Robert L. Carithers Jr. MD, FACP1
James D. Perkins MD2
1Professor of Medicine and Director, Hepatology Section, Division of Gastroenterology, Department of Medicine, and Medical Director, Liver Transplantation Program, University of Washington School of Medicine
2Professor, Department of Surgery, and Chief, Division of Transplantation, University of Washington School of Medicine
The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
More than 6,000 liver transplantations are performed annually in the United States.1 Enhancements in patient selection, surgical technique, and the availability of powerful immunosuppressive agents have resulted in steady improvement in patient survival. As a result, liver transplantation has been accepted as the standard of care for patients with severe acute or chronic liver disease in whom conventional modalities of therapy have failed. The major obstacle to the procedure is the critical shortage of donor organs.
Candidates for Transplantation
Any patient with acute or chronic liver failure is a potential candidate for liver transplantation; there are a number of common indications [see Table 1].2 The three most important questions addressed during the evaluation of candidates for liver transplantation are the following:
The methods of evaluating candidates for transplantation include careful history and physical examination; cardiopulmonary testing, including echocardiography, dobutamine stress testing, pulmonary function testing, and cardiac catheterization; measurement of creatinine clearance; abdominal imaging studies to evaluate portal vein patency and to detect hepatocellular carcinoma; and a thorough evaluation of social factors and support.2 Echocardiography is useful in assessing left ventricular function and detecting pulmonary hypertension, which is seen in as many as 5% of cirrhotic patients.3 Color flow Doppler studies of the portal vein are used to gauge the integrity of portal vein flow. If extensive portal vein thrombosis is detected, the transplant surgeon can obtain extra donor vessels to bypass the blockade if necessary. Computed tomographic angiography permits detection of small hepatocellular carcinomas and aberrant arterial blood supply to the liver. Rigorous evaluation of the patient for any addictive behavior and assessment of the patient's social support system allow the transplant team to plan in advance for any needed services, which may include counseling, specialized addiction treatment, housing, transportation, and financial assistance for medications and other expenses.
Contraindications to Transplantation
Patients with severe neurologic or cardiopulmonary disease cannot withstand the stress of transplantation surgery. Patients with cirrhosis who have severe pulmonary hypertension rarely survive the operation and perioperative period.4 Other contraindications to transplantation include severe or morbid obesity, extrahepatic malignancies, systemic infection, and cholangiocarcinoma.5 The most common surgical contraindication to liver transplantation is thrombosis of the portal vein and other splanchnic veins to such an extent that viable portal blood flow cannot be achieved.6 Finally, the most frequent contraindications to liver transplantation are ongoing destructive behavior resulting from drug or alcohol addiction and the inability of the patient to comply with the complex medical regimen required after the operation.
Timing of Transplantation
Determining the optimal time to refer patients for evaluation and to perform the operation can be as important to the outcome as patient selection. A few simple clinical approaches have proved useful in determining the prognosis of patients with liver disease. These include use of the Child-Turcotte-Pugh (CTP) classification [see Table 2]; use of the Model for End-Stage Liver Disease (MELD) for predicting survival in patients with liver disease; determination of the degree of ascites; and identification of other complications of cirrhosis.7,8
MELD, which employs a scoring system based on the serum bilirubin level, the serum creatinine level, and the international normalized ratio (INR) for prothrombin time, is now used for the allocation of donor organs in patients on liver transplantation waiting lists in the United States.9,10 MELD scores range from 6 to 40, with higher scores representing sicker patients, who are granted earlier access to donor organs.11 The United Network for Organ Sharing provides on their Web site a resource for calculating MELD scores for individual patients.12The MELD score can accurately predict 3-month mortality of patients with chronic liver disease who are on the liver waiting list [see Figure 1].11 The MELD score also is an accurate predictor of survival after liver transplantation.13 By comparing pretransplantation and posttransplantation outcomes, it has been shown that for patients who undergo liver transplantation for chronic liver failure, survival is improved only in those with MELD scores greater than 15 at the time of the operation.14
Table 1 Common Indications for Liver Transplantation
Table 2 Child-Turcotte-Pugh (CTP) Classification*
The MELD score, CTP classification, and assessment of the complications of cirrhosis are the most useful tools for determining the optimal referral of patients to transplant centers.8 It is recommended that patients who show evidence of hepatic dysfunction (i.e., a MELD score of 10 or higher and a CTP score of 7 or higher) or who experience their first major complication (e.g., ascites or hepatic encephelopathy) should be referred to centers for potential transplantation.2 Development of other, more ominous complications of cirrhosis (e.g., hepatocellular carcinoma, spontaneous bacterial peritonitis, and hepatorenal syndrome) indicate the need for immediate referral of patients to a transplant center.
