AASLD practice guidelines: Evaluation of the patient for liver transplantation
Authors: Karen F. Murray, Robert L. Carithers
Journal: Hepatology (2005)

These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic [Medline search]; (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the AGA Policy Statement on Guidelines2; (4) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a category to be assigned and reported with each recommendation (Table 1).3 These recommendations are fully endorsed by the AASLD and the American Society of Transplantation. AASLD, American Association for the Study of Liver Diseases; MELD, model for end-stage liver disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; CTP, Child-Turcotte-Pugh; PELD, pediatric end-stage liver disease; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HCC, hepatocellular carcinoma; HPS, hepatopulmonary syndrome; NASH, nonalcoholic steatohepatitis. Liver transplantation has had a profound impact on the care of patients with end-stage liver disease and is the most effective treatment for many patients with acute or chronic liver failure resulting from a variety of causes. Before transplantation, patients with advanced liver disease usually died within months to years. These patients now have the opportunity for extended survival with excellent quality of life after liver transplantation.4 Furthermore, the costs of liver transplants have steadily declined in recent years.5 Most liver transplants are performed using a whole liver from a deceased donor. During transplantation, the donor liver is placed in the orthotopic position, hence the term orthotopic liver transplantation. However, because of the unique anatomical organization of the liver, donor organs can be divided and the separate parts transplanted into two recipients (split liver transplantation).6 Using this technique, a portion of the left lobe of an adult donor organ can be transplanted into a child and the remaining portion used to transplant the liver into an adult.7-10 Under ideal circumstances, a deceased donor organ also can be split and transplanted into two adult recipients.10 The same surgical techniques can be used to facilitate transplantation using living donors, where only a portion of the donor liver is removed for transplantation. Living donor transplantation for children, using a portion of the left lobe, is a well-established procedure.7, 8 Living donor transplantation for adults, in which the donor right lobe typically is transplanted, also is performed at many transplant centers, although donor safety remains an ongoing concern.11, 12 Perioperative complications typically are higher with these various techniques; however, long-term patient survival seems comparable with that of deceased whole liver transplantation.10, 13 Liver transplantation is a complex, time-consuming operation that requires vascular reconstruction of the hepatic artery, the portal vein, and the hepatic venous drainage to the inferior vena cava. Biliary reconstruction usually is accomplished using an end-to-end anastomosis of the proximal donor bile duct to the distal recipient duct; however, in recipients with diseased ducts, the donor duct is usually anastomosed to the jejunum using 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. The outcome of all patients who receive liver transplants in the United States and Europe is continuously tracked in comprehensive databases: the United Network for Organ Sharing (UNOS) and the European Transplant Registry (ELTR), respectively. Using outcomes from these databases, computer models are available to address specific issues of organ allocation and to track the efficacy of cadaveric and living-related transplants both nationally and at individual centers.14 The dramatic increase in transplants over the past two decades seems to have had a favorable impact on chronic liver disease mortality in the United States.15 Nevertheless, many issues remain, including specific indications and contraindications to liver transplantation, the optimum timing of the operation, and the most appropriate use of scarce donor organs. Liver transplantation is indicated for acute or chronic liver failure from any cause. The major conditions that lead to the need for transplantation in adults and children are summarized in Table 2. The first step in considering a patient for potential liver transplantation is determining the need for the operation. The second step is to confirm that all other effective treatments have been attempted. Finally, the patient's likelihood of being an appropriate candidate for transplantation should be carefully assessed by a transplantation center. The natural history of the patient's disease must be carefully compared with the anticipated survival after liver transplantation. The clinical tools most widely used to determine prognosis in patients with chronic liver diseases include disease-specific indices for primary biliary cirrhosis and sclerosing cholangitis, the Child-Turcotte-Pugh (CTP) classification, the prognostic model for end-stage liver disease (MELD), as well as the impact of specific complications of cirrhosis on patient survival. The Mayo Clinic prognostic model for primary biliary cirrhosis (PBC) is the best-validated tool for determining prognosis in groups of patients with chronic liver disease.16, 17 However, this model is useful only for patients with PBC. A number of disease-specific models also have been developed for determining the prognosis of patients with primary sclerosing cholangitis (PSC).18 However, in addition to being useful only for patients with this disease, it is not clear whether any of the PSC models add to simple means of assessing prognosis, such as the CTP classification.19 The CTP classification, which was designed