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The University of Toronto Liver Transplant Program:

Toronto Hospital, Hospital for Sick Children

Alan W. Hemming, Mark S. Cattral, Paul D. Greig,

Riccardo A Superina, Leslie B. Lilly, and Gary Levy.

 The University of Toronto Liver transplant program was initiated in 1985. Over the past decade it has developed into the largest program in Canada, performing between 80 and 100 liver transplants per year. This chapter serves to describe our program and its results, highlighting our interest in fulminant liver failure, primary non-function, viral hepatitis, and transplantation for malignancy.

 Program structure

The University of Toronto liver transplant program operates jointly out of The Toronto Hospital and the Hospital for Sick Children. Although these institutions are independent, geographic proximity and a close working relationship have fostered the development of living related and split liver transplantation. Since its inception, our program has promoted a combined surgical and medical approach to the management of patients with liver disease. Presently, hepatologists and surgeons manage patients on a rotational basis in both the preoperative and post transplant period. Outpatient management is handled similarly. Daily ward rounds are attended by both a surgeon and a hepatologist, which provides an optimal environment for teaching fellows and residents. Each week, the adult and pediatric teams meet to discuss new candidates for transplantation, to match potential adult and pediatric recipients for split liver transplantation, and to assess candidates for living related donation. The liver transplant program falls under the umbrella of the multiorgan transplantation program ,which includes transplantation activity in liver, kidney, heart, lung and kidney/pancreas. All transplant patients are managed in a single unit and most members of all transplant disciplines share a common office area.

Patient Selection

Patient selection criteria at the University of Toronto are generally similar to those used by other programs. Each potential recipient is assessed by a multidisciplinary team to determine candidacy and potential intra- and post-operative problems.

It has been our policy that patients with chronic liver disease, who have deteriorated to Grade 4 hepatic encephalopathy requiring ventilatory support, are not given priority as our results in this setting have been uniformly poor. Instead, they are supported with intensive medical management until they improve, at which time their candidacy is reassessed.

Alcohol related liver disease represents 12% of patients transplanted at our center. These patients with alcoholic liver disease are accepted for transplantation only after documentation of a 6 month abstinency period, demonstration of insight into their alcohol problem, and the presence of a good social support structure. A similar set of criteria are used for those patients with end stage liver disease secondary to hepatitis C acquired from intravenous drug use.  

Immunosuppression

We began our program using sequential immunosuppression consisting of Minnesota antilymphocyte globulin (MALG) induction along with cyclosporin A(CsA) and methylprednisilone. With MALG induction we observed acute rejection in approximately 55% of transplants. When MALG was no longer available a regimen of immediate intravenous CsA and methylprednisilone was used with oral CsA (Sandimmune) introduced with clamping of the T-Tube and return of bowel function (postoperative day 5). In many patients, a prolonged course of intravenous CsA was required before adequate absorption of Sandimmune could be established. Day to day variation in absorption made dosing management problematic. Using CsA and methylprednisilone, we saw no difference in the incidence of acute rejection as compared to our experience with MALG. Recently the new microemulsion formulation of CsA ( Neoral) has become available. The improved absorption characteristics of Neoral led us to conduct an open label comparison of 21 patients that received Neoral 12-15mg/kg/day divided twice daily without intravenous CsA to a control group of patients that received intravenous CsA and subsequently oral Sandimmune(1). Both groups received the same dose of methylprednisilone. Only one severely cholestatic patient in the Neoral group required the use of intravenous CsA for inability to maintain adequate trough CsA levels (Cmin). Both groups demonstrated similar Cmin and there was no difference in toxicity. Acute rejection in the Neoral group was significantly lower than in the group receiving intravenous CsA at 3 months (25%vs 65%). Thus, we no longer use intravenous CsA for induction immunosuppression. Our program remains interested in the investigation of new immunosuppressive agents and has developed a clinical trials unit for this purpose. Recruitment for the Canadian Liver Transplant Study Group trial of Neoral vs Tacrolimus and steroid reduction has recently been completed and patients are now in follow-up with analysis expected in mid to late 1997. We expect to begin enrollment of patients in a multicenter trial on the use of mycophenolate mofetil by the end of 1996 and to begin a phase 1 trial of rapamycin derivative in early 1997.  

