Corman, J

Groth, CG

Gustafsson, A

Iwatsuki, S

Kashiwagi, N

Schroter, G

Starzl, TE

Torisu, M

Name not available

Some aspects of the protein metabolism in human liver transplant recipients

D-Scholarship@Pitt

Some Aspects of the Protein Metabolism in Human Liver Transplant Recipients C. G. Groth, N. Kashiwagi, M. Torisu, G. Schroter, A. Gustafsson, J. Corman,S. Iwatsuki, T. E. Starzl In early experimental and clinical studies, the not unexpected finding was reported that most of the electrophoretically measurable protein fractions declined rapidly after the im-plantation of a poorly functioning hepatic ho-mograft. In contrast, these fractions were well maintained after provision of a well functioning graft. A similar relationship between quality of graft function and pro-,ein levels was found also for the liver-based clotting factors. The changes in these latter factors were very rapid and reflec-ted changes in consumption as well as synthesis [Z]. Studies of Complement Recently, the plasma proteins of the complement system were assayed in five recipients of hepatic homografts [3]. All the patients were in terminal liver failure due to cirrhosis, chronic hepatitis or Wilson's disease. Following replacement of the patients' diseased livers with well functioning homo-This work was supported by research grants from the Veterans Administration, by grants RR-oOOSl and RR-00069 from the general clinical research centers program of the Divi-sion of Research Resources, National Institutes of Health, and by grants AI-AM-08898, AM-07772. and HE-09UO of the United States Public Health Service. grafts, total complement activity as well as the C4 and C3 component activities, rose from distinctly low to normal levels. At the same time, the Cs component incre-ased from low to high normal (Figure 1). In contrast, the Cz and C9 components remained normal throughout, while C1 showed variable changes. Good subsequent CHoO 11111tS/1ll1 C4 ul1lts/1ll1 : thousands I ~f ~ ;1!1) before after before after C J 1I111ts/ml C" Illg I III I I thousands I 150 I '0) t-18 125 8 100 6 75 4 50 2 25 0 , , 0 Ilt'fOle (dtl:r befolt, dll,;1 Fig. 1 Levels of total complement activity (CH 50) and of the components C4, C3 and CS, before and 7-10 days after orthotopic he-patic transplantation. Each line represents an individual patient. Normal range is indicated by a heavy line along the ordinate. 58 graft function was accompanied by normal complement levels except in one patient who exhibited supernormal values for sev-eral months. Some of the recipients developed postoper-ative liver function abnormalities that were thought to be due to homograft rejection. Concomitantly, there were marked de-creases in total complement activity and in the C4 and C3 components (Figure 2). One of these patients later developed biliary obstruction which required surgical correction. At this time there were no changes in the complement system. Two other patients had temporary liver dysfunction at a time when steep rises in Australia antigen titers indicated the occur-rence of serum hepatitis. In one of these patients, a transient decrease in complement activities was recorded, but in the other, the complement remained unaffected. Based on the above data, it has been con-cluded that complement assays might aid in the otherwise equivocal diagnosis of re-jection. In addition, as has been completely discussed elsewhere [3], the data are con-sistent with the hypothesis that the liver is a main or possibly even the sole source of the C4, C3 and C5 components of the complement system. Inborn Errors of Protein Metabolism In several liver transplant recipients, the genetically determined phenotypes of the a-globulins haptoglobin and group spe-cific component have converted to those of the donors. This indicated that the hepa-tic homograft retained its metabolic specifi-city in a new host and that liverbased in-born errors of metabolism should be correctable by the provision of a new, normal liver. There have not yet been any successful liver transplantations for proven inborn Some Aspects of the