I s t h e Pa t i e n t a Ca n d i d a t e f o r L i v e r Tra n s p l a n t a t i o n ?

Alyson N. Fox,
KEYWORDS  Liver failure  Transplantation  Hepatic decompensation  Liver disease  Transplant evaluation
MD, MSCE
a,b,

*, Robert S. Brown Jr,

MD, MPH

a,c

Liver transplantation provides a lifesaving alternative to medical therapy for patients with a variety of liver diseases. The goal of liver transplantation is to prolong both the length and quality of life in a recipient. The major indications for liver transplantation include acute and irreversible liver failure, hepatic decompensation caused by chronic liver disease, primary hepatic malignancy, and metabolic disorders. Both the number of patients listed for liver transplantation and the number of liver transplants performed in the United States continues to grow annually. In 2010, approximately 11,350 patients were added to the national liver transplant waiting list and approximately 6000 were removed because of receipt of a deceased or living-donor transplant.1 Despite growing numbers of patients listed for liver transplantation and the ability to successfully perform liver transplants, the availability of donor organs remains limited. Consideration for liver transplant involves a rigorous evaluation process that is time consuming, expensive, and potentially dangerous when it includes invasive testing. With donor organs remaining a scarce resource and the process of transplant evaluation being so complex, it is critical to distinguish the patients who will most benefit from transplantation.
HISTORICAL PERSPECTIVE

In the last 50 years, liver transplantation has emerged as a life-prolonging technique for patients suffering from end-stage liver disease. The first liver transplant was performed in 1963, but it was not until the 1980s that liver transplantation became a common procedure. Advances in surgical technique, immunosuppressive medications, and prevention of postoperative infections allowed liver transplantation to

Center for Liver Disease and Transplantation, New York Presbyterian Hospital, New York, NY, USA; b Weill Cornell Medical Center, 1305 York Avenue New York, NY 10021, USA; c Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032, USA * Corresponding author. Weill Cornell Medical Center, 1305 York Avenue New York, NY 10021, USA. E-mail address: alf9011@med.cornell.edu Clin Liver Dis 16 (2012) 435448 doi:10.1016/j.cld.2012.03.014 1089-3261/12/$ see front matter 2012 Elsevier Inc. All rights reserved. liver.theclinics.com

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become a life-sustaining possibility.2 During the past 20 years, the expertise with transplant surgery and transplant medicine has evolved to the point at which there are currently more than 6000 liver transplants performed annually in the United States.
DETERMINING THE SEVERITY OF ILLNESS AND ORGAN ALLOCATION: FROM CHILDTURCOTTE-PUGH TO THE MODEL FOR END-STAGE LIVER DISEASE SCORE

A key concept in deciding whether a patient is an appropriate candidate for transplantation is determining the severity of illness as it relates to prognosis. In those under consideration for transplantation because of chronic liver diseases, the ChildTurcotte-Pugh (CTP) score and the Model for End-Stage Liver Disease (MELD) score have been instrumental in helping clinicians gauge mortality risk and necessity of transplantation. The CTP score takes into account the presence of hepatic encephalopathy, ascites, the serum bilirubin, albumin, and increase in prothrombin time to more than the control values.3 Between 1 and 3 points are assigned for each degree of variation among these 5 parameters and, based on the total number of points assigned, an individual is classified as class A (56), B (79), or C (1015). Child class A represents compensated disease with better prognosis and class C represents severely decompensated disease with poor prognosis. Before 2002, the CTP score was used to grade severity of illness and prioritization for the liver transplant waiting list. Under this system, patients were listed for liver transplantation using a status code (1, 2a, 2b, 3) based on their CTP class and whether they were at home, in the hospital, or in the intensive care unit. Priority was given to the patients with longer waiting time within each status. Because each status was broad, there were many patients in each group and thus waiting time was a significant driver of transplant priority. Thus, under this system, it was common for available organs to go to people whose liver disease was less decompensated (eg, a Child-Pugh score of 11 vs 14) if they had been on the waiting list longer. A more severity-based system was clearly needed. In addition, because the CTP score incorporates subjective data into its calculation (ie, ascites and encephalopathy), a more objective disease severity index was sought to make the system more reproducible between centers. The MELD score is a mathematically derived score based on measurement of the serum bilirubin, International Normalization Ratio, and creatinine. Because its calculation is based on biochemical parameters that are increased in the presence of liver disease, the MELD score increases concomitantly with increasing severity of liver disease. The MELD scoring system was initially developed to predict survival after elective transjugular intrahepatic shunt placement in patients with end-stage liver disease.4 It was later validated to predict survival in those with advanced liver disease, including those on the transplant waiting list, and in February 2002 was adopted by the United Network for Organ Sharing (UNOS) as the preferred scoring system for organ allocation.5 In this system, waiting time is deemphasized because it is not carried forward as the MELD increases and is only used to break ties at a given MELD score. The cornerstone of MELD-based allocation ensures that those with the highest scores (the sickest patients) receive organs first despite competing factors such as cause of liver disease or list waiting time. After the introduction of the MELD allocation system, analyses of list dynamics revealed a decreased waiting time, decreased list size (6% reduction), decreased list registration (12% reduction between February 2002 and February 2003), and increased rates of transplantation (6% increase).6,7 It also reduced waiting list mortality without adversely affecting posttransplant survival, thus increasing the survival benefit of transplantation. Based on these results, the

