Liver Transplantation
Introduction
Liver transplantation—the replacement of the native, diseased liver by a normal organ (allograft)—has matured from an experimental procedure reserved for desperately ill patients to an accepted, lifesaving operation applied more optimally in the natural history of end-stage liver disease. The preferred and technically most advanced approach is orthotopic transplantation, in which the native organ is removed and the donor organ is inserted in the same anatomic location. Pioneered in the 1960s by Starzl at the University of Colorado and, later, at the University of Pittsburgh and by Calne in Cambridge, England, liver transplantation is now performed routinely worldwide. Success measured as 1-year survival has improved from ~30% in the 1970s to about 90% today. These improved prospects for prolonged survival, dating back to the early 1980s, resulted from refinements in operative technique, improvements in organ procurement and preservation, advances in immunosuppressive therapy, and, perhaps most influentially, more enlightened patient selection and timing. Despite the perioperative morbidity and mortality, the technical and management challenges of the procedure, and its costs, liver transplantation has become the approach of choice for selected patients whose chronic or acute liver disease is progressive, life-threatening, and unresponsive to medical therapy. Based on the current level of success, the number of liver transplants has continued to grow each year; in 2005, approximately 6000 patients received liver allografts in the United States. Still, the demand for new livers continues to outpace availability; in the same period, more than 17,000 patients in the United States were on a waiting list for a donor liver. In response to this drastic shortage of donor organs, many transplantation centers have begun to supplement cadaver-organ liver transplantation with living-donor transplantation.
Indications
Potential candidates for liver transplantation are children and adults who, in the absence of contraindications (see below), suffer from severe, irreversible liver disease for which alternative medical or surgical treatments have been exhausted or are unavailable. Timing of the operation is of critical importance. Indeed, improved timing and better patient selection are felt to have contributed more to the increased success of liver transplantation in the 1980s and beyond than all the impressive technical and immunologic advances combined. Although the disease should be advanced, and although opportunities for spontaneous or medically induced stabilization or recovery should be allowed, the procedure should be done sufficiently early to give the surgical procedure a fair chance for success. Ideally, transplantation should be considered in patients with end-stage liver disease who are experiencing or have experienced a life-threatening complication of hepatic decompensation or whose quality of life has deteriorated to unacceptable levels. Although patients with well-compensated cirrhosis can survive for many years, many patients with quasi-stable chronic liver disease have much more advanced disease than may be apparent. As discussed below, the better the status of the patient prior to transplantation, the higher will be the anticipated success rate of transplantation. The decision about when to transplant is complex and requires the combined judgment of an experienced team of hepatologists, transplant surgeons, anesthesiologists, and specialists in support services, not to mention the well-informed consent of the patient and the patient's family.
Transplantation in Children
Indications for transplantation in children are listed in Table 304-1. The most common is biliary atresia. Inherited or genetic disorders of metabolism associated with liver failure constitute another major indication for transplantation in children and adolescents. In Crigler-Najjar disease type I and in certain hereditary disorders of the urea cycle and of amino acid or lactate-pyruvate metabolism, transplantation may be the only way to prevent impending deterioration of CNS function, despite the fact that the native liver is structurally normal. Combined heart and liver transplantation has yielded dramatic improvement in cardiac function and in cholesterol levels in children with homozygous familial hypercholesterolemia; combined liver and kidney transplantation has been successful in patients with primary hyperoxaluria type I. In hemophiliacs with transfusion-associated hepatitis and liver failure, liver transplantation has been associated with recovery of normal Factor VIII synthesis.
Table 304-1 Indications for Liver Transplantation
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Children
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Adults
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Biliary atresia
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Primary biliary cirrhosis
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Neonatal hepatitis
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Secondary biliary cirrhosis
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Congenital hepatic fibrosis
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Primary sclerosing cholangitis
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Alagille's diseasea
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Autoimmune hepatitis
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Byler's diseaseb
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Caroli's diseasec
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1-Antitrypsin deficiency
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Cryptogenic cirrhosis
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Inherited disorders of metabolism
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Chronic hepatitis with cirrhosis
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Wilson's disease
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Hepatic vein thrombosis
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Tyrosinemia
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Fulminant hepatitis
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Glycogen storage diseases
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Alcoholic cirrhosis
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Lysosomal storage diseases
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Chronic viral hepatitis
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Protoporphyria
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Primary hepatocellular malignancies
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Crigler-Najjar disease type I
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Hepatic adenomas
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Familial hypercholesterolemia
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Nonalcoholic steatohepatitis
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Primary hyperoxaluria type I
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Familial amyloid polyneuropathy
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Hemophilia
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aArteriohepatic dysplasia, with paucity of bile ducts, and congenital malformations, including pulmonary stenosis.
bIntrahepatic cholestasis, progressive liver failure, mental and growth retardation.
cMultiple cystic dilatations of the intrahepatic biliary tree.
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Transplantation in Adults
Liver transplantation is indicated for end-stage cirrhosis of all causes (Table 304-1). In sclerosing cholangitis and Caroli's disease (multiple cystic dilatations of the intrahepatic biliary tree), recurrent infections and sepsis associated with inflammatory and fibrotic obstruction of the biliary tree may be an indication for transplantation. Because prior biliary surgery complicates, and is a relative contraindication for, liver transplantation, surgical diversion of the biliary tree has been all but abandoned for patients with sclerosing cholangitis. In patients who undergo transplantation for hepatic vein thrombosis (Budd-Chiari syndrome), postoperative anticoagulation is essential; underlying myeloproliferative disorders may have to be treated but are not a contraindication to liver transplantation. If a donor organ can be located quickly, before life-threatening complications—including cerebral edema—set in, patients with acute liver failure are candidates for liver transplantation.
Routine candidates for liver transplantation are patients with alcoholic cirrhosis, chronic viral hepatitis, and primary hepatocellular malignancies. Although all three of these categories are considered to be high risk, liver transplantation can be offered to carefully selected patients. Currently, chronic hepatitis C and alcoholic liver disease are the most common indications for liver transplantation, accounting for over 40% of all adult candidates who undergo the procedure. Patients with alcoholic cirrhosis can be considered as candidates for transplantation if they meet strict criteria for abstinence and reform; however, these criteria still do not prevent recidivism in up to a quarter of cases.
