Advances in liver transplantation

New strategies and current care expand access, enhance survival

Tram T. Tran, MD; Nicholas Nissen, MD; F. Fred Poordad, MD; Paul Martin, MD

VOL 115 / NO 5 / MAY 2004 / POSTGRADUATE MEDICINE

CME learning objectives

• To learn common indications for and contraindications to liver transplantation
• To recognize which manifestations of decompensation in patients with cirrhosis warrant referral to a transplant center
• To understand the main primary care issues related to management in patients after liver transplantation

The authors disclose no financial interests in this article. They disclose unlabeled uses of interferon and ribavirin in transplant patients and sirolimus in liver transplant recipients.

Preview: Liver transplantation revolutionized the management of liver disease. Although the number of patients who could benefit from a transplant far exceeds the number of available cadaveric donors, new strategies, such as splitting cadaveric organs and using living donors, have expanded access to transplantation. Here, a team of transplant physicians highlights these new strategies, as well as the long-term management issues of special relevance to primary care physicians caring for transplant recipients. Tran TT, Nissen N, Poordad FF, et al. Advances in liver transplantation: new strategies and current care expand access, enhance survival. Postgrad Med 2004;115(5):73-85

The first human liver transplantation was performed in 1963 (1), but it has been only in the last two decades that orthotopic liver transplantation has achieved 1-year survival rates of 80% to 90% (2). According to the United Network for Organ Sharing (UNOS), there are more than 17,000 patients on the national waiting list for a liver transplant. Yet, in 2002, only 5,329 liver transplantations were performed (3).

This large disparity between the number of available "deceased" donor organs and qualified recipients awaiting liver transplantation has created ongoing debate about selection criteria, the timing of transplantation, and attempts to expand the donor pool as mortality for listed patients rises.

Indications and contraindications

Liver transplantation is indicated for most causes of acute or chronic liver disease. Cirrhosis is the reason for more than 80% of transplantations performed in adults, and hepatitis C and alcoholic liver disease are the two most common diagnoses in these cases (2). Other indications include the cholestatic liver disorders (primary biliary cirrhosis, primary sclerosing cholangitis, biliary atresia), chronic hepatitis (hepatitis B, autoimmune hepatitis), metabolic diseases (Wilson's disease, nonalcoholic steatohepatitis), fulminant hepatic failure, and nonmetastatic hepatocellular carcinoma (figure 1). Major pediatric indications for transplantation include biliary atresia and metabolic liver disease.

Although nonmetastatic primary hepatic cancer was once viewed as an ideal indication, a high rate of tumor recurrence has led to a more limited role for liver transplantation. Unfortunately, treatment methods short of transplantation have not improved survival rates significantly (4). In patients with hepatocellular carcinoma who are under consideration for a liver transplant, acceptable tumor dimensions are (1) a single lesion less than 5 cm or (2) two or three lesions of which the largest is not more than 3 cm in diameter (5). Survival rates are comparable to those for patients without a complicating hepatocellular carcinoma who receive a transplant.

The preoperative metastatic workup includes a bone scan, a computed tomographic scan of the chest, and evaluation to verify the absence of vascular invasion. Not infrequently, a small, "incidental" hepatocellular carcinoma is discovered in the native liver after transplantation. In these cases, the carcinoma is typically less than 2 cm in diameter, had not been detected by preoperative imaging, and does not adversely affect survival. An area of active investigation is the role of chemoembolization to reduce tumor burden before transplantation.

There are relatively few absolute contraindications to liver transplantation. Generally accepted ones include AIDS, extrahepatic malignancy, cholangiocarcinoma, active untreated sepsis, advanced cardiopulmonary disease, active alcoholism or substance abuse, and anatomical abnormality precluding liver transplantation. In most transplant centers, a selection committee composed of hepatologists, transplant surgeons, psychiatrists, and social workers determines the overall suitability of the transplant candidate. Transplant centers are increasingly offering liver transplantation to patients who have HIV infection without AIDS.

