Starzl performed the first human liver transplant in 1963 in a 3-year-old boy with biliary atresia. The first successful liver transplant was not performed until 1967 when a 1-1/2-year-old girl with hepatocellular carcinoma was transplanted; she died of recurrent tumor after 17 months. One-year survival in the early years was 25-35% using methylprednisolone and azathioprine as immunosuppressives; however, with the introduction of cyclosporine in the early 1980s, liver transplantation became a clinical reality and now offers one and five-year survivals in excess of 80% and 60% respectively.

With the dramatic improvement in results, liver transplantation became the recognized management for end-stage liver disease. The number of liver transplant centers in North America was more than 130 in 1993, and now more than 3,000 liver transplants are performed yearly in the United States alone. In Canada, there are active centers in Halifax, NS; Montreal, PQ; Toronto and London, ON; Edmonton, AB; and Vancouver, BC. Over 300 liver transplants are performed yearly in Canada. One-year survival rates of 80-90% are now expected. The rate-limiting step in the application of transplantation to liver disease has become donor availability.

A patient should be considered for liver transplantation when the diagnosis of irreversible end-stage liver disease is made. The most common indications for liver transplantation in adults and children are listed in Table 23. The selection of appropriate candidates out of a large number of patients with liver disease combined with the relative scarcity of available organs requires a strict individual assessment, which must to a certain extent be tailored to the cause of liver failure. The indications for referral for transplantation in patients with chronic liver disease are outlined in Table 24. Transplantation for hepatitis B remains controversial, and physicians should be aware of their transplant center's policy when considering patients for referral. Exclusion of patients with contraindications to liver transplantation (Table 25) allows the best use of scarce donor resources while maximizing patient benefit.

The principles behind the liver transplant workup are to definitively establish the etiology of the liver disease and to identify contraindications to surgery. Assessment of patients by a multidisciplinary team that includes medical, surgical, anesthetic, social and psychiatric specialists is done to ensure the success of the transplantation process.

Once the patient is declared a candidate for liver transplantation, he or she goes onto a liver transplant list awaiting a suitable donor. For patients on the waiting list, time to transplantation varies from center to center, but organ allocation for any given patient depends on the length of time that the patient has been on the list as well as the severity of the patient's liver disease. While awaiting organ replacement, transplant candidates may present with complications that require urgent attention, such as gastrointestinal bleeding, spontaneous bacterial peritonitis, hepatic encephalopathy or other complications related or unrelated to the underlying liver disease. In addition, patients may deteriorate in the course of their disease and become too sick to tolerate transplantation. Many programs expect 15-20% of listed patients to die or be delisted before an organ becomes available.

With improving results of liver transplantation, patients who once were transplanted only for treatment of life-threatening complications are now being transplanted earlier in the course of their disease. Today many patients undergo liver transplantation because of quality of life issues such as extreme fatigue, pruritus and inability to hold employment or participate in the activities of daily living. It is clear that transplantation should be considered prior to catastrophic complications and the need for life support, although waiting times can be expected to increase as patients are referred and listed earlier.

Technical details of the procedure are beyond the scope of this discussion; however, there are several salient points to be reviewed. During the procedure the liver is mobilized and both inflow to the liver and inferior vena caval return to the heart are interrupted. This may cause hemodynamic instability, which if not correctable requires the use of venovenous bypass in which IVC and portal blood are diverted through a bypass circuit to the axillary vein. The liver is subsequently removed and the new graft sewn in place. Although the liver is flushed of the high potassium preservation solution prior to reperfusion, there can be significant cardiac abnormalities upon reperfusing the liver. These intraoperative events demand a thorough preoperative assessment of cardiac status.

Issues that must be addressed in the postoperative period include management of fluid and electrolytes, respiratory function, monitoring of neurologic status, immunosuppression and graft function.

In most cases patients are quickly extubated within 24 hours of surgery. However, ventilatory support may be needed for an extended period, particularly when there is delayed graft function, presence of severe pleural effusions, pulmonary infiltrate and diaphragmatic dysfunction or paralysis.

Abnormalities of coagulation are sensitive markers of hepatic dysfunction and correction of coagulation by the administration of exogenous factors is avoided unless active bleeding is ongoing. Coagulation is routinely assessed by measurement of INR/prothrombin time, partial thromboplastin time and/or assay of coagulation factors V or VII. Following successful liver transplantation, coagulation parameters should return to normal levels within 48 hours in most patients. The failure of coagulation parameters to normalize is an ominous sign of graft failure and suggests the need for retransplantation.

Renal insufficiency, occasionally requiring dialysis, is not uncommon postoperatively in liver transplant patients. Renal failure may be due to a combination of factors including pre-existing renal disease, hepatorenal syndrome, intraoperative blood loss and hypotension leading to tubular necrosis, drug-induced nephrotoxicity (especially cyclosporine or FK-506), poor liver function and sepsis.