Patients with chronic hepatitis C have early allograft and patient survival comparable to those of other subsets of patients after transplantation; however, reinfection in the donor organ is universal, recurrent hepatitis C is insidiously progressive, the impact of antiviral therapy is limited, allograft cirrhosis develops in 20–30% at 5 years, and cirrhosis and late organ failure are being recognized with increasing frequency beyond 5 years. In patients with chronic hepatitis B, in the absence of measures to prevent recurrent hepatitis B, survival after transplantation is reduced by approximately 10–20%; however, prophylactic use of hepatitis B immune globulin (HBIg) during and after transplantation increases the success of transplantation to a level comparable to that seen in patients with nonviral causes of liver decompensation. The specific oral antiviral drugs lamivudine, adefovir dipivoxil, and entecavir can be used both for prophylaxis against and for treatment of recurrent hepatitis B, facilitating further the management of patients undergoing liver transplantation for end-stage hepatitis B; most transplantation centers rely on a combination of HBIg and antiviral drugs to manage patients with hepatitis B. Issues of disease recurrence are discussed in more detail below.
Patients with nonmetastatic primary hepatobiliary tumors—primary hepatocellular carcinoma (HCC), cholangiocarcinoma, hepatoblastoma, angiosarcoma, epithelioid hemangioendothelioma, and multiple or massive hepatic adenomata—have undergone liver transplantation; however, for some hepatobiliary malignancies, overall survival is significantly lower than that for other categories of liver disease. Most transplantation centers have reported 5-year recurrence-free survival rates in patients with unresectable HCC for single tumors less than 5 cm in diameter or for three or fewer lesions all less than 3 cm comparable to those seen in patients undergoing transplantation for nonmalignant indications. Consequently, liver transplantation is currently restricted to patients whose hepatic malignancies meet these criteria. Expanded criteria for patients with HCC are being evaluated. Because the likelihood of recurrent cholangiocarcinoma is very high, only highly selected patients with limited disease are being evaluated for transplantation after intensive chemotherapy and radiation.
Contraindications
Absolute contraindications for transplantation include life-threatening systemic diseases, uncontrolled extrahepatic bacterial or fungal infections, preexisting advanced cardiovascular or pulmonary disease, multiple uncorrectable life-threatening congenital anomalies, metastatic malignancy, active drug or alcohol abuse (Table 304-2). Because carefully selected patients in their sixties and even seventies have undergone transplantation successfully, advanced age per se is no longer considered an absolute contraindication; however, in older patients a more thorough preoperative evaluation should be undertaken to exclude ischemic cardiac disease and other comorbid conditions. Advanced age (more than 70 years), however, should be considered a relative contraindication—that is, a factor to be taken into account with other relative contraindications.
Other relative contraindications include portal vein thrombosis, HIV infection, preexisting renal disease not associated with liver disease, intrahepatic or biliary sepsis, severe hypoxemia (PO2 less than 50 mmHg) resulting from right-to-left intrapulmonary shunts, portopulmonary hypertension with high mean pulmonary artery pressures (more than 35 mmHg), previous extensive hepatobiliary surgery, any uncontrolled serious psychiatric disorder, and lack of sufficient social supports. Any one of these relative contraindications is insufficient in and of itself to preclude transplantation. For example, the problem of portal vein thrombosis can be overcome by constructing a graft from the donor liver portal vein to the recipient's superior mesenteric vein. Now that highly active antiretroviral therapy has dramatically improved the survival of persons with HIV infection, and because end-stage liver disease caused by chronic hepatitis C and B has emerged as a serious source of morbidity and mortality in the HIV-infected population, liver transplantation has now been performed successfully in selected HIV-positive persons who have excellent control of HIV infection. A multicenter National Institutes of Health (NIH) consortium is currently studying outcomes of liver transplantation in HIV-infected recipients.
Table 304-2 Contraindications to Liver Transplantation
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Absolute
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Relative
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Uncontrolled extrahepatobiliary infection
Uncorrectable, life-limiting congenital anomalies
Active substance or alcohol abuse
Advanced cardiopulmonary disease
Extrahepatobiliary malignancy (not including nonmelanoma skin cancer)
Metastatic malignancy to the liver
Life-threatening systemic diseases
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Prior extensive hepatobiliary surgery
Previous extrahepatic malignancy (not including nonmelanoma skin cancer)
Severe malnutrition/wasting
Severe hypoxemia secondary to right-to-left intrapulmonary shunts (PO2 less than 50 mmHg)
Severe pulmonary hypertension (mean PA pressure more than35 mmHg)
Uncontrolled psychiatric disorder
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Technical Considerations
Cadaver Donor Selection
Cadaver donor livers for transplantation are procured primarily from victims of head trauma. Organs from brain-dead donors up to age 60 are acceptable if the following criteria are met: hemodynamic stability, adequate oxygenation, absence of bacterial or fungal infection, absence of abdominal trauma, absence of hepatic dysfunction, and serologic exclusion of hepatitis B and C viruses and HIV. Occasionally, organs from donors with hepatitis B and C are used, e.g., for recipients with prior hepatitis B and C, respectively. Donor organs with antibody to hepatitis B core antigen (anti-HBc) can also be used when the need is especially urgent, and recipients of these organs are treated prophylactically with HBIg and other antiviral drugs. Cardiovascular and respiratory functions are maintained artificially until the liver can be removed.
Transplantation of organs procured from deceased donors who have succumbed to cardiac death can be performed successfully under selected circumstances, when ischemic time is minimized and liver histology preserved. Compatibility in ABO blood group and organ size between donor and recipient are important considerations in donor selection; however, ABO-incompatible, split liver, or reduced-donor-organ transplants can be performed in emergency or marked donor-scarcity situations. Tissue typing for HLA matching is not required, and preformed cytotoxic HLA antibodies do not preclude liver transplantation. Following perfusion with cold electrolyte solution, the donor liver is removed and packed in ice. The use of University of Wisconsin (UW) solution, rich in lactobionate and raffinose, has permitted the extension of cold ischemic time up to 20 h; however, 12 h may be a more reasonable limit. Improved techniques for harvesting multiple organs from the same donor have increased the availability of donor livers, but the availability of donor livers is far outstripped by the demand.