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implementation of the MELD system has objectively improved the state of liver transplantation in the United States.
WHO BENEFITS FROM LIVER TRANSPLANTATION?

Simply stated, a patient needs to be sick enough to derive a benefit from transplantation, but well enough to survive a complex surgical procedure. During its advanced stages, cirrhosis is associated with a high rate of morbidity and mortality. After experiencing a first decompensation event (Box 1), prognosis is poor.8 Thus, expectant medical management of those with cirrhosis in an attempt to prevent complications is paramount. A higher MELD score connotes more severe illness, and the MELD score is known to accurately predict 3-month mortality in those awaiting transplantation.9 It is therefore reasonable that those whose mortality without a transplant exceeds mortality with a transplant are the ideal candidates for transplantation. A pivotal study by Merion and colleagues10 helped to better define the survival benefit of liver transplantation. By comparing the mortality between those listed and those transplanted, the investigators were able to show that, at low MELD scores, undergoing transplantation is associated with a significant risk of death. A MELD score of 15 to 17 represented a transition point beyond which there was a survival benefit at 1 year observed with transplantation. With a longer time horizon (35 years), all but those with a MELD score less than 10 benefit from transplantation.
MINIMAL LISTING CRITERIA

Before the implementation of the MELD score as the method of liver allocation, the liver transplant community held a meeting in 1997 to compose minimal listing criteria for transplantation. It was determined that listed patients should have a predicted 1year survival rate without transplantation of 90% or less. Based on the published data at the time, the patient cohort meeting these criteria were those patients with Child-Pugh scores of 7 or greater.11 In December of 2003, another meeting was held to analyze the patterns in organ allocation after the first 18 months of MELDbased allocation.12 Among the topics discussed was the issue of minimum listing criteria. With the practice of minimum listing as CTP score greater than or equal to 7, a considerable percentage of patients meeting the criteria had low MELD scores. At that time, Organ Procurement and Transplantation Network (OPTN) data indicated that approximately 17% of transplants were occurring in those with MELD scores of 7 to 15 at the time of removal from the list. However, there was great variability based on

Box 1 Complications of liver disease warranting transplant evaluation Refractory ascites Hepatic encephalopathy Portal hypertensive bleeding Hepatocellular malignancy Pruritus Recurrent cholangitis Hepatopulmonary syndrome Portopulmonary hypertension

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region. Although the group recognized that the 18-month data suggested that there were likely sufficient data to support the establishment of a minimal listing MELD score, no such criteria were established. Despite the lack of national guidelines on this issue, many centers have established a MELD cut point, at less than which they consider patients too early for transplant consideration. However the MELD score may not accurately portray an individual patients severity of illness because the MELD score lacks subjective information that can strongly affect quality of life, particularly complications of portal hypertension. In cases in which the calculated MELD is low but the patient has severe encephalopathy, uncontrolled ascites, or frequent gastrointestinal bleeding, consideration is typically given to listing despite a low MELD score. The American Association for the Study of Liver Diseases (AASLD) guidelines recommend that patients with cirrhosis should be referred for transplant evaluation when they develop a decompensation or when they reach a CTP score of greater than or equal to 7 or MELD score greater than or equal to 10.13
THE EVALUATION PROCESS

