis Alternate day prednisne therapy. tcyciphsphamide yr F 7/15/78 Secndary biliary cirrhsis yr M 2/3/80 Alpha-l-antitrypsin deficiency disease Alive mre than 7 yr Full-time wrk, nrmal liver functin Alive mre than 7 yr Full-time schl. nrmal liver functin Alive mre than 7 yr Full-time wrk, nrmal liver functin Alive mre than 6 yr Nt wrking, nrmal liver functin Died at 6 yr Dead: 1 st graft, chrnic rejectin; died after 2nd graft, pancreatitis and sepsis Alive mre than 6 yr Husewife, nrmal liver functin Alive mre than 6 yr Full-time schl, nrmal liver functin Alive mre than 6 yr Full-time schl. nrmal liver functin Alive mre than 6 yr Husewife Alive mre than 6 yr Husewife Alive mre than 6 yr Husewife Alive mre than 6 yr FUll-time schl. nrmal liver functin Alive mre than 5 yr Husewife, chrnic rejectin; ttal bilirubin, 3 mg/l00 ml Alive mre than 4 yr, Husewife, nrmal liver functin 11 m Alive mre than 4 yr, 8 Husewife, nrmal liver functin, 1 m child since transplant Alive mre than 4 yr, 6 Full-time schl, nrmal liver functin m /0" /0' /0' 400 Nne fr the last 2 yr /0' /5"

4 _ IWATSUKI, SHAW, AND STARZL 100 Table 3. Main Indicatins fr Liver Transplantatin and Five-Year Survival in Adult Patients (Age, ;,,:19 Years) Type f Indicatin N. f Patients 5-yr Survivrs YEARS AFTER TRANSPLANT Fig 1. The survival curve f 170 patients wh had received rthtpic liver transplantatin with aathiprine. prednisne. and ALG between 1963 and A ttal f 23 patients (eight in the pediatric and 15 in the adult age grups) had primary liver malignancy at the time f transplantatin. Five f the tumrs were incidental t anther disease and were nt the principal indicatins fr transplantatin (Table 2t). Tw f the five patients (OT 33 and 147) with incidental primary liver malignancies are living 142/ 3 and 6 1/ 2 years after transplantatin; bth are free f malignancy (Table 1). Only ne (5.5%) f 18 patients in whm malignant tumrs were the principal indicatin fr transplantatin lived fr mre than five years. This exceptinal patient (OT 114) has n evidence Table 2. Main Indicatins fr Liver Transplantatin and Five-Year Survival in Pediatric Patients (Age,,",,18 Years) Type f Indicatin N. f Patients 5-yr Survivrs Biliary atresia 51 7 (13.7%) Inbrn metablic errrs 13 7 (53.8%) Chrnic aggressive hepatitis 13 3 (23.1%) Primary liver malignancyt 3 0 Nenatal hepatitis 2 0 Cngenital hepatic fibrsis 2 1 (50.0%) Secndary biliary cirrhsis:j: 2 1 (50.0%) Ttal 86 19(22.1%) "Alpha-1-antitrypsin deficiency disease. nine; Wilsn's disease. tw; tyrsinemia, ne; and type IV glycgen strage disease, ne. tfive ther patients had incidental malignancies (fur hepatmas and ne hepatblastma) in their excised livers. The principal diagnsis in these five cases was biliary atresia (three), alpha-1-antitrypsin deficiency (ne). and cngenital tyrsinemia (ne). :j:secndary t trauma r chledchal cyst (ne each). Chrnic aggressive hepatitis Alchlic cirrhsis Primary liver malignancy' Sclersing chlangitis Primary biliary cirrhsis Alpha-1-antitrypsin deficiency Secndary biliary cirrhsist Hemchrmatsis Prtprphyria Budd-Chiari syndrme Acute hepatitis B Ttal (21.2%) 3 (20.0%) 1 (6.7%) 1 (16.7%) 1 (50.0%) 1 (100.0%) 14 (16.7%) "Hepatma, seven; duct cell carcinma (Klatskinl. five; chlangicarcinma, ne; hemangiendthelial sarcma, ne; and unclassified sarcma, ne. tone example each f pssible duct hypplasia and chledchal cyst. Bth patients had had multiple peratins. f tumr recurrence nearly nine years after transplantatin (Table 1). Only three patients were knwn t be psitive fr HBsAg prir t transplantatin and three mre patients became psitive after