Listing and timing of transplantation

One of the critical concerns in transplantation is appropriate timing. For acute liver failure, the underlying cause is the single best predictor of outcome if a transplant is not received (6). Fatty liver of pregnancy, acetaminophen ingestion, and hepatitis A have an excellent prospect for spontaneous recovery, whereas nonacetaminophen drug toxicity, fulminant Wilson's disease, and fulminant hepatic failure of unclear cause have a poor prognosis if transplantation is not performed. The criteria of King's College, London, are used by many centers to predict the outcome of acute liver failure and the need for liver transplantation (table 1).

Table 1. King's College criteria for liver transplantation in fulminant hepatic failure

Patients with acetaminophen toxicity pH <7.3      or Prothrombin time >6.5 INR and serum creatinine level >3.4 mg/dL (301 micromoles/L) Other patients Prothrombin time >6.5 INR      or Three of the following variables: Age <10 yr or >40 yr Cause: non-A, non-B hepatitis, halothane hepatitis, or idiosyncratic drug reaction Duration of jaundice before encephalopathy >7 days Prothrombin time >3.5 INR Serum bilirubin level >17.6 mg/dL (301 micromoles/L) INR, international normalized ratio. Adapted from O'Grady et al (6).

A major issue in long-term management of cirrhosis is appropriate timing of referral for transplantation evaluation. Although the major morbidity and mortality in chronic liver disease are related to complications of cirrhosis, well-compensated cirrhosis can remain stable for many years. Fattovich and colleagues (7) reported a 5-year survival probability of 91% in a cohort of 384 cirrhotic patients with hepatitis C. In this study, the predictors of decompensation included age greater than 54 years, presence of stigmata of chronic liver disease, a platelet count below 130 x 10³/microliter, and a bilirubin level greater than 1.0 mg/dL (17 micromoles/L). However, once an index manifestation of decompensation had occurred (eg, variceal hemorrhage, ascites), survival dropped to 50% at 5 years, suggesting that referral for liver transplantation should be considered once an index complication has developed.

Although variceal hemorrhage is the most dramatic and immediately life-threatening presentation of cirrhosis, the onset of ascites or hypoalbuminemia also predicts long-term survival. Thus, the patient with evidence of progression of cirrhosis (table 2) should be offered the option of referral to a transplant hepatologist to obtain an opinion about further management, including liver transplantation. In addition, prevention and management of several other complications of cirrhosis need to be considered (table 3).

Table 2. Biochemical and clinical indications for liver transplantation in chronic liver disease

Cholestatic liver disease Serum bilirubin level >10 mg/dL (171 micromoles/L) Intractable pruritus Progressive bone disease Recurrent bacterial cholangitis Hepatocellular liver disease Serum albumin level <3.0 g/dL Prothrombin time >3 sec above control Both cholestatic and hepatocellular liver disease Recurrent or severe hepatic encephalopathy Refractory ascites Spontaneous bacterial peritonitis Recurrent portal hypertensive bleeding Severe chronic fatigue and weakness Progressive malnutrition Development of hepatorenal syndrome Detection of small hepatocellular carcinoma Adapted from Keefe EB. Selection of patients for liver transplantation. In: Maddrey WC, Sorrell MF, eds. Transplantation of the liver. 2nd ed. Norwalk, Conn: Appleton & Lange, 1995:13-61.

Table 3. Management of compensated cirrhosis

Screening for hepatocellular carcinoma Use of screening endoscopy to detect varices Prophylaxis for bacterial peritonitis Vaccinations Hepatitis A Hepatitis B Influenza Pneumococcal disease Treatment of vitamin deficiencies Screening for and treatment of osteoporosis Management of ascites Screening for and management of diabetes Routine health maintenance