The evaluation process for liver transplantation seeks to define the patients who will obtain the most benefit from transplantation, have the best chance for postoperative recovery and survival, and who will be good stewards for the limited resource (the organ graft) they receive.14 The process involves intense medical, psychiatric, social, and financial screening to identify those who might have contraindications to solid organ transplantation (Table 1). Once the screening is completed, a committee, usually composed of hepatologists, transplants surgeons, transplant coordinators, psychiatrists, and social workers, convenes to determine who is most appropriate for listing based on both objective and subjective measures. When a person is deemed suitable for transplantation, they are placed on the national UNOS waiting list.
INDICATIONS FOR LIVER TRANSPLANTATION AND SPECIAL CONSIDERATIONS BY DIAGNOSIS Hepatitis C

Cirrhosis caused by chronic hepatitis C infection remains the leading indication for liver transplantation in the United States (Fig. 1, Table 2). Without curative treatment before transplantation, nearly all grafts become reinfected immediately after transplantation.15 In the posttransplant setting, hepatitis C virus (HCV) infection seems to be accelerated, such that those transplanted for HCV experience high rates of graft dysfunction and loss with decreased survival compared with those transplanted for other indications.16,17 To prevent graft compromise, consideration should be given to treating those with compensated disease who are awaiting transplantation with modified interferon and ribavirin dosing, especially if the genotype is favorable.18 This strategy may be helpful to prevent graft infection; however, treatment in this setting may be poorly tolerated. Once transplantation has occurred, consideration should be given to antiviral therapy, although it is associated with its own set of unique challenges in the posttransplantation setting.
Hepatitis B

Before the use of hepatitis B immune globulin (HBIG) as immunoprophylaxis after transplantation for chronic hepatitis B, recurrence of hepatitis B virus (HBV) in the liver allograft occurred in up to 80%, and was usually complicated by graft dysfunction and death. Because of these outcomes, HBV was initially viewed as a contraindication to

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Table 1 Components of evaluation for liver transplantation Medical evaluation Review of medical records History and physical examination by transplant hepatologist and transplant surgeon Electrolytes, liver function tests, complete blood count, coagulation studies, hepatitis serologies, markers for autoimmune, inherited and metabolic liver diseases, blood typing with antibody screen, RPR, EBV, CMV, HIV testing, thyroid function studies Abdominal sonogram with Doppler evaluation Contrast-enhanced abdominal imaging Bone density scan CT scan of the chest (if HCC) Electrocardiogram Echocardiogram (with agitated saline injection) Nuclear stress test (if age >45 y or cardiac risk factors are present) Coronary catheterization (if stress test is abnormal or high risk for cardiac disease) Right heart catheterization (if increased pulmonary pressures on noninvasive studies) Cardiology consultation PPD testing Chest radiograph Pulmonary function testing Room air arterial blood gas Shunt fraction study if evidence of intrapulmonary shunt Pulmonary consultation Carotid Doppler if age >60 y Neuroimaging and neurology consultation if history of neurologic disorder PAP smear Mammogram Colonoscopy PSA Psychiatry consultation Social work consultation Financial counselor consultation Nutritionist consultation

Laboratory evaluation

Radiology

Cardiac evaluation

Pulmonary evaluation

Neurologic evaluation

Age-appropriate cancer screening

Psychosocial evaluation

Abbreviations: CMV, cytomegalovirus; CT, computed tomography; EBV, Epstein-Barr virus; HCC, hepatocellular carcinoma; HIV, human immunodeficiency virus; PAP, Papanicolaou; PPD, purified protein derivative; PSA, prostate-specific antigen; RPR, rapid plasma reagin.

transplantation. Control of the virus before transplantation is critical in preventing graft reinfection. With the availability of antiviral medications with a high genetic barrier to resistance, suppression of the virus before transplantation is feasible. The combination of HBIG with oral antivirals has allowed HBV-infected patients to go from having the poorest posttransplantation outcomes to having survival rates among the best of all transplant recipients.19 With the use of HBIG and oral nucleos(t)ide therapy, the 5year graft survival for those transplanted for HBV is 85% and retransplantation for recurrent HBV cirrhosis is rare.

