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Hepatic resection versus transplantation for hepatocellular carcinoma

During the 10-year period (1980 to 1989), 76 patients with hepatocellular carcinoma (HCC) were treated by subtotal hepatic resection (HX) and 105 patients by orthotopic liver transplantation (TX) under cyclosporine-steroid therapy. Overall 1- to 5-year survival rates of the HX group were 71.1%, 55.0%, 47.2%, 37.2%, and 32.9%, respectively, and those of the TX group were 65.7%, 49.0%, 39.2%, 35.6%, and 35.6%, respectively. The survival rates after HX and after TX correlated well with pTNM stages and were similar in each stage between the two groups. However, when HCC was associated with cirrhosis of the liver, the survival rates after TX were significantly better than those after HX at each stage of pTNM classification. The tumor-recurrence rate was high both after HX (50%) and TX (43%), particularly in advanced stages of pTNM classification (60% or more). Twelve patients after HX and 13 patients after TX lived more than 5 years during this 10-year period. Fibrolamellar HCC and early stages of HCC were highly represented among the long-term survivors. Further improvement in survival rates depends on nonsurgical anti-cancer therapy before and/or after surgical removal of HCC.

The Incidence, Timing, and Management of Biliary Tract Complications After Orthotopic Liver Transplantation

ObjectiveThis study analyzed the incidence and timing of biliary tract complications after orthotopic liver transplantation (OLTx) in 1792 consecutive patients. These results were then compared with those of previously reported series. Finally, recommendations were made on appropriate management strategies. Summary Background DataTechnical complications after OLTx have a significant impact on patient and graft survival. One of the principle technical advances has been the standardization of techniques for biliary reconstruction. Nonetheless, biliary complications still occur. A 1983 report from the University of Pittsburgh reported biliary complications in 19% of all transplants, and an update in 1987 reported biliary complications in 13.2% of transplants. MethodsThe medical records of all patients who underwent liver transplantation and were hospitalized between January 1, 1988 and July 31, 1991 were reviewed. The case material consisted of the medical records of 217 patients treated for 245 biliary complications. ResultsPrimary biliary continuity was established by either choledochocholedochostomy over a T-tube (C-C, n = 129) or a Roux-en-Y choledochojejunostomy with an internal stent (C-RY, n = 85). The overall incidence for biliary complication in this large series was 11.5%. Strictures (n = 93) and bile leak (n = 58) were the most common complications (69.6%). Most billary complications (n = 143, 66%) occurred within the first 3 months after surgery. In general, leaks occurred early, and strictures developed later. Bile leaks were equally frequent in both C-C and C-RY (27.1% and 25.9%, respectively); strictures were more common after a C-RY type of reconstruction (36.4% and 52.9%, respectively). Twenty-one patients died, an incidence of 9.6%. Fifteen of the 21 biliary-related deaths were among patients treated for rejection before the recognition of biliary tract pathologic findings. ConclusionsProgress has been made on improving the result of biliary reconstruction after OLTx. Nonetheless, patients continue to experience biliary complications after OLTx, and these complications cause considerable loss of grafts and life. If significant additional improvement in patient and graft survival are to be obtained, the technical performance of OLTx must continue to improve.

Baboon-to-human liver transplantation

Our ability to control both the cellular and humoral components of xenograft rejection in laboratory experiments, together with an organ shortage that has placed limits on clinical transplantation services, prompted us to undertake a liver transplantation from a baboon to a 35-year-old man with B virus-associated chronic active hepatitis and human immunodeficiency virus infection. Liver replacement was performed according to conventional surgical techniques. Immunosuppression was with the FK 506-prednisone-prostaglandin regimen used routinely for hepatic allotransplantation, to which a daily non-myelotoxic dose of cyclophosphamide was added. During 70 days of survival, there was little evidence of hepatic rejection by biochemical monitoring or histopathological examination. Products of hepatic synthesis, including clotting factors, became those of the baboon liver with no obvious adverse effects. Death followed a cerebral and subarachnoid haemorrhage that was caused by an angioinvasive aspergillus infection. However, the underlying cause of death was widespread biliary sludge that formed in the biliary tree despite a seemingly satisfactory choledochojejunostomy. During life and in necropsy samples, there was evidence of the chimerism that we believe is integral to the acceptance of both xenografts and allografts. Our experience has shown the feasibility of controlling the rejection of the baboon liver xenograft in a human recipient. The biliary stasis that was the beginning of lethal infectious complications may be correctable by modifications of surgical technique. In further trials, the error of over-immunosuppression should be avoidable.