Most liver transplantations are performed using a whole cadaveric liver placed in the orthotopic position. To increase the overall organ supply and especially to aid young children, for whom there is a perennial shortage of donor organs, a cadaveric liver can be divided into parts for more than one recipient [see Figure 2]. The same techniques can be used with living donors, with only part of the liver being removed for transplantation. Living related donor transplantation for children is a well-established procedure.15 Living related donor transplantation for adults is also being performed at many transplantation centers, although donor safety remains a major concern.16,17
Liver transplantation is a complex, time-consuming operation that requires vascular reconstruction of the hepatic venous drainage to the inferior vena cava, to the hepatic artery, and to the portal vein. The hepatic vein of the donor organ is anastomosed to the inferior vena cava of the recipient; the donor hepatic artery is anastomosed to the recipient hepatic artery; and the portal vein is reconstructed by a vein graft or patch. Biliary reconstruction is usually accomplished by use of an end-to-end anastomosis of the proximal donor bile duct attached to the distal recipient duct; however, in recipients with diseased ducts, the donor duct is usually anastomosed to the jejunum by way of a Roux-en-Y loop.
A number of complications can be anticipated after liver transplantation, including perioperative and surgical complications, immunologic and infectious disorders, and a variety of medical complications.
Complications of Transplantation
Perioperative and Surgical Complications
The most serious immediate complication seen after liver transplantation is nonfunction of the transplanted liver, which occurs in 5% to 10% of cases. In these cases, patients fail to recover neurologic function; coagulopathy fails to improve spontaneously; and there is progressive jaundice and acidosis. Emergent retransplantation is the only recourse for these patients.
Other important surgical complications encountered after liver transplantation include hepatic artery thrombosis, portal vein thrombosis, and biliary tract complications (e.g., bile leaks and obstruction). Biliary tract complications are the most common; fortunately, most can be managed effectively with endoscopic techniques.18 Hepatic artery thrombosis is a much more serious complication that can result in the need for retransplantation. A variety of surgical and nonsurgical factors are associated with an increased risk of hepatic artery thrombosis. Included among the nonsurgical factors are immunologic status, hypercoagulable states, tobacco use, and cytomegalovirus infection.19
Immunologic Complications (Graft Rejection)
Two types of allograft rejection are seen after liver transplantation: cellular and ductopenic. Cellular rejection, which is usually manifested by elevated aminotransferase levels, is most commonly seen 6 to 10 weeks after transplantation. The diagnosis is confirmed by liver biopsy, which reveals cellular invasion of small bile ducts and vascular endothelium. Most patients respond rapidly to increased immunosuppression. Ductopenic rejection is a more indolent process that usually presents as progressive jaundice months to years after transplantation. Liver biopsies reveal gradual disappearance of intrahepatic bile ducts. Most patients with this condition ultimately require retransplantation.
Infections remain among the most serious complications encountered after liver transplantation. Many potential pathogens (e.g.,Pneumocystis jiroveci and cytomegalovirus) can usually be prevented with aggressive prophylaxis. In the early postoperative period, the most common pathogens are fungal and nosocomial bacterial infections. Candidiasis and aspergillosis, which remain the most serious infections encountered after liver transplantation, often occur in malnourished, critically ill patients.20 During the first few months after surgery, cytomegalovirus infection and recurrent hepatitis B and C virus infections become much more prominent. Infection with antimicrobial-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus faecium(VREF), is associated with increased postoperative mortality.21
Figure 1. Survival as a Function of MELD Score
Estimated 3-month survival as a function of the MELD score.11
Figure 2. Division of Liver for Transplantation
The liver can be divided into a number of sections, any combination of which can potentially be used for transplantation.