Most patients wake up within several hours of liver transplantation, whereas patients with fulminant hepatic failure may require one to three days to return to normal neurologic status after liver transplantation. Narcotics and sedatives are kept to a minimum in the immediate postoperative period. Confusion and seizures can occur and are usually related to metabolic disturbances (low serum magnesium levels), but are a known complication of cyclosporine and FK-506. At the University of Toronto all patients are placed on a continuous infusion of magnesium sulfate for the first 72 to 96 hours postoperatively, followed by oral supplementation.

15.6.1 IMMUNOSUPPRESIVE AGENTS CURRENTLY IN USE

15.6.1.1 Cyclosporine

The introduction of cyclosporine is considered one of the most important factors that has improved the results of liver transplantation. Since its early introduction in late 1978, the one-year graft survival has increased from 30 to >70%. Cyclosporine binds to a specific cell protein, cyclophillin, and through a series of intracellular events prevents activation of T cells and the production of interleukin-2 (IL-2). The drug is given preferentially by the oral route or by slow intravenous infusion. The dosage of cyclosporine is adjusted to maintain a trough cyclosporine level of 300-400 ng/mL (monoclonal radioimmunoassay) in the early postoperative period. Cyclosporine A is lipid-soluble and absorption is dependent upon the availability of bile. Therefore, until adequate bile flow is restored, adequate cyclosporine levels are difficult to obtain. The introduction of a micoemulsion formulation of cyclosporine, Neoral^®, which is less bile acid-dependent in its absorption, has all but eliminated the need for the intravenous formulation. Daily monitoring of cyclosporine levels in the immediate postoperative period is mandatory, as the compound has a narrow therapeutic index (efficacy vs toxicity). Cyclosporine interacts with many drugs, such as antibiotics and calcium channel blockers, and caution must therefore be exercised in giving any drug to patients who are taking cyclosporine.

Common side effects of cyclosporine include renal dysfunction, hypertension, increased susceptibility to infections, malignancy (especially post-transplant lymphoproliferative disease), hypertrichosis, tremor, headaches and gum hyperplasia. Other less common side effects include confusion, seizures, agitation, hearing loss, anorexia, diarrhea, nausea and vomiting, abdominal discomfort and gynecomastia.

15.6.1.2 FK-506 (Tacrolimus^®; Prograf^®)

FK-506 binds to FK-binding protein and subsequently inhibits T-cell activation by blocking IL-2 production in a similar fashion to cyclosporine. Tacrolimus^® and Prograf^® have been approved by the FDA for liver transplantation in the United States. Tacrolimus^® is undergoing evaluation in Canada. Toxicity and efficacy are similar to those of cyclosporine, although recent multicenter trials suggest there may be a slightly decreased incidence of rejection, which to date has not translated to improved graft survival.

15.6.1.3 Corticosteroids

All patients receive methylprednisolone preoperatively. There are probably as many steroid protocols as transplant programs; at the University of Toronto a preoperative dose of 500 mg Solu-Medrol^® is given. Subsequently this is reduced rapidly to a dose of 0.3 mg/kg/day. Short-term side effects include an increased incidence of infections (bacterial and fungal), hyperglycemia and impaired wound healing.

15.6.1.4 Antilymphocyte products

Antilymphocyte products can be monoclonal (OKT3) or polyclonal (ALG, RATS, ATG). In either case the aim of therapy is to prevent rejection by depleting lymphocytes. The use of these products has been associated with higher rates of viral infections, in particular cytomegalovirus (CMV) as well as an increased risk of lymphoproliferative disorders. OKT3 has been associated with side effects secondary to the release of tumor necrosis factor and IL-1 that can range from mild flu-like symptoms to life-threatening pulmonary edema and circulatory collapse. In liver transplantation these drugs have shifted from being used for induction of immunosuppression to the treatment of refractory rejection.

15.6.2 NEW IMMUNOSUPPRESIVE AGENTS

15.6.2.1 Mycophenolate (Mofetil^®; Cellcept^®)

T and B cells are primarily dependent on the de novo pathway of purine synthesis and have less ability to use the salvage pathway. Mycophenolate inhibits the de novo pathway of purine synthesis and hence should specifically inhibit T and B cell proliferation with little effect on other major organs. Mycophenolate has recently been shown to reduce acute rejection in renal transplantation by 50% and is presently undergoing trials in liver transplantation.

15.6.2.2 Rapamycin

Rapamycin is a new agent that has structural similarities to FK-506. Its mechanism of action, however, is dramatically different in that it appears to block the release of IL-2 at a step after gene transcription and therefore may be synergistic with cyclosporine. Phase I trials in liver transplantation with rapamycin are just beginning.