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Fig. 1. Distribution of Diagnoses US Waitlist Characteristics, 2008. (Courtesy of the US Department of Health and Human Services. Available at: http://optn.transplant.hrsa.gov.)

Alcohol-related Liver Disease

Alcohol-related liver disease is the most common cause of cirrhosis in the United States. Despite this, it is not the leading indication for transplantation, because active alcohol use represents an absolute contraindication to transplantation, and because, in those with decompensation caused by alcohol-related liver disease, abstinence can reverse the severity of illness such that transplantation may be avoided. In those with a history of excessive alcohol use, most centers require a period of documented abstinence before consideration of transplantation. Typically, many centers require this period to be at least 6 months in duration.20 Although a time frame of 6 months is not based on rigorous well-controlled data, it is known that longer abstinence periods predict lower rates of alcohol recidivism. In addition, the rationale behind a 6-month sobriety period is that 6 months may be adequate time to allow for hepatic recovery if the alcoholic injury is reversible with abstinence, which could prevent an unnecessary transplant in a patient who will recover without the need for transplantation. This period also allows those at risk for return to drinking to be identified and allows intensive therapy and counseling. In those who can achieve the period of abstinence, a transplant team may rely heavily on a social worker, counselor, or psychiatry consultant and a structured rehabilitation program to maximize the likelihood of a successful intervention. Although recidivism after transplantation is common (w30%), problem drinking is rare, and recurrent alcohol use rarely causes significant graft dysfunction and is not associated with decreased survival.21
Cholestatic Liver Disease

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the 2 adultonset cholestatic disorders that commonly lead to end-stage liver disease requiring transplantation. PBC is associated with all of the complications typical of cirrhosis and, in addition, patients may suffer from xanthelasma, metabolic bone disease, and intractable pruritus. The pruritus that accompanies PBC can be so detrimental to quality of life that additional MELD exception points can be assigned when the native MELD score is low. The Mayo Risk Score is a model developed in the late 1980s that incorporates patient age, total bilirubin, serum albumin, prothrombin time, and severity of edema to predict survival in patients with PBC.22 Although this

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Table 2 Medical conditions for which liver transplantation is indicated Viral Autoimmune liver disease Alcohol-related liver disease Inherited/metabolic liver diseases Hepatitis C Hepatitis B Hereditary hemochromatosis a-1-Antitrypsin deficiency Wilson disease Nonalcoholic fatty liver disease Tyrosinemia Type IV glycogen storage disease Neonatal hemochromatosis Amyloidosis Hyperoxaluria Urea cycle defects Amino acid defects Primary biliary cirrhosis Primary sclerosing cholangitis Biliary atresia Alagille syndrome Progressive familial intrahepatic cholestasis Cystic fibrosis Bile duct loss Hepatocellular carcinoma Cholangiocarcinoma Fibrolamellar carcinoma Epithelioid hemangioendothelioma Hepatoblastoma Metastatic neuroendocrine tumor Budd-Chiari syndrome

Cholestatic liver disease

Malignancy

Polycystic liver disease Vascular disorder Fulminant hepatic failure Retransplantation

risk score is not used as an allocation tool for transplantation, it can be helpful to predict which patients should be considered for transplant evaluation. Based on the minimal listing criteria mentioned earlier, it has been suggested that patients with a Mayo Risk Score that denotes greater than 10% 1-year mortality risk should be sent for transplant evaluation.11 Outcomes of transplantation for PBC are good, with survival rates at 1 year, 5 years, and 10 years of 83%, 78%, and 67% respectively.23 Compared with those not undergoing transplantation, the survival benefit of transplantation for PBC is clear. PBC is a condition that can recur after transplantation, but it is unclear whether or not this affects survival.23 Severity of illness from PSC has also been modeled with a Mayo Risk Score by using age, bilirubin, albumin, aspartate aminotransferase, and history of variceal bleeding to determine survival.24 Patients with PSC are another group who may be at a disadvantage for transplantation with MELD-based allocation. PSC can be associated with recurrent bouts of cholangitis and those episodes can be used to petition for MELD exception points as a way to augment the native MELD score. Because up to 90% of those with PSC may be affected by inflammatory bowel disease (IBD) and the