Complications of Immunosuppressive Therapy
A number of immunosuppressive agents are now available for use after solid-organ transplantation. These agents include cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, sirolimus, and corticosteroids, as well as various polyclonal or monoclonal antilymphocyte preparations.22 Most liver transplant recipients receive either cyclosporine or tacrolimus in combination with one or more other immunosuppressive agents.
Complications from cyclosporine and tacrolimus
Cyclosporine and tacrolimus are both associated with a number of complications, including renal dysfunction, neurologic toxicity, hypertension, pancreatic injury, and a variety of metabolic abnormalities. Renal failure occurs in 10% of patients who take cyclosporine or tacrolimus within 10 years after transplantation.23 Patients with a glomerular filtration rate of less than 40 ml/min/kg body surface area 1 year after transplantation are at high risk for subsequent renal failure. Replacing calcineurin inhibitors with other immunosuppressive agents, such as mycophenolate mofetil, sirolimus, or both, may improve renal function in some patients, although monotherapy with either of these agents is associated with a slight increase in the risk of rejection.24 Some patients receiving cyclosporine or tacrolimus experience severe neuropsychiatric complications, including psychosis, seizures, and apraxia.25 Many patients who take these drugs complain of headaches, tremors, and severe musculoskeletal pains. Hypertension, which is quite common in patients who take either cyclosporine or tacrolimus, is thought to result from peripheral and renal vasoconstriction.26 Pancreatic damage with development of type 1 (insulin-dependent) diabetes mellitus is more common after the use of tacrolimus. Patients who take either drug can experience hyperkalemia, hyperuricemia, and elevated cholesterol and triglyceride levels.27 Switching patients from cyclosporine to tacrolimus appears to reduce the severity of hyerlipidemias in some patients.28,29 Treatment with low-dose cerivastatin or pravastatin also has been shown to significantly improve lipid profiles without adversely affecting liver function.30 Cyclosporine, but not tacrolimus, is associated with gingival hyperplasia and excessive hair growth, particularly on the arms and face.
Complications from azathioprine, mycophenolate mofetil, and sirolimus
Azathioprine and mycophenolate mofetil can cause bone marrow depression with leukopenia, thrombocytopenia, and anemia. A number of patients who take mycophenolate mofetil also experience gastrointestinal side effects, including nausea, abdominal pain, and diarrhea. Long-term corticosteroid therapy is associated with obesity, hypertension, glucose intolerance, cataracts, osteoporosis, and hypercholesterolemia. Side effects of sirolimus include gastrointestinal symptoms and marked elevations of serum lipids, particularly when sirolimus is used in combination with cyclosporine.31
Complications from drug-drug interactions
Both cyclosporine and tacrolimus are extensively metabolized in the liver, primarily via the cytochrome P-450 IIIA enzyme. As a result, both drugs are prone to numerous drug-drug interactions.22 The most dramatic examples include interactions with ketoconazole and phenytoin. Ketoconazole inhibits the P-450 IIIA enzyme and can result in marked increases in circulating levels of cyclosporine and tacrolimus. In contrast, phenytoin induces the enzyme, resulting in enhanced metabolism of cyclosporine and tacrolimus and difficulty maintaining adequate circulating levels of both drugs. A number of other commonly used drugs have lesser but important effects on cyclosporine and tacrolimus metabolism. Awareness of these interactions is important in managing patients after transplantation.
Figure 3. Evaluation of Patients with Type 1 Diabetes for Pancreas Transplantation
Algorithm for evaluation of patients with type 1 (insulin-dependent) diabetes mellitus being considered for pancreas transplantation.