Results

From October 1985 to November 1996, 735 adult and pediatric liver transplants were performed. The number of adult and pediatric transplants is shown in Figure 1. As is the case for most programs we are presently limited by the availability of suitable donor organs. Our waiting list has 40-60 patients at any given time and 10-15% die each year due to organ unavailability. Indications for transplantation are shown in Figure 2. In our adult population, end stage liver disease secondary to viral hepatitis (B and C) is the most common indication for transplantation. Retransplantation was performed in 7% of patients with transplantation of a third liver in 0.2% of patients.

Overall patient and graft survival is shown in Figure 3, however changes in our program during its evolution have led us to divide the ten year time period into three eras. (Figure 4)

During both periods 1985-88 and 1989-1992 one and three year adult patient survival were 75% and 70% respectively. This improved from 1993 to present with one and three-year patient survival increased to 86% and 81% respectively. The improvement in survival has been largely in the immediate post-operative period and represents better patient selection, improved operative technique and perioperative management. Survival rates for disease-specific indicators are shown in Table 1. Hepatitis B has proven to be a difficult challenge and our early results have modified our management over the course of the program. Causes of late graft loss are shown in Table 2. Recurrent disease in the graft remains the commonest cause of late graft loss and poses an ongoing challenge. The remainder of this chapter will deal with advances at our center in treatment for patients who have previously been known to have poor outcomes including fulminant hepatic failure, primary graft non-function, hepatitis B and C, transplantation for malignancy and will also discuss the causes of late graft loss. 

Fulminant Hepatic Failure

Fulminant hepatic failure (FHF) remains a serious medical problem with mortality rates ranging from 34% to 90% depending upon the etiology and stage of hepatic encephalopathy. To date there is no effective medical treatment for patients with fulminant hepatic failure. During this past decade, liver transplantation has revolutionized the treatment of patients with FHF. Advances in perioperative management, surgical technique, and immunosuppression, have led to one year survival rates in excess of 60%. However, survival for patients with stage four hepatic encephalopathy remains only 40-50%. The difficulty in predicting the natural history of the disease makes the decision to intervene with liver transplantation controversial. The high mortality rate associated with fulminant hepatic failure and the lack of specific interventions make early diagnosis and markers of prognosis of paramount importance in making management decisions, including proceeding to liver transplantation. We investigated the role of transjugular liver biopsy (TJLB) in the management of patient’s with FHF and assessed its predictive value for outcome in comparison with the King’s College criteria (2). Sixty one patients were analyzed who had presented to our institution with a presumed diagnosis of FHF. TJLB was safely and successfully performed in 60 of the 61 patients. In 34 of 54 patients (63%) the presumed clinical diagnosis was confirmed by TJLB; in 11 patients the procedure served to clarify clinical uncertainty, whereas in 9 of 54 (16.7%) the diagnosis was changed. The percentage of hepatic necrosis was the only histologic parameter to have significant discriminatory prognostic value with only 2 of 19 survivors having greater than 70% necrosis. In six of eight non survivors and two survivors with non acetaminophen induced FHF, in whom the King’s College criteria were inconclusive, the percentage of necrosis correctly predicted the patient’s outcome. We have found this procedure useful, allowing us to firmly establish the diagnosis of FHF, discriminate between survivors and non survivors and permits us to proceed to transplantation earlier allowing better outcomes.

Despite the proven success of transplantation for FHF, the severe shortage of organs limits accessibility. Less than 10% of eligible patients are estimated to receive transplantation. This argues for additional therapies to either prolong the course of FHF until a suitable organ becomes available or to reverse the process. Based on the beneficial effects of prostaglandins in various animal models of experimental liver injury (drug, ischemic, toxin and viral), studies were undertaken in our center to test prostaglandins in patients with necroinflammatory liver disease (3). Our first trial initiated in 1989 suggested that early treatment with PGE could attenuate the course of FHF and improve survival. Four subsequent open trials, conducted by other groups further explored the role of PGE in patients with fulminant and subfulminant viral hepatitis, and drug injury. However, the results of these studies were mixed with some showing a beneficial effect and others showing no benefit. Recently, a large randomized controlled double-blind trial was undertaken at our centre to confirm the protective role of PGE in acute liver failure (4). In this study, 41 consecutive patients with fulminant hepatic failure were treated with either intravenous prostin VR (PGE1) or placebo. Eight of 20 patients (40%) in the PGE1 group and 8 of 21 (38%) in the placebo group survived (p=ns). However, when patients were stratified according to the cause of FHF, PG significantly improved the survival of those with drug and toxin induced liver injury compared with placebo (55% versus 38%). Furthermore, the data suggested that treatment of patients early in the course of FHF (Grades I and II hepatic encephalopathy) was more effective (50% survival versus 38.5% ) than in the later stages. Thus, although this trial failed to show an overall benefit for PGE1 therapy in patients with FHF, our results and those of others suggest PGE1 may be useful in patients when given early in the course of the syndrome.