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risk of developing colorectal neoplasia in those with PSC is even greater than with IBD alone, it is critical that these patients undergo routine endoscopy before and after transplantation to detect gastrointestinal malignancy.25
Inherited/Metabolic Liver Disease

a-1-Antitrypsin deficiency, hereditary hemochromatosis, Wilson disease, and nonalcoholic fatty liver disease (NAFLD) are all causes of cirrhosis and can lead to endstage liver disease. This cluster of diseases is marked by systemic involvement that can occasionally preclude safe liver transplantation. a-1-Antitrypsin deficiency is a cause of panlobular pulmonary emphysema and liver disease in those with the PiZZ phenotype. Both acute and chronic liver disease can develop in childhood or adulthood. In adults, liver disease typically does not present until the fifth decade. Because of the coexistent lung disease seen in this condition, a thorough pulmonary evaluation should be mandated during transplant evaluation. Both adult and pediatric patients undergoing liver transplantation for a-1-antitrypsin deficiency have excellent outcomes with 1-year, 3-year, and 5-year survival reported at 89%, 85%, and 83% respectively for adults and 92%, 90%, and 90% in children.26 Hereditary hemochromatosis (HH) is a disorder of iron overload that results in hepatic damage and cirrhosis. Survival after transplantation for HH is low compared with other causes, with 1-year, 3-year, and 5-year survival rates of 64%, 48%, and 34%.27 These low survival rates may be attributed to increased rates of infectious and cardiac complications seen in this population.28,29 It is therefore critical that patients with HH undergo a rigorous cardiac assessment before transplantation to identify potential problems. Wilson disease is a rare disorder that results in abnormal copper accumulation in the liver, brain, and eye. Patients with this disorder can present with either chronic liver disease or an acute fulminant disease. Liver transplantation in the fulminant setting universally requires transplantation, because most patients do not recover hepatic function. Survival after transplantation is excellent, with one series showing 1-year, 3-year, and 5-year survival at 89.1%, 82.9%, and 75.6%, respectively.30 Because neuropsychiatric symptoms are found in one-third of patients with Wilson disease, it is important to have both a comprehensive neurologic and psychiatric assessment before transplantation, because patients with neuropsychiatric symptoms can have decreased survival after transplantation.30 A diagnosis of NAFLD accounted for 1.2% of liver transplants in 2001 and has risen steadily such that, in 2009, it accounted for 9.7% of all transplants.31 Survival after transplantation is comparable with survival for other indications. Because NAFLD is associated with the metabolic syndrome, it is crucial to carefully screen patients for conditions such as cardiovascular disease, renal disease, insulin resistance, and hyperlipidemia during the transplant evaluation, because these conditions are associated with an independent risk of mortality.
Autoimmune Liver Disease

Autoimmune hepatitis that is unrecognized or unresponsive to treatment can develop into progressive liver disease resulting in cirrhosis and decompensation. Liver transplant outcomes for autoimmune liver disease are favorable; however, age at transplantation greater than 50 years has been associated with impaired survival.32 After surgery, episodes of acute cellular rejection are more common in those with autoimmune liver disease.33 Because autoantibodies persist after transplantation, recurrent disease is known to occur and, although usually treatable with augmentation of immunosuppression, can lead to progressive graft dysfunction and affect survival.34,35

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Vascular Disorders of the Liver

Disorders such as Budd-Chiari syndrome or sinusoidal obstruction syndrome (formerly known as veno-occlusive disease) can result in liver failure when they occur rapidly. Although shunt procedures can be temporizing, many patents have progressive liver disease and require transplantation. Because most patients with Budd-Chiari syndrome have underlying hematologic disorders, they can be at risk for recurrent thrombosis despite transplantation and usually require lifelong anticoagulation. Transplant survival outcomes vary, with some groups reporting 5-year survival of 65% and some reporting better rates at 88%.36,37 Aggressive anticoagulation therapy after transplantation may decrease thrombotic complications and enhance survival.
Fulminant Hepatic Failure