Currently in the United States, all donor livers are distributed through a nationwide organ-sharing network [United Network of Organ Sharing (UNOS)] designed to allocate available organs based on regional considerations and recipient acuity. Recipients who have the highest disease severity generally have the highest priority, but allocation strategies that balance highest urgency against best outcomes continue to evolve to distribute cadaver organs most effectively. Allocation based on the Child-Turcotte-Pugh (CTP) score, which uses five clinical variables (encephalopathy stage, ascites, bilirubin, albumin, and prothrombin time) and waiting time, has been replaced by allocation based upon urgency alone, calculated by the Model for End-Stage Liver Disease (MELD) score. The MELD score is based upon a mathematical model that includes bilirubin, creatinine, and prothrombin time expressed as international normalized ratio (INR) (Table 304-3). Neither waiting time (except as a tie breaker between two potential recipients with the same MELD scores) nor posttransplantation outcome is taken into account, but the MELD score has been shown to be the best predictor of pretransplantation mortality, satisfies the prevailing view that medical need should be the decisive determinant, and eliminates both the subjectivity inherent in the CTP scoring system (presence and degree of ascites and hepatic encephalopathy) and the differences in waiting times among different regions of the country. Under the CTP or the MELD system, highest priority (status 1) continues to be reserved for those patients with fulminant hepatic failure. Because candidates for liver transplantation who have HCC may not be sufficiently decompensated to compete for donor organs based upon urgency criteria alone, and because protracted waiting for cadaver donor organs results often in tumor growth beyond acceptable limits for transplantation, such patients are assigned disease-specific MELD points (Table 304-3).
Table 304-3 United Network for Organ Sharing (UNOS) Liver Transplantation Waiting List Criteria
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Status 1
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Fulminant hepatic failure (including primary graft nonfunction and hepatic artery thrombosis within 7 days after transplantation as well as acute decompensated Wilson's disease)a
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The Model for End-Stage Liver Disease (MELD) score, on a continuous scale,b determines allocation of the remainder of donor organs. This model is based upon the following calculation:
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3.78 X loge bilirubin (mg/100 mL) + 11.2 X loge international normalized ratio (INR) + 9.57 X loge creatinine (mg/100 mL) + 6.43 (X 0 for alcoholic and cholestatic liver disease, X 1 for all other types of liver disease).c,d,e
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aFor children less than 18 years of age, Status 1 includes acute or chronic liver failure plus hospitalization in an intensive care unit or inborn errors of metabolism. Status 1 is retained for those persons with fulminant hepatic failure and supersedes the MELD score.
bThe MELD scale is continuous, with 34 levels ranging between 6 and 40. Donor organs usually do not become available unless the MELD score exceeds 20.
cPatients with stage T2 hepatocellular carcinoma receive 22 disease-specific points. An fetoprotein level = 500 ng/mL is considered as stage I hepatocellular carcinoma even without evidence for a tumor on imaging.
dCreatinine is included because renal function is a validated predictor of survival in patients with liver disease. For adults undergoing dialysis twice a week, the creatinine in the equation is set to 4 mg/100 mL.
eFor children less than 18 years of age, the Pediatric End-Stage Liver Disease (PELD) scale is used. This scale is based on albumin, bilirubin, INR, growth failure, and age. Status 1 is retained, but the PELD replaces Status 2 and 3.
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Living-Donor Transplantation
Occasionally, especially for liver transplantation in children, one cadaver organ can be split between two (one adult and one child) recipients. A more viable alternative, transplantation of the right lobe of the liver from a healthy adult into an adult recipient, has gained increased popularity. Living-donor transplantation of the left lobe (left lateral segment), introduced in the early 1990s to alleviate the extreme shortage of donor organs for small children, accounts currently for approximately a third of all liver transplantation procedures in children. Driven by the shortage of cadaver organs, living-donor transplantation involving the more sizable right lobe is being considered with increasing frequency in adults; however, living-donor liver transplantation cannot be expected to solve the donor organ shortage. About 300 such procedures were done in 2005, representing only about 5% of all liver transplant operations done in the United States.
Living-donor transplantation can reduce waiting time and cold-ischemia time; is done under elective, rather than emergency, circumstances; and may be lifesaving in recipients who cannot afford to wait for a cadaver donor. The downside, of course, is the risk to the healthy donor (a mean of 10 weeks of medical disability; biliary complications in ~5%; postoperative complications such as wound infection, small-bowel obstruction, and incisional hernias in 9–19%; and, even, in 0.2–0.4%, death) as well as the increased frequency of biliary (15–32%) and vascular (10%) complications in the recipient. Potential donors must participate voluntarily without coercion, and transplantation teams should go to great lengths to exclude subtle coercive or inappropriate psychological factors as well as outline carefully to both donor and recipient the potential benefits and risks of the procedure. Donors for the procedure should be 18–60 years old; have a compatible blood type with the recipient; have no chronic medical problems or history of major abdominal surgery; be related genetically or emotionally to the recipient; and pass an exhaustive series of clinical, biochemical, and serologic evaluations to unearth disqualifying medical disorders. The recipient should meet the same UNOS criteria for liver transplantation as recipients of a cadaver donor allograft. The multicenter NIH A2ALL Study is collecting comprehensive data regarding outcomes of adult-to-adult living-donor liver transplantation.
Surgical Technique
Removal of the recipient's native liver is technically difficult, particularly in the presence of portal hypertension with its associated collateral circulation and extensive varices. Further complicating removal is the presence of scarring from previous abdominal operations. The combination of portal hypertension and coagulopathy (elevated prothrombin time and thrombocytopenia) may translate into large blood product transfusion requirements. After the portal vein and infrahepatic and suprahepatic inferior vena cavae are dissected, the hepatic artery and common bile duct are dissected. Then the native liver is removed and the donor organ inserted. During the anhepatic phase, coagulopathy, hypoglycemia, hypocalcemia, and hypothermia are encountered and must be managed by the anesthesiology team. Caval, portal vein, hepatic artery, and bile duct anastomoses are performed in succession, the last by end-to-end suturing of the donor and recipient common bile ducts or by choledochojejunostomy to a Roux-en-Y loop if the recipient common bile duct cannot be used for reconstruction (e.g., in sclerosing cholangitis). A typical transplant operation lasts 8 h, with a range of 6–18 h. Because of excessive bleeding, large volumes of blood, blood products, and volume expanders may be required during surgery; however, blood requirements have fallen sharply with improvements in surgical technique and experience.