Delayed complications from immunosuppressive drugs
Most of the delayed complications seen after liver transplantation are secondary to the long-term use of immunosuppressive drugs. The most common of these complications include renal dysfunction, hypertension, diabetes, hyperkalemia and hyperuricemia, hyperlipidemia, obesity, and malignancies.32 Hypertension can usually be effectively managed with a combination of calcium channel blockers and beta blockers.33 Transient hyperkalemia can be managed effectively with sodium polystyrene sulfonate. If hyperkalemia is sustained, fludrocortisone can be used. Although many patients experience hyperuricemia after liver transplantation, very few experience gout. Treatment of gout is difficult because allopurinol can interfere with azathioprine metabolism, which can result in profound, life-threatening leukopenia, and because nonsteroidal anti-inflammatory drugs often worsen renal dysfunction. The necessity for treatment of hyperlipidemia after liver transplantation remains unclear. Obese patients who have undergone liver transplantation need a regular exercise program, limited caloric intake, and reduction or discontinuance of corticosteroids.34 After age-related cardiovascular complications, malignancies are the leading cause of late death in liver transplant recipients. The most common tumors seen in these patients are lymphoproliferative disorders associated with chronic viral infections and skin cancers (e.g., squamous cell carcinoma and Kaposi sarcoma).35 Many more recipients of liver transplantation are now receiving the bulk of their care from general internists, gastroenterologists, and primary care physicians. As a result, recognition of potential long-term complications and the need for appropriate immunizations and regular screening visits have become increasingly important.36
Certain patients require specific management after liver transplantation because of potential disease-specific complications. For example, progressive liver disease can develop rapidly in patients with hepatitis B and can become fatal within a year after transplantation. However, if they are treated with aggressive antiviral therapy before and after transplantation, these patients have an excellent outcome, with minimal risk of severe recurrent disease.37 Most potential transplant candidates now receive antiviral therapy with lamivudine, adefovir, or entecavir before the operation to reduce levels of circulating virus. Some patients with decompensated cirrhosis have such a dramatic response that transplantation can be postponed indefinitely.38 After surgery, most patients now receive continuous treatment with hepatitis B immune globulin and antiviral agents to prevent recurrent disease.39 There is concern about the emergence of viral mutations after long-term therapy with any of the antiviral agents; however, patients who have strains resistant to one form of therapy have been successfully treated with other agents.40
Patients with chronic hepatitis C virus infection who undergo liver transplantation invariably have persistent infection after the operation. Long-term survival of these patients is significantly worse than for patients who receive transplantation for other conditions.41 The optimal management of these patients, which may include pretransplantation and posttransplantation antiviral therapy and retransplantation, remains unclear.42 Donor age, early graft dysfunction, and the type of immunosuppression have emerged as important factors influencing the severity of postoperative disease.43 Because chronic liver disease secondary to hepatitis C is the leading indication for liver transplantation, management of such cases is an issue of increasing importance.
Patients with genetic hemochromatosis also have a significantly worse outcome compared to patients who have undergone liver transplantation for other indications. This is particularly true for patients who are homozygous for the C282Y mutation or heterozygous for the C282Y and H63D mutations. Patients without genetic alterations who have hepatic iron overload at the time of transplantation also have poor outcomes.44
Patients with liver disease caused by sclerosing cholangitis often have associated inflammatory bowel disease. Although the transplant effectively addresses their liver disease, these patients remain at high risk for colon cancer. As a result, they require careful monitoring with colonoscopy and biopsies at least annually. If severe dysplasia is detected, these patients can be effectively treated with colectomy.
Liver transplantation has emerged as the optimal treatment for most patients with hepatocellular carcinoma (HCC). Excellent disease-free survival after transplantation is seen in patients who have (1) a single tumor no greater than 5 cm in diameter, or no more than three lesions, none of which are greater than 3 cm in diameter; (2) no radiographic evidence of vascular invasion; and (3) no evidence of metastases on head and chest CT scans and bone scans.45 The issue of long waiting periods before transplantation has been addressed in the new MELD system for allocation of donor organs, which gives patients with HCC who are optimal candidates for transplantation elevated scores to facilitate early transplantation.10
Outcomes after Transplantation
Survival after liver transplantation has improved steadily over the past 10 years. Most centers now report 1-year survival rates of 85% to 90% and 5-year survival rates of 75% to 80%.1,2 During the same interval, the costs have progressively decreased as the result of reduced hospitalization for most patients.46 The quality of life for most patients after successful transplantation is quite good. Most patients have been able to return to work, and physically active recipients have returned to vigorous endeavors, including marathon running and mountain climbing.