Fulminant hepatic failure (FHF) is the rapid development of encephalopathy, coagulopathy, and jaundice in someone without known preexisting liver disease. Acetaminophen toxicity accounts for approximately half of all causes of FHF in the United States.38 Patients can rapidly progress to a state of critical illness. Patients with this condition from any cause should be referred for liver transplant evaluation emergently, because these cases are best managed at a transplant center with expertise in dealing with the complications of FHF. Although some patents recover hepatic function, some causes of FHF are uniformly fatal if transplantation does not occur. There are several tools to help predict which patients will recover and which will ultimately require transplantation, such as the Kings College Criteria, Clichy Criteria, and, more recently, the MELD score.3942 Patients with FHF are given a special UNOS status 1, which gives them priority over all forms of chronic liver disease. This status allows rapid transplantation before developing cerebral edema. Although these prognostic models can be helpful, clinical judgment should take precedence. Transplant outcomes for FHF are excellent, and exceed outcomes for those transplanted for chronic liver diseases.43 Transplants for FHF account for less than 10% of all transplants done annually in the United States.
Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) has become an increasingly important indication for liver transplantation. A landmark study by Mazzaferro and colleagues44 showed that the 4-year survival after transplantation was 75% and the recurrence-free survival was 83% if the intrahepatic tumors were of a certain size and quantity, termed the Milan Criteria (1 lesion 5 cm, or 23 lesions each 3 cm). Patients diagnosed with HCC who are within the Milan Criteria are automatically assigned a MELD priority score of 22. This score increases every 3 months until the patient is either offered a liver, suffers a complication, or until they progress beyond the Milan Criteria. Frequently, these patients have low calculated MELD scores and exception points afford them the chance to be competitive for liver allocation before their malignancy worsens, which would preclude them from transplantation. When patients listed with HCC exception scores of 22 or higher are compared with the cohort of patients with calculated MELD scores in the same range, the patients with HCC have higher rates of transplantation, lower rates of dropout, and receive livers more rapidly once listed.45 All patients with HCC confined to the liver should be evaluated for transplantation, because there are increasing options for those with tumors that exceed the Milan Criteria. It has been shown that extending the size limits beyond the Milan Criteria may be possible without sacrificing survival outcome.46 However, these patients are

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not given additional MELD priority and it can be difficult to access a deceased donor graft. Likewise, tumors beyond the Milan Criteria may be eligible for downstaging with the ultimate goal of transplantation.47 Patients successfully downstaged to within the Milan Criteria can petition for MELD exception points.
Cholangiocarcinoma

Early experience with liver transplantation for cholangiocarcinoma (CCA) was associated with high recurrence rates and poor survival.48 Only recently, under a specific protocol requiring neoadjuvant chemotherapy and radiation (either external beam or brachytherapy), have patients with stage I and II hilar CCAs achieved 1-year, 3-year, and 5-year survival rates of 92%, 82%, and 82%.49 Currently, only select US centers offer transplantation for CCA under these highly specialized protocols with high rates of dropout on the waiting list. However, early referral to one of those centers for transplant consideration is warranted in those with limited stage disease.
CONTRAINDICATIONS TO LIVER TRANSPLANTATION

The contraindications for liver transplantation are divided into those that are absolute and those that represent relative contraindications (Table 3). In general, contraindications are factors that either make the surgical risk prohibitive or the likelihood of longterm survival or quality of life after transplantation low.
Absolute Contraindications

Because the goal of liver transplantation is to prolong survival, it is critical to select recipients who have an acceptable chance of survival during and after transplantation. On its own, end-stage liver disease can be debilitating and can cause severe systemic illness. It is therefore crucial to exclude those who have a high mortality resulting from conditions other than liver disease. Severe cardiopulmonary disease or other severe comorbidities pose a risk that is independent of liver disease. Patients with such conditions are at high risk from operative and postoperative death. Transplantation is contraindicated in those with uncontrolled hepatocellular carcinoma, because rates of recurrence are high. For those with extrahepatic malignancies, most centers require low projected 5-year rates of recurrence, and some a period of recurrence-free survival, before transplantation. Once on immunosuppression after transplantation, patients are at a higher risk for developing de novo malignancy and may be at increased risk for recurrent malignancy.50
Table 3 Contraindications to liver transplantation Absolute Contraindications to Transplant Severe cardiopulmonary disease Other outstanding comorbidity Hepatic malignancy with vascular invasion or beyond transplantable criterion Extrahepatic malignancy Active infection Relative Contraindications to Transplant Advanced age Obesity Psychiatric disease

