Corman, J

Dubois, RS

Groth, CG

Halgrimson, C

Rodgerson, DO

Starzl, TE

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1 t I • ., I 1 l Reprinted from Em.vme Therapy in Genetic Di,ca>e, Hirth Defect, lql~inal ArtICle SeTle> March z~1T:1K \"01 IX. :-;" ~K C"l1\Tl"h! ([; The '"tiona] Foundntinn Printed in thi- [~nitcd -"DtaI·fDK~ (1/ Arnc,.ica Hepatic Transplantation in Wilson Disease* CARL G. GROTH, M.D.; RECBEN S. DUBOIS, M.D.; JACQUES CORMAN, M.D.; CHARLES HALGRIMSON, M.D.; DENIS O. RODGERSON, Ph.D. AND THOMAS E. STARZL, M.D., Ph.D. Two teen-age males with Wilson disease underwent orthotopic liver transplantation 32 and 12 months ago. One of the patients had normal serum ceruloplasmin and copper before as well as after operation. In the other case, these measures rose from low to normal values after transplantation. Both boys had increased cupriuresis after the operation. Biopsy specimens of the graft in one of the patients have shown no accumulation of copper. Wilson disease is an inborn error of metabolism characterized by an elevated copper content in the liver, brain and other organs. a low lewl of the copper-binding plasma protein ceruloplasmin. low total serum copper and ele\'ated urinary copper excretion. Pigmentation of the cornea with copper is visible on slit-lamp examination as the so-called Kayser-Fleischer ring. Any or all of these diagnostic criteria except the first mentioned may. however, be absent and the primary genet ic abnormality in Wilson disease remains obscure. 1 Earlier, clinical emphasis was usually on neurologic symptoms but in more recent years it has become apparent that almost all patients suffering from this disease have cirrhosis of the liver. Two teen-age boys with advanced Wilson disease have been treated with orthotopic hepat ic transplan-tation at our institution. One of them was in terminal hepatic failure 2 while in the other the indication for the procedure was cirrhosis of the liver and se\'ere neurologic involvement not controlled by conven-tional chelating therapy. • Aided by research grants from the Veterans Administration, by Grants RR-0005! and RR-00069 from the general clinical re-search centers program of the Division of Research Resources, National Institutes of Health and b\· USPHS Grants AI· 101/6-01. AI-AM-08898, AM-O/IIi. GM-OIB86 and HE-091l0. Groth-Associate Professor of Surgery. University of Colorado School of Medicine. Denver. Dubois-Assistant Professor of Pediatrics, University of Colo-rado School of Medicine. Corman-Assistant Professor of Surgery. University of Colorado School of Medicine. Halgrimson-Assistant Professor of Surgery. University of Colo-rado School of Medicine. Rodgerson-Assistant Professor of Pediatrics, University of Colorado School of Medicine. Starzl-Professor and Chairman of Surgery, University of Colo-rado School of Medicine. CASE REPORTS Case 1. Clinical Course. An ll-yr-old boy was admitted in July 1969, in hepatic precoma. The diagnosis of a liver disorder had been established at the age of P when an open liver biopsy showed "postnecrotic" cirrhosis. At that time serum copper and urinar:, copper excretion were normal. In April 1969, he was admitted to another hospital with symptoms of advanced liver disease and a biopsy again showed cirrhosis with the additional finding of Mallory bodies. This biopsy was interpreted as being consistent with Wilson disease. There were no Kayser-Fleischer rings and serum ceruloplasmin was within normal limits. When the patient was transferred to our institution 2 rna later. he had massive ascites. The serum bilirubin was 20.6 mg per 100 m!. the serum albumin 1.5 gm per 100 m!' the prothrombin time 13S'C of normal and hlond ammonia 43:2 f.lg nitrogen per 100 m!. Serum ceruloplasmin values were 26-31 f.lg per 100 f.ll using an enzymatic assay (normal 2:2-43 J.1.g per 100 ILl). Shortly after arrival the patient developed upper gastrointestinal hemorrhage and became agonal. At this time the patient's liver was removed and replaced with an orthotopic