Ideally, the goal of therapy for FHF is to support liver function until time of transplant or until the patient’s own liver regenerates. Strategies that we are considering include an artificial hepatic support device (5) or orthotopic auxiliary transplantation of a reduced sized liver graft. After auxiliary liver transplant some patients have had successful regeneration of the native liver allowing for cessation of immunosuppression.

Studies Of Initial Graft Function

Initial liver function is a major determinant of morbidity and mortality following liver transplantation. In particular, the development of primary graft non-function (PNF) is a devastating complication that in its worst form resembles fulminant hepatic failure and requires urgent retransplantation. PNF rates of 5% to 10% were reported prior to 1990 and a number of donor-specific factors have been identified which predict the development of initial poor function (IPF) or PNF in the immediate post-operative period. In an analysis of the first 100 donors of adult grafts at the University of Toronto, the following donor factors were found to be independent predictors of IPF or PNF: age > 40 years, bilirubin > 20 mmol/l, hospitalization > 3 days (6). Hepatic steatosis has also been found to be an important risk factor for IPF or PNF and presently we will not use a graft with > 50% steatosis. We will however, use grafts with 30-50% steatosis, but only if the cold ischemic time of the graft is short. Studies performed in our laboratory have demonstrated that the sinusoidal lining cell is particularly sensitivie to cold ischemic injury which is distinct from warm ischemia. Cold ischemia also results in activation of sinusoidal endothelium, platelet trapping, with resultant sinusoidal thrombosis (7). Prostaglandins have significant effects on the hepatic microcirculation including vasodilatation. Furthermore, they have immunomodulatory effects on the Kuppfer cell including suppression of production of proinflammatory cytokines. Prostaglandins have also been demonstrated to have cytoprotective effects in a number of experimental models of acute liver injury including drug-induced toxic injury (acetaminophen, galatosamine, ethanol and carbon tetrachloride), warm ischemia, and viral hepatitis. In an open-label study of the effect of intravenous PGE1 in 10 patients with PNF, 8 responded with decreases in AST and prothrombin time within 12 hours. The 80% graft survival compared favorably to the 17% graft survival observed in the control non-treated group of 6 patients with a similar degree of initial graft failure. (8) This observation has been confirmed in 3 other open studies, and the routine used of PGE has been associated with PNF rates of less than 5%. Moreover, in a prospective randomized trial of PGE1 (n=78) versus placebo (n=82), the PGE group had improved renal function and a shorter ICU and total hospitalization stay. There was, however, no difference in the incidence of PNF or acute rejection. At our centre, the incidence of PNF has decreased over the past 5 years independent of the use of prostaglandins. At the University of Toronto, the incidence of adult graft loss from PNF within the first week following transplantation from 1991 - 1996 is less than 2%, compared with 5% seen from 1985 - 1990. This has occurred despite the expansion of donor criteria. Mean donor age has increased from 33 to 40 years with 13% of donors greater than 60 years of age in the recent period as compared to 4% of donors graete than 60 years in our early period. The oldest organ used has been from an 88 year old donor receiving inotropic support which had excellent function. The reasons for the reduction in IPN and PNF may include improved donor management, a policy of keeping the cold ischemic time to under 12 hours and caution in the use of steatotic livers. With this approach since 1993, prostaglandin has been instituted in only 5 patients over the past 3 years.