to stratify the risk of portacaval shunt surgery in patients with cirrhosis and variceal bleeding, has gained favor over the past decade as a simple method for determining the prognosis of patients with chronic liver disease (Table 3).20, 21 Although never formally validated as a prognostic tool, the CTP score is useful as a rapid means of assessing the relative risk of mortality among groups of patients with cirrhosis. The CTP score is as effective as quantitative liver function tests in determining short-term prognosis among groups of patients awaiting liver transplantation.22 Although its limitations have been well described, the CTP score has been widely adopted for risk-stratifying patients before transplantation because of its simplicity and ease of use.23 More than one third of patients with CTP scores of 10 or more (class C) who are waiting for transplantation can be expected to die within 1 year.19, 22 In contrast, patients with CTP scores of 7 to 9 (class B) have an 80% chance of surviving 5 years, and those with CTP scores of 5 to 6 (class A) have a 90% chance of surviving more than 5 years without transplantation.19, 24, 25 The MELD was originally developed to assess short-term prognosis in patients undergoing transjugular intrahepatic portosystemic shunts (TIPS). Among patients who had undergone this procedure, serum bilirubin, international normalized ratio of prothrombin time (INR), serum creatinine, and diagnosis seemed to be the best predictors of 3-month postoperative survival.26 Using the MELD model, patients are assigned a score in a continuous scale from 6 to 40, which equates to estimated 3-month survival rates from 90% to 7%, respectively.26 Subsequent studies of this model demonstrated its usefulness as an effective tool for determining the prognosis of groups of patients with chronic liver disease.27 A modification of this model is now used to prioritize patients for donor allocation in the United States. The modified MELD score has been shown useful both in predicting short-term survival in groups of patients on the waiting list for liver transplantation as well as the risk of postoperative mortality.28, 29 A similar model has been developed for pediatric end-stage liver disease (PELD). The variables included in this model are: age younger than 1 year, serum albumin level, serum bilirubin, INR and growth failure (<2 SD below the age-based mean).30, 31 The higher the PELD score, the lower the likelihood of 3-month survival without transplantation. This model has been useful in predicting deaths of pediatric patients waiting for transplantation.32 Calculation of individual MELD or PELD scores for patients can be determined at http://www.unos.org/resources/meldpeldcalculator.asp. The development of ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, or hepatorenal syndrome also have a significant impact on the prognosis of patients with cirrhosis. The 5-year survival rate of individuals in whom any of these complications develop is only 20% to 50% of patients with compensated cirrhosis.33, 34 The most ominous complications are spontaneous bacterial peritonitis and rapid-onset (type I) hepatorenal syndrome. Less than half of those in whom spontaneous bacterial peritonitis develops can be expected to survive 1 year, whereas the median survival among patients with type I hepatorenal syndrome is less than 2 weeks.35, 36 The natural history of disease should be compared with the expected survival after liver transplantation. Current survival rates 1, 3, and 5 years after liver transplantation in the United States are 88%, 80%, and 75%, respectively (http://www.optn.org/latestdata/step2.asp). As a result, patients with a MELD score of 15 or more and a CTP score of 7 or more can be expected to achieve improved survival with liver transplantation.25, 28, 29 Because complete evaluation for transplantation can take weeks to months and patients must wait for variable periods of time before receiving a deceased donor organ, referral before the patient's anticipated mortality exceeds that of the estimated postoperative survival is important. Patients with cirrhosis should be referred for transplantation when they develop evidence of hepatic dysfunction (CTP ≥ 7 and MELD ≥ 10) or when they experience their first major complication (ascites, variceal bleeding, or hepatic encephalopathy) (II-3). Children with chronic liver disease should be referred when they deviate from normal growth curves or develop evidence of hepatic dysfunction or portal hypertension (II-3). Patients with type I hepatorenal syndrome should have an expedited referral for liver transplantation (II-3). Because of the need for long-term immunosuppressive therapy, liver transplantation can be associated with higher mortality and long-term morbidity than many alternative treatments for patients with various chronic liver diseases. As a result, every therapeutic option should be carefully considered before committing a patient to this operation. Examples of alternative treatments are detailed in Specific Indications for Liver Transplantation.. However, in patients with severe liver disease in whom the outcome of another treatment is uncertain, it is reasonable to begin evaluation for transplantation while assessing the outcome of the alternative form of therapy. Examples include immunosuppressive therapy for patients with severe autoimmune hepatitis, chelation therapy for patients with severe chronic Wilson disease, and antiviral therapy for patients with decompensated cirrhosis secondary to chronic hepatitis B. Every option for disease-specific treatment should be considered in patients with chronic liver disease. Only when there is no effective alternative therapy or when treatment has been shown to be ineffective should liver transplantation