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Recent Developments in |
Liver Transplantation | ||
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Contents |
Tables and Figures
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Transplantation is one of the most complex and challenging fields in medicine today. Advances in the transplant arena have come in all areas of the discipline, but the most important have been in the field of immunosuppression. The first successful liver transplant was performed in 1967,1,2 but nearly 15 years elapsed until breakthroughs in immunosuppression improved survivals from a dismal 20% to 30% at one year to almost 80% today.3,4
During the last decade, one-year patient survivals have reached 85% to 95% in certain patient groups.5 These remarkable results can be attributed to multiple factors including improvement in preservation techniques, advances in intraoperative anesthetic management, refinement of surgical techniques, better understanding of immunosuppressive management, and the introduction of new agents to treat the infectious complications posttransplant.
Liver transplantation is now generally accepted as the primary treatment for end-stage liver disease. Today, many patients are considered for transplantation who previously would have been excluded based on their age, medical condition, and/or technical considerations. Table 1 lists the indications for liver transplantation at Baylor University Medical Center.
We have found that many high-risk patients can be transplanted and can survive the early postoperative period, but they may not leave the transplant center. The most important factor predicting outcome following transplantation is timely referral of the patient to a transplant center. Figure 1 clearly demonstrates the difference in survival between patients who are home-bound (UNOS 2) versus those who are hospital-bound (UNOS 3) or ICU-bound (UNOS 4) at the time of transplantation. Since the opening of our program in 1985, we have educated our referring physicians on the importance of early referral, prior to the development of the complications of end-stage liver disease: severe gastrointestinal hemorrhage, hepatorenal syndrome, severe malnutrition, etc.
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Table 1.Diagnoses of patients transplanted at BUMC from April 1985 to March 1994 (n=934) |
Figure 1.Patient survival based on pretransplant status. UNOS 2 represents home-bound patients, UNOS 3 represents hospital-bound patients, and UNOS 4 represents ICU-bound patients (old system).
The absolute and relative contraindications to transplantation at Baylor are listed in Table 2. Relative contraindications should be considered on a case-by-case basis.
The basic operative procedure is well established and, in most situations, the transplant takes 5 to 8 hours to complete. Several aspects of the intraoperative management are noteworthy.
The thrombelastograph (TEG) is a mainstay of the anesthesiologist's armamentarium for diagnosis and management of coagulation problems intraoperatively. The TEG allows specific therapy directed at the deficient arm of the coagulation cascade, thus effectively and quickly correcting nonsurgical causes of bleeding.6 This simple, quick procedure can be performed repeatedly during the procedure.
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Table 2.Contraindications to liver transplantation |
The cell saver is used in all cases except known or suspected hepatocellular carcinoma.7,8 The cell saver collects the patient's own blood and autotransfuses it, decreasing the amount of banked blood needed and thus decreasing the risk of infection transmitted from donated blood. Processing banked blood through the cell saver quickly and easily removes most of the potassium, citrate, and serum present,9 helping to prevent the myocardial effects of hyperkalemia and decreasing the risk of blood transfusion reactions.
The key to successful postoperative management is the early recognition of problems. An excellent clinical indicator of early graft function is the quality of the bile. The bile should be viscous and dark brown in color. If the bile is pale in color and watery in consistency, primary nonfunction, rejection, or vascular thrombosis should be suspected.
Maintenance immunosuppression is tailored to the patient's pretransplant condition. Table 3 outlines the management of immunosuppression according to patient group. Azathioprine is restarted if patients develop rejection or if they have compromised renal function and cannot tolerate a full dose of cyclosporine or tacrolimus.
Tacrolimus has recently been approved for use in transplantation. It appears to be a more effective immunosuppressive agent than cyclosporine; ie, there is less rejection, so lower doses of OKT3 are needed to manage patients.10,11 Tacrolimus also has a more favorable lipid profile than cyclosporine,12 but diabetogenicity appears to be greater.10 Long-term studies will be needed to better delineate which drug will provide the greatest benefit to patients.