HIV infection Surgical challenges: prior extensive intraabdominal surgeries, extensive vascular thrombosis

Active substance abuse Poor psychosocial support Poor compliance

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Active, uncontrolled infection, particularly with resistant bacteria or fungi, at the time of transplantation is associated with poor survival. Psychosocial contraindications to transplantation are as important as medical contraindications. Patients being considered for transplantation need to have an adequate psychosocial support system, because the medical illness and transplantation process can be stressful. In addition, a care partner other than the medical team is necessary to provide care and support during the postoperative period. Because many patients with liver disease have a history of significant substance abuse, strict abstinence from addictive drugs and alcohol is of paramount importance. Abuse of any substance, even legal prescription drugs, is prohibited. Some centers require abstinence from smoking cigarettes as well. In addition, poor compliance with medical advice and instructions represents a contraindication to transplantation. Because organs represent a scarce resource, it is critical that recipients adhere to immunosuppression regimens and, most often, pretransplant behaviors portend posttransplant behaviors.
Relative Contraindications

Relative contraindications to transplantation are often not based on data and can vary widely from center to center. Relative contraindications can sometimes be corrected. The evaluation of patients with advanced age is commonly faced by most transplant centers. As the population ages, many older individuals present with indications for transplantation. Although no firm age cutoff exists, there is heightened concern to transplanting patients older than 70 years, because mortality and risk for malignancy are higher. More important perhaps than chronologic age is physiologic age, which is relevant when examining patients overall risk and benefit from transplant. Obesity is a growing epidemic and many patients seen for liver transplant evaluation are overweight or obese by body mass index (BMI) classification. Analysis has shown that the 1-year and 2-year mortality after transplantation are significantly higher in those with morbid obesity, and 5-year mortality was significantly higher both in those defined as severely obese and morbidly obese, owing to increased adverse cardiovascular events.51 Based on these data, many centers have established BMI criteria for listing. A history of psychiatric disease is not a firm contraindication for transplantation, but those with preexisting psychiatric illness need to be under the care of a mental health professional and have their disease well controlled before being considered for transplantation. Human immunodeficiency virus (HIV) infection was previously considered an absolute contraindication to transplantation, because there was great concern about the tolerability of combined effect of viral and medication-induced immune suppression. With the advent of highly active antiretroviral (HAART) medications, liver transplantation in the HIV population has become an acceptable procedure. In the last decade, transplantation of HIV-positive patients has become increasingly prevalent, although total numbers still remain low (0.3% of total liver transplants in the United States between 1999 and 2008).52 Although cutoff values for CD4 count targets may vary between centers, it is generally accepted that the HIV viral load should be fully suppressed. Disease-specific issues such as multidrug-resistant disease, opportunistic infection, and HIV-associated malignancies or wasting still represent contraindications to transplantation. Patients with HIV should be referred to a transplant center with expertise in managing the specific issues related to the management of HIV infection both before and after transplantation. In addition, complicated surgical anatomy can represent a relative contraindication to transplantation. Those with prior abdominal surgeries and with extensive portal/

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mesenteric vascular thromboses can present a considerable surgical challenge. Contrast-enhanced cross-sectional imaging studies can be valuable in providing a road map and may facilitate anticipation of using vascular grafts or alternative techniques. Close evaluation by the transplanting surgeon is advised.
Delisting

Despite extensive work-up before transplantation, those affected by complications related to cirrhosis or end-stage liver disease often have a complicated course. Once listed for transplantation, patients should be regularly evaluated by the transplant team to assess for changes in their medical and psychosocial circumstances. As with fulminant liver failure, many potential recipients improve and do not require transplantation. In some, the condition worsens to the point at which the risk of transplantation outweighs the benefit. In the latter group, consideration should be given to temporary or permanent delisting.
SUMMARY

Identifying whether someone is a good candidate for liver transplantation is a complex process that requires a team approach. There are several medical and psychosocial considerations involved, each of which is thoroughly explored during the evaluation process. Both the indications and contraindications to transplant can change over time, reflecting advances in understanding of and ability to treat certain disease processes. Ultimately, the goal of liver transplantation remains to provide a survival benefit to those with acute or chronic liver diseases.
REFERENCES

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