be considered (II-3). However, in critically ill patients in whom the outcome of medical therapy is uncertain, it is appropriate to simultaneously begin specific treatment for the disease and to initiate evaluation for potential liver transplantation (III). Can the patient survive the operation and the immediate postoperative period? Can the patient be expected to comply with the complex medical regimen required after liver transplantation? Does the patient have other comorbid conditions that could so severely compromise graft or patient survival that transplantation would be futile and an inappropriate use of a scarce donor organ? A careful history and physical examination; Cardiopulmonary assessment, including cardiac echocardiography, pulmonary function tests, dobutamine stress testing, and cardiac catheterization in selected patients; Laboratory studies to confirm the etiology and severity of liver disease; Creatinine clearance; Laboratory studies to determine the status of current or previous hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus, cytomegalovirus, and human immunodeficiency virus (HIV) infections; and Abdominal imaging to determine hepatic artery and portal vein anatomy and the presence of hepatocellular carcinoma (HCC). Specific medical, surgical, and psychosocial issues that are important in the evaluation of potential liver transplant recipients include the following. There is no specific age limitation to successful liver transplantation.37, 38 However, older patients have diminished long-term survival after transplantation compared with younger individuals, primarily because of an increased risk of death from malignancies.39, 40 Perioperative mortality after liver transplantation is high in patients with coronary artery disease.41 Dobutamine stress echocardiography, in most but not all studies, seems to be an effective screening test for occult coronary disease in this setting.42-44 However, cardiac catheterization should be performed in patients with positive stress tests to confirm and to delineate further the extent of the coronary disease.41, 42 Chronic smokers, patients over the age of 50, and those with a clinical or family history of heart disease or diabetes should undergo evaluation for coronary artery disease (III). Dobutamine stress echocardiography appears to be an effective screening test in this setting; however, positive test results should be confirmed with cardiac catheterization (II-2). The hepatopulmonary syndrome (HPS) consists of the clinical triad of chronic liver disease, arterial deoxygenation, and widespread intrapulmonary vasodilation. Preoperative evaluation of patients suspected of having HPS should include arterial blood pO2 determination, transthoracic contrast echocardiography, arterial oxygen response to 100% oxygen administration, and quantification of intrapulmonary shunting using a macroaggregated albumin (MAA) scan.45 With careful management, moderate abnormalities of gas exchange are not a deterrent to successful liver transplantation. However, patients with severe hypoxia have increased perioperative mortality.45, 46 Preoperative PaO2 of 50 mmHg or less alone or in combination with a MAA shunt fraction of 20% or more are the strongest predictors of postoperative mortality.45 The median survival of patients with cirrhosis and severe HPS is less than 12 months.47 Because the condition is reversible after liver transplantation, HPS has become an indication for urgent transplantation.48, 49 Patients with clinical evidence of HPS and PaO2 of less than 60 mmHg on room air with no underlying lung disease can receive enhanced prioritization for organ allocation to allow them a reasonable possibility of receiving a deceased donor organ within 3 months. Given the ominous prognosis of severe HPS and the potential reversibility of the condition, transplantation seems to be a reasonable, albeit high-risk, option for these patients. Because patients with cirrhosis and severe hepatopulmonary syndrome have an extremely poor prognosis without transplantation, they should have an expedited referral and evaluation for liver transplantation (II-2). Portopulmonary hypertension is seen in 2% to 4% of patients with cirrhosis.50, 51 In a retrospective analysis of 1205 consecutive patients who underwent liver transplantation, 81 (7%) had mild pulmonary hypertension (systolic pulmonary artery pressure, 30-44 mmHg), 14 (1%) had moderate pulmonary hypertension (systolic pulmonary artery pressure, 45–59 mmHg), and 7 had severe pulmonary hypertension (systolic pulmonary artery pressure, ≥60 mmHg) before surgery. The presence of mild and moderate pulmonary hypertension did not influence the outcome of the procedure. In contrast, among patients with severe pulmonary hypertension, the postoperative mortality was 42% at 9 months and 71% at 36 months. Only 2 of the 7 patients with severe pulmonary hypertension survived transplantation with good quality of life. The remaining 5 continued to deteriorate with progressive right heart failure, with no evidence that transplantation ameliorated the pulmonary hypertension.52 A number of studies have found that mild pulmonary hypertension is not associated with an increased risk of liver transplantation.52-54 However, severe pulmonary hypertension is associated with high perioperative mortality and, if not successfully treated, is a contraindication to liver transplantation.52, 53 Nevertheless, patients with severe pulmonary hypertension who have been sucessfully treated with medical therapy have undergone transplantation safely. In most of these patients, pulmonary hypertension gradually resolves within 4 to 6 months after transplantation and medical therapy can be discontinued.55-57 Doppler echocardiography is a sensitive method of