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Assessment of Liver Transplantation

Health Technology Assessment Reports, 1990 Number 1

, M.D., Ph.D.

Created: .


The Office of Health Technology Assessment (OHTA) evaluates the safety and effectiveness of new or unestablished medical technologies that are being considered for coverage under Medicare. These assessments are performed at the request of the Health Care Financing Administration (HCFA). They are the basis for recommendations to HCFA regarding coverage policy decisions under Medicare.

Questions about Medicare coverage for certain health care technologies are directed to HCFA by such interested parties as insurers, manufacturers, Medicare contractors, and practitioners. Those questions of a medical, scientific, or technical nature are formally referred to OHTA for assessment.

OHTA's assessment process includes a comprehensive review of the medical literature and emphasizes broad and open participation from within and outside the Federal Government. A range of expert advice is obtained by widely publicizing the plans for conducting the assessment through publication of an announcement in the Federal Register and solicitation of input from Federal agencies, medical specialty societies, insurers, and manufacturers. The involvement of these experts helps assure inclusion of the experienced and varying viewpoints needed to round out the data derived from individual scientific studies in the medical literature.

After OHTA receives information from experts and the scientific literature, the results are analyzed and synthesized into an assessment report. Each report represents a detailed analysis of the safety, clinical effectiveness, and uses of new unestablished medical technologies considered for Medicare coverage. These Health Technology Assessment Reports from the basis for the Public Health Service recommendations to HCFA and are disseminated widely. Individual reports are available to the public once HCFA has made a coverage decision regarding the subject technology.

OHTA is part of the Agency for Health Care Policy and Research (AHCPR), Public Health Service, Department of Health and Human Services.

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  • Office of Health Technology Assessment
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Liver transplantation is by far the most technically difficult of all solid organ transplants. It is an extremely expensive and complicated operation that can extend the lives of certain patients with end-stage liver disease (ESLD). While substantial uncertainties still exist about its optimal use and ultimate benefits for patients in some disease categories, for other patients orthotopic liver transplantation (OLT) has clearly advanced to the status of an established treatment. The steadily improving one-and two-year survival rates of 50-80 percent and 20-80 percent, respectively, suggest that the procedure may be done safely and effectively in carefully selected individuals.

When the 1983 Public Health Service (PHS) report on liver transplantation was published, only 375 liver transplants had been performed in the United States (1). That report welcomed the improved survival rates resulting from cyclosporine and new surgical techniques that substantially reduced biliary tract complications, then known as the "Achilles heel" of liver transplantation. From among the data available at that time, the use of liver transplantation was found to be an acceptable therapeutic modality in children with ESLD such as biliary atresia.

In 1983 only a few limited studies identified patients in specific disease categories likely to benefit from OLT. However, with the proliferation of centers performing OLTs, substantial data for some ESLD categories have accumulated correlating patient diagnosis with outcome. This has improved patient selection and, as a result, outcomes.

Since the last report, the number of centers in the United States has increased fourfold and the number of transplantations has increased about tenfold. Although the number of institutions capable of performing the procedure has increased significantly, it remains insufficient to meet the needs of the estimated 4,000-10,000 candidates each year. Of the 3,500 liver transplantations already performed in the United States, about one-third or 1,182 were performed in 1987 alone. The number of liver transplants being performed is limited not only by the number of capable institutions, but also by the limited availability of organs (grafts) and the cost --approximately $150,000-$259,000 per case.

Diagnosis often influences which ESLD patients are selected for OLT. Patients whose ESLD is caused by external agents such as infections and toxins represent at least 40 percent and close to 50 percent of all recipients of liver transplants in the United States and Europe. Individuals with systemic diseases of unknown cause account for 30-40 percent, those with malignancies account for 10-30 percent, and those with congenital and inherited disorders affecting the liver represent less than 10 percent.

Diagnosis is also related to survival. For example, about 64 percent of persons with certain inherited disorders of the liver survived at least five years, while only about 7 percent of those with bile duct cancer survived three years. According to data gleaned from the experiences at various liver transplantation centers, the outcome in patients with liver diseases caused by hepatitis B virus depends on whether the patient tests positive or negative for the antigen

Other factors that influence the outcome in patients undergoing an OLT include cardiovascular complications, renal and pulmonary failure, biliary leakage and obstruction, recurrence of primary disease in the graft, and rejection of the donor liver. Since the 1983 report, use of new immunosuppressive agents such as Orthoclone OKT3, more widespread use of retransplantation and donor-recipient tissue matching, and the use of non-invasive as well as invasive diagnostic techniques for early detection of complications have further improved outcomes of OLT.

Hard data on cost of the procedure as well as its impact on the patient's quality of life are still scarce, as was true in the 1983 report.

This document updates the 1983 PHS report on liver transplantation by furnishing to the Health Care Financing Administration new data on which to base its recommendations for covering this procedure. It reviews diagnosis-specific survival rates, complications of the procedure, and improved techniques for reducing morbidity and mortality associated with liver transplantation. It also identifies patients most likely to benefit from the procedure.

Chapter 1 Candidates for Liver Transplantation

At least 4,600 persons who die each year in the United States from end-stage liver disease may be acceptable candidates for liver transplantation. Of that number, 60-70 percent can be expected to survive one year or more.

Since the 1983 Public Health Service (PHS) report on liver transplantation, liver transplantation technology has been disseminated worldwide (1). The United States has seen a tenfold increase in the number of procedures performed, with 3,500 liver transplants completed at over 50 centers through 1987 (2).

The U.S. experience with liver transplants through 1983 consisted of approximately 375 patients. Thus, it was difficult to evaluate fully the impact of the procedure or define its ultimate benefits to many potential recipients.

Much has changed. In the last four years, an additional 3,000 patients have been transplanted in the United States and over 30 new liver transplant centers have been established. The growth in the capacity to perform liver transplants has made the procedure more available to potential candidates and has generated additional data to evaluate which patients are potential candidates.

These new data, many of which are referenced in this report, also provide a more meaningful basis on which to answer the questions raised in the previous PHS report, "Which patients with which diseases and at what point in their clinical course are likely to benefit from transplantation of the liver?"

Unlike renal failure, where hemodialysis may be instituted to support those functions normally performed by the healthy kidney, no mechanism currently exists to artificially support functions performed by the liver. Therefore, proponents suggest that the at-risk population includes a large number of patients whose only alternative is death. Survival rates vary among centers, appear to be unrelated to volume when the number of transplants are done at a rate of one or more per month, and perhaps are related to numerous other characteristics including disease diagnosis.

Impact of Diagnosis

The diagnosis of a potential candidate for liver transplantation can affect the individual's selection for the procedure and survival. For example, in children, extrahepatic biliary atresia (EBA) accounts for 90 percent of end-stage liver disease (ESLD). Thirty-six percent of the 350-450 children born in the United States with EBA each year are expected to respond to surgical interventions such as the Kasai procedure (portoenterostomy). This leaves approximately 200-300 children born annually whose life expectancy would be less than three years unless transplantation of the liver were undertaken.

In contrast to ESLD in pediatric patients, adults have a wide variety of diagnoses which may lead to ESLD and eventually result in orthotopic liver transplantation (OLT). Although the diagnoses leading to OLT represent a range of processes, they may be grouped into an etiologic classification as shown in Table 1.

Table 1. Etiologic classification of diagnoses leading to OLT.


Table 1. Etiologic classification of diagnoses leading to OLT.

For category 1 diseases, the process is congenital or acquired, but the primary disorder originates in the liver and results in hepatocellular dysfunction or intrahepatic substance accumulation.

Category 2 diseases have an external agent as the cause of the disease affecting the liver. Hepatitis B virus-induced diseases (hepatitis, cirrhosis) have been shown to recur in the transplanted liver when the patient has been found to be surface antigen (HBsAg) positive and especially e antigen (HBeAg) positive (3). Although active alcohol abuse was considered a contraindication to OLT, some centers performed transplantations in selected patients who were considered to have favorable prognoses for treatment of the primary alcohol problem (4,12). Outcomes in these patients have been good (5). Toxic exposures to industrial chemicals, mushroom poisoning, etc., have responded well to OLT in situations where it has been available.

Category 3 consists of diseases that are systemic but result in endstage liver disease. The etiology is unknown and the possibility exists for recurrent disease in the graft. An example is primary biliary cirrhosis. An autoimmune disease most frequently found in middle-aged women, it has been associated with a variety of autoimmune conditions. It is a chronic, progressively destructive cholangitis that has not responded to various medical protocols. Patients usually present with jaundice, fatigue, pruritus, and hepatomegaly. Laboratory studies demonstrate antimitochondrial antibodies and these have been found after transplantation as well (6).

Sclerosing cholangitis is a chronic, cholestatic disease of unknown etiology characterized by inflammation and fibrosis of the biliary tract. Although it occurs as a primary disease, it has been associated with inflammatory bowel disease.

Category 4 diseases consist of malignancies that are either primary hepatic or metastatic cancers. Some diagnoses have been associated with better prognoses than others, although the rule is that the disease recurs in the graft with high probability (7).

U.S. vital statistics data provide information on the frequency with which these diseases are found in the population (8). Table 2 displays the numbers of deaths due to these diagnoses and the mortality rates for 1985.

Table 2. Mortality and mortality rates for hepatic diseases in the United States, 1985.


Table 2. Mortality and mortality rates for hepatic diseases in the United States, 1985.

Estimates of the need for liver transplantation range from 10-40 per million population (9). Only a small percentage of patients dying of liver disease are viewed as being eligible for OLT.

Patient Selection

Decisions on patient selection for transplantation have raised many medical and bioethical questions. No program yet has based candidate selection on diagnosis as a primary significant predictive variable. Van Thiel and associates described a consensus process where determinations of acceptability of recipients to undergo liver transplantation are made by a Transplantation Committee at the University of Pittsburgh, an approach now in widespread use (4).

Although many candidates may be referred for OLT, the patient selection criteria will determine which patients are actually accepted for the procedure. Table 3 shows the number of patients who underwent OLT for the listed diagnoses at selected centers during the 1980-1987 period.

Table 3. Number of adults undergoing OLT, 1980-1987[*].


Table 3. Number of adults undergoing OLT, 1980-1987[*].

Data from the European Liver Transplant Registry indicate that cancer patients were recipients of 33 percent of the adult liver transplants; patients with primary biliary cirrhosis accounted for 19.5 percent and those with other cirrhosis, 30 percent (10). Schade reported that the distribution of cases in 1986 at the University of Pittsburgh included 18 percent primary biliary cirrhosis, 46 percent post-necrotic cirrhosis, 11 percent sclerosing cholangitis, 8 percent fulminant hepatic failure, and 7 percent primary liver malignancy (11).


Although any patient with incurable liver disease may be considered a candidate for OLT, most transplant teams exclude certain categories of patients from surgical consideration for a variety of reasons. Consensus and uniformity are still lacking among transplant institutions on what factors represent true contraindications to OLT.

Contraindications included sepsis unresponsive to treatment, encephalophathy with evidence of irreversible brain damage, congenital anomalies that prevent surgery, primary hepatic malignancies extending beyond the margin of the liver, metastatic hepatobiliary malignancy, severe hypoxemia due to right-to-left intrapulmonary shunt, and severe renal or cardiopulmonary disease. In the past, portal vein thrombosis had been an absolute contraindication but with the success of vein grafts, despite the high risks involved, it is now only considered a relative contraindication.

Other relative contraindications include intrahepatic or biliary sepsis and prior abdominal surgery, especially when performed in the right upper quadrant of the abdomen. The presence of HBeAg is a contraindication because of the high probability of infection of the new graft. On the other hand, the presence of the HBsAg is a relative contraindication. Although most patient revert to the antigen-positive state following OLT, trials are underway using interferon with transplantation in an effort to suppress viral activity.

Timing of Surgery

Timing of liver transplantation is believed to affect the results of the surgery, yet clinical parameters vary between centers. Van Thiel and colleagues identified the Pittsburg criteria for determining when a patient should undergo OLT (4). In general, OLT is desirable before the development of absolute contraindications and irreversible deterioration of the patient caused by primary hepatic disease.

In laboratory terms, the procedure is indicated when the bilirubin exceeds 20 mg per deciliter, the albumin falls below 1.8 gm per deciliter, or the patient develops encephalopathy that is "unresponsive to the combination of a low-protein diet (less than 40 gm per day), lactulose and neomycin" (4). Tzakis and associates further suggested OLT for patients who had developed intractable ascites, had low-grade encephalopathy, or had developed portal hypertension and upper gastrointestinal bleeding (12). They also suggested OLT before the onset of advanced hepatic cirrhosis.