Orthotopic liver transplantation for primary sclerosing cholangitis.

The incidence or diagnostic rate of sclerosing cholangitis is increasing. Because of the lack of effective medical or surgical therapy for patients with end-stage liver disease and sclerosing cholangitis, results with orthotopic liver transplantation were examined. The results of 55 consecutive liver replacements for this disease were reviewed. The 1− and 2-year actuarial survival rates are 71% and 57%, respectively. Orthotopic liver transplantation for end-stage liver disease from sclerosing cholangitis has emerged as the most effective therapy.

Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy : a clinicopathologic study of 96 patients

The effect of conversion from cyclosporine-steroid immunosuppression to the new agent FK506 was studied in 96 liver allograft recipients who were experiencing graft dysfunction or cyclosporine toxicity. Patients were stratified according to the cause of graft dysfunction that ultimately led to conversion to FK506. Response to FK506 introduction was monitored pathologically and biochemically. The outcome of a switch from CsA to FK506 was highly favorable in patients experiencing acute and the early stages of chronic rejection, despite optimal conventional therapy. Patients with later stages of chronic rejection did not respond to conversion to FK506 and most eventually lost their liver grafts in this process. Patients in whom we had difficulty separating chronic rejection from chronic persistent or low-grade chronic active hepatitis were mostly unaffected by conversion to FK506. Active hepatitis was a poor indication for conversion, because most of the patients experienced graft failure or died from liver failure. As a group, there was no statistically significant change in renal function 180 days after conversion to FK506. These findings expand the experience with FK506 in human liver allograft recipients.

Incidence, prevalence, and clinical course of hepatitis C following liver transplantation

Hepatitis C virus (HCV) is the agent responsible for posttransfusion hepatitis. The incidence, timing, and clinical course of HCV positive hepatitis in liver transplant recipients are unknown. Three hundred and seventeen donor-recipient liver transplant pairs were grouped on the basis of their pretransplant HCV antibody status. The biopsy findings were examined. Four distinct groups were identified on the basis of HCV serology: group I, both were negative; group II, donor was negative and recipient was positive; group III, donor was positive and recipient was negative; group IV, both were positive. The prevalence of anti-HCV positivity in recipients was 13.6%. The rate of seroconversion was 9.2%. Histologic hepatitis not ascribable to any specific cause other than non-A, non-B (NANB) hepatitis occurred in 13.8%. The incidence of histologic chronic active hepatitis was 1.6%, and none progressed to cirrhosis. The concordance rate for a positive anti-HCV serology and NANB hepatitis was 2.8%. Of the 35 patients (group II and IV) with positive anti-HCV serology pretransplant, only 17 were positive posttransplantation. Based on these data it can be concluded that posttransplant NANB hepatitis occurred in 13.8% of liver recipients. Twenty percent of these were anti-HCV positive. Progression to histologic chronic active hepatitis occurs over a period of 1-5 years in 1.6% of cases.

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.

AUGMENTATION OF RAT LIVER REGENERATION BY FK 506 COMPARED WITH CYCLOSPORIN

The immunosuppressive drug, FK 506, increased the regeneration response that follows 40% and 70% hepatectomy in rats. The effect was similar to that obtained with cyclosporin.