hepatic homograft from a cada\'eric donor. J Posttransplantation there was an immediate clearing of the sensorium. a fall in the serum bilirubin and blood ammonia levels, an increase in the total serum protein, and a normalization in the prothrombin time (Fig. 1). The patient was treated with an immunosuppressi\'e regimen that included azathioprine. prednisone and antilym-phocyte globulin. Two early rejection episodes occurred, 1 after a few days and the other after 3 wk. At the time of the 2nd episode there was an extreme degree of hyper-bilirubinemia and raIsed alkaline phosphatase (Fig. 1). Reversal of the rejection was followed by 1 yr of normal graft function but the succeeding yr again saw 2 episodes of moderate graft dysfunction. Presently, :2 yr and 8 rna after transplantation, the patient is clinically well with a biliru-bin of 1.8 mg per 100 m!. He has had no demonstrable neurologic impairment after transplantation. No dietary limitations have been imposed and chelating agents have never been administered except during a brief test. Birth Defects: OriRinal Article Series. Vol. IX, No.2; March 1973 106 Carl C. Groth, M.D. ct al 107 ------------------------------------------------------------------------studies ut thf' Copper Metabolism after Transplanta-linn. The patient'" diseased !i,'er contained 2J6 /-Ig copper per gm wet wt (normal less than 20). Following the trclDsplantat ion there was a massi,'e cupriuresis which declined to normal (less than 30 /-Ig per 24 hr) after several mo (Fig. 2). At the end of 7 mo a 3-day course of D-penicillamine 0.5 g/day) was given and there was a 20-fold increase in urine copper excretion, which then rapidly returned to normal (Fig. 2). This increase is somewhat higher than that found in normal persons. From 15 mo onwards urine excretion has again been slightly to moderately elevated (maximum 255 /-Ig per 24 hr). During the 2 yr and 8 mo of follow-up, serial serum ceruloplasmins have varied from 29,5 to 55 mg per 100 ml and coincidentally measured total serum coppers have ranged from 80 to 171 /-Ig per 100 ml (normal 70-118). Homograft biopsies obtained 6, 17 and 28 rno after transplantat ion contained 15, 13 and 7 /-Ig copper per gm wet wt. Ca.,<;e 2. Clinical course. This boy was found to have cirrhosis of the liver at 11 yr of age when he presented with ascites and a serum bilirubin of 9.5 rng per 100 ml. The following yr he showed an improvement but at.13 yr he was admitted to our institution following 2 episodes of hema-SGOT (I v) ALKALINE PI-IOSPHLTASE (i u) SERUM PRC·T tIN OT 27 II YO Cf (3 m:\ ."f-Of' C 10 2C 30 ~ 5C 6C 7'C!K:2 16 20 24 28 32 36 40 44 48 52 14 1£ 18 TJI.4E IN DAYS TIME IN W£El<S MONTHS Fig. I. The course and the immunosuppressive treatment in Case 1. (Adapted from Lancet i:505, 1971.) \00°1 A. .... :9 74 ) '00 480 :')ZO TIME IN DAYS POST - TRANSPLANTAT!ON Fig. 2. Urinary excretion of copper after transplantation in ('ase 1. (Aclapted from Lancet i:505, 1971.) temesis. At this time, Kayser-Fleischer ring-s were detected and serum ceruloplasmin was found to be distinctly subnormal at 1.0-1.7 mg per 100 ml. Total serum copper was low, 22.4-35 /-Ig per 100 ml, while the urinar.v excretion of the metal was elevated to 340-520 /-Ig per 24 hr. An open liver biopsy revealed "postnecrotic" cirrhosis, the copper content of the specimen was 392 /-Ig per gm wet wt. The diagnosis of Wilson disease was thus established and the patient was put on a low-copper diet and chel ating therapy was instituted with D-penicillamine and triethyline tetra-mine dihydrochloride. 