The ideal timing of transplantation for chronic liver disease is when the patient's chance of surviving 1 to 2 years is less than 50% but before the patient has multisystem complications. Once a multisystem failure has occurred, survival after transplantation is only 20% to 30% (8). The prognosis of patients with cirrhosis is currently determined using both disease-specific and non-disease-specific clinical tools. The Child-Turcotte-Pugh score (table 4) has been used most often to assess prognosis in cirrhotic patients. In 1997, a consensus conference of the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases developed uniform minimal listing criteria for transplantation on the basis of a 1-year survival rate of less than 90% for non-disease-specific cirrhosis (9). These criteria include immediate need for a liver transplant, an estimated 1-year survival of less than 90%, a Child-Turcotte-Pugh score of 7 or greater (Child class B or C), and portal hypertensive bleeding or a single episode of spontaneous bacterial peritonitis, regardless of the Child-Turcotte-Pugh score (9).

Survival and outcome for the cholestatic forms of cirrhosis--notably, primary biliary cirrhosis and primary sclerosing cholangitis--are not reliably predicted by the Child-Turcotte-Pugh score and require the use of other criteria for listing. The Mayo prognostic model for primary biliary cirrhosis, which takes into account age, prothrombin time, and bilirubin and albumin levels, and the Mayo risk score for primary sclerosing cholangitis, which uses age, history of variceal bleeding, and levels of bilirubin, aspartate aminotransferase, and albumin, have been shown to predict survival more accurately than the Child-Turcotte-Pugh score. Patients should be listed for liver transplant when their Mayo risk score predicts a survival rate of less than 95% for 1 year.

The liver transplant allocation policy previously used by UNOS defined five categories of patients: status 1, 2A, 2B, 3, and 7. Patient status was based on the patient's Child-Turcotte-Pugh score and waiting time on the transplant list.

In 1998, the US Department of Health and Human Services redefined the policies and principles for organ allocation, whereby equitable organ allocation among transplant candidates was to be based purely on medical urgency--a change that minimizes the importance of waiting time. With this mandate, the Organ Procurement and Transplantation Network (OPTN), along with UNOS, in 2002 endorsed a new system based on the Model for End-Stage Liver Disease (MELD) score for patients who are not status 1 or in fulminant liver failure (see box at the end of this article).

Advances in immunosuppression

Early transplantation immunosuppression regimens consisting of azathioprine (Imuran) and corticosteroids resulted in poor survival of patient and graft. It was the development of more potent immunosuppressive drugs--most notably cyclosporine (Neoral, Sandimmune) and subsequently tacrolimus (Prograf), which target specific components of the immune response--that greatly improved survival rates.

Posttransplantation immunosuppression consists of induction and maintenance medication regimens as well as treatment protocols for acute cellular rejection. The highest risk of acute cellular rejection occurs early in the posttransplant period, so intravenous corticosteroids are used initially and tapered rapidly over several days and oral corticosteroids are used in the long term.

The foundation for maintenance immunosuppression at most transplant centers consists of a calcineurin inhibitor (cyclosporine or tacrolimus) started immediately after surgery and given with corticosteroids. Mycophenolate mofetil (CellCept), an inhibitor of inosine monophosphate dehydrogenase, or azathioprine, an inhibitor of synthesis of DNA and RNA, may be used as an adjuvant agent to permit lower doses of the calcineurin inhibitors in an effort to reduce toxicity (table 5).

In the stable patient, maintenance immunosuppression generally permits lower therapeutic levels of tacrolimus or cyclosporine. Complete withdrawal of oral corticosteroids within 12 months of liver transplantation has become standard in non-autoimmune-mediated liver disease to reduce the risk of recurrent disease, especially in patients who receive a transplant because of chronic viral hepatitis.

Sirolimus (Rapamune) is a newer immunosuppressive agent that is structurally similar to tacrolimus but acts by inhibiting lymphocyte proliferation. In preliminary studies, it appeared less nephrotoxic than tacrolimus, and when used in combination with tacrolimus or cyclosporine, it may allow use of lower levels of the calcineurin inhibitors (10). However, enthusiasm for its use in liver transplantation has been tempered by potentially severe side effects, including delayed wound healing and vascular complications (11). Hence, its role in transplant recipients has been curtailed.