Hepatitis B

Because of the demographics of the greater Toronto area, cirrhosis caused by hepatitis B has been an important indication for transplantation within our program. Sixty-nine transplants have been performed in patients who were hepatitis B surface antigen (HBsAg) positive. In nineteen patients with hepatitis B, hepatocellular carcinoma represented the primary indication for transplantation; seven patients were transplanted for fulminant disease, and the remainder of hepatitis B patients were transplanted for end stage liver disease and cirrhosis. Severe recurrent disease in the allograft has been observed, particularly in recipients with markers of ongoing viral replication at the time of transplantation . Left untreated, recurrent hepatitis B led uniformly to rapidly progressive liver disease, and viral recurrence was the primary cause of patient death in 30% of transplants. A number of measures have been proposed in an effort to prevent graft reinfection. Patients who were HBV-DNA negative at the time of transplant were less likely to develop recurrent disease and, when it occurred, the recurrence was delayed. Thus, only patients who are DNA negative are currently considered for transplantation within our program. A reduction in the recurrence of HBV has been observed with the use of hepatitis B immune globulin (HBIG) administered during both the anhepatic phase and then post transplant titrated to maintain measurable HBsAb levels. In recent years, several patients have remained free of recurrent disease as long as antibody levels greater than 500 units/ml were maintained. Nevertheless, this measure clearly only postpones recurrence, even if HBIG is maintained indefinitely. Furthermore, this approach represents a considerable cost, inconvenience and drain on limited supplies. Thus, we are no longer using this approach.

Our group has used PGE in patients who had recurrent hepatitis B, and a series of 14 patients has been reported in detail. (9) During treatment, both serum and liver markers of viral replication decreased or even disappeared, with a concomitant attenuation of biochemical and histological evidence of liver inflammation. The best results were achieved in patients treated early after recurrence, although even patients in early liver failure appeared to receive some benefit from the drug. Initial treatment was with intravenous PGE, and the patients tolerated conversion to the oral preparation well. Currently, a number of patients remain on PGE for greater than 40 months post transplant, with no evidence of recurrent hepatitis B.  

Lamivudine (3TC) has recently been demonstrated to be effective in lowering HBV-DNA levels in the non transplant setting. Our program is currently involved in a multinational trial examining the role of this nucleoside analogue in the prevention and treatment of recurrence in transplant recipients(10). In the prevention trial, patients were treated for a minimum of 28 days prior to transplantation, and then maintained on the drug for a minimum of one year while DNA levels and other parameters suggesting recurrent disease were monitored. All patients enrolled lost serum HBV DNA by 2 months post-transplant. However, long-term follow-up has not yet been reported.

For patients receiving lamivudine (100 mg/day) for recurrent hepatitis, although all patients lost serum HBV DNA, at least two patients have had reappearance of HBV DNA at 6 months. Two patients have lost HBeAg, but none have lost HBsAg. In the few cases of breakthrough, there have been no changes in liver biochemistry or clinical symptoms. Furthermore, genetic analysis revealed mutations in the YMDD locus of the HBV reverse transcriptase gene. While early these results are encouraging and suggest that lamivudine may allow HBV patients to be considered for transplantation. 

Hepatitis C

End stage liver disease due to chronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation in most centers. In our program, one-third of transplants are now being performed for HCV. Persistence of HCV is universal after transplantation, and up to 60% of patients have an acute flare of recurrent hepatitis during the first 6 months. Over time, the majority of patients develop evidence of chronic hepatitis. Interestingly, HCV has not adversely affected 5-year patient and graft survival rates. There is however, a growing concern that with further follow-up, patients with hepatitis C will have a higher rate of graft loss. 

Our postoperative management of patients infected with HCV has evolved over the past 5 years. We generally use less immunosuppression than in patients who are not infected with HCV: prednisone dosage is tapered faster and in many cases eliminated by 6 months; and antimetabolites (azathioprine, mycophenolate mofetil) are not used. We are also more cautious about accepting the diagnosis of rejection from biopsies obtained for evaluation of elevated liver tests. In the majority of patients, the necroinflammatory activity appears to be due to HCV rather than to rejection. 

During the past 4 years we have also conducted an uncontrolled open-labeled study of ribavirin in liver allograft recipients with recurrent hepatitis C (11). Study inclusion criteria included serum aminotransferase activity > 2 x upper level of normal for at least 6 consecutive weeks, active hepatitis by biopsy, and the presence of HCV -RNA in serum by PCR. To date, only 19 patients transplanted during this period have met these criteria. Ribavirin was initially administered at dosages of 1000-1200 mg daily in two divided doses. In all patients, serum ALT values fell shortly after initiation of therapy. Only 5 (26%) had complete normalization of all liver tests, however. Comparison of pre- and 6 month post-treatment liver biopsies revealed that there was no significant difference in the overall hepatitis activity index; however, there was an improvement in the degree of necroinflammation. Ribavirin had no effect on the serum concentration of HCV - RNA. Overall, ribavirin has been generally well tolerated. Ribavirin-induced hemolysis has occurred in all patients, including significant anemia in 8 patients which improved after reduction of drug dosage. 