Chapter 2 New Techniques and Survival

Improved OLT techniques have substantially enhanced patient outcome since the early days of the procedure. Cyclosporine and innovative surgical techniques to reduce biliary tree complications were the major procedural improvements cited in the 1983 PHS report on liver transplantation. Since then, the availability of the monoclonal antibody, OKT3, more extensive use of retransplantation, newer noninvasive diagnostic techniques, and sophisticated donor-recipient matching have further boosted survival rates.


Liver transplantation consists of surgically replacing an end-stage diseased liver with a healthy one. The liver is obtained from a brain-dead donor with sustained cardiopulmonary function. It is harvested from the donor and preserved by immersion hypothermia in media such as Collins' solution (a high-potassium, low-sodium preparation). The organ is then implanted in situ in a hepatectomized patient (orthotopic liver transplantation) or ectopically as an auxiliary organ (heterotopic liver transplantation (HLT)).

Theoretically, the latter technique could be applied in patients with potentially reversible liver disease, where the graft may be removed at a later time when the native organ has recovered, or when previous abdominal surgery or disease sufficiently distorted the anatomy to render hepatectomy and liver replacement technically impossible. However, because of discouraging results with this technique worldwide. HLT has been abandoned in favor of OLT (13).

Numerous OLT techniques have been developed for implanting the liver and establishing biliary and vascular continuity between the graft and recipient. The first replacement of a human liver was attempted by Starzl at the University of Colorado on March 1, 1963.

Liver transplantation during the 1960s was marked by a record of consecutive failures with patients dying from infection, hemorrhage, and other problems. By 1979, the results reported in two large series demonstrated definite improvements in surgical outcome. Nevertheless, perioperative mortality and short-term mortality remained unacceptably high.

Changes in biliary reconstruction techniques in 1976 significantly reduced the incidence of ascending cholangitis and sepsis and improved one-year survival (14,15). By 1988, OLT procedures had been even further refined.

Immunosuppressive Agents

Rejection of the donor liver was treated by various combinations of pharmacologic agents or thoracic duct drainage with generally unsatisfactory results until the introduction of cyclosporine in 1978 and, more recently, antithymocyte globulin (ATG) and OKT3. The following list shows the combination of agents used in immunosuppression in patients receiving liver transplant:

A List of Agents Used in Immunosuppression

AgentYear Introduced
Azathioprine/steroid combination1963
Thoracic duct drainage (adjunct)1963
ALG (antilymphocyte globulin) (adjunct)1966
Cyclophosphamide/steroid combination1970
Cyclosporine/steroid combination1980
ATG (antithymocyte globulin)1986
OKT3 (monoclonal antibody)1986

Most of these agents were described in the 1983 PHS report on liver transplantation (1). and are briefly reviewed here.

During the 1960s, azathioprine and steroids were used in combination and sometimes with adjunctive antilymphocyte globulin (ALG) with variable success (16). The combination of azathioprine and prednisone proved to be a less than optimal therapy because of the adverse side effects. Corticosteroids increased the risk of hypertension, osteoporosis, psychiatric complications, infections, and Cushing's syndrome --as well as the risk of growth retardation in Azathioprine oversuppressed the immune system and bone marrow and was thought to be associated with increased risk of tumorigenesis over prolonged periods of administration (17).

In 1979, Calne first used cyclosporine in human kidney, pancreas, and liver transplants and demonstrated its effectiveness in preventing rejection of these grafts (18). Since 1979, comparative data have been generated comparing patient and graft survival with cyclosporine versus earlier agents.

Currently, the treatment of acute rejection begins with a trial of a high dose of intravenous bolus steroids which may be repeated as necessary. If response to steroids is not seen, some transplant centers may administer ATG (19,20). ; others will use OKT3, a pan-anti-T-cell monoclonal antibody.

OKT3 was first introduced into clinical trial for the treatment of renal rejection in 1981 when azathioprine and prednisone were the major immunosuppressants (21). OKT3 has been used with rather impressive results, not only in treating renal rejection, but also in acute hepatic rejection during use of cyclosporine and steroids as baseline immunosuppressants. Since the use of OKT3 in liver transplant patients in 1984, a consensus seemed to appear in the published reports that OKT3 may be superior to steroids for reversing liver graft rejection in recipients who failed initial steroid therapy (21,21-24).

Starzl and Fung, with a continued follow-up by Fung and associates, reported their initial pilot trials of OKT3 therapy in 52 liver and 10 kidney transplant recipients whose baseline immunosuppression therapy was cyclosporine and steroids (24,25). Originally, a randomized trial on the treatment of acute rejection was planned between OKT3 therapy versus high-dose steroids. As it progressed, favorable responses of the OKT3-treated group and a high degree of resistance to treatment in the steroid-treated group became obvious. For this reason randomization was terminated and OKT3 was given to all patients who failed high-dose steroid therapy.

When OKT3-treated patients were analyzed according to the timing of therapy, the best response to OKT3 was found in the group in which therapy was started between 10 and 90 days postoperatively (group 2). Seventy-three percent of these patients had complete suppression of the rejection phenomenon; 18 percent had partial suppression and 9 percent were nonresponsive. Patients in group 2 did not have renal failure. Acute hepatic rejection responses were documented by liver biopsies. Lesser degrees of usefulness of OKT3 were seen in the group receiving early treatment with OKT3, less than 10 days postoperatively (group 1), and in the late treatment group given OKT3 more than three months postoperatively (group 3).

Together, groups 1 and 3 had a 67 percent favorable response to OKT3 either partial or complete. This response occurred despite their disadvantageous bias, namely, poor renal function in 44 percent of patients in group 1 and histological evidence of chronic rejection (in addition to acute rejection) in 75 percent of patients in group 3. Follow-up evaluation at seven months indicated the rates of graft function were 66 percent, 81 percent, and 52 percent for groups 1, 2, and 3, respectively. At an average follow-up of 12.2 months, graft function rates were 61 percent, 77 percent, and 33 percent for groups 1, 2, and 3, respectively (25). Thirty-five (67) of the 52 OKT3-treated patients with liver transplants had satisfactory hepatic function of their original grafts. Fifteen percent of patients during OKT3 therapy had major infections, including Pneumocystis carinii, cytomegalovirus, bacterial sepsis, and cutaneous herpes simplex.

Mortality was 23 percent among the liver transplant patients during the follow-up period of 12.2 months. Ten (25) of the 40 patients who responded to OKT3 developed recurrent rejection. Five were successfully treated with high-dose steroids; the other five required retransplantation.

In a clinical trial conducted by Cosimi and associates, 28 patients who failed to respond to a high dose of steroids for treatment of acute hepatic rejection were randomly assigned to OKT3 or to continued high-dose steroids with an opportunity to switch therapy groups after six days (22). The investigators found better, but not statistically significantly improved, survival of patients and primary grafts among the OKT3-treated group than among the steroid-treated group. The OKT3-treated group appeared to have a lower incidence of infectious complications than the steroid-treated group. With either treatment, an encouragingly low overall retransplantation rate of 3.6 percent (1 of 28 patients) and 14 percent mortality were reported in this study.

In another prospectively designed study by Colonna and associates, 25 patients with acute hepatic rejection who failed to respond to high-dose steroids and/or antithymocyte globulin therapy were given OKT3 (21). Fifty-six percent (14 patients) had a complete response, 40 percent (10 patients) had a partial response, and 4 percent (1 patient) did not respond to OKT3. Of those with partial response, 60 percent were successfully "rescued" by subsequent high-dose steroids, that is, their rejection phenomenon was suppressed. An encouraging 80 percent of the grafts were "rescued" during the follow-up period of 8 +/-4.9 months. Retransplantation was 8 percent and mortality was 12 percent in this study. Recurrent rejection in OKT3-treated patients was 40 percent; all but two patients responded to a repeated cycle of steroidal therapy.

While steroids appeared to be more toxic than OKT3 in one study, OKT3 itself was not without adverse side effects (22). , which are detailed later in this report as one of the complications of OLT.

Anti-idiotypic (Id) antibodies may pose a threat to the repeated or prolonged application of OKT3. Jaffers and associates reported that more than half of OKT3-treated kidney allograft recipients developed anti-Id antibodies, a prominent feature of the immune response to monoclonal antibodies (26). Although anti-OKT3 antibodies were described as transient and did not affect therapeutic outcome, there was a potential for blocking the therapeutic effectiveness of OKT3.

In a recent study by Fung and associates, anti-OKT3 antibodies were found during OKT3 treatment of patients in whom such antibodies were not detected prior to therapy (25). Three patients were treated again with OKT3 for rejection of second hepatic grafts in spite of failing the first course of OKT3. Reversal of rejection was successful in two of these patients; their adverse reaction to OKT3 was noted to be no worse than that in the average patient undergoing initial therapy. The third patient developed a high titer of anti-OKT3 antibodies. He eventually rejected the second graft but was successfully rescued with a third transplantation. Symptoms and serological findings supported the diagnosis of a delayed serum-sickness reaction in this patient.


Retransplantation of the liver, a technique to manage transplant rejection, has become more widespread in recent years and has improved survival rates. In fact, some authors have concluded that survival after retransplantation approaches that of a primary graft (27). It is performed with varying frequency by different centers. The indications for the procedure are rejection, primary non-function of a graft, or technical failures (vascular thrombosis, complications of biliary tract reconstruction, errors in operative technique).

The frequency of retransplantation worldwide ranges from 8-30 percent. An average prevalence of 9 percent is seen among the European centers, with little change in recent years (10,28-30). In the United States, there has been a significant increase in recent years since the introduction of cyclosporine --from approximately 12 percent to 30 percent (20,27). Survival outcomes have also improved. The group at Pittsburgh reported a 49 percent one-year survival after retransplantation since the introduction of cyclosporine (27). This contrasts with the poor results obtained under conventional immunosuppressive therapy which yielded a failure rate of 80 percent with a significantly shorter survival outcome (31).

As the incidence of retransplantation increases, transplantation of third liver grafts has been reported at several centers (2,10,27,30). At Pittsburgh, between 1980 and 1984, the prevalence of third liver grafting was 3.5 percent or 9 of 254 cases (27). Transplantation of fourth grafts has also been reported, although this is much less frequent. Gordon provided data on the most recent experience with hepatic retransplantation at Pittsburgh (32). Of 1,000 transplants performed between 1980 and 1987, 246 were retransplantations. One hundred ninety-six (19.6) patients received a second graft, 45 (4.5) received a third, and five (0.5) received a fourth. The one-year survival rate for all patients receiving retransplantations was almost 50 percent; their five-year survival rate was almost 40 percent. Indications for retransplantation were rejection (41), technical failure (33), primary graft failure (24), and infection (2).

One-year actuarial survival was 64 percent for rejection, 30 percent for primary graft failure, and 40 percent for technical failure. Patients receiving one graft had a better survival (78 at one year, 70 at five years) than those receiving two or three grafts (47 and 49 at one year and 38 and 36 at five years, respectively). The five patients receiving four OLTs had one-and four-year actuarial survival rates of 60 percent. In all, there was a 2.2 graft per patient ratio in those retransplantations performed.

The three most common reasons cited for retransplantation were rejection, primary non-function of a graft, and technical failures. Rejection was the most common cause. Slightly more than half of the retransplantations were due to rejection (2,27,30). Technical failures were more prevalent in children than in adults, 32 percent versus 8.3 percent (P=0. 05) (27).

According to Shaw and associates, neither the incidence nor the cause of retransplantation were found to bear any significant relationship to the original disease for which transplantation was performed (27). With the exception of patients with hepatic tumor, none of whom required retransplantation, or patients with primary biliary cirrhosis or primary sclerosing cholangitis, none experienced technical failures.

When looking at causes of retransplantation, non-functioning primary grafts had the worst six-month survival rate. In this series, moreover, there were four deaths among patients who received third liver grafts. The reasons for their third grafting were graft non-function in two patients and rejection in the other two. Sepsis with multiple-organ failure was by far the largest contributor to the death of retransplantation patients (27). This was also the case in single transplant patients (33). Death following third grafting was due to fungal septicemia in one and intracranial hemorrhage secondary to severe hypoxia in another. The other two patients died of sepsis, liver failure (hepatic coma stage III and IV), and renal failure (27).

These data seem to suggest that patients in a state of severe neurological dysfunction that is likely to be irreversible (hepatic coma stage III or IV) are poor candidates for second and third transplantation.

