Giles, G

Halgrimson, CG

Lilly, JR

Martineau, G

Penn, I

Putnam, CW

Schroter, G

Starzl, TE

Takagi, H

PubMed

Name not available

Indications for orthotopic liver transplantation: with particular reference to hepatomas, biliary atresia, cirrhosis, Wilson's disease and serum hepatitis

D-Scholarship@Pitt

I \ Indications for Orthotopic Liver Transplantation: With Particular Reference to Hepatomas, Biliary Atresia, Cirrhosis, Wilson's Disease and Serum Hepatitis By T. E. STARZL, G. GILES, J. R. LILLY, H. TAKAGI, G. MARTINEAU, G. SCHROTER, C. G. HALGRIMSON, 1. PENN AND C. W. PUTNAM HEPATIC TRANSPLANTATION has passed through the feasibility stage of development since survival of humans for as long as 2~ years has been achieved following removal of the liver and its replacement (orthotopic transplantation) with a cadaveric homo-graft. Consequently, the position will be taken that liver transplantation is a legiti-mate albeit imperfect form of treatment. With this attitude, there is not a question about the propriety of clinical hepatic transplantation but only about the circum-stances under which it should be consid-ered. The opinions to be developed will be based primarily upon our own experience with orthotopic transplantation,1 although the reader is also referred to the important observations of Calne,2 Fortner et al.,3 and Birtch and Moore.4 METHODS Thirty-three consecutive orthotopic liver re-cipients, aged 11 months to 68 years, were treated from March 1963 to January 1970 by techniques described elsewhere.1 The first 25 cases were thoroughly documented in a recent book;1 the last eight have not been previously reported. In addi-tion, a more recently treated patient will be men-tioned briefly because of the specially interesting circumstances of treatment in the presence of Australia antigenemia. Immunosuppression of the first seven recipients was ,vith azatllioprine and prednisone. All subsequent patients were also From the Departments of Surgery and Pediatrics, University at Colorado School of Medicine, and Denoer Veterans Administration Hospital, Denver, Colo. Supported by USPHS Grants AM-12148, AI-AM-08898, AM.(J7772, Al.(J4152, RR-00051, RR-00069, HE"()911O and GM.(J1686. given heterologous antilymphocyte globulin (ALG). RESULTS Hepatoma The preoperative diagnosis of hepatoma was the reason for proceeding with the liver replacement of 12 of the 33 patients including six of the first eight. Six of these 12 recipients had underlying cirrhosis of the Laennec, postnecrotic and biliary varie-ties in three, two and one instances, re-spectively. The biliary cirrhosis was in a 10-year-old child with biliary atresia. An additional unsuspected small hepatoma was found in the liver of another child treated for intrahepatic biliary atresia, making a total of 13 cases available for observation. Early deaths. Seven of the 12 patients with prospectively diagnosed primary can-cer of the liver died from 6~ to 39 days after orthotopic hepatic homotransplanta-tion. Five of these cases were among the first seven in our experience; an important contributory cause of failure was the invari-able use of livers that had been badly damaged by ischemia.1 The other two pa-tients who were treated at a later time died of technical accidents with subphrenic abscesses and bile peritonitis, respectively. At autopsy, an exhaustive search was made to determine if any metastases had been missed with the preoperative survey and the operative examination. No residual tumor was found in 6 of the 7 recipients. In the other patients who died 7~ days after transplantation, there had been previously 30R TRANSPLANTATION PROCEEDINGS, VOL. III, No.1 (MARCH), 1971 L"'DlCATIONS FOR ORTHOTOPIC LIVER TRANSPLANTATIONS 309 Table I.-Fate of Six Patients Who Received Liver Replacement for Indication of Hepatoma and Lived Long Enough After Operation to Permit Observations About Course of Malignancy Patient Metastases Number First Location Metastases Organs Detected First Treatment of to Ultimately Cause of Death ( days postop. ) Metastases Metastases Homograft Involved & Time OT 8 90 Lungs Vincristine sulfate; Yes Brain., lungs, liver, other Carcinomatosis, 5 FU; surgical exci- abdominal organs 400 days sion of intra abdomi-nal masses; local Xray therapy to pelvis OT 14 380 Diaphragm, liver, Yes Mediastinum, pleural Carcinomatosis; dis-retroperitoneal cavity, diaphragm, ruPted cholecyto-space retroperitoneal space, duodenostomy,432 liver, pancreas, other days" abdominal organs OT 15 60 Lungs Yes Lungs, liver, diaphragm Carcinomatosis, 339 days OT 23 29 Lungs Yes Brain, lungs. liver Carcinomatosis, retroperitoneal space 143 days OT 26 59 Lungs No Lungs Gastrointestinal hem-orrhage, 76 days OT 33 t None found Alive, 9 months .. Retransplantation had been carried out at 380 days, at which time the first metastases were discov-ered. By the time of death 52 days later, the extension of the metastases was pronounced. t The diagnosis was an incidental finding in the liver specimen which had been removed because of biliary atresia. unsuspected spread to a lumbar vertebra. Prolonged survival. The other six: re-cipients, including the one with an inci-dental hepatoma, lived through the immedi-ate effects of the operation and became available for longer term studies. In all six, hepatic cell carcinoma (hepatoma) was the histologic diagnosis. Five of the patients died 76, 143, 339, 400, and 432 days after operation (Table 1). Recurrent neoplasm was responsible for the death of four