Complications common to any surgical procedure can occur with liver transplantation. However, there are several adverse events peculiar to liver transplantation. The most concerning of postoperative complications is primary nonfunction (PNF) of the new graft. The incidence of PNF ranges from 2 to 10% and becomes evident by coagulation parameters that worsen and cannot be corrected, increasing acidosis and deterioration in the patient's mental status. The etiology of PNF is unclear, and the treatment is urgent retransplantation. Primary graft dysfunction of a less significant degree has been managed with some success with prostaglandin E₁ and/or N-acetylcysteine.

Vascular thromboses that occur in the early postoperative period are generally technical in nature. Although thrombectomy of both portal vein and hepatic artery has been reported with some success, retransplantation is usually required should these vessels thrombose.

The bile duct has been termed the Achilles heel of liver transplantation. Problems occur in 10-30% of cases. Early leaks are secondary to ischemia, sepsis or severe rejection.

Acute allograft rejection occurs in 40-60% of transplant patients, usually in the first three months after transplantation. Rejection is suspected in patients with rising liver enzymes. Patterns of enzyme elevation can be either hepatocellular (high AST) or cholestatic (high bilirubin and alkaline phosphatase). Fever, malaise and right upper quadrant discomfort are late signs and should not be required for diagnosis of rejection. Diagnosis is confirmed by liver biopsy. Histologic findings include periportal inflammation with mononuclear cells and eosinophils, bile duct injury and endophlebitis. Episodes of cellular rejection usually respond to high-dose steroid therapy. Those patients whose rejection fails to respond to steroids are usually treated with a 7-14 day course of antithymocyte globulin (monoclonal or polyclonal). Recently, FK-506 has shown some success in treating rejection refractory to either steroids or OKT3. Failure to respond to immunosuppressive therapy may result in ductopenic rejection (chronic rejection) leading to biliary cirrhosis, which may result in the need for retransplantation in 5-10% of all transplanted patients.

The major cause of death following liver transplantation is related to infections. Immunosuppressed patients are at risk for bacterial, viral and fungal infections. Bacterial infections with non-opportunistic organisms are usually seen in the early postoperative period. Opportunistic bacterial infections are seen one to four months or more after transplantation. Wound infections and intra-abdominal sepsis account for the majority of bacterial infections seen in transplanted patients. Viral infections are seen frequently in immunosuppressed patients and usually occur at six weeks or later. Cytomegalovirus (CMV) is present in over half of the population and in non-immunosuppressed patients is virtually nonpathogenic. However, CMV infection in transplanted patients may account for 30% of the infections seen and is a source of morbidity and a small mortality. CMV infection is characterized by high fever, usually associated with anorexia, malaise and arthralgias; the diagnosis is confirmed by viral antigen assay and liver biopsy. The therapy for CMV infection includes the reduction of immunosuppression and the use of anti-viral agents such as ganciclovir or CMV immune globulin. Other viral infections seen in transplanted patients include herpes simplex, Epstein-Barr virus, varicella zoster and adenovirus. Fungal infections have been noted in up to 20% of patients and carry with them a 20-100% mortality rate. Infections in general are usually proportional to the degree of immunosuppression.

A one-year survival of >80% after liver transplantation is now not uncommon. Most mortality occurs within the first 90 days. After one year, few patients or grafts are lost. Furthermore, 60% of patients return to gainful employment, demonstrating that this procedure is not only of benefit to the patient, but to society as a whole. Though there are few reports of cost effectiveness, investigators in Pittsburgh have demonstrated that liver transplantation is less expensive than costs of caring for similar patients treated for complications of cirrhosis. Patients with diseases such as cholestatic liver disease that tend not to recur after liver transplantation have an excellent long-term prognosis (greater than 80% five-year survival). In contrast, patients transplanted for viral hepatitis, and in particular hepatitis B, have a poorer long-term outlook as a result of the problem of recurrent disease. For this reason, hepatitis B patients are generally not candidates for liver transplantation except under experimental protocol. Highly selected patients with asymptomatic small hepatocellular carcinomas can have an excellent long-term survival if they do not have co-existent viral hepatitis B infection.

Liver transplantation in the pediatric age group is limited by the shortage of pediatric donors. As a result, reduced-size liver transplantation, where an adult liver is cut down to pediatric size, has been developed. Split liver transplantation, whereby a donor liver is given to two recipients, has been performed with success and is being applied with increasing frequency now that many of the technical hurdles have been overcome. Living-related liver transplantation is performed routinely in some centers with greater than 80% one-year survival.

Isolated hepatocyte transplantation may offer treatment of metabolic liver diseases and has been successful in the laboratory setting. Artificial support systems have shown initial promise in fulminant hepatic failure and may reduce the need for transplantation.

The elusive goal of tolerance has been produced in animal models and if induced in humans would obviate the need for immunosuppression and its associated complications. Xenotransplantation sits on the horizon; the use of transgenic animals may eventually offer a solution to the shortage of donor organs and permit a wider application of liver transplantation to liver disease.