Shaw and colleagues reported on the Pittsburgh experience in retransplantation (27). Of the initial 170 patients who received OLT using azathioprine and prednisone immunosuppression, 21 required retransplantation. Subsequently, 69 of 323 OLTs, where cyclosporine and prednisone were used, have had retransplantation; nine of the 69 were third transplants. One-year survival rates were 49 percent for the cyclosporine group versus 14 percent for the azathioprine patients. Patients with primary non-function of grafts had significantly worse survival than those with technical complications or graft rejection (18 versus 60 and 58, respectively).

Of the nine patients receiving tertiary grafts, five patients (three children, two adults) were alive 7-19 months after surgery. The authors concluded that survival after retransplantation approaches that of a primary graft and that failure of a second graft does not preclude survival after a third OLT.

Ringe and colleagues reported the Hannover experience with hepatic retransplantation (30). Of 170 patients undergoing OLT, 14 required a second OLT and two of these patients received a third OLT. The indications for retransplantation were similar to those cited above, with rejection being the main indication, and technical failure and graft non-function as indications for other retransplantations. Four of 14 patients survived 10-28 months. The two patients who received a third transplant did not The authors advocated continued use of retransplantation since it offers a second chance to patients whose first graft failed.

Diagnostic Techniques

Numerous technical problems such as biliary leaks or obstruction can be corrected if detected early. Many patients ultimately require angiographic or interventional radiologic procedures to diagnose postoperative complications. In one group of postoperative studies, nearly two-thirds of the patients were diagnosed to have complications considered threatening to survival (34). The other third were found to have complications considered compromising to the transplant function.

Ultrasound and computerized tomography (CT) are currently used as screening tests before or instead of invasive diagnostic procedures such as percutaneous cholangiography or biopsy and provide a safer alternative for detecting complications after OLT (34,35). However, a recent study found ultrasound to be relatively insensitive (46 sensitivity) as a screening tool for detection of postoperative biliary complications and recommended that percutaneous transhepatic cholangiography may be preferred for this purpose (36).

Magnetic resonance imaging (MRI) is a recent imaging technique useful in evaluating transplant recipients (37). Not only is it noninvasive, but it also has excellent soft tissue sensitivity. Tissue characterization by either CT or ultrasound is difficult.

Donor-Recipient Matching

ABO blood group matching, a technique performed routinely as part of donor-recipient matching, has been shown effective in preventing rejection of the donor liver. Although ABO matching has been routinely performed in OLT to avoid hyperacute rejection from ABO incompatibility, ABO nonidentical but compatible grafts have been used since the liver was known to be less rejection-prone than the kidney (38).

In a recent review of 672 OLTS performed in 520 patients at Pittsburgh within a five-year period, Gordon and associates demonstrated that ABO compatibility was clearly advantageous in OLT (39). There were significantly fewer graft failures among ABO-identical adult grafts when compared to ABO-incompatible or nonidentical grafts, particularly with primary grafts. In spite of this difference in graft survival rates, the use of ABO mismatched or incompatible grafts in urgent cases or when donor availability is severely limited, such as is the case with small children, may result in survival with or without need for retransplantation.

Previous reports suggested that the liver was resistant to hyperacute rejection from preformed anti-T-lymphocyte antibodies (38,40,41). For this reason, HLA typing and lymphocytotoxic crossmatching have been performed only retrospectively and played no role in recipient selection, unlike routine ABO blood group matching (2,31).

In a recent study by Gordon and associates, neither a high level of panel-reactive antibody of a recipient nor a positive crossmatch for donor-specific preformed lymphocytotoxic antibody was associated with decreased patient or graft survival for both primary grafts or retransplantations (40). In addition, the authors found no significant differences in the frequency of retransplantation for rejection between positive and negative crossmatches based on the histological findings in the removed grafts. These findings contrasted with those of renal transplantation where graft rejections were directly related to ABO incompatibility and to positive lymphocytotoxic crossmatches (42-44).

In renal transplantation, a highly significant correlation of HLA matching with one-year graft survival was found in patients with or without the use of cyclosporine therapy (42,43). In contrast, cadaver renal grafts with no mismatch of HLA-B and HLA-DR had about 20 percent higher success rates than grafts with four mismatches. Recently, however, in liver transplants, some correlation between HLA matching and the development of rejection was reported by Donaldson and associates of King's College (45). The donor and recipient HLA status of 62 OLTs were studied with reference to the vanishing bile duct syndrome (VBDS), a variant of chronic hepatic rejection. They found that a complete donor-recipient HLA class I (HLA-A,-B) mismatch was significantly more common in those with VBDS (P=0.025). Unexpectedly, a complete mismatch for HLA class II (HLA-DR) antigens was less common in those with VBDS than in those with a match (P=0.02).

The combined conditions of a complete mismatch for class I and a partial or complete class II match had a highly significant association with VBDS. The importance of lymphocytic crossmatch and HLA matching in association with VBDS has also been studied by Batts and associates of the Mayo Clinic (46). Their findings contrast with those of the groups at Pittsburgh and at King's College (40,45). They found a strong correlation between positive lymphocytic crossmatch and VBDS occurring within the first 120 days after OLT. A similar finding was observed with an overall HLA class II mismatch but with a borderline statistical significance. However, a mismatch at the DQ locus showed an increased association with VBDS.

Recent studies have shown that graft survival was better in those with one or two HLA-A (class I) mismatches when compared to grafts with no mismatch (P=0. 03) (32). Similar data for matching at HLA-DR (class II) was not statistically significant (P=0.08). The paradoxical effect of HLA matching was suggested as possibly due to a dual effect of HLA antigen engaging with self-recognition as well as alloreactivity. However, the investigators cautioned that it was too early to project these results into the practical realm of liver transplantation until greater understanding is achieved through more extensive experience.

Patient Selection

Improved donor-recipient matching, better immunosuppressive agents, and retransplantation are not the only contributors to improved OLT patient survival. Better selection of patients has also played an important role. Data being accumulated at the National Institutes of Health indicate that the health status of the patient at the time of surgery appears to be a critical determinant, regardless of diagnosis, in the outcome of patients undergoing OLT (47).

Before 1981, patients undergoing transplants tended to be critically or terminally ill and unlikely to do well when transplanted. The trend now is to perform transplantation at an earlier stage of illness when the patient is not so sick, thus improving the chances of a better outcome. Several studies have been done to assess the impact on survival of various patient factors such as preoperative status, age, and diagnosis.

The growing number of patients undergoing OLT therapy provides the opportunity to analyze the survival data for adult OLT in order to identify predictors of outcome. Brems and colleagues conducted a retrospective review of OLT at their institution (48). For the 72 patients in this study, no effect on survival was seen for age, underlying liver disease, previous operations, presence of hepatic encephalopathy, preoperative laboratory values, or duration of donor ischemia.

On the other hand, two postoperative variables --severe rejection and postoperative hemodialysis -- did have statistically significant associations with patient outcome. The small number of patients in this study may have limited the authors' ability to identify other significant variables.

Age has been reported to have an effect on patient survival following OLT. Starzl and associates reported differences between pediatric and adult liver transplant recipients with conventional immunosuppressive therapy (49). Although a difference was initially seen between pediatric and adult patients undergoing OLT, the more recent data from Starzl's group indicated virtually identical actuarial survival curves for both groups (50,51). The Pittsburgh data also indicated that, although actuarial survival was better for patients less than 50 years old, this difference was not statistically significant compared to the survival of patients 50 years and older.

Other authors have observed that the preoperative state of the patient influenced postoperative survival. Williams and associates in one study noted that the severity of the patient's condition prior to OLT correlated with six-month mortality (52). Of the patients who were in an intensive care unit prior to surgery, 56 percent died within six months compared to 14 percent of other inpatients and 10 percent of patients who were out of the hospital prior to surgery.

In separate reports, results of selected laboratory studies were correlated with survival. Cuervas-Mons and colleagues, in a retrospective study of 93 patients undergoing OLT, looked at risk factors for postoperative death and postoperative early major bacterial infection (53). Preoperative serum creatinine was the best predictive factor for both outcomes. It accurately predicted results in 69 percent of patients with infection and predicted survival in 79 percent of patients.

Bontempo and associates evaluated results of OLT in 70 patients undergoing transplantation between 1981-1985 to determine the effect of preoperative diagnosis and coagulation studies on postoperative survival (54). Mean coagulation abnormality scores that were calculated on the basis of preoperative laboratory values significantly correlated with the volume of blood replacement and survival for six months or longer. The volume of blood replacement itself was associated with survival.

In addition, the authors examined survival by diagnostic group. Eighteen patients with primary biliary cirrhosis had a survival rate (six months or more) of 67 percent, 11 patients with neoplasms had a survival rate of 55 percent, and 22 patients with postnecrotic cirrhosis had a survival rate of 45 percent. For eight patients with sclerosing cholangitis, the survival rate was 25 percent and, in 11 patients with miscellaneous diagnoses, the survival rate was 18 percent. The authors concluded that the preoperative diagnosis and coagulation status may be predictive of both blood loss and survival.


Many reports in the literature reflect the improved survival of OLT patients that has paralleled the development of new techniques and better patient selection. Between 1963 and 1976, Starzl and colleagues performed 111 liver transplants, achieving a one-year survival rate of approximately 33 percent (49). Although they obtained a 50 percent one-year survival rate in a small group of patients who underwent transplantation in 1976-1978, this outcome was not sustained in 29 cases undergoing OLT in 1978-1979, when the one-year survival rate was approximately 39 percent.

Rolles and associates at Cambridge reported an overall one-year survival rate of 7.5 percent for 40 patients receiving OLT between 1968 and 1974 (55). Between 1975 and 1982, annual one-year survival figures at their center ranged from 11 percent in 1978 to a high of 50 percent in 1980. The small number of pediatric cases and the large number of primary hepatic malignancies were cited as the reasons for the differences in patient survival compared to those at Pittsburgh.

By the early 1980s, several developments had occurred which contributed to the improved survival rates for OLT that are experienced today. The introduction of cyclosporine as an immunosuppressive agent is credited by some authors for much of the increase in patient survival observed since 1980 (49). Other authors maintain that improvements in anesthetic techniques, post-operative monitoring, patient selection, timing of the OLT procedure, and improvements in operative techniques, such as veno-venous bypass and biliary anastomosis, have all played roles in the improved survival data (56). Recently published overall one-year survival rates range from 54.1-84. 5 percent (57-59).

Various studies of children with certain metabolic diseases have reported one-year survival rates ranging from 74-100 percent and five-year survival of 62-80 percent. Data on survivorship among adults with inborn errors of metabolism are not widely available but may be similar to that reported in children. Most institutions have a small number of adult patients with metabolic diseases and report survival outcomes ranging from 0-100 percent. Pittsburgh has the largest group with 35 adult patients receiving OLT for inborn errors of metabolism. They reported a one-year rate for this group of 58 percent (50).

Adults with diseases caused by external agents, such as the hepatitis B (HB) virus, experience a variety of outcomes which depend on the specific cause of liver disease. Despite early optimism for long-term success in transplanting patients with fulminant HB infection or those with chronic HB, the overall incidence of recurrence of the primary disease in the graft remained as high as 50-100 percent for liver transplant recipients with chronic HB and 66 percent for those with fulminant HB. Several institutions reported similar experiences. At the New England Deaconess Hospital and at Pittsburgh, patients with cirrhosis, chronic active hepatitis, and fulminant hepatic failure had different survival rates if they were HBsAg-positive versus those who were HBsAg-negative. Patients with cirrhosis or hepatitis who were antigen-positive had lower one-year survival rates of 33-48 percent. Hepatitis patients who were antigen-negative had one-year survival rates of 75-78 percent.

Pittsburgh reported a one-year survival rate of 57 percent in those HBsAg-positive patients with fulminant hepatic failure compared to the one-year survival rate of 78 percent in antigen-negative patients. Rush-Presbyterian-St. Luke's Medical Center achieved a 60 percent one-year survival rate in patients with non-A, non-B viral hepatitis undergoing OLT. One-year survival rates of 80 percent and 70 percent for chronic active hepatitis were achieved by UCLA and the Mayo Clinic, respectively. By comparison, the European Liver Transplant Registry reported a one-year survival rate of 55 percent of posthepatic cirrhosis (10).

A recent report indicated that patients with alcoholic cirrhosis had a one-year survival rate of 73 percent and a three-year survival rate of 68 percent (5). in contrast to an earlier report that showed less favorable outcomes in a small number of cases (60). Overall survival of patients with hepatitis or some form of cirrhosis has increased to 70 percent at one year in the postcyclosporine era (after 1979) compared to 54 percent at one year in the precyclosporine era.