We found the discordance between the biological and biochemical response to ribavirin intriguing. The mechanism of action of ribavirin was investigated further in a murine model of hepatitis in our laboratory (manuscript in preparation). In this model, ribavirin had no effect on viral replication, but the proinflammatory response of macrophages to the virus was markedly depressed. Moreover, the T helper cell response was shifted towards a TH-1 rather than a TH-2 response. These data suggest that the beneficial effect of ribavirin is via modulation of the host's immune response to the virus rather than direct viral inhibition.

Although ribavirin clearly improves serum aminotransferase activity, the benefit was temporary, as relapse occurred soon after cessation of therapy. The lack of improvement in the hepatitis activity index after 6 months of therapy also raises concern about its long-term impact. In our opinion, ribavirin as single drug therapy will not be efficacious in patients with recurrent hepatitis after transplantation. The combination of ribavirin with another anti-viral agent such as interferon may prove to be more effective, as some recent pilot studies have suggested.

Transplantation for Malignancy.

Transplantation for malignancy remains controversial. Our early experience with cholangiocarcinoma in 6 patients yielded an 83% one year survival; however, only 1 of 6 is presently alive with the others succumbing to recurrent tumor. This recurrence rate is unacceptable and cholangiocarcinoma has become a contraindication to transplantation at our center. Two patients were transplanted for metastatic neuroendocrine tumors. Both died of recurrent tumor and we now feel that metastatic neuroendocrine tumor is not an indication for transplantation.

Our experience with transplantation for hepatocellular carcinoma has been more encouraging and has been reported previously( 12). Currently 54 patients have undergone liver transplantation for HCC at our center. All patients underwent standard pretransplant assessment including careful history and physical examination, hematological and biochemical evaluation, viral serology and PCR analysis for HBV DNA in HBsAg-positive patients, alpha feto protein, ultrasound/doppler examination of the liver, and liver biopsy. Patients underwent a metastatic screen including CT scan of the abdomen and chest, bone scan, and cytological examination of ascitic fluid if present. The presence of distant metastases, vascular invasion or extrahepatic spread into local lymph nodes, diaphragm or chest wall excluded patients from further transplant evaluation. Non-cirrhotic patients were listed for transplant only if their symptoms were limited to mild or moderate intermittent pain and if there was no ascites or jaundice. Patients with a single tumor nodule less than 10 cm were still considered for OLT in the absence of other contraindications. Multifocality was not considered an absolute contraindication, although the presence of greater than 3 nodules was a relative contraindication. Biopsy specimens of lesions were obtained in all non-cirrhotic patients and in cirrhotic patients with normal coagulation parameters and no ascites. Patients with poorly differentiated tumor were not considered for transplantation. No adjuvant therapy was administered either pre- or post-OLT. When a suitable donor organ became available, an intraoperative evaluation of the tumor was made, including multiple biopsies of regional lymph nodes. A back-up patient was available if transplantation was not possible. The recipient operation was performed in standard fashion. Post-transplant immunosuppression therapy was reduced in an attempt to decrease tumor recurrence.

There was no evidence of extrahepatic spread, macroscopic vascular invasion or lymph node metastasis in any of the patients who were transplanted. Overall 5 year Kaplan Meier survival was 42%(Figure 5). Patients transplanted for HCC who were infected with hepatitis B did very poorly; only two of 19 patients with Hepatitis B transplanted for HCC are currently alive and both have recurrent hepatitis B. Patient deaths were largely due to recurrent hepatitis B. In contrast, those not infected with HBV had a 68% five year survival rate (Figure 6). Only two patients have died of recurrent tumors, both of whom had hepatomas larger than 5 cm at transplantation. Our present policy is to exclude HBV positive patients, and patients with tumors greater than 5 cm. Although presently we do not transplant HBV positive patients with HCC, we may well have to re-evaluate this position once the appropriate use of lamivudine becomes clear.