detecting the presence of pulmonary hypertension.51, 58-60 However, the positive predictive value of the test is low. Therefore, positive results should be confirmed with right heart catheterization. All patients undergoing evaluation for potential liver transplantation should undergo screening for pulmonary hypertension (II-3). Doppler echocardiography is an excellent screening test in this setting; however, positive test results should be confirmed with right heart catheterization (II-2). Patients with severe pulmonary hypertension should be considered for liver transplantation only if the condition can be effectively controlled with medical therapy (II-3). Obesity, which is a common problem in patients being considered for liver transplantation, has an adverse impact on both immediate and long-term survival. Most patients in the United States who underwent liver transplantations between 1988 and 1996 were overweight (body mass index [BMI] > 25 kg/m2).61 Obesity was more common in women and in patients with cryptogenic cirrhosis. Morbid obesity (BMI > 40 kg/m2) was associated with decreased 30-day, 1-year, and 2-year postoperative survival. Five-year survival was reduced both in patients with morbid and severe obesity (BMI > 35 kg/m2).61 In one survey of more than 200 liver transplant recipients, 60% reported a lifetime history of smoking.62 A number of recent studies have demonstrated the deleterious effects of smoking on outcomes after transplantation. The risk of hepatic artery thrombosis appears to be significantly increased among chronic smokers.63 This effect disappears in chronic smokers who discontinue nicotine use 2 years before transplantation.63 Long-term postoperative survival of smokers also is decreased because of an increase in cardiac mortality and death from malignancies.40 Morbid obesity should be considered a contraindication to liver transplantation (II-3). All patients considered for liver transplantation should be encouraged to undergo efforts to abstain from smoking (III). A number of studies have identified elevated serum creatinine as an independent risk factor for the development of renal failure and decreased survival after liver transplantation.64-66 Acute renal failure from the hepatorenal syndrome usually improves dramatically after liver transplantation and does not appear to have an impact on posttransplant survival.67, 68 In contrast, patients with preexisting chronic renal disease have diminished survival and an increased risk of requiring dialysis after transplantation.64 However, it can be quite difficult to distinguish these two conditions in patients with severe liver disease.69 Combined liver and renal transplantation is an attractive option for selected patients with preexisting renal disease who develop liver failure.70, 71 However, given the large number of patients on renal transplant waiting lists, the benefit of performing combined liver and renal transplantation must be weighed against the risk of depriving renal transplant recipients of donor organs.72 The serum creatinine level is one of the major variables in the MELD model used to allocate donor organs for liver transplantation.28 As a result, an increasing number of patients with renal insufficiency are being selected for liver transplantation. There is concern that this may decrease overall survival rates and also may increase the need for combined liver and kidney transplants.66, 72 This area needs continued research and reevaluation. Additional details on the medical management of hepatorenal syndrome are included in the Practice Guidelines on Management of Patients with Ascites Due to Cirrhosis, which can be found at http://www.aasld.org/netforumaasld/eweb/docs/ascites.pdf. The presence of renal insufficiency is an important predictor of postoperative renal failure and mortality after liver transplantation, and hence a thorough pretransplantation evaluation of renal function is important (II-2). Because rapidly progressive hepatorenal syndrome (type 1) has an ominous prognosis and usually is reversed by transplantation, patients with this condition should have an expedited referral for evaluation (II-3). Selected patients with chronic renal and liver disease should be considered for combined liver–kidney transplantation (III). Patients with a history of extrahepatic malignancy are at high risk for recurrent disease because of the immunosuppression required after liver transplantation. Thus, it is prudent to defer transplantation for a reasonable period after cure of any such malignancy. However, at present there is no consensus on the optimum window of time between presumed cure of various extrahepatic malignancies and liver transplantation. This is an area in need of continued evaluation. Because the natural history and chance of recurrence varies with different tumors, close consultation between a patient's oncologist and transplantation physicians should occur before evaluation for liver transplantation in patients with extrahepatic malignancies (III). Osteoporosis is a common complication among patients with cirrhosis.73 This is particularly true for post-menopausal women, patients with cholestatic disorders such as PBC and PSC, and patients who have received prolonged corticosteroid therapy.74 However, osteoporosis also is common in patients with chronic hepatitis C and alcoholic cirrhosis.75, 76 Osteoporosis is of particular concern in patients being considered for liver transplantation because of the loss of bone density and the risk for pathological fractures that can occur in the perioperative period.77 All patients with chronic liver disease should be screened for osteoporosis during evaluation for liver transplantation (II-3). In those with significant bone loss, efforts to improve bone density and to