Pancreas transplantation, which aims at providing physiologic insulin replacement, is a therapy that reliably achieves euglycemia in patients with type 1 diabetes mellitus. Islet transplantation (engrafting only the insulin-producing B cells of the pancreas) is an exciting alternative that is still in its clinical infancy.47,48,49 Two major difficulties prevent this technique from becoming widespread: (1) more than one pancreas is required to provide the recipient with enough islet cells to become euglyce-mic; and (2) the meticulous technique used for obtaining islet cells for transplantation varies from center to center.50
Since the first vascularized pancreas transplantation in 1966, more than 23,000 have been performed worldwide.51,52 Approximately 78% of pancreas transplantations have been performed with simultaneous kidney transplantations from the same donors (i.e., simultaneous pancreas and kidney [SPK] transplantation), with the recipients being those in whom renal failure is imminent or those who are already on dialysis.52 Of the remaining transplantations, 16% have been performed as a pancreas after kidney (PAK) transplantation in diabetic patients who have had a previous kidney transplant, and 7% have been performed as a pancreas transplantation alone (PTA) in diabetic patients who have not yet experienced significant renal failure.52
The goals of pancreas transplantation are to improve the quality of life for patients with type 1 diabetes mellitus, reverse the metabolic abnormalities caused by the disease, and prevent the secondary complications of the disease. Despite these lofty goals, postoperative complications and the need for long-term immunosuppression have rendered pancreas transplantation controversial except in a select subpopulation of patients.
Candidates for Transplantation
During evaluation, it is essential to confirm the diagnosis of type 1 diabetes mellitus, to confirm that secondary complications of diabetes are present, to determine the candidate's ability to undergo a major operation, and to rule out any contraindications to the operation.53 The type of procedure to be performed is determined by the renal function status of the potential recipient [see Figure 3].
Figure 4. Enteric Drainage Technique
Enteric drainage technique for a whole pancreas graft that incorporates anastamosis of the intact duodenum to a roux-en-Y limb of recipient jejunum.69 (IVC—inferior vena cava)
Contraindications to Transplantation
Patients with insufficient cardiovascular reserve (e.g., those who recently had a myocardial infarction), patients with a left ventricular ejection fraction below 50%, or patients with coronary angiographic evidence of significant uncorrectable coronary artery disease should not undergo pancreas transplantation53 [see Figure 3]. Unnecessary loss of pancreas grafts is avoided by excluding patients with current major psychiatric illness or evidence of significant noncompliance. In addition, transplantation should not be considered in patients with an active infection or malignancy.
Other contraindications are controversial and depend on the individual transplantation center. Extremity amputations necessitated by vascular disease usually indicate severe generalized vasculopathy and suggest a condition in which pancreas transplantation would not be beneficial. Patients whose weight is greater than 130% of their ideal body weight often have insulin resistance and, as a result, are not helped by transplantation.53 Continued cigarette use often indicates poor compliance in patients who have already been strongly encouraged to stop smoking. Severe neurogenic bladder dysfunction usually predicts a complicated postoperative course and is considered a contraindication at some centers.
Pancreas transplantation includes placement of the pancreas graft, usually in the right lower quadrant, with the reconstructed arteries of the pancreas anastomosed to the common iliac artery [see Figure 4].54 To provide drainage for pancreatic exocrine excretions, the increasingly favored procedure is to anastomose the duodenum of the graft to the recipient's small bowel as opposed to the mobilized urinary bladder.52,54,55 The venous drainage of the graft is achieved by anastomosing the portal vein either to the mobilized common iliac vein or to the portal vein.54,55 In SPK transplantation, the kidney is placed in the left lower quadrant.
In the immediate postoperative period, specific care should be directed toward monitoring cardiovascular function.54 Insulin infusions are generally given for a few days to rest the transplanted islets. Because many patients have some form of diabetic gastropathy, a nasogastric tube is required for 4 to 7 days postoperatively. A urinary catheter is required for an extended period to reduce the risk of complications from neurogenic bladder dysfunction.