Protein Metabolism errors of hepatic metabolism. However, two teenage boys have undergone liver replace-ment for Wilson's disease, a disorder that has been speculated to be due to some fundamental hepatic defect. The course of the first patient has been reported earlier [1]. Following transplantation, there was a marked cupriuresis and biopsy specimens have shown no accumulation of copper in the graft as had occurred in the native liver. The patient is presently alive and well three years after transplantation. The second patient when first seen by us at age 11, had cirrhosis of the liver, a very low level of the coppercontaining serum protein ceruloplasmin, a high liver copper, Kayser-Fleischer rings, and the characteristic histopathologic findings in a liver biopsy of Wilson's disease. In spite of treatment with chelating agents, the patient became severely crippled by neuro-logical symptoms. At the age of 14, he underwent orthotopic hepatic transplan-tation. Except for an early period of graft dysfunction, probably caused by serum he-patitis, liver function has been norma) during a follow-up of 15 months (Figure 3). After transplantation, serum ceruloplasmin and total serum copper rose to norma) levels and have remained 50. An initially elevated urinary excretion of copper has declined toward normal (Figure 3). Biopsy specimens of the homograft have shown no accumulation of copper. The findings are consistent with the hypothesis that the ~ Fig. 2 Changes in the complement system in a patient who developed liver dysfunction 3 weeks after operation presumably due to re-jection. Note the concomitant marked drop in total .complement and several of the compo-nents. Subsequently, biliary tract obstruction was diagnosed without the occurrence of chan-ges in complement. The patient succumbed 16 days later; shortly before death complement levels again decreased (By permission of Clin. Exp. Immuno!.). · ....... __ ... _._----Some Aspects of the Protein Metabolism CH50 (units/mil IA50 (reciproc;al of titer) C1 C4 C2 C3 C9 (units/mil Clq (mg/ml) C4 (mg/mil C3 (mg/ml) C5 (mg/ml) SGOT(I.U.) ~RDDDp_qgrg Bilirubin (mgI100ml) Total Protein Albumin rKRl1?_b~lin Azathioprine (mg/day) PrednisonE> (mg/day) ALG Hepatic Transplantation • o 10 20 ..... "" ..... ......... 30 40 59 1-60 Time in days 60 Ceruloplasmin (mg/100ml) Total Serum Copper (ug/100ml) Urine Copper Excretion ().Jg/24 hr) SGOT ow-SGPT (I.U.J----Alcaline Phosphatase (I.u.) Bilirubin (mg/100ml) Hepatic Transplantation Some Aspects of the Protein Metabolism Prednisone rmI i'ng/day) nl11llttlllflrttllltt 1 Hydrocortisone RMa~ Cyclophosphamide Azathioprine ~g/dayF -CJ o 10 20 60 70 80 90 100 110 120130 140 Days 7 9 11 13 Months Fig.3 The course of the second patient treated with orthotopic hepatic transplantation for Wilson's disease at the University of Colorado. Note the prompt recovery of serum cerulo-plasmin after transplantation. metabolic defect in Wilson's disease is liver-based, although they do not prove it. Summary The important relationship between he-patic homograft quality and the mainte-nance of plasma proteins is reemphasized. The results of serum complement assays in liver transplant recipients are presented. The recovery of the copper-containing protein cer-uloplasmin after hepatic transplantation for Wilson's disease along with a cessation of hepatic copper accumulation is described. References: 1. Dubois, R. S., G. Giles, D. O. Rodgerson, 7. Lilly, G. Martineau, C. G. Halgrimson, G. Schroter, T. E. Starz!: Orthotopic liver transplantation for Wilson's disease. Lancet 111971, 505 2. Starzl, T. E. C. W. Putman: Experience in Hepatic Transplantation. Philadephia, Saun-ders, 1969 3. Torisu, M., T. Yokoyama, P. F. Kohler, A. L. Durst, C. Martineau, G. Schroter, H. Amemiya, C. C. Groth, T. E. Starzl: Serum complement after orthotopic transplantation of the human liver. Clin. expo Immuno!. In press, 1972 

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Some aspects of the protein metabolism in human liver transplant recipients

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