The outcome of liver transplants in patients with systemic disorders of unknown origin that are likely to recur in the graft has been mixed. Patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) have quite favorable survivals of 75-80 percent at one year and up to 70 percent at five years after transplantation (50).

At the institutions surveyed, PBC, PSC, and cirrhosis were the most common diagnoses in adults undergoing OLT. One-year survival rates for PBC ranged from 57-92 percent (61). Recurrence of the primary disease had been a concern for PBC patients undergoing OLT since Neuberger and colleagues (6). reported disease recurrence in three patients. This report was challenged as presenting findings consistent with, but no diagnostic of, recurrent PBC (62). Other authors reported the lack of recurrent disease in the graft (63,64). One-year survival rates for PSC ranged from a low of 33 percent, reported by Pittsburg for those patients in whom an incidental malignancy was found, to 90 percent by other centers.

The outcomes of liver transplantations in the small numbers of patients with other systemic diseases have not been as good nor as consistent (12,14,65-67). Conditions include Budd-Chiari syndrome, veno-occlusive disease, amyloidosis (primary or secondary), lupoid hepatitis, or hepatitis associated with some forms of autoimmune vasculitis involving the liver. These conditions merit further research into a possible role of transplantation.

Survival outcome for patients transplanted for malignancy has been poor. Neoplastic disease has had a high frequency of recurrence. In many instances, early survival was comparable to that with other non-neoplastic diagnoses but tumor recurrences within one year resulted in low survival rates (7,68). The European centers consistently included larger numbers of patients with malignancy in their OLT series. Rolles reported a series of 137 patients (receiving 138 transplants) of whom 40 had liver tumors (55). Sixteen patients had recurrence, with 13 of the patients surviving more than one year. Of the 24 patients without a tumor recurrence, 19 died (although 16 survived more than one year) and five remained alive from five months to over seven years.

In 29 percent of all patients in the European Liver Transplant Registry who underwent OLT, cancer was the indication for the procedure (10). The one-and two-year actuarial survival rates for these cancer patients were 42 percent and 30 percent, respectively, based on the results of transplants performed since 1985.

Iwatsuki and colleagues reported the Pittsburg center's experience with cancer patients treated by OLT (50). For the 36 patients with primary hepatic malignancy, one-and five-year actuarial survival rates were 65 percent and 29 percent, respectively. Of the 27 patients who survived longer than six months, 13 developed tumor recurrence. Survival rates for the eight patients with epithelioid hemangioendothelioma (88 at one year, 68 at four years) were better than those for the 18 patients with hepatoma (55 surviving at one year, 25 at four years). Seventeen patients who received OLT for liver failure were found to have a malignancy at surgery. One of these patients died of recurrent hepatoma; the other 16 were reported alive three to six years later and were tumor-free.

Pichmayr summarized the European experience in OLT for malignancy and reported in detail on the program in Hannover (7). Data from seven European centers (totaling 296 patients) indicated survival rates (one year, five years) for hepatocellular carcinoma (90, 10), hepatocellular carcinoma with cirrhosis (23, 20), cholangiocarcinoma (26, 2), bile duct carcinoma (39, 0), metastatic disease (30, 0), and other primary liver tumors (25, 6).

The majority of the patients undergoing OLT in Hanover were found to have undiagnosed extrahepatic tumor at surgery; some patients were subsequently found to have had malignancies which were unrecognized at surgery. Tumor recurrence was said to be the rule, although specific data were not presented.

Substantial differences in survival were noted between patients who had negative lymph nodes versus those with positive lymph nodes. The actuarial survival cirrhosis was 11 percent at one and two years, if they had positive lymph nodes, and 75 percent if their nodes were negative. For patients with proximal bile duct tumors, the one-and two-year rates were 13 percent and 0 percent, respectively, if lymph nodes were positive, compared with 100 percent and 83 percent when the lymph nodes were negative. The author concluded that OLT for selected tumor patients was justified and that, considering the long-term survivors for each diagnosis, the stage of disease at surgery may be a better indicator of outcome than the diagnosis.

In a recent review of liver transplantation, Starzl noted that, although the prognosis for patients with certain kinds of tumors was better than for others, the survival outcome of patients with tumors was generally poor (69). He further noted that the rate of recurrence of the original tumor was overwhelming. He cautioned that ruling out the possibility that the tumor had spread beyond the liver should be a crucial condition of candidacy since tumor recurrence was the most common cause of death after liver transplantation.

Quality of Life

The studies assessing quality of life (QOL) of OLT recipients are few and the results inconsistent on what constitutes QOL (70). Gordon notes, "It is often said that transplant patients trade one disease for another, that is, end-stage organ failure for chronic immunosuppression" (32).

Although cyclosporine and OKT 3 have improved long-term survival after OLT, what quality of life do these patients survive for? To answer this question, Gordon and associates, University of Pittsburg, classified 264 (28 azathioprine-and 236 cyclosporine-treated) long-term survivors into six categories: 1) fully rehabilitated, for example, working or attending school full time; 2) partially rehabilitated, that is, working or attending school part time or having only mild disability; 3) not working or attending school, that is, disabled but not institutionalized, yet requiring close medical supervision or intermittent hospitalization; 4) institutionalized but not requiring intensive care; 5) hospitalized in intensive care; and 6) hospitalized on life support systems (32).

Only five patients were severely disabled and one was in significant jeopardy at the time of the 1987 personal communication from the group at Pittsburgh. A total of 224 patients (84.9) were fully rehabilitated and leading what could be considered a normal life and requiring only routine monthly medical checkups. Thirty-four patients (12.9) were partially disabled, but able to remain at home without special medical assistance. They were working or attending school part time.

The Pittsburgh group concluded that, for certain patients, liver transplantation offers "not only a chance at a longer and better quality survival, but genuine likelihood of cure and restoration of health" (32).

While the Pittsburgh group used patient functioning as an indicator for assessing quality of life, others have looked at such factors as "perceived satisfaction" (71). For example, Christopherson believes that the impact of the illness and of subsequent medical intervention in the lives of the patients and their families must be factored into QOL assessment (71).

She notes that the only QOL parameters agreed upon as reliable and valid are "alive versus dead" and, if alive, "hospitalized versus not hospitalized." Yet she regrets that "despite their ease of measurement, these parameters say little about other issues of importance to individual patients and their families." She notes that the length of the patient's survival also affects the patient's and family's assessment of QOL.

Chapter 3 Morbidity and Mortality

The introduction of cyclosporine-steroid therapy and new surgical techniques such as veno-venous bypass were discussed in the 1983 PHS report on liver transplantation. These, along with the new techniques discussed in this report, have played important roles in lowering the morbidity and mortality rate of OLT (31,72,73). In addition, innovative diagnostic procedures that permit early detection of many potentially fatal complications have resulted in prompt treatment that further improved postoperative management of OLT patients (33,35).

As a result, the one-year survival of patients following OLT (54.1 to 84.5) has improved substantially since the early days of the procedure. Nevertheless, the complications of OLT are many and common.

Table 4 lists liver transplantation complications reported to date. In the published literature, some reported only the single most important cause contributing to death (33,74). In other reports, either multiple causes were listed or the precise cause of death was not specified. Furthermore, there was great diversity in the presentation of morbidity and mortality data on the outcome of OLT; for example, data on adults and children were often not separated.

Table 4. Liver transplantation complications.


Table 4. Liver transplantation complications.

The majority of patients had more than one postoperative complication (2,14,75,76). Death was usually caused by multiple factors (33,76,77). ; thus, it was difficult to determine its primary cause in those cases. Other important variables such as patient selection, patient condition prior to surgery, and preexisting anatomical conditions were not indicated and need to be taken into consideration as well.

An overall early postoperative mortality rate of 37 percent in a group of 129 adult OLT recipients (March 1981-June 1984), exclusive of intraoperative deaths, was reported recently by Cuervas-Mons and associates (33). The mean interval between transplantation and early death was 46.4+/- 6.1 days with a range of 4-296 days.

In a later series, 216 one-year survivor records (56 adults, 44 children) were reviewed for late postoperative morbidity and mortality after liver transplantation (78). The one-year actual survival rate was 69 percent; actuarial survival rates for the subsequent two to five years were 64 percent, 62 percent, 60 percent, and 60 percent, respectively. The chance of dying after the first year was 13 percent among one-year survivors.

The European Liver Transplant Registry reported on 1,194 of 1,218 patients who underwent OLT up to 1985 at 32 centers and for whom information on primary transplantation was available (10). The overall 30-day (perioperative) mortality was 30 percent, with 27 percent for elective and 38 percent for emergency transplantation. Fourteen percent of the series consisted of children under 15 years of age, while 47 percent were 35-55 years old, and 3 percent were older than 65.

Mortality after OLT occurred predominantly in the early months (14,33,72). This pattern has not changed since the earlier report of Starzl (74). In the Pittsburgh series of 129 OLT adult recipients, 42.5 percent (17 of 40) of the early deaths (within 10 months) occurred in the first months of OLT and 75 percent (30 of 40) occurred within the first 60 days of transplantation (33). Kirby and associates of the University of Birmingham reported a series of 46 OLT patients in whom 73. 7 percent of all deaths occurred within the first month of the operation (76).

Intraoperative, Early and Late Postoperative Complications

Fatal complications reported to have occurred in the intraoperative period included exsanguination, cardiovascular collapse, pulmonary embolism, air embolism, and an inadequate portal vein (33,52,59,76,77,79,80).

The incidence of intraoperative death (within 24 hours of surgery) was about 5 percent in one series (33). The incidence of severe hemorrhage resulting in intraoperative death was 3.7 percent at Pittsburgh and 2 percent at Boston (33,59). The Cleveland, UCLA, and Mayo clinics reported no intraoperative deaths in their initial series (2,75,81).

According to European multicenter collaborative data, 14 percent of 585 deaths in their registry were caused by hemorrhage. About 75 percent of these patients died within the first week of surgery (10).

In the initial British series of Birmingham, among 46 patients (aged 11-60 years) hemorrhage contributed to two of the three deaths that occurred within 48 hours (76). Severe hemorrhage (defined as more than 70 units of blood lost) was also reported in seven other patients in this series. Six died during their hospitalization period (4-42 days). Five (55) of the nine patients who developed severe perioperative hemorrhage had had previous upper abdominal surgery.

In a recent series reported by Williams and associates of Cambridge University, hemorrhage was the cause of death in five of nine adults who died within four weeks of transplantation (77). In addition, hemorrhage complicated by infections was seen as a frequent cause of early postoperative deaths in OLT patients (33,76).

Biliary Tract Complications

In spite of improvements in many aspects of liver transplantation, technical failures, including biliary tract and vascular complications, still result in considerable morbidity and mortality after transplantation (82-84). Complications of the biliary tree, common in the early days of transplantation and a significant cause of early technical failures, are no longer considered the "Achilles heel" of liver transplantation. Earlier reports attributed 20 percent of deaths to biliary tract failure. These results have improved through greater use of duct-to-duct anastomosis (choledochocholedochostomy) performed over a t-tube.

Recently, the reported incidence of biliary tract complications varied from 13-30 percent (2,82,83). The problems occurred in the first few weeks after transplantation and accounted for 21 percent of all deaths related to technical complications (82). Since the use of choledochocholedochostomy and choledochojejunostomy, more successful biliary constructions have been achieved (31,74,82).

In a recent review of 393 consecutive liver transplants in 313 patients performed at the University of Pittsburgh between March 1980 and December 1984, both surgical techniques were used with a success rate of 91.3 percent (82). In this series, other methods of surgical reconstruction (Table 5, compiled by Pittsburgh group). were associated with high failure rates of such technical complexity that the researchers believed they did not justify their use. Choledochojejunostomy over an internal stent to a Roux-en-Y limb of proximal jejunum (RYCJ-S) was used in 126 children and 49 adults. Choledochocholedochostomy over a t-tube (CC-T) was used in 135 adults and 24 children. Over a short follow-up period of 12 to 18 months, the overall failure rates of RYCJ-S and CC-T were 5. 1 percent and 12.6 percent, respectively ( Table 5).

Table 5. Primary biliary complications according to technique of reconstruction[*].


Table 5. Primary biliary complications according to technique of reconstruction[*].

Overall, the incidence of biliary tract complications in this series was 13.2 percent which also accounted for slightly more than half of all the technical failures. Biliary leakage and obstruction were the most common complications, with about 10 percent of all biliary tract complications resulting in death.