of the recipients. The fifth (OT 26) died of other causes but had developed a metastasis to the left lung. The most common sites of spread (Table 1) were the lungs and the liver homo grafts (four examples each). The only patient with hepatoma still sur-viving is the 4-year-old girl with biliary atresia whose tumor was not known in ad-vance to be present. In this case sera were examined by Dr. Elliot Alpert of the Peter Bent Brigham Hospital, Boston, for the presence of the fetoprotein which when found essentially always signifies the diag-nosis of hepatoma.5 Fetoglobulin was found in the preoperative sample. Mter transplan-t tation, the abnonnal protein persisted for \ '\ more than 5 months, but in diminishing quantities until it finally disappeared. The child is in excellent condition 9 months postoperative with no evidence of recur-rence. Biliary Atresia There were 15 patients, aged 11 months to 5 years, with biliary atresia (13 extra-hepatic and two intrahepatic), including the child whose excised liver was later dis-covered to contain a small hepatoma. Early deaths. There were six: deaths within the first 40 postoperative days. These were caused by hepatic necrosis probably due to postmortem donor ischemia (two examples), thrombosis of the hepatic artery or portal vein (one example each), non-thrombotic occlusion of the hepatic artery (one example), and generalized infection and pneumonia associated with partial biliary tract obstruction and cholangitis. Apart from the small size of the struc-tures that had to be anastomosed, the atresia patients presented problems caused by a high incidence of anomalies. Three of the six early deaths listed above We1'e due 310 to technical accidents in patients who had anatomic variations including a hypoplastic portal vein, a fan-like hepatic arterial sup-ply of diminutive host vessels too tiny to permit anastomosis, and a peculiar malrota-tion in which the portal vein passed an-terior to the duodenum. These and other anomalies which constitute a special hazard in recipients with biliary atresia have been described elsewhere.! Later deaths. Four of the nine patients who lived beyond 40 days died after 61, 105, 133 and 186 days. All four deaths were caused by regional hepatic gangrene of which the essential cause was apparently too little immunosuppression. \Vith the cor-rection of this defect in treatment and with attention to fixation of the liver to prevent distortion of the blood vessels,1 the compli-cation of septic hepatic infarction was eliminated and has not been observed since November 1967. Three of the other five recipients are still alive after 9, 12, and 26 months. The two other children died after 13~ and 30 months. The original homograft of both of these patients underwent slow rejection. In the first case, retransplantation was carried out after 68 days. The second transplant then supported life for a year before fail-ing. The other child died 2~ years after a first orthotopic transplantation and 2)~ weeks after regrafting. The second trans-plantation was greatly complicated by the fact that the portal and superior mesenteric veins had thrombosed and undergone ca-vernous transformation. The immediate cause of death was bacterial peritonitis. Cirrhosis Six patients were treated, with the dis-appointing record of five early deaths. Rea-sons for the heavy acute mortality included the wretched condition of the recipients at the time of operation, major hemorrhage due to portal hypertension and the depres-sion of normal coagulation, and technical or metabolic mishaps. STABZL ET AL. Alcoholic cirrhosis. Three patients aged 33, 39, and 50 years died 10, 13 and 3 days respectively after operation. Obstruction of the homograft biliary drainage system had been accidentally produced in one recip-ient. The second developed bile peritonitis after disruption of a choledochocholedocho-stomy. The third suddenly became un-conscious a few hours post-transplantation and never awakened; the cause for the neurologic calamity was not evident at autopsy. Postnecrotic cirrhosis. The two recipients, aged 8 and 15, had evidence after trans-plantation of massive liver necrosis. They failed to wake from anesthesia and died after ~ and 9 days. Wilson's disease. The ll-year-old child was admitted in hepatic precoma. After liver replacement, he had a grave rejection crisis, the most severe one we have ever seen with recovery. His bilirubin rose to 48.6 mg. per cent but eventually the process was reversed, so that now he has com-pletely normal liver function 14 months later. A number of special studies are being reported by DuBois and his associates.6 Briefly, the copper content of the excised liver was 216 f1.g./ Gm. wet tissue weight (normal less than 15 f1.g. ). The preoperative ceruloplasmin was 30 mg. per cent (low normal) and the urine copper 50 f1.g./24 hours. After transplantation the ceruloplasmin rose to 40 mg. per cent. The urine copper increased to more than 300 f1.g./ 24 hours, before slowly returning to normal (less than 30 f1.g./ day) in the ensuing weeks. After 6 months, a homograft biopsy was obtained. The copper content was less than 15 f1.g./Gm. wet tissue. The Question of Hepatitis Another case will now be recorded in ad-dition to the 33 consecutive ones compiled 9 months or longer ago. On August 8, 1970, a 28-year-old woman with chronic active hepatitis was treated with orthotopic liver INDICATIONS FOR ORTHOTOPIC LIVER TRANSPLANTATIONS 311 transplantation. For at least 2 years before