Late Graft Loss Following Liver Transplantation

We have assessed late graft loss in our adult recipients to determine underlying etiology (13).Five hundred and thirty-three (533) grafts transplanted into the first 489 adult patients at the University of Toronto from October 1985 to April 1996 were analyzed to allow a minimum follow-up of three months. In the initial 3-month postoperative period, 101 grafts were lost (81% 3-month graft survival). The 432 surviving grafts were the subject of further analysis. Patients were allowed up to 3 diagnoses as indications for transplant (e.g. Hepatitis C, alcohol and hepatocellular carcinoma) for analysis by disease. Primary Biliary Cirrhosis (PBC), Primary Sclerosing Cholangitis (PSC) and Autoimmune hepatitis were grouped as "Immune Diseases". Causes of late death following liver transplantation were reduced to 5 categories: recurrent disease, technical/surgical complications (late vascular or biliary tract complications), complications of immunosuppression (chronic rejection and de-novo malignancies), sepsis/infection, and other (including cardiac, neurologic, etc.).  

Late graft loss (Table 2) was significantly higher for HBV+ patients with hepatocellular carcinoma (HCC/HBV+) and for Hepatitis B positive (HBV+) patients (71% and 41% respectively) than for HBV negative patients (20%, p<0.001). In the HCC/HBV+ group, the cause of graft loss was recurrent HBV; no patients developed recurrent HCC. Of the 35 HCC/HBV- patients, only 2 grafts were lost to recurrent HCC; the 6-year graft survival was similar to those transplanted for benign diseases (non-HBV). The actuarial survival of 372 non-HBV+ grafts was 92% at 1-year and 80% at 6-years. 

Recurrent disease accounted for 3% of non-HBV graft loss (Table 1). No grafts have been lost to recurrent hepatitis C or PBC. In the 45 patients with PSC, 4 grafts have been lost to a bile duct obliterative lesion that was labeled as chronic rejection, although this may have been recurrent PSC. Of the 6 patients transplanted for cholangiocarcinoma, 5 have died from recurrent disease. The two patients transplanted for metastatic neuroendocrine tumors also have died of recurrent disease. 

Complications of immunosuppression resulted in the loss of 5% of the 432 grafts . Graft loss to chronic rejection was infrequent (3%) but was significantly (p<0.005) higher in those transplanted for autoimmune hepatitis (12%) and PSC (9%). Two percent of grafts were lost to new malignancies (lymphoproliferative disease, Kaposi's Sarcoma and other cancers). Sepsis or infection accounted for 3% of graft loss. 

Of the 13 grafts lost to technical /surgical complications, 12 were lost to late hepatic artery thrombosis or aneurysm and one was lost to biliary tract complications. The other causes of graft loss (3%), were unexpected deaths from complications such as myocardial infarction or neurologic events.

Summary

The University of Toronto program began in 1985 at a time when the procedure had already evolved from an experimental form of surgery to an accepted treatment for many forms of liver failure. The program was established not only to provide clinical care for patients but also to address academically the barriers which impeded success. The program brought together experts in medicine, surgery, pathology, and the basic sciences of immunology, virology and molecular biology.

Our group has had a special interest in transplantation for viral hepatitis. We demonstrated the role of HBV DNA as a prospective factor in both viral recurrence and survival. We further studied a number of agents to prevent re-infection including PGE, HBIG and more recently lamivudine. Although the short term results of transplantation for HCV appear excellent, reinfection of the graft and development of chronic hepatitis and cirrhosis may make long term results problematic. We therefore have directed attention to studies of pathogenesis and treatment of HCV in liver transplantation. Our studies have demonstrated a unique role for ribavirin as an immunomodulatory agent which can benefit the course of post transplant HCV. Future studies will examine combination therapy in an attempt to eradicate the virus.

Our group also has been interested in PNF and FHF and have demonstrated a positive effect of PGE in this setting. As we look to the future, the greatest challenges facing transplantation are shortage of organ donors and the toxic effects of long term immunosuppression. Our group now has established research efforts both in tolerance induction and xenotransplantation which we feel are necessary to make transplantation an effective, universal treatment for end-stage organ failure.