The UCLA group reported 24 percent overall biliary complications in their first 100 liver transplants performed in 83 patients (2). There were 67 CC-T, and 33 RYCJ-S anastomoses performed in this series. Sixteen (24)complications were observed after CC-T and the majority of these were associated with peritonitis after t-tube removal or with t-tube malposition. Eight (24) complications were observed after RYCJ-S techniques; five were related to the duct-jejunal anastomosis and three to the jejunojejunal anastomosis.

Others have had successful experience with Roux-en-Y hepaticojejunostomy. Bismuth and associates reported uneventful early postoperative periods among their first 55 OLT patients with this procedure (20). Biliary complications occurred in 5.5 percent of patients in the first few months after the operation. All stenoses recurred at the anastomoses but all were surgically corrected. There were no deaths related to biliary complications.

In the small series reported from Groningen, CC-T technique was performed in the majority of the patients, of who nearly 90 percent were adults (85). Biliary tract complications occurred in 15 of 49 (31 percent;) OLTs performed in 46 patients. Two of these 15 patients (13) died as a result of biliary tract complications.

Vascular Complications

Vascular complications, while correctable, resulted in death more than two-thirds of the time and were a frequent cause of retransplantation. Recently, noninvasive diagnostic techniques such as ultrasound and magnetic resonance imaging (MRI) have replaced invasive procedures like angiography for evaluating these complications (37,86,87).

The incidence of vascular complications after OLT was reported to be 5-10 percent (82,84,87,88). Overall vascular complications occurred in 6 percent of adult and 16 percent of pediatric grafts (87). Thrombosis or stenosis of the hepatic artery or portal vein were among the more commonly detected findings.

The most frequent and lethal vascular complication was hepatic artery thrombosis (HAT). Its incidence was approximately 4-10 percent according to recent literature reviews (2,59,75,81,84,87,88). Due to the smaller caliber of donor arteries, pediatric OLT patients had a higher incidence of HAT regardless of the reconstruction technique used.

Although one-third of donors had hepatic artery anomalies, Todo and associates did not find an increased incidence of HAT with anomalies of hepatic artery in contrast to an earlier report (84,89). According to Tzakis and associates, the incidence of HAT was 12 percent in pediatric and 3 percent in adult recipients following OLT (84). HAT was the second most common technical complication after those of the biliary tract.

HAT usually presented in one of three clinical settings: fulminant hepatic necrosis, delayed biliary leak, or relapsing bacterial infection. These complications usually appeared between the second and the tenth week after liver transplantation. Although some HAT cases were surgically correctable, more than half resulted in death and were responsible for 66 percent of all the technically related deaths (82). Mortality with HAT was much higher in adults (83.3) than in children (37.5) (84).

In another study, all adults with complete hepatic artery occlusion required immediate retransplantation, but one-fourth of the children with HAT survived without retransplantation during follow-up period of 3-42 months (87). Most of these children were later shown to have hepatopetal arterial collaterals. However, in general, children with HAT also require immediate retransplantation.

Portal vein thrombosis (PVT) and inferior vena caval thrombosis (IVCT) were the least common vascular complications after OLT. Their incidences were 1.8 and 0.8 percent, respectively (90). Almost all of these complications occurred in pediatric recipients.


Today infectious complications are the most common cause of death in liver transplant recipients and account for 52.5 percent of early deaths (33).

The frequency and type of infections reported seemed to vary from center to center, perhaps partly due to the different regimens and doses of immunosuppressive and antimicrobial agents administered. The cause of death was difficult to identify when a serve infection coexisted with multiple-organ failure or graft rejection.

The incidence of overall infection after OLT has been reported to range from 45-79 percent (2,21,91). According to a recent review by Cuervas-Mons and associates, 50 percent of deaths due to infection occurred during the first month after transplantation (33). ; 90 percent of infection-related deaths occurred within two months. Of the 40 early deaths following OLT in this study, septicemia was present in about half of them. In 81 percent of these or 42.5 percent of all deaths, bacterial sepsis was considered the cause of death. Coexisting disseminated fungal infection was seen in 23 percent of the deaths with bacterial sepsis. Overall, 17 percent of the deaths caused by infections were caused by disseminated fungal infection and 2.5 percent by viral infection.

Significantly different mortality rates were observed in patients with early major bacterial infection (71) and those without (8) (53). Sepsis, pneumonia, and abdominal abscess were the most common early bacterial infections following OLT. Of the various bacterial agents isolated from these patients, Pseudomonas was the most frequent.

The incidence of fungal infection in the early postoperative period was reported at 42 percent (91,92). Most of these occurred in the first month, with Candida and Aspergillus being the main causative organisms. When compared to infections among other organ transplant recipients, fungal infection during cycloporine therapy was more common in OLT patients. These infections were not seen in cardiac and renal transplant patients (91). One group attributed its low rate of fungal and bacterial infections in OLT patients to the routine use of selective bowel decontamination (93).

At some centers, viral infections were reportedly more common than fungal infections after OLT (75,76,81). Infections with cytomegalovirus (CMV), perhaps virus group, and Epstein-Barr virus (EBV) were significant complications following organ transplantation. The incidence of overall CMV infections after OLT was 70 percent (half of these had viremia) followed by herpes simplex in 45 percent and perpes zoster in 5 percent of patients (91). CMV infection occurred in about 70-100 percent of organ transplant recipients and significantly affected the morbidity and mortality (91,94).

Although fatality among OLT recipients is not usually related to CMV infection, deaths caused by this infection have been reported (33,52,81,95,96). Seventy-five percent of patients with CMV infection developed CMV hepatitis (95). Patients who were seronegative for CMV and received an organ from a seropositive donor had the most serious CMV inclusion disease. Various means, including the use of hyperimmune CMV globulin, have been used to prevent this infection in organ transplant recipients (97).

Conflicting reports on the effectiveness of anti-CMV globulin in the prevention of CMV infection may be attributed to different globulin preparations and to the varying dosages used in these studies (95,98-100). A French study reported that anti-CMV globulin was incapable of preventing CMV infection but was able to reduce the severity of the disease (96).

Two studies supported the use of "protective matching" of donor-recipient pairs, which required a matching of a CMV-seronegative recipient with a CMV-seronegative donor and the use of CMV-negative blood and blood products for transfusion in the prevention of primary CMV infection (97).

When compared with azathioprine (Aza)-treated patients, cyclosporine-treated patients had fewer infectious complications, (91,101) except for their increased incidence of Pneumocystis carinii infections (102).


Rejection of the donor liver is the most common complication of OLT and occurs in the majority of patients. Despite the routine use of immunosuppressive agents, the estimated incidence of some degree of rejection ranges from 60-100 percent (2,59,75,76,104). Attempts have been made to identify a subset of OLT recipients who may be at high risk for rejection. However, to date no definite conclusion can be made regarding the relationship between rejection and pre-OLT liver disease (103,104).

Williams and associates observed 17 occasions of biopsy-documented rejection in a series of 55 liver transplantations in 50 patients (52). In another group of patients, the lowest estimated incidence rate of histologically proven hepatic rejection following adult OLT was at least 37 percent (103). Histologic evaluations were available for 62 of 95 adult recipients. The author inferred that a higher actual incidence of rejection was very

In patients with severe or irreversible rejection, which did not respond to immunotherapy or for whom another donor organ was not available, death was the expected outcome of graft failure. Graft rejection was the main cause of death in 8-10 percent of all OLT cases in two series (10,60). Based on data from Pittsburgh, rejection was the cause of 7.5 percent of 40 early deaths (within 10 months) following liver transplant in adults (33). It should be noted, however, that in the Pittsburgh series, if a major infection coexisted with graft rejection in a patient, the infection was considered the primary cause of death. Thus, the incidence of rejection may be underestimated.

Among 216 one-year survivors of OLT, 25 patients (11) encountered moderate to severe rejection after the first year (78). Six of the 25 patients (24) with rejection died --two prior to retransplantation and four after retransplantation. The retransplantation procedure was performed in only 11 patients. Twelve patients survived with their original grafts within the follow-up period. At Pittsburgh, rejection was by far the most common cause of retransplantation, 62.5 percent (15 of 24) in adults and 52 percent (13 of 25) in children (60).

Since the diagnosis of rejection is difficult, if not impossible, to establish based on clinical presentations and biochemical test results, histopathological examinations of percutaneous hepatic biopsy specimens have been used to diagnose and guide the management of rejection after OLT (103,105-107). The main histological characteristics of acute and chronic hepatic rejection were believed by some to be similar to those of renal rejection, namely, mononuclear cell infiltration in acute rejection and intimal arterial thickening in chronic rejection. However, hyperacute rejection due to preformed anti-T-lymphocyte antibodies, which is seen in renal transplantation, has not been seen in OLT (40,74). Nevertheless, there have been discrepancies in the published reports on histological descriptions of what is "acute" or "chronic" rejection and what specific histological features may have prognostic significance (45,103-108). Most of the reports seemed to agree that acute rejection is a reversible process whereas chronic rejection is not reversible.

The most worrisome condition of hepatic rejection is the chronic irreversible type. The term "vanishing bile duct syndrome" (VBDS) has been used to refer to a type of chronic irreversible rejection that is characterized by the absence of identifiable interlobular bile ducts (45). A small study recently suggested that "acute VBDS" can also occur with a short clinical course within 100 days after OLT (104).

A type of graft-versus-host (GVH) reaction has been observed in OLT patients who received ABO mismatched grafts (109). These patients presented with transient hemolytic anemia; short-lived anti-recipient ABO antibodies were also detected. Unlike rejection, this form of immunologic reaction was usually self-limited and required only supportive treatment, although more serious reactions were reported (110,111).

There is increasing interest in the field of liver transplantation to search for a meaningful relationship between HLA matching, preformed antibody as well as blood groups, and graft survival. This knowledge may be vital for improving the donor selection process, preventing the disaster of irreversible rejection, and providing an effective, low-risk alternative treatment.

Side Effects of Drugs Used to Treat Rejection

A final set of problems related to rejection is the sometimes severe side effects of the drugs used in treating rejection --steroids and immunosuppressive agents such as cyclosporine, azathioprine, antithymocyte globulin (ATG), and the OKT3 monoclonal antibody. The present trend seems to favor the use of OKT3 in the treatment of acute hepatic rejection resistant to high-dose steroids, especially in patients with additional renal complications for whom the nephrotoxicity of cyclosporine is of concern.

While in one study steroids might have appeared to be more toxic than OKT3, OKT3 itself was not without adverse effects that were similar to those reported with antilymphocyte globulin (ALG) preparations used more than 15 years ago (22,25). Toxicity of OKT3 consisted of a symptom complex of pyrexia; chills; chest discomfort and tightness; dyspnea; gastrointestinal symptoms of nausea, vomiting, or diarrhea; rash; and pruritus (21-24). These symptoms were severe in the first few days after the first injection and less so after the second injection. Whether repeated or prolonged use of OKT3 may prove to be successful without significant hypersensitivity reactions is not known.

Cyclosporine, a potent immunosuppresive drug, was first introduced into clinical transplantation in 1978 by Calne and associates (112). Because of several concerns about the effects of the drug in their renal transplant patients, especially its nephrotoxicity, Starzl and co-workers undertook a combined therapy of cyclosporine and steroids in 1981 in order to reduce cyclosporine's untoward effects. This double-drug therapy has since become the basic immunosuppressive treatment of all the liver transplantation centers in this country (73). However, the details of this regimen, including doses, the desirable maintenance blood level of cyclosporine, and blood-level monitoring techniques vary from center to center.

While it has been shown that cyclosporine and steroid therapy improved one-year survival of OLT patients, the long-term complications of cyclosporine are not fully understood. The use of steroids and cyclosporine requires careful dosage adjustment. Frequently, insufficient use will result in graft loss due to rejection. Overusage will result in nephorotoxicity or devastating opportunistic infections. Intestinal absorption of cyclosporine after OLT has been known to be unpredictable (31). Furthermore, there have been suggestions that various agents and conditions may be associated with increased cylosporine blood levels and may therefore precipitate toxicity. The reportedly toxic associations with cyclosporine include high-dose methylprednisolone, hypomagnesemia, and hypertriglyceridemia (113-116).

Although the toxic effects of cyclosporine are often caused by a high dosage, toxicity also may occur in patients despite having a desirable "non-toxic" blood level (31). This may lead to difficulty in the clinical management of OLT recipients, not to mention rejection and other OLT complications that may also confound the diagnosis of cyclosporine toxicity. Minor side effects included increased body and facial hair and gum hypertrophy, all of which were improved when the cyclosporine dose was lovered (14).