operation and even on the day of liver re-placement, immunodiffusion tests for the Australia antigen' had been positive. On the morning after operation, the Australia antigen had disappeared and it has not since heen found in any of the subsequent blood specimens. One month after opera-tion, the patient has not had a rejection and is in excellent condition. DISCUSSIOK The main objective of this paper was to review the indications for orthotopic liver transplantation. Because of the high rate of recurrent carcinoma in our own ex-perience, it has become policy in cases of hepatoma to consider liver replacement only under the most exceptional circum-stances. This does not mean that some recipients with hepatoma cannot be cured nor does it imply criticism of other trans-plantation groups who persist in similar therapeutic efforts. In fact, one of our recipients and one of CaIne's have no evidence at all of tumor recurrence and have probably been cured. Whatever the virtues and faults of liver replacement for hepatoma, by far the more desirable candidates for the procedures are those without neoplasms. On the average, the performance of orthotopic transplanta-tion for benign disease is more difficult since the patients tend to be sicker and to have more advanced portal hypertension. Ivloreover, if the diagnosis is biliary atresia, an increased incidence of vascular anoma-lies can be anticipated.1 Nevertheless, the longest survivors in the world after liver transplantation are patients who had biliary atresia. So far there have been few patients with cirrhosis who have bene:6.ted from liver transplantation. A reluctance to recommend such drastic therapy except in the agonal stages of the disease probably has been the main reason. Now that long-term survival and rehabilitation have been shown to be feasible, transplantation should be con-sidered at an earlier time, particularly in cases of postnecrotic cirrhosis in which the maximum value of medical management and of abstinence from alcohol has already been realized. However, an important question must be answered in a number of such candidates concerning the cause for the progression of the hepatic disease. In the last 2 years, many patients with "chronic aggressive hepatitis" leading to fatal cirrhosis have had demonstrated in their serum the "hepatitis-associated" or Australia antigen. The existing evidence suggests that the Australia antigen is the actual serum hepatitis virus.7 If this were true, antirejec-tion therapy could be predicted to per-petuate and even aggravate the systemic virus infection by reducing host im-munologic reactivity. The course of the patient whose Australia antigen test promptly became negative after liver replacement was decidedly against such pessimism, even though a follow-up is available for only a month. The immediate disappearance of the Australia antigen provided striking evidence for an essentially exclusive hepatic source of the antigenic factor, at least in the patient under discussion, whether this was the actual virus or something manufactured by the liver after induction by the virus. Observations of the child with Wilson's disease for 14 months after liver replace-ment provided another example of the im-portant ancillary information that has come from transplantation research. Insofar as can be determined in this recipient, an in-born error of copper metabolism was cured by provision of a new liver. It is possible that further studv of this and similar cases will permit identincation of the basic defect in Wilson's disease and resolution of the controversies8 about its etiology. SUMMARY Orthotopic liver transplantation has led . \ \ I I 312 to prolongation of useful life. Among the first 33 recipients at the University of Colorado, there were eight who survided a year or longer, as well as a ninth who is in perfect health after nine months. The prime indication for orthotopic liver trans-plantation is nonneoplastic hepatic disease. Treatment of hepatomas by liver replace-ment has been followed by a high incidence STARZL ET AL. of tumor recurrence. As of November 16, 1970 the patient whose Au antigen became negative after transplantation had no difficulty for 2~ months. Then, the Au antigen became posi-tive again and within a few days she de-veloped clinical and laboratory evidence of acute hepatitis from which she is now recovering. REFERENCES 1. Starzl, T. E.: Experience in Hepatic Trans-plantation. Philadelphia, Saunders, 1969. 2. CaIne, R. Y.: Transplantation Proc. 2:69, 1969. 3. Fortner, J. G., Beattie, J., Jr., Shin, M. H., Kawano, N., and Howland, W. S.: Ann. Surg. 172: 23, 1970. 4. Birtch, A. G., and Moore, F. D.: Trans-plantation Froc. 2:90, 1969. 5. Alpert, M. E., Uriel, J., and deNechaud, B.: New Eng. J. Med. 278:984, 1968. 6. DuBois, R., et al.: Unpublished. 7. Blumberg, B.S., Sutnick, A. 1., London, W. T., and Millman,!.: New Eng. J. Med. 283: 349,1970. 8. Walshe, J. M.: In Schiff, L. (Ed.): Diseases of the Liver. Philadelphia, Lippincott, 1969, pp. 796-814 . 

Indications for orthotopic liver transplantation: with particular reference to hepatomas, biliary atresia, cirrhosis, Wilson's disease and serum hepatitis.

http://d-scholarship.pitt.edu/3618/1/31735062108356.pdf

Indications for orthotopic liver transplantation: with particular reference to hepatomas, biliary atresia, cirrhosis, Wilson's disease and serum hepatitis.

Abstract

Similar works

Full text

Available Versions

Name not available

Name not available

D-Scholarship@Pitt