prevent pathological fractures should be pursued both before and after transplantation (III). The early experience with liver transplantation for patients with HIV infection was discouraging. Most patients died within a few years after transplantation from overwhelming infections.78-80 However, even in these early series, there were a few long-term survivors. With the widespread use of highly active antiretroviral therapy (HAART), both the natural history of HIV infection and the outcome after transplantation have improved dramatically. In addition, cirrhosis secondary to chronic hepatitis C has emerged as a leading cause of death among individuals with well-controlled HIV infection. As a result, an increasing number of patients with HIV infection are being referred for liver transplantation. Recent results suggest that short-term survival after transplantation in patients with HIV infection that is well controlled with HAART is comparable with that seen in HIV-negative recipients.81, 82 Most patients have undetectable HIV RNA after the operation; however, a number of serious interactions have been reported between antiretroviral drugs and the immunosuppressive agents used after liver transplantation.83, 84 In addition, severe recurrent hepatitis C has been observed in a number of patients.82, 85, 86 Because of these various issues, the care of transplantation recipients with HIV infection requires a well-coordinated, multidisciplinary team with expertise both in transplantation and HIV management.87 Liver transplantation in patients with HIV infection requires a well-coordinated, multidisciplinary team with expertise both in transplantation and HIV management (III). The most commonly encountered surgical contraindication to liver transplantation is absence of a viable splanchnic venous inflow system, either from portal vein thrombosis or cavernous transformation of the portal vein in children. Thrombosis of the main portal vein can be successfully bypassed; however, if the entire portal venous system is occluded or atrophied, attempts at transplantation are associated with a high risk of graft loss and perioperative mortality.88-91 Computed tomographic and magnetic resonance angiography can provide accurate preoperative assessment of both hepatic arterial anomalies and the integrity of portal inflow to the liver.92-94 Such studies also are valuable in assessing both the donor and recipient vasculature before living-related transplantation.95 Patients with occlusion or hypoplasia of the splanchnic blood supply require careful anatomical evaluation before transplantation because of the increased risk of perioperative mortality and graft loss (II-3). Psychosocial issues often are the greatest deterrent to successful liver transplantation. Significant psychiatric disorders must be under excellent medical control with assurance that the patient can be compliant after transplantation. In addition, patients must have adequate support from family or friends during the perioperative period. Prisoners and children with mental retardation pose significant logistical and ethical challenges. The most frequently encountered contraindication to transplantation is continued destructive behavior resulting from drug and alcohol addiction. Medical compliance must be effectively addressed before patients are considered for transplantation. Any form of addictive behavior also should be addressed and be well controlled before patients are accepted for transplantation. This may require extensive counseling and inpatient or outpatient treatment programs. Three small studies have indicated that posttransplantation outcome and compliance among patients on methadone maintenance is comparable with that of other transplant recipients, although more pain medications and higher doses of methadone may be required during the perioperative period.96-98 Individuals should meet reasonable expectations of compliance before placement on a donor waiting list (II-3). However, before a candidate is refused liver transplantation, every effort should be made to provide expert counseling and treatment of disorders that may adversely affect postoperative compliance (III). Patients receiving methadone maintenance who are otherwise good candidates for transplantation should not be denied consideration for the operation (II-2). Cirrhosis secondary to chronic noncholestatic disorders is the most common indication for liver transplantation in adults, accounting for more than 60% of all transplants performed annually. Included among this group are patients with end-stage liver disease secondary to chronic viral hepatitis, autoimmune hepatitis, and alcoholic cirrhosis. Postoperative survival for this group of patients is slightly less than for transplantation recipients with cholestatic liver disorders (1 year, 86%; 3 years, 77%).99 It is estimated that 15% to 20% of patients with chronic HCV infection develop cirrhosis within 20 years of disease onset.100 Chronic alcohol abuse appears to accelerate this process.101 Although the 10-year survival rate of patients with well-compensated cirrhosis is more than 80%, 5-year survival is less than 50% after complications develop.33 Patients with cirrhosis secondary to chronic hepatitis C also have a 2% to 8% annual risk of developing HCC.102 End-stage liver disease secondary to chronic hepatitis C virus infection accounts for an estimated 4,500 in-hospital deaths annually in the United States.103 As a result, this condition has become the leading reason for liver transplantation among adults. Persistent viremia with HCV is virtually universal after liver transplantation, and the majority of patients develop recurrent liver injury.104, 105 Postoperative survival in early studies appeared to approximate that of patients trans