Other serious adverse effects of cyclosporine include nephyrotoxicity, neurotoxicity, and hepatotoxicity. Nephrotoxicity is the most commonly recognized toxic effect of cyclosporine therapy, not only in renal transplantation but also in transplantation of the liver and other organs (117-121).

Renal impairment was a common postoperative complication in adult OLT patients who received cyclosporine therapy (2,76,78,119-127). About 11-40 percent of the recipients required hemodialysis (2,76,120). Mortality in those who required hemodialysis was high (2,76). Significant correlation of hemodialysis and early mortality also was shown in one study (2). Although overall normalization of renal function was observed in about half of the renal impaired patients, the long-term effects of cyclosporine on renal function need to be studied further (120).

Reported neurological side effects of cyclosprine include tremor, quadriparesis, ataxia, urinary retention, paraesthesia, drowsiness, amnesia, confusion, seizure, status epilepticus, cerebral blindness, and coma (113,116,128-136).

Neurological disorders that occurred in OLT recipients while receiving cyclosporine therapy were reported by several institutions (2,19,75,76,137,138). The incidence of cyclosporine-associated neurological complications in OLT recipients was approximately 25-33 percent, and the incidence of cyclosporine-related seizure was 20-25 percent (2,19,76,137,138). Some researchers believe that seizures may be a result of cyclosporine's fluid-retaining properties, which were also aggravated by the use of corticosteroids (138).

In another series, a 33 percent (17 of 52) incidence of serious neurological complications occurred following OLT as reported by Adams and associates of Birmingham (19). Seizures were the most common neurological manifestations in this series with an incidence of 25 percent (13 of 52). The median interval between surgery and the development of seizures was seven days. Children seemed to be more susceptible to cyclosporine-related seizures than adults as previously suggested by some (132,133).

Other serious neurological complications observed in this series were: cerebral pontine myelinolysis in one patient (displayed in the form of disorientation and progressive quadriplegia), cerebral infarction and hemorrhage in another patient (necropsy showed fungal infections), and psychosis in four others.

De Groen and associates reported three liver transplant recipients experiencing severe central nervous system toxicity associated with the use of cyclosporine, as had been previously described by Berden and associates and Rubin and Kang (131,135,137). These neurological manifestations included confusion, cortical blindness, weakness, quadriplegia, seizures, and coma.

Hepatotoxicity is another side effect of cyclosporine. Calne and associates in 1978-1979 described a transient rise in serum bilirubin and alkaline phosphatase levels in the early postoperative period of organ-transplanted recipients receiving cyclosporine (18,112). Subsequently, cyclosporine-related liver dysfunction characterized by elevated serum levels of bilirubin, alkaline phosphatase, and transaminase were reported in several renal transplant series, as well as in heart and in bone-marrow transplanted patients (101,128,139-141).

In renal transplant recipients, up to 20 percent of cyclosporine-treated patients developed abnormal liver function (101,139,140). However, most of the hepatotoxicity was described as mild and tended to resolve with cyclosporine dose reduction. Klintmalm and associates later reported the association of hepatotoxicity in renal transplant patients with high plasma cyclosporine levels (142). In heart transplant recipients, who were without congestive heart failure, a cholestatic pattern of hepatic enzyme elevation was found in patients receiving cyclosporine therapy. Cyclosporine hepatotoxicity in OLT can be difficult to recognize; it may be mistakenly diagnosed as rejection.

The pathophysiology of cyclosporine hepatotoxicity remains unknown and few histopathologic studies involving humans are available. Careful monitoring of cyclosporine drug levels and avoidance of concomitant use of other drugs known to increase cyclosporine levels may help prevent this side effect.

Recurrence of Primary Malignancy

Recurrence of original disease following transplantation remains a significant complication in patients with malignancy and in those with hepatitis B infection (143). Recurrence of malignancy has resulted in a high mortality rate. Usually recurrence developed within one year of transplantation. The overall incidence of recurrent primary carcinoma was observed to be in the range of 35-74 percent, with 43-80 percent of these cancer recurrences leading to death (14,50,66,144).

The overall recurrence rates for malignant tumors were significant. Generally, metastatic tumors had the highest rate of recurrence and epithelioid hemangioendothelioma appeared to have had the lowest. Bile duct carcinoma, hepatocellular carcinoma, and fibrolamellar carcinoma also had significant recurrence rates. However, conflicting results were seen in bile duct tumor and fibrolamellar carcinoma. Certain tumors with lymph node-negative stages appeared to have had better results after transplantation. The biological nature and stages of the tumors seemed to influence the recurrence frequency and survival outcome. More experience with longer follow-up is necessary in order to define which tumors may be suitable for OLT.

Microscopic metastasis in the regional lymph nodes at the time of hepatectomy appears to be a prognosticator of poor long-term outcome. Despite careful pretransplant assessment of the extrahepatic spread of liver tumor (employing ultrasonography, computerized tomography, angiography, and colloid scan, or diagnostic laparotomy in those who did not have surgical exploration prio to the referral), microscopic metastases can be missed and mortality is commonly seen within a year (145).

Data from Pittsburgh consistently demonstrated that tumor recurrence persists as a significant problem after liver transplantation for cancer. While this group observed some individual long-term survivors, most of the survivors were short-term.

In Europe, OLT for liver malignancy was more common than in the United States until 1984, when the European proportion of OLTs performed on cancer patients began to fall (10). A retrospective analysis of the European data that included the Hannover experience with OLT for malignant tumors and experiences at six other European centers was done in an attempt to define a specific tumor stage at which liver transplantation might be considered effective (7). The analysis involved patients with hepatocellular carcinoma without cirrhosis and patients with proximal bile duct tumors. Either type of tumor with a lymph node-negative tumor stage appeared to have a relatively favorable outcome at one end two years --in contrast to metastatic tumors that appeared to have had a poor prognosis, with survival usually not exceeding one year. The authors, acknowledging that these interpretations are questionable due to the small data base and the short observation period, suggested that lymph node-negative tumor stages without other signs of extrahepatic involvement might be considered an indication for liver transplantation.

Many unanswered questions remain. For instance: 1) Why did some patients with an unfavorable tumor such as cholangiocellular carcinoma enjoy prolonged survival even in the presence of metastases? 2) Is an effective pretransplant assessment of prognosis available? 3) Does the risk of tumor recurrence and metastases, in addition to many other associated morbidity and mortality risks, outweigh the benefit from liver transplantation? 4) Is it possible to predict which patient with which tumor, if any, might benefit from liver transplantation? 5) What effect, if any, does immunossuppression have on cancer immune surveillance in patients who have undergone transplantation? While it is increasingly believed that immunosuppression may have contributed to growth and metastases of malignant tumors (146). , this remains to be determined.

Recurrence of Primary Biliary Cirrhosis

Conflicting reports exist regarding recurrence of primary biliary cirrhosis (PBC) in transplanted patients(62,143,147,148). However, reported cases were few, and the recurrent disease was not severe (6,66).

Mild recurrence of PBC was reported in a few patients after three to five years of transplantation experience at one center (6,14). Another four cases with compatible or suggestive histological evidence of PBC recurrence were reported from the same institution recently, but evidence to support recurrence was less than definitive (65). There has been increased acceptance that histological features of bile duct damage are inconclusive for PBC since they are also seen in chronic rejection (62,66,143,147,148).

According to a recent communication from Pittsburgh, their experience with 161 patients transplanted for primary biliary cirrhosis so far has no confirmed cases of recurrent disease in the donor grafts (32). However, this may be because PBC may respond to the immunosuppressive theraphy used to modify or preclude rejection. At Groningen, four patients with PBC were alive five to seven years after transplantation (85). All were reported to show no evidence of recurrence.

Although PBC is an immunologic disease, its etiology and pathogenic mechanism are still unknown. Further research is needed before precise diagnostic criteria confirming occurrence or recurrence of the disease can be established.

Recurrence of Hepatitis B

The incidence of recurrence of chronic hepatitis B infection is 50-100 percent (2,19,50,66). Approximately 26 percent of the recurrence resulted in fatality (50).

Despite the use of hepatitis B immunoglobulin and alpha-interferon therapy at one center during the perioperative period, recurrence of hepatitis B was widely reported (2,14,50,149). Furthermore, early mortality in patients with chronic active hepatitis B is also noted to be high, 33 percent and 50 percent, respectively, in the Pittsburg and the British series (50,66). Iwasuki and associates suggested that immunologic impairment of the carries may play an important role. Overall, HBsAg carries had a significantly lower survival rate than the non-carriers, 57 percent versus 78 percent one-year actuarial survival (5).

In the case of fulminant viral hepatitis B infection, reappearance of HBsAg or recurrence of hepatitis has been reported. In a study of 29 liver transplant performed at Pittsburgh for acute and subacute hepatic failure in adults, the only survivor among four patients with acute, fulminant hepatitis B infection developed positive HBsAG after transplantation but was doing well without clinical or biochemical evidence of liver disease (150). According to a recent communication from Pittsburgh, 40 patients with fulminant hepatic failure received transplants at that institution (32). Six of seven recipients who had fulminant hepatitis B were surviving between six months and two years post-transplant. Four of the six surviving recipients developed recurrent hepatitis 11 to 15 months following surgery.

In recent years, development of superinfection with hepatitis D virus (HDV) in hepatitis B carries has been observed (151,152). Rizzetto and associates reported a series of nine such cases receiving transplants in Italy between 1983 and 1986 (152). They found a recurrence rate of 71 percent.

Published data on fulminant hepatic failure from several other centers, including some European centers, did not mention recurrence of viral hepatitis in those patients who had either hepatitis A or non-A, non-B viral hepatitis (153-157). At King's College in England, concern was raised over recurrence of non-A, non-B viral hepatitis in patients transplanted for fulminant hepatic failure. Portmann found no evidence of recurrence with either hepatitis A or non-B viral hepatitis (66). Four patients with non-A, non-B viral hepatitis were transplanted; two of them were alive at five and 43 months, and the other two died on the seventh and ninth postoperative days. O'Grady and associates of the same institution reported that the two patients with non-A, non-B viral hepatitis, who died several days after transplantation, probably had recurrence of the disease (158).

Recurrence of Other Diseases

Disease recurrence also has been in patients with Budd-Chiari syndrome, autoimmune chronic active hapatitis (CAH), and primary sclerosing cholangitis (PSC).

The development of thrombosis of large vessels in patients with Budd-Chiari syndrome or the recurrence of the primary disease were serious complication that led to death or retransplantation (66,159). Other hematologic complications in this disease were detected within one year after transplantation, but most of these patients were alive 3.7 to 9.3 years post-transplantation.

Recurrences of automatic chronic active hepatitis (CAH) have been mild. In autoimmune CAH, the condition reported in one patient improved and resolved after the adjustment of immunosuppressive theraphy (65). No unknown case has since been documented (66).

Little is known about PSC recurrence except that it has been reported in few patients who were known to have bowel disease prior to transplantation (61). A recent communication from the Pittsburgh group reported that bile duct cancer was found in 9.6 percent of 83 patients receiving transplants for PSC (32). Survival rates for such patients were significantly lower than those for patients without bile duct cancer (32).

Lastly, although recurrence of alcoholic cirrhosis may be possible in patients who return to their previous drinking habits after transplantation, this recurrence may be unlikely in view of the small proportion of alcoholics who develop cirrhosis and then only after many years of excessive alcohol consumption. Nonetheless, with the possibility of some risk of redeveloping alcoholic liver disease, along with other potential problems that may arise from continued alcohol abuse and may potentially impair the course of recovery from surgery or of compliance with the immunosuppressive therapy, most centers consider indications of a favorable clinical prognosis for treatment and recovery from alcohol abuse or alcoholism as a requisite for liver transplantation in patients with alcoholic cirrhosis. Whether abstinence for 6 months to 2 years is evidence of recovery or whether there are other factors, such as family and social support, that are predictive of a favorable outcome for the treatment of alcohol abuse or alcoholism is not known.

Recurrence of alcoholic cirrhosis would not be expected in the absence of the toxic agent, ethyl alcohol. Thus, the absence of recidivism to alcohol abuse should negate the potential for development of alcoholic liver disease. Favorable survival rates and low rates of return to alcohol use of about 11.5 percent among patients transplanted for alcoholic cirrhosis have been reported (5,160). Further observations of these and other patients with alcoholic liver disease receiving liver transplants will provide information on potential recidivism to alcohol use and possibilities of any recurrence of liver disease.