Treatment of acute allograft rejection, which is of most concern in the initial few months after transplantation, requires intravenous corticosteroids in high doses that are tapered over several days. Acute rejection that does not respond to corticosteroids may require higher levels of tacrolimus or the addition of other agents, including mycophenolate mofetil and muromonab-CD3 (Orthoclone OKT3), which is a monoclonal preparation of antibodies directed against CD3 cells. Chronic rejection typically develops later in the posttransplantation course and is characterized by vanishing bile ducts (ductopenia). It may respond to enhanced immunosuppression with tacrolimus but can lead to the need for retransplantation.

Long-term management issues

As the number of liver transplant recipients continues to increase, primary care physicians are playing a larger role in their care. Along with general preventive medicine, primary care management issues specifically related to transplant recipients include obesity, hyperlipidemia, hypertension, diabetes, osteoporosis, and malignancy.

Routine health maintenance as recommended by the US Preventive Services Task Force (12) should be applied to transplant recipients. These measures include annual physical examinations and age-appropriate screening for high cholesterol levels, hypertension, diabetes, and cancer of the breast, colon, and cervix.

Significant weight gain and obesity are common in patients after liver transplantation. Reasons include prednisone use, appetite stimulation by antirejection regimens, an increased sense of well-being after long-term illness and, often, absence of dietary restrictions imposed before transplantation. Appropriate dietary counseling and an exercise program should be initiated in these patients.

Hyperlipidemia characterized by a mixed profile of elevated cholesterol and triglyceride levels is noted in as many as 30% of transplant recipients. Elevated lipid levels may be associated with allograft vasculopathy. The etiology of hyperlipidemia is multifactorial and includes obesity, medication use (eg, sirolimus-induced, cyclosporine inhibition of bile-acid synthesis), and risk factors existing before transplantation. Treatment of hyperlipidemia is the same in transplant recipients as in other patients, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") are safe and well tolerated. However, nicotinic acid, bile acid binders, and fibric acid derivatives are generally avoided because of their potential hepatotoxicity or interference with other medications.

Systemic hypertension is seen in 55% to 85% of patients after liver transplantation, a response that can be attributed partly to the immunosuppressive regimen (13). The prevalence of hypertension increases with length of time from transplantation. In the majority of cases, antihypertensive medication is required, and calcium channel blockers have proved to be effective without significant nephrotoxicity. Use of diltiazem hydrochloride and verapamil hydrochloride may alter cyclosporine and tacrolimus levels. If a calcium channel blocker does not adequately control blood pressure, a beta-blocker, such as labetalol hydrochloride (Normodyne, Trandate), or a centrally acting agent, such as clonidine hydrochloride (Catapres), may be required.

Impaired glucose tolerance and diabetes are common in cirrhotic patients because of peripheral insulin resistance, which predisposes them to posttransplant diabetes. The diabetogenic potential of immunosuppressives is an important exacerbating factor. Treatment of diabetes in transplant recipients is based on the same principles as in patients who have not received a transplant. However, metformin hydrochloride (Glucophage) is best avoided. Side effects of oral hypoglycemic agents, including hepatotoxicity, should be monitored, and a reduction in dosage of calcineurin inhibitors, as well as corticosteroid withdrawal, may be considered by the transplant team.

Osteopenia is often seen in patients with cirrhosis and typically is due to osteoporosis rather than osteomalacia, although the latter can occur in severely cholestatic patients. Factors implicated, apart from calcium and vitamin D deficiency, include low muscle mass, immobility, long-term corticosteroid use, poor nutrition, and alcohol abuse. After transplantation, rapid bone loss occurs in the first 3 to 6 months, but recovery of bone mass can continue for up to 7 years.