'In spite of increased cupriuresis the patient's neurologic status deteriorated, with athetot.ic movements, dvsarthria and mental disturbance. At 14 yr of -age, in March 1971, the patient underwent orthotopic hepatic transplantation. At this time t he serum bilirubin was 2.9 mg per 100 m\, serum albumin was 2.9 gm per 100 rnl, and prothrombin time 44'ic of normal. Postoper-ative immunosuppression was the same as in Case 1, except that cyclophosphamide was given instead of azathi-oprine during the 1st 9 mo. Following 1 mo of normal graft function, the serum bilirubin and the alkaline phosphatase rose rapidly to reach a maximum of 9.7 mg per 100 ml and 952 IU, respectively (Fig. 3). The concurrent finding of Australia antigenemia suggested serum hepatitis. The bilirubin returned to normal in 1 mo while the alkaline phosphatase required several rno to recover (Fig. 3). Presently, 12 mo after transplantation, graft function is normal. During the 1st postoperative rna there was an improve-ment in the patient's neurologic status but subsequently the symptoms from the nervous system have recurred intermittently. The Kayser-Fleischer rings have not changed during the 12 mo of follow-up. Studies of Copper Metabolism after Transplantation. The removed, native liver contained 184 /-Ig copper per gm wet wt. After the hepatic transplantation, serum cerulo-CERULOPLASMIN (mg/lOOmll TOTAL SERUM COPPER (»g/lOOml! HEPATIC TRANSPLANTATION 80 70 60 ~l 40 ;0 20 10 Ot-4--------------------------------400 300 200 D~t-4=~-----------------------------URINE 500 600  COPPER EXCRETION;gg \ 1\ (,IIg/24 h'l ~gg \rJ ~ "-----ALKALINE PHOSPHATASE (W) BILIRUBIN (mg/lOOmll PREDNISONE (mg/doyl CYCLOPHOSPHAMIDE (mg/doyl a 1000 ml ~~K logt-~=::::=:::KKKK--------------------~ 10 l~~----~~~~~~~~====-== 200 100 o 100 200 ~~~A~~~~~ o 10 20 30 40 50 60 70 80 90 100 110 t20 130 140 150 DAYS AFTER TRANSPLANTATION Fig. 3. The course and the immunosuppressive treatment in Case 2. 108 HEPA TIC TRANSPL4NTA TION IN WILSON DISEASE plasmin and copper rose. to reach normalleveb after :2 wk (Fig. 3). Urinary copper excretion fluctuated between 60 and 600 ~g per 24 hr for 4 mo and then stabilized around 100 ~g (Fig. 3), Discussion Since most of the symptoms and signs of Wilson disease were lacking in the first of these two patients. the diagnosis was missed and chelating therapy had never been instituted. Following operation, the high copper concentration in the native liver and the presence of Mallory bodies in the specimen estab-lished the diagnosis. In addition, indirect evidence of extensive copper deposition in extrahepatic tissues was provided by the cupriuresis which followed operation. In contrast, the second patient had every classic manifestation of Wilson disease and low-copper diet and therapy with chelating drugs had been tried for more than 1 year. In spite of this, the patient's neurologic symptoms progressed to a stage where he was severely crippled. Following hepatic transplantation, both patients had an increased excretion of copper. In the second patient. low serum ceruloplasmin and copper rose to normal levels. Biopsy specimen of the graft in one of the patients has shown no accumulation ofthe metal. These findings are consistent with the hypothesis that the metabolic defect in Wilson disease is liver based. However, the facts that urinary copper excre-tion has stayed moderately elevated in both cases, and that the Kayser-Fleischer rings of the second patient are unchanged, indicate that the ex-trahepatic copper stores remain abnormal in these patipnts. REFERENCES 1. Beam, A. G.: Wilson's disease. In The Metabolic Basis of Inherited Disease. 3rd Ed, eds, J. B. Stanbury. J. B. Wing-aarden and D. S. Fredrickson. McGraw-Hill, New York, 1033, 1972. 2. Dubois, R. So; Giles, G.; Rodgerson, D.O.; Lilly, J.; Martineau. G.; Halgrimson, C. G.: Shroter, G.; Starzl, T. E.: Sternleib, 1. and Scheinberg, 1. H.: Orthotopic liver tram;plantation for Wilson's disease. Lancet i:.505. 1971. 3. Starzl, T. E. and Putnam, C. W.: Experience in Hepatic Transplantation. W. B. Saunders, Philadelphia, 1969. 4. Dubois, R. S.: Rodgerson, D.O.: Slovis, T. L.; Hambidge, K. M. and Bianili, T. A.: Use of triethylene tetramine dihydro-chloride in the management ofWilson's disease. Lancet ii:775. 1970. 

Hepatic transplantation in Wilson disease.

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Hepatic transplantation in Wilson disease.

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