As noted above, emerging alternatives to orthotopic liver transplantation include split-liver grafts, in which one donor organ is divided and inserted into two recipients; and living-donor procedures, in which the left (for children) or the right (for adults) lobe of the liver is harvested from a living donor for transplantation into the recipient. In the adult procedure, once the right lobe is removed from the donor, the donor right hepatic vein is anastomosed to the recipient right hepatic vein remnant, followed by donor-to-recipient anastomoses of the portal vein and then the hepatic artery. Finally, the biliary anastomosis is performed, duct-to-duct if practical or via Roux-en-Y anastomosis. Heterotopic liver transplantation, in which the donor liver is inserted without removal of the native liver, has met with very limited success and acceptance, except in a very small number of centers. In attempts to support desperately ill patients until a suitable donor organ can be identified, several transplantation centers are studying extracorporeal perfusion with bioartificial liver cartridges constructed from hepatocytes bound to hollow fiber systems and used as temporary hepatic-assist devices, but their efficacy remains to be established. Areas of research with the potential to overcome the shortage of donor organs include hepatocyte transplantation and xenotransplantation with genetically modified organs of nonhuman origin (e.g., swine).
Postoperative Course and Management
Immunosuppressive Therapy
The introduction in 1980 of cyclosporine as an immunosuppressive agent contributed substantially to the improvement in survival after liver transplantation. Cyclosporine, a calcineurin inhibitor, blocks early activation of T cells and is specific for T cell functions that result from the interaction of the T cell with its receptor and that involve the calcium-dependent signal transduction pathway. As a result, the activity of cyclosporine leads to inhibition of lymphokine gene activation, blocking interleukins 2, 3, and 4, tumor necrosis factor , and other lymphokines. Cyclosporine also inhibits B cell functions. This process occurs without affecting rapidly dividing cells in the bone marrow, which may account for the reduced frequency of posttransplantation systemic infections. The most common and important side effect of cyclosporine therapy is nephrotoxicity. Cyclosporine causes dose-dependent renal tubular injury and direct renal artery vasospasm. Following renal function, therefore, is important in monitoring cyclosporine therapy, perhaps even a more reliable indicator than blood levels of the drug. Nephrotoxicity is reversible and can be managed by dose reduction. Other adverse effects of cyclosporine therapy include hypertension, hyperkalemia, tremor, hirsutism, glucose intolerance, and gum hyperplasia.
Tacrolimus (originally labeled FK 506) is a macrolide lactone antibiotic isolated from a Japanese soil fungus, Streptomyces tsukubaensis. It has the same mechanism of action as cyclosporine but is 10–100 times more potent. Initially applied as "rescue" therapy for patients in whom rejection occurred despite the use of cyclosporine, tacrolimus was shown in two large, multicenter, randomized trials to be associated with a reduced frequency of acute rejection, refractory rejection, and chronic rejection. Although patient and graft survival are the same with these two drugs, the advantage of tacrolimus in minimizing episodes of rejection, reducing the need for additional glucocorticoid doses, and reducing the likelihood of bacterial and cytomegalovirus (CMV) infection has simplified the management of patients undergoing liver transplantation. In addition, the oral absorption of tacrolimus is more predictable than that of cyclosporine, especially during the early postoperative period when T-tube drainage interferes with the enterohepatic circulation of cyclosporine. As a result, in most transplantation centers tacrolimus has now supplanted cyclosporine for primary immunosuppression, and many centers rely on oral rather than intravenous administration from the outset. For transplantation centers that prefer cyclosporine, a new, better-absorbed microemulsion preparation is now available.
Although tacrolimus is more potent than cyclosporine, it is also more toxic and more likely to be discontinued for adverse events. The toxicity of tacrolimus is similar to that of cyclosporine; nephrotoxicity and neurotoxicity are the most commonly encountered adverse effects, and neurotoxicity (tremor, seizures, hallucinations, psychoses, coma) is more likely and more severe in tacrolimus-treated patients. Both drugs can cause diabetes mellitus, but tacrolimus does not cause hirsutism or gingival hyperplasia. Because of overlapping toxicity between cyclosporine and tacrolimus, especially nephrotoxicity, and because tacrolimus reduces cyclosporine clearance, these two drugs should not be used together. Since 99% of tacrolimus is metabolized by the liver, hepatic dysfunction reduces its clearance; in primary graft nonfunction (when, for technical reasons or because of ischemic damage prior to its insertion, the allograft is defective and does not function normally from the outset), tacrolimus doses have to be reduced substantially, especially in children. Both cyclosporine and tacrolimus are metabolized by the cytochrome P450 IIIA system, and therefore drugs that induce cytochrome P450 (e.g., phenytoin, phenobarbital, carbamazepine, rifampin) reduce available levels of cyclosporine and tacrolimus; drugs that inhibit cytochrome P450 (e.g., erythromycin, fluconazole, ketoconazole, clotrimazole, itraconazole, verapamil, diltiazem, nicardipine, cimetidine, danazol, metoclopramide, bromocriptine, and the HIV protease inhibitor ritonavir) increase cyclosporine and tacrolimus blood levels. Indeed, itraconazole is commonly used to help boost tacrolimus levels. Like azathioprine, cyclosporine and tacrolimus appear to be associated with a risk of lymphoproliferative malignancies (see below), which may occur earlier after cyclosporine or tacrolimus than after azathioprine therapy. Because of these side effects, combinations of cyclosporine or tacrolimus with prednisone and azathioprine—all at reduced doses—are preferable regimens for immunosuppressive therapy.