For patients awaiting a liver transplant, thyroid function and serum levels of calcium, phosphorus, and parathyroid hormone should be evaluated and bone densitometry performed. In addition to calcium and vitamin D supplementation, use of calcitonin or bisphosphonates may be considered if bone densitometry indicates osteoporosis or if corticosteroids are used in the long term. Once-weekly oral dosing with alendronate sodium (Fosamax) or risendronate sodium (Actonel) is well tolerated and convenient.

Skin cancer, lymphoma, and oropharyngeal cancers may occur more frequently in transplant recipients. Patients who received a transplant because of primary sclerosing cholangitis and have inflammatory bowel disease remain at high risk for colonic dysplasia and colon cancer. Routine examination and screening should be performed regularly.

Patients who received a transplant more than 6 months previously should be vaccinated for influenza, pneumococcal disease, and tetanus. Live vaccines, such as those for measles, mumps, and rubella and the live oral polio vaccine (Orimune), should not be given.

Recurrent disease after transplantation

With improved long-term posttransplant survival, disease recurrence has become more evident. In the early 1990s, hepatitis B recurrence was seen in more than 80% of patients 2 months after transplantation and accounted for 73% of all deaths in patients who received a liver transplant for this indication (14). Effective antiviral prophylaxis with a high dose of hepatitis B immunoglobulin (HBIG), which more recently has been combined with lamivudine (Epivir), has virtually eliminated hepatitis B recurrence (15).

The major challenge in managing patients with hepatitis B virus infection perioperatively is to provide adequate immunoprophylaxis in a cost-effective manner, given the high cost of long-term HBIG use, especially when administered intravenously. Intramuscular HBIG prophylaxis with titration of the dose to the titer of antibody to hepatitis B surface antigen is a strategy being used by some transplant centers to reduce the cost and side effects of intravenous HBIG. Although reinfection rates have been dramatically reduced with HBIG prophylaxis and lamivudine, other issues, such as viral resistance and optimal duration of HBIG therapy, have yet to be resolved.

After transplantation, hepatitis C recurrence is nearly universal, and histologic changes occur in 50% to 80% of patients (16). A recent analysis of the UNOS database (17) showed diminished 5-year survival rates for hepatitis C-positive transplant patients compared with hepatitis C-negative recipients (56.7% versus 65.6%). According to a report from King's College (18), protocol biopsies taken at 5 years after transplantation showed that 20% of patients who received a liver transplant because of hepatitis C infection already had evidence of allograft cirrhosis. This finding indicates an accelerated course compared with that in immunocompetent hosts. Recent data on use of pegylated interferon alfa or combination inter-feron and ribavirin in management of recurrent hepatitis C are promising. Until more is known about host and viral factors that may predispose transplant patients to aggressive recurrent disease, treatment and the timing of its initiation remain undefined.

Recurrence of hepatocellular carcinoma can be minimized by exclusion of high-risk candidates who have features predictive of tumor recurrence, as previously discussed (19). Because of rapid tumor recurrence, cholangiocarcinoma has historically been a contraindication to transplantation. Recent protocols with adjuvant external beam radiation and chemotherapy have shown early promise and may allow carefully selected patients with primary sclerosing cholangitis and cholangiocarcinoma to receive a liver transplant (20).

Graft failure secondary to recurrence of primary sclerosing cholangitis, primary biliary cirrhosis, or autoimmune hepatitis has been observed in a subset of patients, although it develops less often or less rapidly than in viral hepatitis. A report from the Mayo Clinic (21) described recurrence of primary sclerosing cholangitis in 20% of liver transplant recipients. In the majority of patients, recurrent disease was mild, but 8% of patients required retransplantation. Recurrent histologic primary biliary cirrhosis was noted in 8 (9.6%) of 83 patients who received a transplant for this condition, and although clinical disease was typically mild, graft loss has been reported (22).

In one series (23), recurrent autoimmune hepatitis was noted in 13 (27.7%) of 47 patients. Risk of recurrence increased on prednisone withdrawal or with lower immunosuppression. Hence, patients who receive a transplant because of autoimmune liver disease may not tolerate complete prednisone withdrawal.