transplantatin. Nne f the three patients wh had psitive HBsAg prir t transplantatin lived five years, but all three patients (OT 77, 115, and 137) wh became psitive fr HBsAg after transplantatin lived five years r lnger. Because HBsAg antigen detectin was nt as accurate years ag as it is nw and was nt perfrmed regularly after transplantatin, the true incidence and influence f HBsAg n survival culd nt be determined in this study. Causes f Death After Five Years Only tw patients died after five years. A by wh was 11 years ld at the time f transplantatin (OT 27), died a few days befre the six-year mark, f chrnic liver failure. The cause f this liver failure was uncertain because the patient had undergne several reperatins fr biliary duct strictures; these culd nt be cmpletely crrected. In additin, medical attentin fr this patient was nt sught at his lcal hspital until he became critically ill. Autpsy was nt

5 5-YEAR SURVIVAL POST-LIVER TRANSPLANT 263 granted. It was speculated at that time that he might nt have had adequate medicatin, if any, fr several mnths prir t his death. During his survival perid, he btained a junir high schl educatin and he had been lking fr wrk (Table 1). Anther patient (OT 137) died after exactly six years. She develped chrnic rejectin five years after transplantatin. Aathiprine was discntinued and cyclsprine therapy was begun. Despite a favrable respnse t this change, the graft functin cntinued t deterirate. She died frm necrtiing pancreatitis and abdminal sepsis 15 days after retransplantatin. She had finished high schl and was married befre her death (Table 1). Rehabilitatin: Quality f Life Nine children wh were belw schl age at the time f transplantatin are all attending schl, ne (OT 33) being a cllege student. Of ten children wh were in schl befre transplantatin, seven graduated, and the ther three are cntinuing their educatin. Of the seven wh graduated, all wrked except the ne wh died (OT 27). Tw f them married. Amng the 14 adult patients, 12 are wrking full-time including nine husewives. Of the nine husewives, fur als held full-time r partime jbs utside f the hme. One wman gave birth twice t healthy babies and anther wman als has had a nrmal baby. Tw men culd nt keep their regular ccupatins because f bth scial and medical reasns (Table 1). Thus, all but tw f the 33 five-year survivrs were rehabilitated. The quality f life has been satisfactry. CONCLUSION Althugh these results are far inferir t thse btained in recent years with cyclsprine and lw-dse sterid therapy, each f these 170 heres r herines cntributed t the mass f scientific data and t the develpment f the surgical techniques that have becme rutine tday. Even nw, their cntributins cntinue, and demnstrate that survival between five and ten years is mre than 90%, and that rehabilitatin and quality f life are excellent, allwing imprtant cmmunity service, parenthd, and ther nble human functins. ACKNOWLEDGMENT The authrs express their greatest appreciatin t the patients and families wh have devted themselves t the develpment f liver transplantatin, and t the many physicians, nurses, and ther hspital and labratry persnnel wh have directly and indirectly served and cared fr the patients wh needed this therapy years ag befre it had been standardied. J. Starl TE (with the assistance f Putnam CW): Experience in Hepatic Transplantatin. Philadelphia, Sa unders, Starl TE, Prter KA, Putnam CW, el al: Surg GyneclObstet 142:487, 1976 REFERENCES 3. Starl TE, Kep LJ, Halgrimsn CG, el al: Gastrenterlgy 77:375, Starl TE, Iwatsuki S, Van Thiel DH, et al: Hepatlgy 2:614,1982