Rejections are initially treated with a methylprednisolone bolus followed by a five-day taper. If steroid therapy fails, then a 12- to 14-day course of 5-10 mg of OKT3 is given. If rejection persists at this point and the patient is on cyclosporine, conversion to tacrolimus as a rescue protocol is then instituted. We strongly advise against multiple courses of monoclonal antibody or antilymphocyte globulin therapy, due to the risk of lymphoproliferative disorders with these agents.13
Mycophenolate mofetil (capsules), which has recently been approved by the Food & Drug Administration, is expected to be a major addition to immunosuppressive therapy. Exactly how the drug will fit into the treatment of liver transplant patients is currently being explored.
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Table 3.Baylor University Medical Center Liver Transplantation Immunosuppressive Protocol |
At BUMC the overall survival in 857 patients at 1, 3 and 5 years are 83.5%, 78%, and 68.6%, respectively. Specific subsets of our patient population are discussed below.
Hepatitis C is one of the more common indications for transplantation. In these patients, transplanters worry whether the virus will cause recurrent disease in the graft.14,15 Seventy-two patients transplanted with the diagnosis of hepatitis C were recently reviewed. Follow-up was 3 to 25 months with a mean of 11.7 ± 5.8 months. Fifty-eight of these patients received livers from hepatitis C-negative donors, while 14 received livers from hepatitis C-positive donors. Table 4 compares the two groups. There appears to be no difference in outcome between patients who received livers from hepatitis C-positive and hepatitis C-negative donors. The disease recurs in about one-third of patients, and this proportion may increase as follow-up lengthens. The clinical significance of recurrent disease is unclear, but it appears to be less aggressive than with recurrent hepatitis B.
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Table 4.Comparison of hepatitis C-positive and -negative donors for patients who are hepatitis C-positive and the recurrence of hepatitis C posttransplant |
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Table 5.Percent survival in hepatitis B surface antigen-positive patients with reference to e-antigen status |
Hepatitis B remains a controversial indication for orthotopic liver transplantation.16-19 We have transplanted 61 patients who were hepatitis B surface antigen-positive. Patients who are e-antigen negative have a lower incidence of recurrent disease than those who are e-antigen positive, but it is not clinically significant. Table 5 compares our results in patients who are hepatitis B surface antigen-positive according to their e-antigen status. The survival of patients who are hepatitis B surface antigen-positive falls below that of all other patients transplanted at approximately 18 months following transplantation. Despite these poor results, we believe transplantation should be attempted in these patients. We recommend the use of adjuvant therapy in an effort to prevent recurrent disease.20 We previously used Hepatitis B Immunoglobulin (HBIG) during the anhepatic phase and again 48 hours postoperatively. At this time, we are using HBIG daily for seven days during the anhepatic phase, and monitoring HBsAb levels to maintain a level >500 IU/ml.
The outcome for patients with hepatitis B who have been retransplanted is variable. Crippen et al20 reported the results of a multicenter survey evaluating risk factors for poor outcome. Patients who were retransplanted for recurrent hepatitis had a 5% long-term survival. In contrast, patients initially transplanted for hepatitis who underwent retransplantation for other complications (eg, primary nonfunction, rejection, etc.) had a 60% survival. It appears that retransplantation is contraindicated only in the setting of recurrent viral infection when no other antiviral intervention is implemented.
Unresectable hepatocellular carcinoma carries a poor prognosis; few survive more than one year. Liver transplantation provides the only possible hope for these patients.21 We feel that these patients should be given a chance at transplantation, but we recommend the use of adjuvant chemotherapy. We have obtained promising results using a neoadjuvant doxorubicin chemotherapy protocol. Thirty-three patients received preoperative as well as postoperative chemotherapy; 14 patients diagnosed with incidental hepatomas received only postoperative chemotherapy. Table 6 compares the outcomes. We believe that neoadjuvant chemotherapy improves both overall survival and disease-free interval for this high-risk group of patients.