Retransplantation for recurrent disease is a difficult ethical issue faced by transplant teams in this era of intractable organ shortage. Perioperative risk, survival, and quality of life, as well as the presence of comorbidities such as renal failure related to immunosuppression toxicity, need to be weighed in the decision to perform a retransplantation.

Novel liver replacement strategies

To maximize donor organ access for adult and pediatric patients, novel surgical and liver replacement procedures have been developed. Newer surgical techniques include cadaveric and living-donor split liver transplantation. Liver replacement strategies such as xenotransplantation, hepatocyte transplantation, and bioartificial liver support devices are being evaluated.

Cadaveric split liver transplantation creates two functioning allografts: a left lateral segment (segments II and III) for a child and a right trisegment (segments IV through VIII) for an adult (figure 2). The potential advantage is an increase in the total number of transplants performed from a static cadaveric donor organ supply. Disadvantages include greater technical complexity, longer procurement times, and feasibility in only a subset of donor organs.

Living-donor transplantation was initially performed in pediatric patients and used an adult donor's left lateral segment. Access to living-donor liver transplantation had a dramatic impact on reducing mortality in the pediatric transplant waiting list, and excellent recipient and graft survival results were reported.

Living-donor liver transplantation in adults is an even more technically challenging endeavor. An adult requires a greater volume of the donor organ, making the left lateral portion inadequate; generally, donor liver volume must equal about 1% of recipient body weight. Currently, the right lobe (segments V through VIII), the extended right lobe (segments IV through VIII), or the left lobe (segments II through IV) is used for living-donor transplants in adults. Right-lobe grafts are most commonly used, extended right-lobe grafts are occasionally used to ensure adequate liver volume, and left-lobe grafts can be used for patients who weigh less than 60 kg (132 lb).

A living-donor candidate is extensively evaluated, as outlined in table 6. Histologic abnormalities, often not detectable on routine biochemical and serologic testing, may be evaluated by liver biopsy. Our findings on biopsies of 56 living-donor candidates showed that 17 (30%) had steatosis, 4 (7%) had chronic hepatitis, and 5 (9%) had granulomas (24). Thus, liver biopsy should be considered as part of donor evaluation. In one center, after complete evaluation, only 15 of 100 living-donor candidates underwent the transplantation procedure (25).

Table 6. Evaluation of living-donor candidates for liver transplantation

Blood group compatibility Comprehensive history taking and physical examination Routine laboratory studies, including viral serologies and HIV test Anatomical imaging Liver volume Vascular anatomy Biliary anatomy Pulmonary function tests Cardiac clearance Psychosocial evaluation Life circumstances Motivation Understanding Independent advocate's opinion Review of candidacy with prospective donor Presentation to selection committee

Advantages of living-donor transplantation include expansion of the donor pool, ability to assess graft quality before transplantation, and elective transplantation before significant debilitation of the recipient. Disadvantages are that living-donor transplantation requires greater technical skill in surgery and exposes the donor to the morbidity and mortality of major abdominal surgery. Donor morbidity is estimated to be 10% to 20%; major complications are biliary leaks, gastrointestinal complications, and vascular injury. Donor mortality is estimated to be between 0.2% and 1% (26). Patients with small hepatocellular carcinomas and those with primary sclerosing cholangitis who are at risk for cholangiocarcinoma may particularly benefit from timely living-donor transplantation.

The major obstacles to xenotransplantation, or cross-species transplantation, are the potential spread of infection from the donor animal to the human recipient and hyperacute and vascular rejection resulting from the immunologic response of the human recipient. Pig and baboon livers have been transplanted with very limited success; future genetic engineering of a chimeric transgenic animal may make long-term xenograft function a reality.

Attempts to use hepatocytes harvested from human or animal livers to treat metabolic liver disorders, acute liver failure, and hepatic encephalopathy have shown only modest success because of problems with cell viability and engraftment. Hepatocyte transplantation appears to be a promising direction for future development and may play a crucial role as both a method of gene transfer and a treatment option for acute and chronic liver disease.