In patients with pretransplantation renal dysfunction or renal deterioration that occurs intraoperatively or immediately postoperatively, tacrolimus or cyclosporine therapy may not be practical; under these circumstances, induction or maintenance of immunosuppression with monoclonal antibodies to T cells, OKT3, may be appropriate. Therapy with OKT3 has been especially effective in reversing acute rejection in the posttransplant period and is the standard treatment for acute rejection that fails to respond to methylprednisolone boluses. Intravenous infusions of OKT3 may be complicated by transient fever, chills, and diarrhea, or by pulmonary edema, which can be fatal. When this drug is used to induce immunosuppression initially or to provide "rescue" in those who reject despite "conventional" therapy, the incidence of bacterial, fungal, and especially CMV infections is increased during and after such therapy. In some centers, ganciclovir antiviral therapy is initiated prophylactically as a routine along with OKT3. Because OKT3 is such a potent immunosuppressive agent, its use is more likely to be complicated by opportunistic infection or lymphoproliferative disorders; therefore, and because of the availability of alternative immunosuppressive drugs, OKT3 is used less often nowadays. Another immunosuppressive drug being used for patients undergoing liver transplantation is mycophenolic acid, a nonnucleoside purine metabolism inhibitor derived as a fermentation product from several Penicillium species. Mycophenolate has been shown to be better than azathioprine, when used with other standard immunosuppressive drugs, in preventing rejection after renal transplantation and has been adopted as well for use in liver transplantation. The most common adverse effects of mycophenolate are leukopenia and gastrointestinal complaints. Rapamycin, an inhibitor of later events in T cell activation, is approved for use in kidney transplantation but is not approved for use in liver transplant recipients because of the association with an increased frequency of hepatic artery thrombosis in the first month posttransplantation. Studies to examine the safety and efficacy of conversion to rapamycin from calcineurin inhibitors are ongoing. Because of its profound antiproliferative effects, rapamycin has also been suggested to be a useful immunosuppressive agent in patients with a prior or current history of malignancy, such as HCC. Further evaluation is underway.
The most important principle of immunosuppression is that the ideal approach strikes a balance between immunosuppression and immunologic competence. In general, given sufficient immunosuppression, acute liver allograft rejection is nearly always reversible. On the one hand, incompletely treated acute rejection predisposes to the development of chronic rejection, which can threaten graft survival. On the other hand, if the cumulative dose of immunosuppressive therapy is too large, the patient may succumb to opportunistic infection. In hepatitis C, pulse glucocorticoids or OKT3 use accelerate recurrent allograft hepatitis. Further complicating matters, acute rejection can be difficult to distinguish histologically from recurrent hepatitis C. Therefore, immunosuppressive drugs must be used judiciously, with strict attention to the infectious consequences of such therapy and careful confirmation of the diagnosis of acute rejection. In this vein, efforts have been made to minimize the use of glucocorticoids, a mainstay of immunosuppressive regimens, and steroid-free immunosuppression can be achieved in some instances. In this regard, patients who undergo liver transplantation for autoimmune diseases such as primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis, are less likely to achieve freedom from steroids.
Postoperative Complications
Complications of liver transplantation can be divided into hepatic and nonhepatic categories (Tables 304-4 and 304-5). In addition, both immediately postoperative and late complications are encountered. Patients who undergo liver transplantation as a rule have been chronically ill for protracted periods and may be malnourished and wasted. The impact of such chronic illness and the multisystem failure that accompanies liver failure continue to require attention in the postoperative period. Because of the massive fluid losses and fluid shifts that occur during the operation, patients may remain fluid-overloaded during the immediate postoperative period, straining cardiovascular reserve; this effect can be amplified in the face of transient renal dysfunction and pulmonary capillary vascular permeability. Continuous monitoring of cardiovascular and pulmonary function, measures to maintain the integrity of the intravascular compartment and to treat extravascular volume overload, and scrupulous attention to potential sources and sites of infection are of paramount importance. Cardiovascular instability may also result from the electrolyte imbalance that may accompany reperfusion of the donor liver as well as from restoration of systemic vascular resistance following implantation. Pulmonary function may be compromised further by paralysis of the right hemidiaphragm associated with phrenic nerve injury. The hyperdynamic state with increased cardiac output that is characteristic of patients with liver failure reverses rapidly after successful liver transplantation.
Table 304-4 Nonhepatic Complications of Liver Transplantation
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Fluid overload
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Cardiovascular instability
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Arrhythmias
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Congestive heart failure
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Cardiomyopathy
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Pulmonary compromise
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Pneumonia
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Pulmonary capillary vascular permeability
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Fluid overload
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Renal dysfunction
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Prerenal azotemia
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Hypoperfusion injury (acute tubular necrosis)
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Drug nephrotoxicity
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Renal blood flow secondary to intraabdominal pressure
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Hematologic
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Anemia 2° to gastrointestinal and/or intraabdominal bleeding
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Hemolytic anemia, aplastic anemia
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Thrombocytopenia
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Infection
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Bacterial: early, common postoperative infections
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Fungal/parasitic: late, opportunistic infections
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Viral: late, opportunistic infections, recurrent hepatitis
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Neuropsychiatric
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Seizures
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Metabolic encephalopathy
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Depression
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Difficult psychosocial adjustment
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Diseases of donor
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Infectious
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Malignant
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Malignancy
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B-cell lymphoma (posttransplantation lymphoproliferative disorders)
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De novo neoplasms (particularly squamous cell skin carcinoma)
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Table 304-5 Hepatic Complications of Liver Transplantation
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Hepatic Dysfunction Common after Major Surgery
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Prehepatic
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Pigment load
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Hemolysis
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Blood collections (hematomas, abdominal collections)
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Intrahepatic
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Early
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Hepatotoxic drugs and anesthesia
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Hypoperfusion (hypotension, shock, sepsis)
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Benign postoperative cholestasis
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Late
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Transfusion-associated hepatitis
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Exacerbation of primary hepatic disease
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Posthepatic
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Biliary obstruction
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Renal clearance of conjugated bilirubin (renal dysfunction)
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Hepatic Dysfunction Unique to Liver Transplantation
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Primary graft nonfunction
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Vascular compromise
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Portal vein obstruction
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Hepatic artery thrombosis
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Anastomotic leak with intraabdominal bleeding
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Bile duct disorder
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Stenosis, obstruction, leak
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Rejection
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Recurrent primary hepatic disease
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Other immediate management issues include renal dysfunction. Prerenal azotemia, acute kidney injury associated with hypoperfusion (acute tubular necrosis), and renal toxicity caused by antibiotics, tacrolimus, or cyclosporine are encountered frequently in the postoperative period, sometimes necessitating dialysis. Hemolytic uremic syndrome can be associated with cyclosporine, tacrolimus, or OKT3. Occasionally, postoperative intraperitoneal bleeding may be sufficient to increase intraabdominal pressure, which, in turn, may reduce renal blood flow; this effect is rapidly reversible when abdominal distention is relieved by exploratory laparotomy to identify and ligate the bleeding site and to remove intraperitoneal clot.