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Table 6.Outcomes in patients with known hepatomas treated with neoadjuvant perioperative plus postoperative chemotherapy compared with those with incidental hepatomas treated only postoperatively |
Unfortunately, results with adjuvant chemotherapy for cholangiocarcinoma have not been as favorable as those with hepatocellular carcinoma.22 The adjuvant protocol which we utilized combined chemotherapy with radiotherapy. The patients tolerated this treatment without any apparent ill effects. Unfortunately, this protocol did not prevent or reduce the recurrence rate. Seventeen patients have been transplanted at BUMC for cholangiocarcinoma. The one-year survival and disease-free survival are 53% and 40%, respectively. The two-year disease-free survival is only 33%. These results do not differ from those in previously reported series in which adjuvant therapy was not used. Thus, we recommend that until a better adjuvant protocol is developed, patients with cholangiocarcinoma should not undergo liver transplantation.
Over the last several years, the proportion of liver transplants performed for Laënnec's cirrhosis has increased from less than 10% to approximately 30% in most institutions, and it is expected to reach as high as 50% to 60% at some centers in the near future. We have transplanted 88 patients with a diagnosis of Laënnec's cirrhosis. Their 1-, 3-, and 5-year survivals are similar to those of patients transplanted for other indications, suggesting that this is not a high-risk group.
To acheive this good result, very strict guidelines have been established for candidates with a history of significant substance abuse.23 In our opinion, the candidate must have, at the minimum, six months of abstinence. More importantly, he or she must have insight into his or her substance abuse problem and must be willing to accept on-going therapy to prevent recidivism. To the best of our knowledge, 19 of 88 patients have relapsed (a return to drinking after the transplant), but only 5 of the 19 patients have refused or failed therapy and continued to drink.We believe that a thorough psychosocial and psychiatric assessment can identify a group of patients with Laënnec's cirrhosis who can benefit from transplantation.
Over the past decade, advanced age has evolved from an absolute to a relative contraindication to liver transplantation. As older patients are being considered for and successfully transplanted, the mean age of our candidates has risen to almost 50 years.
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Table 7.Comparison of patients 60 years of age or greater to those less than 60 years of age at the time of transplant |
A recent review of our patient population revealed that 15.7% of patients were 60 years or older at the time of transplant. Table 7 compares patients aged 60 years or older to those less than 60 years of age. Elderly patients and those in the intensive care unit do much worse than all other patient groups, and it is our belief that these patients should be carefully screened before acceptance as transplant candidates.
As survival following liver transplantation has lengthened, we have begun to ask whether these patients can expect a normal life span once they have reached a certain point posttransplant. To better understand this issue, we have evaluated our patients for the causes of late graft loss. Five hundred consecutive transplants in 434 patients were reviewed; 362 survived for more than one year, and 39 patients had late graft loss. Table 8 reveals the causes of graft loss more than one-year posttransplant. Seventy-one percent of the causes of late graft loss can be grouped within one of four diagnoses: chronic rejection, recurrent hepatitis, recurrent malignancy, and arterial thrombosis.24 As further progress is made in the field of transplantation, these problems should decrease in frequency. Better immunosuppression should address the issues of chronic rejection and rejection-induced arterial thrombosis. Better adjuvant therapy will prevent both recurrent hepatitis and recurrent malignancy.
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Table 8.Causes of late graft loss |
Despite late graft losses, long-term survival following liver transplantation is still excellent. The probability of maintaining a graft for at least five years, if the patient has survived the first year after transplantation, is 80% to 85%. Most of the graft losses occurred during the second year posttransplant, and therefore, if the patient has survived two years after transplantation, the probability of long-term survival is improved even further.
With major health care reform inevitable, decisions must be made about the best use of health care dollars. Admittedly, liver transplantation is a high cost procedure, and some have questioned whether it represents the best deployment of limited financial resources. To help evaluate the utility of liver transplantation, we prospectively studied the quality of life of transplanted patients at our institution over an eight-year period.
We found that liver transplantation clearly led to improved quality of life by the end of the first posttransplant year. These changes were sustained through the fifth posttransplant year and beyond. Self-image, functional ability, and perception of health status were significantly improved. Ill health interference in daily life continued to decrease as time from transplantation advanced. Employment at one year was statistically less than pretransplant, but by two years, employment had reached pretransplant levels. By five years it was significantly greater than pretransplant, with 54% of patients actively employed at five years and 70% employed at sometime during their fifth year posttransplant. Such success suggests that liver transplantation should continue to be a part of our health care system.
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