Liver support devices, including the bioartificial liver and the extracorporeal liver-assist device, are hybrid mechanical systems that perfuse blood or plasma through a hepatocyte-containing device to remove cytotoxic elements. Both of these systems have undergone phase 1 clinical evaluation with mixed success.

Comment

The major factor limiting the use of liver transplantation is donor shortage. Although the availability of living-donor organs has improved access for patients awaiting a liver transplant, the allocation of cadaveric donor organs will remain a controversial issue unless the donor pool can be greatly expanded.

References

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9. Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transpl Surg 1997;3(6):628-37
10. Watson CJ, Friend PJ, Jamieson NV, et al. Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 1999;67(4):505-9
11. Trotter JF. Sirolimus in liver transplantation. Transplant Proc 2003;35(3 Suppl):193-200S
12. US Department of Health and Human Services. Guide to clinical preventive services: report of the US Preventive Services Task Force. 2nd ed. Baltimore: Williams & Wilkins, 1996
13. Textor SC, Canzanello VJ, Taler SJ, et al. Hypertension after transplantation. Liver Transpl Surg 1995;1(5 Suppl 1):20-8
14. Todo S, Demetris AJ, Van Thiel D, et al. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease. Hepatology 1991;13(4):619-26
15. Markowitz JS, Martin P, Conrad AJ, et al. Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatology 1998;28(2):585-9
16. Fukumoto T, Berg T, Ku Y, et al. Viral dynamics of hepatitis C early after orthotopic liver transplantation: evidence for rapid turnover of serum virions. Hepatology 1996;24(6):1351-4
17. Forman LM, Lewis JD, Berlin JA, et al. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122(4):889-96
18. Gane EJ, Portmann BC, Naoumov NV, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med 1996;334(13):815-20
19. Marsh JW, Dvorchik I, Subotin M, et al. The prediction of risk of recurrence and time to recurrence of hepatocellular carcinoma after orthotopic liver transplantation: a pilot study. Hepatology 1997;26(2):444-50
20. De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl 2000;6(3):309-16
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The Model for End-Stage Liver Disease (MELD) score for estimating survival The MELD score was originally developed to assess the prognosis of patients with cirrhosis who were undergoing a transjugular intrahepatic portosystemic shunt procedure (1). The score has been validated to provide, over a wide range of disease severity and etiology, a reliable estimate of short-term survival in patients with end-stage liver disease who are awaiting liver transplantation. The formula for the MELD score and 3-month mortality data are available on the Internet at http://www.mayoclinic.org/gi-rst/mayomodel.shtml. The MELD score offers the advantage of using only objective parameters. In contrast, the Child-Turcotte-Pugh score incorporates the presence of hepatic encephalopathy and ascites, which are prone to observer error. Analysis of the impact of the switch to the MELD score on deaths of patients on the waiting list, early survival of patient and graft, and waiting list registrations was recently reported by Freeman and associates (2). The investigators noted a 3.5% reduction in deaths while on the waiting list, unchanged early graft and patient survival as compared with the previous allocation system, and a 12% reduction in the number of newly listed patients (mainly in patients with low MELD scores). References Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33(2):473-5 Freeman RB, Wiesner RH, Edwards E, et al. Results of the first year of the new liver allocation plan. Liver Transpl 2004;10(1):7-15

Dr Tran is assistant professor of medicine, Dr Nissen is assistant professor of surgery, Dr Poordad is assistant professor of medicine, and Dr Martin is professor of medicine, University of California, Los Angeles, David Geffen School of Medicine at UCLA. In addition, Dr Tran is assistant director, Dr Nissen is assistant surgical director, Dr Poordad is associate director, and Dr Martin is medical director, liver transplant program, Cedars-Sinai Medical Center, Los Angeles. Correspondence: Paul Martin, MD, Liver Transplant Program, Cedars-Sinai Medical Center, 8635 W Third St, Suite 590W, Los Angeles, CA 90048. E-mail: martinpx@cshs.org.

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