Anemia may also result from acute upper gastrointestinal bleeding or from transient hemolytic anemia, which may be autoimmune, especially when blood group O livers are transplanted into blood group A or B recipients. This autoimmune hemolytic anemia is mediated by donor intrahepatic lymphocytes that recognize red blood cell A or B antigens on recipient erythrocytes. Transient in nature, this process resolves once the donor liver is repopulated by recipient bone marrow–derived lymphocytes; the hemolysis can be treated by transfusing blood group O red blood cells and/or by administering higher doses of glucocorticoids. Transient thrombocytopenia is also commonly encountered. Aplastic anemia, a late occurrence, is rare but has been reported in almost 30% of patients who underwent liver transplantation for acute, severe hepatitis of unknown cause.
Bacterial, fungal, or viral infections are common and may be life-threatening postoperatively. Early after transplant surgery, common postoperative infections predominate—pneumonia, wound infections, infected intraabdominal collections, urinary tract infections, and intravenous line infections—rather than opportunistic infections; these infections may involve the biliary tree and liver as well. Beyond the first postoperative month, the toll of immunosuppression becomes evident, and opportunistic infections—CMV, herpes viruses, fungal infections (Aspergillus, Candida, cryptococcal disease), mycobacterial infections, parasitic infections (Pneumocystis, Toxoplasma), bacterial infections (Nocardia, Legionella, and Listeria)—predominate. Rarely, early infections represent those transmitted with the donor liver, either infections present in the donor or infections acquired during procurement processing. De novo viral hepatitis infections acquired from the donor organ or, almost unheard of nowadays, from transfused blood products occur after typical incubation periods for these agents (well beyond the first month). Obviously, infections in an immunosuppressed host demand early recognition and prompt management; prophylactic antibiotic therapy is administered routinely in the immediate postoperative period. Use of sulfamethoxazole with trimethoprim reduces the incidence of postoperative Pneumocystis carinii pneumonia. Antiviral prophylaxis for CMV with ganciclovir should be administered in patients at high risk (e.g., when a CMV-seropositive donor organ is implanted into a CMV-seronegative recipient).
Neuropsychiatric complications include seizures (commonly associated with cyclosporine and tacrolimus toxicity), metabolic encephalopathy, depression, and difficult psychosocial adjustment. Rarely, diseases are transmitted by the allograft from the donor to the recipient. In addition to viral and bacterial infections, malignancies of donor origin have occurred. Posttransplantation lymphoproliferative disorders, especially B cell lymphoma, are a recognized complication associated with immunosuppressive drugs such as azathioprine, tacrolimus, and cyclosporine (see above). Epstein-Barr virus has been shown to play a contributory role in some of these tumors, which may regress when immunosuppressive therapy is reduced. De novo neoplasms appear at increased frequency after liver transplantation, particularly squamous cell carcinomas of the skin. Routine screening should be performed.
Long-term complications after liver transplantation attributable primarily to immunosuppressive medications include diabetes mellitus (associated with glucocorticoids) as well as hypertension, hyperlipidemia, and chronic renal insufficiency (associated with cyclosporine and tacrolimus). Monitoring and treating these disorders is a routine component of posttransplantation care; in some cases, they respond to changes in immunosuppressive regimen, while in others, specific treatment of the disorder is introduced.
Hepatic Complications
Hepatic dysfunction after liver transplantation is similar to the hepatic complications encountered after major abdominal and cardiothoracic surgery; however, in addition, there may be complications such as primary graft failure, vascular compromise, failure or stricture of the biliary anastomoses, and rejection. As in nontransplant surgery, postoperative jaundice may result from prehepatic, intrahepatic, and posthepatic sources. Prehepatic sources represent the massive hemoglobin pigment load from transfusions, hemolysis, hematomas, ecchymoses, and other collections of blood. Early intrahepatic liver injury includes effects of hepatotoxic drugs and anesthesia; hypoperfusion injury associated with hypotension, sepsis, and shock; and benign postoperative cholestasis.
Late intrahepatic sources of liver injury include posttransfusion hepatitis and exacerbation of primary disease. Posthepatic sources of hepatic dysfunction include biliary obstruction and reduced renal clearance of conjugated bilirubin. Hepatic complications unique to liver transplantation include primary graft failure associated with ischemic injury to the organ during harvesting; vascular compromise associated with thrombosis or stenosis of the portal vein or hepatic artery anastomoses; vascular anastomotic leak; stenosis, obstruction, or leakage of the anastomosed common bile duct; recurrence of primary hepatic disorder (see below); and rejection.
Transplant Rejection
Despite the use of immunosuppressive drugs, rejection of the transplanted liver still occurs in a proportion of patients, beginning 1–2 weeks after surgery. Clinical signs suggesting rejection are fever, right upper quadrant pain, and reduced bile pigment and volume. Leukocytosis may occur, but the most reliable indicators are increases in serum bilirubin and aminotransferase levels. Because these tests lack specificity, distinguishing among rejection and biliary obstruction, primary graft nonfunction, vascular compromise, viral hepatitis, CMV infection, drug hepatotoxicity, and recurrent primary disease may be difficult. Radiographic visualization of the biliary tree and/or percutaneous liver biopsy often helps to establish the correct diagnosis. Morphologic features of acute rejection include a mixed portal cellular infiltrate, bile duct injury, and/or endothelial inflammation ("endothelialitis"); some of these findings are reminiscent of graft-versus-host disease, primary biliary cirrhosis, or recurrent allograft hepatitis C. As soon as transplant rejection is suspected, treatment consists of intravenous methylprednisolone in repeated boluses; if this fails to abort rejection, many centers use antibodies to lymphocytes, such as OKT3, or polyclonal antilymphocyte globulin. Caution should be exercised when managing acute rejection with pulse glucocorticoids in patients with hepatitis C virus (HCV) infection, because of the high risk of triggering recurrent allograft hepatitis C.