De Novo Malignancies

Malignancies arising de novo may increase the risk of death following OLT. They have been reported from only a few centers (78,161). The incidence of certain de novo malignancies was shown to increase following transplantation in patients who underwent conventional immunosuppressive therapy (161). Among these malignancies were cancers of the skin and lips, lymphomas, and carcinomas of the cervix, uterus, and other organs. According to Penn, lymphomas made up at least 18 percent of the neoplasms seen in organ transplant recipients compared to 34-percent in the general population (161). Under cyclosporine therapy, the incidence of lymphoproliferative disorders in different kinds of organ transplantation varied widely among the studies (139,162-164). However, with the use of lower doses of cyclosporine and steroids, the incidence of lymphomas was much lower than with conventional immunosuppressive therapy.

Chapter 4 Limiting Factors

Although the capacity to perform livers transplantation has increased in recent years, the number of procedures performed is still limited by several factors: the availability of donor organs, the inadequate number of institutions capable of performing liver transplantation, and the high cost of the

Donor Organ Availability

Based on estimates of 4,000-10,000 potential candidates likely to benefit from liver transplants each year in the United States, the maximum organ availability may meet only about one-third of the need.

Procuring vital donor organs continues to pose significant challenges to the transplantation community. The organ procurement and transplantation network links approximately 110 regional procurement programs into a national network to maximize potential for optimal organ matching (165). Organ donors are matched to potential transplant recipients who have already been accepted for transplantation by liver transplant programs and are on waiting lists.

The liver, because of its vital and singular nature, unlike the kidney, precludes any possibility of living donor grafts in adults. Brain-dead donors with intact cardiopulmonary integrity are the paramount source of donor livers. In adults, the difficulties in procurement relate to communicating need, availability, and proper ABO-compatible typing. In children, added to these difficulties are the requirements of identical donor and recipient weight and body size; however, partial-organ transplants of appropriate size and compatibility may be of use in children.

Methods of obtaining donors' or relatives' consent as well as the cooperation of hospitals and procurement centers in facilitating the transfer of organs are presently being evaluated. The Surgeon General as well as Congressional bodies are presently exploring methods of enhancing organ procurement systems in the United States.

Procurement is not the only hurdle to securing a viable donor liver. Once the donated liver is removed, current technology limits the time that it can be maintained prior to implantation (165). Improvement in cold ischemic preservation using the University of Wisconsin solution has extended this time from the 8-12 hours at the time of the 1983 PHS report on liver transplantation to over 24 hours (166). Obviously, the limited storage time of the donor liver restricts the distances it can be transported prior to transplantation.

At the time of the previous report, Starzl had described a technique for harvesting donor livers that allowed preservation up to 12 hours with excellent tolerance to warm ischemia. Also in 1983, Marubayashi reported on the ability of coenzyme Q10 to protect ischemic livers (167). Such methods extending the viability of ischemic organs may enchance the preservation of transplantable grafts. Unlike the pancreas, the liver is very sensitive to warm ischemia. At present two cryopreservation (freezing) techniques have been found applicable in whole or segmental solid organ transplantation. More studies are needed that would address cytochemical aspects of organ preservation such as methods of affecting the transmembrance ionic flux of Ca(++), K(+), and Na(+). These ions tend to injure cytochrome P450 and other energy-generating system within cell in ways that preclude viability under prolonged ischemia. Overcoming these obstacles to preservation should facilities storage and thereby enhance availability of transplantable liver grafts.

Institutional Capacity

The more than 50 centers currently performing liver transplants in the United States are insufficient to meet the needs of potential OLT candidates each New centers continue to be developed, but the substantial costs associated with establishing them, coupled with the limited supply of donor livers, point to a need for organized diffusion of this technology. Centers that may be best able to perform liver transplantation safely and effectively are those that are experienced in other organ transplants, have blood and tissue bank capabilities, participate in an organ procurement program or network, have an institutional review committee for screening potential candidates, and have the broad range of tertiary care, special skills, and facilities required for liver transplantation (168).


The substantial cost of liver transplants is another obstacle that needs to be addressed as more transplantations are contemplated. Estimates of transplantation costs have ranged from lows of $20,000-$50,000 per transplant to a high of $450,000 for multiple transplants (58,169,170). Some recent estimates have cited a "mean working figure" of $150,000 (67,169).

To assess the costs and benefits of liver transplantation, its is important to compare the actual costs of transplantation and follow-up care to the potential of the procedure to prolong useful life and to the cost of supportive care if transplantation is not performed.

Yet, assessing the cost of liver transplantation is difficult for several reasons. Costs of the procedure at various centers vary widely as do the per-patient costs, depending on patient diagnosis and other factors. Moreover, cost data reported in the literature often do not include the same factors and some do not include all the relevant costs, which range from purchase of the donor organ and use of blood products to hospital costs, follow-up outpatient care, and drug costs.

Van Thiel and colleagues did a cost-benefit analysis of liver transplantation in adults at the Universityi of Pittsburg covering the period from 1981 through 1984 (169). They reported preoperative costs to the hospital averaging almost $6,000, with postoperative costs averaging almost $47,000. Other costs they cited included donor organ procurement, blood and blood products, etc. Total inhospital costs were often related to the patient's diagnosis, which affected the amount of time spent in intensive care or recovery, for example. Additional costs to the patient, they cited, include the cost of lifelong medical-surgical follow-up. This included the costs of immunosuppressive medicines and other drugs, such as antithypertensive agents, as well as the costs of care for opportunistic infections, disease recurrence, or new disease acquired from OLT-related blood transfusions, such as non-A, non-B viral hepatitis.

Van Thiel and colleagues concluded optimistically that the cost associated with performing OLT are likely to decline, while the success associated with its application is more likely to increase.

Williams and colleagues agree (170). They concluded that overall survival will improve and costs will decrease. In support of this assumption, they reported that the mean cost of liver transplantation was $174,220 in 1982, $71,i976 in 1983, and $81,338 in 1984, reflecting the overall decreased cost correlating with better outcomes due to improved clinical abilities. They surmised that the stabilization of costs with improving clinical abilities should continue into the future.

They studied a group of patient from 1979 to 1984. The one-year survival in transplant patient without cancer was 71 percent and the mean cost of transplantation was $92,866. They divided the costs of transplantation into preoperative evaluation, hospitalization, and first-year follow-up. The cost of preoperative evaluation was $4,000 for 5.7 days. The cost of hospitalization ranged from $35,000-$320,000, with the length of hospital stay by surviving patients ranging from 17 to 135 days. These hospital charges included large volumes of transfused blood and blood products, operating room charges, and organ procurement.

They divided follow-up costs into the three areas: outpatient care and drug costs; scheduled inpatient evaluation at 3.6 and 12 months after transplantation; and care of complications. They calculated the mean cost of one-year follow-up care at $20,556. Charges for cyclosporine alone ranged from $4,000-$8,000.

Considering that the mean cost oif hospitalization for the last 12 months of life for their patient dying of liver failure without transplantation was $45,643 ($9,125-$131,217), the difference in mean one-year cost between those with transplantation ($92,866) and those without transplantation ($45,643) was approximately $47,000 for their patient during the period of study. When they added the mean cost of first-year follow-up care and the professional fees, the net one-year cost of liver transplantation was estimated to have been about $79,000.

Chapter 5 Discussion and Summary

Transplantation of the liver in adults is a technically feasible, widely accepted, and extensively performed procedure. Although the capacity to perform the procedure has increased significantly in recent years, the availability of organs (grafts), the cost, and the institutional capacity to perform the procedure continue to be major factors in limiting the number of livers being transplanted. The indication for performing liver transplant is terminal liver failure in a patient who has a life expectancy of 12 months or less and who otherwise meets the patient selection criteria proposed for determining candidacy.

Ideally, the selection of patients would be based upon knowledge of those who are most likely to benefit from liver transplants. Identification of such individuals may be facilitated by data being accumulated at various transplant centers relating the outcome for transplant recipients to their diagnostic categories. According to reports published by various groups, 40-50 percent of liver transplant recipients in the United States and Europe had ESLD that was caused by external agents such as drugs, alcohol, and viruses (2,10,60,67). Fewer patients had other disorders such as primary biliary cirrhosis or malignancies, with fewer than 10 percent of the adult cases presenting with congenital and inherited disorders affecting the liver.

Improved Techniques

Many improvements have been incorporated into the procedures contributing to the acceptance of liver transplantation as a viable means to treat certain patients with irreversibly damaged livers. Modifications of surgical techniques addressed problems associated with failures due to biliary tract complications and inadequate circulatory integrity of the graft (38,171). These modifications significantly improved the intraoperative and postoperative outcomes by reducing the complicating problems of renal failure, severe intestinal edema, and congestion.

Noninvasive techniques such as computerized tomography (CT) scanning, magnetic resonance imaging (MRI), and ultrasonography and invasive techniques such as angiography, liver biopsy of the graft, and pecutaneous transhepatic cholangiography have reduced the morbidity and mortality associated with liver transplants by enabling surgeons to more specifically identify problems and to choose appropriate, corrective interventions to avoid preventable graft failures. Retransplantation of patients with rejection or technical failures also appears to have improved the survival rate of transplant recipients (27,32).


The outcome of liver transplantation is dependent upon a number of factors such as the specific disease, stage of disease, immune response, condition of the graft, and health status of the recipient at the time of surgery (74). Numerous adverse effects have been documented among the recipients of liver transplants. Some of these complications typically occur early while others occur late (33,78). Cardiovascular complications, non-function of the graft, sepsis, and failure of other organ systems contribute to death during and immediately after The vast majority of deaths occur within the first two months after transplantation of the liver. Infection was the single most common cause of death, and multiorgan failure and massive hemorrhage the next two most common causes of early death, according to reports from Pittsburgh (33,74). Similar observations were made in Europe according to a report by Bismuth (10).

Graft rejection was found to be an infrequent cause of early death, and the institution of choledochocholedochostomy over at-tube eliminated biliary tree complications as a significant source of early morbidity and mortality in liver transplantations (38).

Vascular complications, mainly hepatic artery thrombosis, remain a major cause of technical failure that frequently leads to death and are a primary cause for retransplantation. From the various reports, it would appear that 3-12 percent of all liver transplants manifest vascular complications that account for many of the technical failures (82,84,87).

The specific disease for which a liver transplant is performed greatly influences the outcome (60,67). This is illustrated in Table 6, which gives the one-and five-year survival rates for adult patients who underwent liver transplantations for the indicated liver diseases.

The five-year survival rates of patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) were reported by the Pittsburgh group to be 65-70 percent respectively, with no evidence of recurrence of the primary disease (50). Although other investigators have reported the PBC may recur in some patients following hepatic grafting, reports from all centers indicate that the outcome in patients with PBC and PSC is among the best achieved in adults undergoing OLT (10,47,50,65-67,147-149).

The outcome in patients with hepatitis B depended upon whether the patient was seronegative or seropositive. Those with HBsAg-negative disease had an excellent five-year survival rate of 71 percent, while those with HBsAg-positive disease had a significantly poorer survival rate of 38 percent with a markedly higher rate of disease recurence.

Although Table 6 gives the three-year survival rate for patients with alcoholic cirrhosis, more recent communications suggest that this rate is being maintained with the passage of time. All indications are that the survival rate for carefully selected patients with alcoholic cirrhosis is good; the rate of return to alcohol use is considered low, about 10-15 percent. Selection of patients on the basis of need for liver transplantation, assessments of the patient's commitment not to drink in the future, and the patients and his/her family's commitments to long-standing recovery programs of alcoholism care were considered important contributing factors to the good outcomes in these patients.

Table 6. Survival of adults undergoing liver transplantation.


Table 6. Survival of adults undergoing liver transplantation.

Because of the rarity in adults of metabolic disorders leading to end-stage liver disease, the transplant experience in such cases is small. Most of the transplants have been performed at Pittsburgh where results in adults with Wilson's disease, hemochromatosis, and alpha-1-antitrypsin deficiency indicate that OLT is a beneficial procedure in patients with these metabolic disorders.

The worst survival probability with OLT was associated with recipients who had malignant disease (6,67,144). The data in Table 6 are those reported by Iwatsuki and Pichlmayr (7,50). Scharschmidt and Iwatsuki observed that recipients with bile duct cancer had the worst prognosis, followed closely by those with hepatocellular carcinoma (67,144). Many of the patients whose primary indication for transplantation was malignancy died within two months of the operation. About 80 percent of the cancer patients receiving OLT had recurrences of their primary malignancies by 17 months after transplantation. These results were recently summarized by Starzl as the "dismal record of transplantation in patients with primary hepatic tumors" (69).