Reversal of hypersplenism following orthotopic liver transplantation

The purpose of this study was to clarify the effect of orthotopic liver transplantation on hypersplenism. In a 1-year period from July 1, 1986 to June 30, 1987, 196 adult patients underwent 233 orthotopic liver transplantations. Of the 58 patients with hypersplenism who were analyzed in this study, hypersplenism was more commonly associated with postnecrotic cirrhosis than other kinds of liver disease (55.3% (47/85) vs. 14.5% (11/76); p less than 0.001). Postoperative platelet counts were statistically higher than preoperative values (p less than 0.05). The latest platelet counts were more than 100,000/mm3 in 53 patients (91.4%). Of the eight patients whose preoperative and postoperative spleen volumes could be compared, all showed the reduction in the spleen size (p less than 0.02). We conclude that orthotopic liver transplantation, which is a radical surgical procedure for portal hypertension, reverses hypersplenism.

Randomised trialomania? The multicentre liver transplant trials of tacrolimus

In 1989-90 our group reported that tacrolimus (FK 506) could systematically control liver allograft rejection that had been intractable despite conventional cyclosporin-based immunosuppression.1,2 The “rescued” patients were maintained on tacrolimus, and manifested no unique or unexpected toxicity. Consequently, a pilot trial was begun in which tacrolimus was substituted for cyclosporin from the time of operation. By early 1990, nearly 200 liver, kidney, and other kinds of organ recipients who had been entered had superior actuarial survival, lower requirement for prednisone, and better quality of life than observed in our past experience.3,4 The upgrading of outlook after liver transplantation3 was as obvious as when cyclosporin succeeded azathioprine as the baseline immunosuppressant a decade before.5 By November, 1993, 1391 primary liver-transplant recipients had been treated in Pittsburgh with the new drug.6 Only 35 (2·5%) of the patients crossed over from tacrolimus to cyclosporin and 15 of these changed back when rejection supervened. The keystone management principle The new drug was user friendly. As with all previous baseline immunosuppressants,7-9 the management secret with tacrolimus was administration of doses up to the limit imposed by the drugs toxicity. Dose-manoeuvrable prednisone or other adjuvant agents were then added as needed to control or reverse rejection, or given prophylactically. Because the dose-limiting side-effects of cyclosporin10 and tacrolimus3,4,11,12 were the same (nephrotoxicity, neurotoxicity, and diabetogenicity), these organ-system-specific toxic manifestations could be used from the first day of treatment to determine dose ceilings; the occurrence of rejection helped to establish the floor. The folly of making invidious toxicity comparisons between cyclosporin and tacrolimus when the scales could be tilted one way or the other by ratcheting the doses up or down was self-evident.12 The only adverse effects observed exclusively with one but not the other drug were dose-related hirsutism, gingival hyperplasia, and facial brutalisation with cyclosporin.10 It was easy, as it had been a decade earlier with cyclosporin,13 to deduce the meaning of trough plasma and blood concentrations (the plasma/blood ratio was about 0·1) and to relate these to toxic manifestations, rejection, and the preceding tacrolimus dose. When we realised that the first Pittsburgh patients had been overdosed, this was corrected in subsequent cases within a few postoperative days or hours by responding to the clinical events with flexible dosing. Nevertheless, we had lowered both the starting intravenous and oral doses in Pittsburgh by January, 1990;12 subsequently these were reduced again.14 These were important revisions no matter what the transplanted organ but especially so with the liver because the metabolism of tacrolimus is more dependent than that of cyclosporin on good hepatic function. 12,15,16 In addition, absorption of tacrolimus is little disturbed compared with that of cyclosporin by the absence of bile or by intestinal disorders. 15 These and other details of the pharmacokinetics of tacrolimus, dose ranges, appropriate management strategies, and adverse events were well worked through by the time of meetings to organise multicentre trials in March, 1990. 3 weeks later, the same data were presented to the American Surgical Association (on April 5, 1990) and a manuscript was published 5 months later on the eve of the multicentre trials.