Complications of Transplantation
Surgical complications of pancreas transplantation have recently been analyzed in a large, prospective, multicenter study.56 Complications can occur within the first 3 postoperative months; such complications include the necessity of reoperation, arterial and venous graft vessel thrombosis, intra-abdominal hemorrhage, and enteric or ureteral leaks. The risk of these complications is increased when donors are older than 45 years of age.56
Immunologic Complications (Graft Rejection)
Rejection, which is the leading cause of graft loss after a successful pancreas transplantation, has decreased markedly in the past few years.52 The gold standard for diagnosis of rejection is histopathologic evaluation of the graft.57 Rejection can be confirmed histologically, because tissue samples of the graft can be obtained by percutaneous biopsies.57
Complications of Medical Therapy
With the increased use of enteric drainage rather than bladder drainage, the complications of dehydration and metabolic acidosis have decreased significantly.55
Tacrolimus and mycophenolate acid have become the mainstay of immunosuppressive therapy for pancreas transplantation. In addition, most pancreas transplant centers now use induction immunosuppressive therapy followed by steroid-free maintenance therapy58; this preventive measure reduces the risk of medical complications caused by corticosteroid therapy.
Graft pancreatitis, which is also a common side effect, is manifested by hyperamylasemia, abdominal pain, and graft tenderness. This complication occurs less frequently than in the past because most pancreas transplants are now enterically drained.
Outcomes after Transplantation
Successful pancreas transplantation results in normalization of glucose and hemoglobin A1c levels.53 Glucose tolerance tests are normal or near normal; however, insulin levels are much higher than normal in recipients of pancreas transplantation. The systemic venous drainage of the graft causes elevated plasma levels of insulin, which is known to be a potent regulator of plasma lipoprotein metabolism. As a result, SPK transplantation recipients have a more favorable lipid profile than patients with type 1 diabetes mellitus who have kidney transplants.59
Effect on Disorders Associated with Type 1 Diabetes Mellitus
A transplanted pancreas can prevent or reduce the nephropathy that eventually develops in diabetic patients with a kidney graft. The presence of a transplanted pancreas can also reduce the risk of diabetic nephropathy in the kidneys of SPK transplant recipients.60 The successful pancreas transplant alone can improve diabetic nephropathy, as evidenced by reduced proteinuria and unchanged creatinine levels and clearance rates at 1 year posttransplantation.61
Pancreas transplantation appears to have a stabilizing effect on retinopathy. In a recent study, pancreas transplantation was associated with improvement or stabilization of diabetic retinopathy in more than 90% of patients. Even in patients whose retinopathy was more advanced before they underwent surgery, the majority experienced no further progression after the transplantation.62
Reestablishment of the euglycemic state by successful pancreas transplantation halts or reverses diabetic neuropathy. In one study, motor nerve conduction increased in patients whose transplantations were successful.63 Changes in autonomic function were favorable, but they did not amount to significant improvement at long-term follow-up.63
Pancreas transplantation has at least a partial beneficial effect on the macroangiopathy of the carotid artery in patients with type 1 diabetes mellitus.64 Also, compared with type 1 diabetes mellitus patients who receive kidney transplants, SPK recipients show improvement of diabetic microangiopathy.62,65 The progression of coronary atherosclerosis in patients with functioning pancreas grafts is reduced.
Patient survival exceeds 96% at 1 year and 90% at 3 years. Graft survival (i.e., complete insulin independence) exceeds 85% at 1 year and 75% at 3 years.46 Patients who undergo SPK transplantation have a markedly improved 10-year survival, compared with diabetic patients who undergo kidney transplantation alone.52,66,67
Quality of Life
Quality of life in terms of general health perception, physical ability, and sexual activity is higher for SPK transplant recipients than for patients with type 1 diabetes mellitus who receive kidney transplants, and it is far higher for SPK transplant recipients than for patients who remain on hemodialysis.68
Figure 2 Tom Moore.
Figure 4 Alice Y. Chen
Editors: Dale, David C.; Federman, Daniel D.