According to the available data in the literature, the results in Table 6 appear to be representative of liver transplantation experiences at major transplant centers. Selected patients with ESLD caused by hepatitis B (seronegative), primary biliary cirrhosis, alcoholic cirrhosis, and sclerosing cholangitis have an excellent probability of benefiting from liver transplantation. Similar optimistic outcomes are assumed for adults with Wilson's disease, hemochromatosis, and alpha-1-anti-trypsin deficiency disease, despite the limited number of transplants performed. On the other hand, the extent of the usefulness of liver transplantation in patients with diseases such as hepatitis B (seropositive), secondary biliary cirrhosis, Budd-Chiari syndrome, and non-A, non-B hepatitis is not clear. More experiences are required before a definitive conclusion can be made.


Transplant rejection remains a significant cause of morbidity and mortality in transplant recipients, although the number of liver recipients dying from graft rejection was reduced and the results of liver transplants were improved greatly with the introduction in 1978 of the immunosuppressive agent, cyclosporine (31,52,163). Consistent with the results of animal studies that showed that the liver was relatively resistant to rejection, no hyperacute rejection of the liver has been noted (171,172). This is in marked contrast to such rejections occurring with the transplantation of the kidney and other organs.

Many reports have suggested that some degree of rejection can be seen in between 60-100 percent of grafts following liver transplant. However, carefully performed biopsy-documented studies have revealed a much lower incidence. Williams demonstrated 17 occasions of rejection in 55 biopsy specimens obtained from 50 patients (107). Similarly, Demetris reviewed the results of 95 biopsies obtained from 62 patients and found a 37 percent rejection incidence (149). Results published from Pittsburgh have indicated that about 8 percent of early deaths were due to rejection (27). Bismuth has indicated a similar 8 percent and Jenkins a 10 percent incidence of rejection as causes of death in European and American liver transplant series, respectively (10,59). However, these low numbers could easily represent underestimates, particularly in situations where a major infection coincides with a rejection episode. Infection would be considered as the primary cause of death in such a case.

Rejection as a cause of late death is usually a low-incidence occurrence. Iwatsuki reported an 11 percent late rejection incidence in one-year survivors of liver transplantation (50). Of those who experienced late rejection, 25 percent died. While acute rejection has been demonstrated to be readily reversible, chronic rejection is not. Either lesion may be difficult to diagnose histologically or to separate from other clinical entities such as recurrence f diseases like primary biliary cirrhosis in the graft. The vanishing bile duct syndrome of chronic rejection appears to be the most resistant to treatment and usually resulted in loss of the graft. Only ABO matching is usually performed by OLT donor-recipient matching. Preliminary results from retrospective HLA matching have shown no correlation between either a high level of antibody match or donor-specific preformed lymphocytotoxic antibody status with graft survival or with risk of rejection in liver transplant recipients (40). While traditional immunosuppressive therapy has had mixed success, newer antithymocyte globulin (ATG) and OKT3 monoclonal antibody promise to improve both the prevention as well as the management of rejection.

Disease Recurrence

Recurrence of primary disease in the graft affects the outcome in liver transplant recipients. Most often the diseases that recur are either malignant diseases that involve the liver or systemic conditions that are associated with circulating antibodies, immunocomplexes, viruses, or other substances that target the liver for injury and ultimate end-stage failure.

Numerous studies have demonstrated cancer recurrence rates 57-100 percent in recipients who were transplanted because of malignancies (10,14,50,63,144,146). Tumor recurrences were reported to be related to whether the malignancy was the primary reason for the transplant or an incidental finding before or after transplantation and upon the type of tumor (144). Recurrence was relatively low in patients with incidentally found malignancies and high in those transplanted primarily to treat malignancy.

The recurrence of hepatitis B in grafts is reported to be as high as 50-100 percent for recipients who had the chronic disease and about 66 percent in those who had the acute disease (65,66,149). Limited experiences with transplanted patients who were seropositive for hepatitis B virus suggest that those with viremia are highly likely to have the disease recur and have poorer outcomes than transplant recipients who are seronegative.

Quality of Life

The quality of life (QOL) following liver transplantation is of considerable interest, but an assessment of this aspect of outcome in liver transplant recipients remains a problem because of the limited and inconsistent nature of the data and lack of consensus on a definition for QOL. Data touching upon aspects of QOL are few and varied, and there is no additional information that would change the prior impression that those who survive more than 6-12 months have reasonable prospects of living with an acceptable to good QOL.


The cost of liver transplants is considerable and poses a formidable obstacle that needs to be addressed as more transplantations are contemplated. Estimates of transplantation costs have ranged from lows of $20,000-$50,000 per transplant t a high of $450,000 for multiple transplants (58,169,170). The wide range in estimates cannot be adequately analyzed because the cost data upon which they were based are fragmentary and inconsistent from one report to another.

Most reported estimates include items such as expenditures or charges and hospital billings or payment information and do not include other information that is needed to compute and compare per case cost, average cost, marginal cost, or cost per one-year survivor. For example, many higher estimates include the increased cost of retransplantation, which is becoming more common (27,50). Other cost factors such as out-of-hospital living costs and costs for medically evaluating patients before and after the transplantation also add to the difficulties of computing the cost of transplantation.

In any case, transplantation is expensive and would have an economic impact. If one assumes that an average cost-per-case were $150,000-$259,000, the aggregate cost for the almost 1,200 transplantations done in 1987 totals about $180-$310 million. This sum would be expected to increase each year as more transplantations are performed. If the cost of each transplantation remains the same, an overall cost stimate for the 4,000-10,000 patients who are projected to benefit annually from liver transplants would range from $0.6-$1.5 billion to as much as 6 billion per year. These estimates represent economic costs but do not consider non-economic costs such as social costs that may be enormous but unmeasurable.

Accepted Theraphy

Orthotopic liver transplantation had been demonstrated as an acceptable alternative therapeutic approach for prolonging thee life of some patients suffering from severe liver disease that had progressed beyond the reach of the then available treatment in 1983 when a Consensus Development Conference was convened at the National Institutes of Health (NIH).

The consensus panel of experts concluded that "in order for liver transplantation to gain its full therapeutic potential, the indications for and the result of the procedure must be the object of comprehensive, coordinated, and ongoing evaluation in the years ahead." The panel recommended the "expansion of this technology to a limited number of centers where performance of liver transplantation can be carried out under optimal conditions" (168). The 1983 NIH consensus panel report was endorsed by the American Medical Association Council of Scientific Affairs and by the American Society for the Study of Liver Disease.

In 1987, the OOffice of Health Technology Assessment (OHTA) received additional information from numerous academic centers and organizations in the form of data and opinions that support their position that liver transplantation is an acceptable therapeutic procedure. These included reports from experts involved in transplant programs at the University of Pittsburgh, the Cleveland Clinic Foundation, the Mayo Clinic, the University of Chicago, Rush-Memorial-Presbyterian-St. Luke's Medical Center, Good Samaritan Hospital of Phoenix, Jefferson Medical College, the Harvard University/Massachusetts General Hospital, the New England Hospital, the LDS Hospital of Salt Lake City, the Society for Surgery of the Alimentary Tract, the American Association for the Study of Liver Disease, and others.


Transplantation of the liver is an established treatment for certain conditions that cause irreversible damage to the liver resulting in end-organ failure. The patient's diseased liver is replaced with a healthy one from a brain-dead donor who is of the same blood type and approximate physical size. Over the last quarter of a century since the procedure was first performed in Denver by Starzl, it has diffused extensively worldwide. By the end of 1987, approximately 3,500 patients had received liver transplants in the United States at over 50 centers.

Liver transplantation is by far the most technically difficult of all solid organ transplants. This very complicated operation is technically feasible and capable of extending the lives of carefully selected patients with end-stage liver disease (ESLD). While substantial uncertainties continue to exist as to its optimal use and ultimate benefits for patients who fall into certain disease categories, the procedure has clearly advanced to the status of an established treatment for others. The long-term quality of life and cost remain as subjects of considerable interest. Details are yet unresolved as to what selection mechanism would best identify candidates most likely to benefit and at what point in the course of their disease a transplant procedure should be undertaken.

Analysis of the existing data from the centers in this country and Europe indicates that the outcome of liver transplantation could be good or bad depending upon the specific disease for which the procedure was done. For example, transplanted patients with primary biliary cirrhosis or primary sclerosing cholangitis show a five-year survival rate of about 70 percent, in contrast to those with malignancies, who show a three-year survival rate of 0-30 percent. Accordingly, it is considered that the outcomes of liver transplantations in patients with end-stage liver disease due to primary biliary cirrhosis or primary sclerosing cholangitis are excellent, while outcomes for those with malignancies are poor. In some end-stage liver diseases the outcomes appear to be reasonable, but more experiences with patients with these diseases are needed before a definitive conclusion concerning the possible usefulness of OLT for these patients can be made. Of interest is that data being collected at NIH indicate that the health status of a patient at the time of surgery may be as important as the disease involved in influencing the outcome.

Organ procurement and availability continue to limit the number of liver transplants that presently and ultimately may be performed. Efforts currently underway may conceivably overcome this obstacle in the foreseeable future. Substantial costs associated with establishing transplant centers coupled with the limited number of procedures capable of being performed each year further point to a need for organized diffusion of this technology.

Centers that may be best able to safely and effectively perform liver transplantation are those that are experienced in other organ transplants, have blood and tissue bank capabilities, participate in an organ procurement program or network, have an institutional review committee to screen potential candidates, and have the broad range of tertiary care, special skills, and facilities required for liver transplantation. Moreover, institutions should be capable of generating a broad range of data that would help resolve unanswered questions on clinical, economic, sociological, and quality of life issues. The collected data should also address the ethical and legal issues. These centers should maintain a staff of appropriately trained and experienced individuals and provide for the training of transplant surgeons.

Further, liver transplant centers should develop procedures that would ensure equal access to transplantation among the eligible candidates awaiting transplants. Criteria and guidelines should be established to generate a list of eligible candidates from which random selections should be made.

Transplant centers should be performing liver transplantation on a sufficiently regular basis to guarantee competence. This will be evidenced by consistently good outcomes in the form of acceptable survival rates in a statistically meaningful minimum number of patients over a minimum of two years. The centers would be expected to control cost and provide adequate numbers of beds to support the program. Finally, transplant programs should not adversely affect a hospital's ability to maintain existing levels of care.

Liver transplantation is a therapy of last resort for patients nearing death from liver failure where alternative therapies are no longer effective. Accordingly, with death being the only alternative, the impressive survival rates that are being demonstrated for selected patients are encouraging. The survival rates depend upon the patient's diagnosis and stage of disease; the quality, age, and state of preservation of the graft; the technical approaches to the operation employed by the surgeon; and the methods used to reduce graft rejection. However, survival figures alone do not adequately address important questions pertaining to outcome, such as morbidity, quality of life, and safety of immunosuppression over prolonged periods of time.

The use of cyclosporine has contributed significantly to the improvement in the outcome of liver transplantation. Additional agents for the prevention of graft rejection, such as antilymphocyte globulin (ALG), OKT3 monoclonal antibodies, and antithymocyte globulin (ATG), are currently being investigated as immunosuppressive agents. Although cyclosporine and the other immunosuppressive agents have reduced the failures from graft rejections, data to assess the possible adverse effects of the prolonged use of these agents in the transplant recipients are not available. Furthermore, there are insufficient follow-up data on the functional, psychological, and affective status of the recipients to evaluate adequately their quality of life after transplantation.

The cost of liver transplants is considerable. While early estimates places the cost of the procedure at $20,000-$50,000, recent analyses suggest a range of $65,000-$450,000 per transplant patient. Data to assess the cost of liver transplantation more consistently are not available because of the variable means used to compute the costs at the different centers. Factors such as charges, expenditures, number of grafts per patient, the variable duration and expenses of pre-transplant and post-transplant evaluation, and morbidity experienced are not accounted for in any systematic way in most of the cost analyses published on liver transplantation.

Now that liver transplantation has diffused to the point that it can be considered an established therapy for a number of patients with terminal liver disease, careful attention should be paid to optimizing the use of scarce societal resources. This includes ot only the economic resources, but also grafts, which are scarce, and institutional resources, which are limited.

The recognition of centers of excellence would help foster improved use of available resources. These centers should have established records of good results and sufficient institutional experience and infrastructure to provide the full rage of essential support to a liver transplant program. Moreover, they should be willing to adhere to guidelines for the selection of patients with a high probability of benefit from OLT. The participation of such centers of excellence in a central registry could prove beneficial. The registry could generate a data base upon which issues surrounding liver transplantation can be brought into sharper focus in the context of risks versus benefits over a long-term follow-up period.


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DHHS Publication No. (PHS) 90-3455


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