References

1. Hemming AW, Cattral MS, Greig, PD, Chung SW, Aljumah AA, Lilly LB, Levy GA. Microemulsion formulation cyclosporine without intravenous cyclosporine in liver transplantation. Transplantation December 1996(In Press)
2. Donaldson BW, Gopinath R, Wanless IR, Phillips MJ, Cameron R, Roberts EA, et al. The role of transjugular liver biopsy in fulminant liver failure: relation to other prognostic indicators. Hepatology 1993;18:1370-74.
3. Sinclair SB, Greig PD, Blendis LM, Abecassis M, Roberts EA. Phillips MJ, et al. Biochemical and chemical response of fulminant viral hepatitis to administration of Prostaglandin E. J. Clin Invest 1989;84:1063-1069.
4. Sheiner P, Sinclair S, Greig P, Logan H, Blendis LM, Levy GA. A randomized control trial of Prostaglandin E2 (PGE2) in the treatment of fulminant hepatic failure (FHF).Hepatology 1992; 16: 88A.
5. Cattral MS, Levy GA. Artificial liver support - pipe dream or reality? New England J Med 1994; 331 :268-69.
6. Greig PD, Forster J, Superina RA, Strasberg SM, Mohamed M, Blendis LM, Taylor BR, Levy GA, Langer B. Donor-specific factors predict graft function following liver transplantation. Trans. Proc. 1990;22(4):2072-73.
7. McKeown C, Edwards V, Phillips MJ, Harvey R, Petrunka C, Strasberg S, Sinusoidal lining cell damage the critical injury in cold preservation of liver allografts in the rat. Transplantation 1988; 46: 178-91.
8. Greig PD, Woolf GM, Sinclair SB, Abecassis M, Strasberg SM, Taylor BR et al. Treatment of primary liver graft non-function with prostaglandin E1. Transplantation 1989;48:447-53.
9. Flowers M, Sherker A, Sinclair SB, Greig PD, Cameron R, Phillips MJ, et al. Prostaglandin E in the treatment of recurrent hepatitis B infection after orthotopic liver transplantation. Transplantation 1994; 58: 183-91.
10. Perrillo R, Rakela J, Martin P, Levy G, Schiff E, Wright T, et al . Lamivudine for hepatitis B after liver transplantation(OLT), Hepatology 1996;24:4:223.
11. Cattral MS, Krajden M, Wanless IR, Rezig M, Cameron R. Greig PD, Chung SW, Levy GA. A pilot study of ribavirin therapy for recurrent hepatitis C virus infection

12. Chung SW, Toth JL, Rezeig M, et al. Liver transplantation for hepatocellular carcinoma. American J. Surg. 1994; 167: 317-321.
13. Philosophe B, Hemming A, Cattral M, Chung S, Lilly L, Levy G, Greig P. Late graft loss following liver transplantation. Trans. Proc. 1996 in press.

TABLE 1

PATIENT SURVIVAL BY DISEASE

HBV - hepatitis B virus PBC - primary biliary cirrhosis

HCV - hepatitis C virus PSC - primary sclerosing cholangitis

Etoh - alcohol HCC B - hepatocellular carcinoma, HBV negative

Crypto - cryptogenic cirrhosis HCCB+ - hepatocellular carcinoma, HBV positive

TABLE 2

CAUSES OF LATE GRAFT LOSS BY DIAGNOSIS

• up to 3 diagnoses were allowed per graft

HCC HBV+ - hepatocellular carcinoma, hepatitis B virus positive

HBV - hepatitis B virus

HCC HBV - hepatocellular carcinoma, HBV negative

HCV - hepatitis C virus

Re-trans - retransplant

Legends for Figures

Figure 1:

Adult and pediatric liver transplants performed from October 1985 to November 1996.

Figure 2:

Etiology of liver disease in adults leading to transplantation.

Figure 3:

Overall patient and graft survival following liver transplantation at the University of Toronto.

Figure 4:

Patient survival grouped by date of transplant. Survival has significantly improved since 1993. P=0.02 log rank.

Figure 5:

Overall survival of 54 patients receiving liver transplantation for hepatocellular carcinoma. 5 year patient survival is 42%.

Figure 6:

Survival of 54 patients receiving liver transplantation for hepatocellular carcinoma compared by hepatitis B status. Hepatitis B patients had significantly poorer survival and patient death was predominantly secondary to graft loss from recurrent hepatitis B infection of the graft.