Chronic rejection is a relatively rare outcome that can follow repeated bouts of acute rejection or that occurs unrelated to preceding rejection episodes. Morphologically, chronic rejection is characterized by progressive cholestasis, focal parenchymal necrosis, mononuclear infiltration, vascular lesions (intimal fibrosis, subintimal foam cells, fibrinoid necrosis), and fibrosis. This process may be reflected as ductopenia—the vanishing bile duct syndrome. Reversibility of chronic rejection is limited; in patients with therapy-resistant chronic rejection, retransplantation has yielded encouraging results.
Outcome
Survival
The survival rate for patients undergoing liver transplantation has improved steadily since 1983. One-year survival rates have increased from ~70% in the early 1980s to 85–90% from 2000 to 2006. Currently the 5-year survival rate exceeds 60%. An important observation is the relationship between clinical status before transplantation and outcome. For patients who undergo liver transplantation when their level of compensation is high (e.g., still working or only partially disabled), a 1-year survival rate of more than85% is common. For those whose level of decompensation mandates continuous in-hospital care prior to transplantation, the 1-year survival rate is about 70%, while for those who are so decompensated that they require life support in an intensive care unit, the 1-year survival rate is ~50%. Since UNOS's adoption in 2002 of the MELD system for organ allocation, posttransplantation survival has been found to be affected adversely for candidates with MELD scores more than 25, considered high disease severity. Thus, irrespective of allocation scheme, high disease severity pretransplantation corresponds to diminished posttransplantation survival. Another important distinction in survival has been drawn between high-risk and low-risk patient categories. For patients who do not fit any "high-risk" designations, 1-year and 5-year survival rates of 85 and 80%, respectively, have been recorded. In contrast, among patients in high-risk categories—cancer, fulminant hepatitis, age more than 65, concurrent renal failure, respirator dependence, portal vein thrombosis, and history of a portacaval shunt or multiple right upper quadrant operations—survival statistics fall into the range of 60% at 1 year and 35% at 5 years. Survival after retransplantation for primary graft nonfunction is ~50%. Causes of failure of liver transplantation vary with time. Failures within the first 3 months result primarily from technical complications, postoperative infections, and hemorrhage. Transplant failures after the first 3 months are more likely to result from infection, rejection, or recurrent disease (such as malignancy or viral hepatitis).
Recurrence of Primary Disease
Features of autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis overlap with those of rejection or posttransplantation bile-duct injury. Whether autoimmune hepatitis and sclerosing cholangitis recur after liver transplantation is controversial; data supporting recurrent autoimmune hepatitis (in up to a third of patients in some series) are more convincing than those supporting recurrent sclerosing cholangitis. Similarly, reports of recurrent primary biliary cirrhosis after liver transplantation have appeared; however, the histologic features of primary biliary cirrhosis and chronic rejection are virtually indistinguishable and occur as frequently in patients with primary biliary cirrhosis as in patients undergoing transplantation for other reasons. The presence of a florid inflammatory bile duct lesion is highly suggestive of the recurrence of primary biliary cirrhosis, but even this lesion can be observed in acute rejection. Hereditary disorders such as Wilson's disease and 1 antitrypsin deficiency have not recurred after liver transplantation; however, recurrence of disordered iron metabolism has been observed in some patients with hemochromatosis. Hepatic vein thrombosis (Budd-Chiari syndrome) may recur; this can be minimized by treating underlying myeloproliferative disorders and by anticoagulation. Because cholangiocarcinoma recurs almost invariably, few centers now offer transplantation to such patients; however, a few highly selected patients with operatively confirmed stage I or II cholangiocarcinoma who undergo liver transplantation combined with neoadjuvant chemoradiation may experience excellent outcomes. In patients with intrahepatic hepatocellular carcinoma who meet criteria for transplantation, 1- and 5-year survivals are similar to those observed in patients undergoing liver transplantation for nonmalignant disease. Finally, metabolic disorders such as nonalcoholic steatohepatitis recur frequently, especially if the underlying metabolic predisposition is not altered.
Hepatitis A can recur after transplantation for fulminant hepatitis A, but such acute reinfection has no serious clinical sequelae. In fulminant hepatitis B, recurrence is not the rule; however, in the absence of any prophylactic measures, hepatitis B usually recurs after transplantation for end-stage chronic hepatitis B. Before the introduction of prophylactic antiviral therapy, immunosuppressive therapy sufficient to prevent allograft rejection led inevitably to marked increases in hepatitis B viremia, regardless of pretransplantation values. Overall graft and patient survival were poor, and some patients experienced a rapid recapitulation of severe injury—severe chronic hepatitis or even fulminant hepatitis—after transplantation. Also recognized in the era before availability of antiviral regimens was fibrosing cholestatic hepatitis, rapidly progressive liver injury associated with marked hyperbilirubinemia, substantial prolongation of the prothrombin time (both out of proportion to relatively modest elevations of aminotransferase activity), and rapidly progressive liver failure. This lesion has been suggested to represent a "choking off" of the hepatocyte by an overwhelming density of hepatitis B virus (HBV) proteins. Complications such as sepsis and pancreatitis were also observed more frequently in patients undergoing liver transplantation for hepatitis B prior to the introduction of antiviral therapy. The introduction of long-term prophylaxis with HBIg revolutionized liver transplantation for chronic hepatitis B. Neither preoperative hepatitis B vaccination, preoperative or postoperative interferon therapy, nor short-term (2 months) HBIg prophylaxis has been shown to be effective, but a retrospective analysis of data from several hundred European patients followed for 3 years after transplantation has shown that long-term (6 months) prophylaxis with HBIg is associated with a lowering of the risk of HBV reinfection from ~75% to 35% and a reduction in mortality from ~50% to 20%.
As a result of long-term HBIg use following liver transplantation for chronic hepatitis B, similar improvements in outcome have been observed in the United States, with 1-year survival rates between 75 and 90%. Currently, with HBIg prophylaxis, the outcome of liver transplantation for chronic hepatitis B is indistinguishable from that for chronic liver disease unassociated with chronic hepatitis B; essentially, medical concerns regarding liver transplantation for chronic hepatitis B have been eliminated. Passive immunoprophylaxis with HBIg is begun during the anhepatic stage of surgery, repeated daily for the first 6 postoperative days, then continued with infusions that are given either at regular intervals of 4–6 weeks or, alternatively, when anti-HBs levels fall below a threshold of 100 mIU/mL. The current approach in most centers is to continue HBIg indefinitely, which can add approximately $20,000 per year to the cost of care; some centers are evaluating regimens that shift to less frequent administration or to intramuscular administration in the late posttransplantation period. Still, occasionally "breakthrough" HBV infection occurs.
Further improving the outcome of liver transplantation for chronic hepatitis B is the current availability of such antiviral drugs as lamivudine, adefovir dipivoxil, and entecavir . When these drugs are administered to patients with decompensated liver disease, a proportion improve sufficiently to postpone imminent liver transplantation. In addition, lamivudine can be used to prevent recurrence of HBV infection when administered prior to transplantation; to treat hepatitis B that recurs after transplantation, including in patients who break through HBIg prophylaxis; and to reverse the course of otherwise fatal fibrosing cholestatic hepatitis. Clinical trials have shown that lamivudine antiviral therapy reduces the level of HBV replication substantially, sometimes even resulting in clearance of hepatitis B surface antigen (HBsAg); reduces alanine aminotransferase (ALT) levels; and improves histologic features of necrosis and inflammation. Long-term use of lamivudine is safe and effective, but after several months a proportion of patients become resistant to lamivudine, resulting from YMDD (tyrosine-methionine-aspartate-aspartate) mutations in the HBV polymerase motif (Chap. 300). In approximately half of such resistant patients, hepatic deterioration may ensue. Fortunately, adefovir dipivoxil is available as well and can be used to treat lamivudine-associated YMDD variants, effectively "rescuing" patients experiencing hepatic decompensation after lamivudine breakthrough. Currently, most liver transplantation centers combine HBIg plus lamivudine or adefovir, and additional antivirals such as the more recently approved entecavir are being introduced as well. Clinical trials are underway to define the optimal application of these antiviral agents in the management of patients undergoing liver transplantation for chronic hepatitis B; conceivably, in the future, combinations of oral antiviral drugs may even supplant HBIg.
Prophylactic approaches applied to patients undergoing liver transplantation for chronic hepatitis B are being used as well for patients without hepatitis B who receive organs from donors with anti-HBc. Patients who undergo liver transplantation for chronic hepatitis B plus D are less likely to experience recurrent liver injury than patients undergoing liver transplantation for hepatitis B alone; still, such co-infected patients would also be offered standard posttransplantation prophylactic therapy for hepatitis B.
Accounting for up to 40% of all liver transplantation procedures, the most common indication for liver transplantation is end-stage liver disease resulting from chronic hepatitis C. Recurrence of HCV infection after liver transplantation can be documented in almost every patient if sufficiently sensitive virus markers are used. The clinical consequences of recurrent hepatitis C are limited during the first 5 years after transplantation. Nonetheless, despite the relative clinical benignity of recurrent hepatitis C in the early years after liver transplantation, and despite the negligible impact on patient survival during these early years, histologic studies have documented the presence of moderate to severe chronic hepatitis in more than half of all patients and bridging fibrosis or cirrhosis in ~10%. Moreover, progression to cirrhosis within 5 years is even more common, occurring in up to two-thirds of patients if moderate hepatitis is detected in a 1-year biopsy. Not surprisingly, then, for patients undergoing transplantation for hepatitis C, allograft and patient survival are diminished substantially between 5 and 10 years after transplantation. In a proportion of patients, even during the early posttransplantation period, recurrent hepatitis C may be sufficiently severe biochemically and histologically to merit antiviral therapy. Treatment with pegylated interferon can suppress HCV-associated liver injury but rarely leads to sustained benefit. Sustained virologic responses are the exception, and reduced tolerability is often dose-limiting. Preemptive combination antiviral therapy with pegylated interferon and the nucleoside analogue ribavirin immediately after transplantation does not appear to provide any advantage over therapy introduced after clinical hepatitis has occurred. Similarly, although interferon-based antiviral therapy is not recommended for patients with decompensated liver disease, some centers have experimented with pretransplantation antiviral therapy in an attempt to eradicate HCV replication prior to transplantation; preliminary results are promising, but interferon treatment of patients with end-stage liver disease can lead to worsening of hepatic decompensation, and HCV infection has recurred after transplantation in some of these recipients. Initial trials of hepatitis C immune globulin preparations to prevent recurrent hepatitis C after liver transplantation have not been successful.
A small number succumb to early HCV-associated liver injury, and a syndrome reminiscent of fibrosing cholestatic hepatitis (see above) has been observed rarely. Because patients with more episodes of rejection receive more immunosuppressive therapy, and because immunosuppressive therapy enhances HCV replication, patients with severe or multiple episodes of rejection are more likely to experience early recurrence of hepatitis C after transplantation. Both high viral load and older donor age have been linked to recurrent HCV-induced liver disease and to earlier disease recurrence after transplantation.
Patients who undergo liver transplantation for end-stage alcoholic cirrhosis are at risk of resorting to drinking again after transplantation, a potential source of recurrent alcoholic liver injury. Currently, alcoholic liver disease is one of the more common indications for liver transplantation, accounting for 20–25% of all liver transplantation procedures, and most transplantation centers screen candidates carefully for predictors of continued abstinence. Recidivism is more likely in patients whose sobriety prior to transplantation was less than 6 months. For abstinent patients with alcoholic cirrhosis, liver transplantation can be undertaken successfully, with outcomes comparable to those for other categories of patients with chronic liver disease, when coordinated by a team approach that includes substance abuse counseling.
Posttransplantation Quality of Life
Full rehabilitation is achieved in the majority of patients who survive the early postoperative months and escape chronic rejection or unmanageable infection. Psychosocial maladjustment interferes with medical compliance in a small number of patients, but most manage to adhere to immunosuppressive regimens, which must be continued indefinitely. In one study, 85% of patients who survived their transplant operations returned to gainful activities. In fact, some women have conceived and carried pregnancies to term after transplantation without demonstrable injury to their infants.
