Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation
Authors: Paul Martin, Andrea DiMartini, Sandy Feng, Robert Brown, Michael Fallon
Journal: Hepatology (2013)

This practice guideline has been approved by the American Association for the Study of Liver Diseases and the American Society of Transplantation and represents the position of both Associations. Guidelines on Evaluation for Liver Transplantation (LT) were published in 2005 by the American Association for the Study of Liver Diseases (AASLD).1 In the interim there have been major advances in the management of chronic liver disease, most notably in antiviral therapy for chronic viral hepatitis. Nonalcoholic fatty liver disease (NAFLD) has assumed increasing prominence as a cause of cirrhosis and hepatocellular carcinoma (HCC) requiring liver transplant.2 Furthermore, individual disease indications for LT such as HCC have been refined3 and specific guidelines have appeared for chronic viral hepatitis.4 Reflecting the need for a multidisciplinary approach to the evaluation of this complex group of patients who have the comorbidities typical of middle age, recommendations have been developed to assist in their cardiac management.5 With an increasing number of long-term survivors of LT there has been a greater focus on quality of life and attention to comorbid conditions impacting recipient longevity.6 The purpose of the current Guidelines is to provide an evidence-based set of recommendations for the evaluation of adult patients who are potentially candidates for LT. 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; (2) guideline policies covered by the AASLD-Policy on Development and Use of Practice Guidelines; and (3) 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. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The classifications and recommendations are based on three categories: the source of evidence in levels I through III; the quality of evidence designated by high (A), moderate (B), or low quality (C); and the strength of recommendations classified as strong or weak.11 Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alono-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924–926. The literature databases and the search strategies are outlined below. The resulting literature database was available to all members of the writing group. They selected references within their field of expertise and experience and graded the references according to the GRADE system. The selection of references for the guideline was based on a validation of the appropriateness of the study design for the stated purpose, a relevant number of patients under study, and confidence in the participating centers and authors. References on original data were preferred and those that were found unsatisfactory in any of these respects were excluded from further evaluation. There may be limitations in this approach when recommendations are needed on rare problems or problems on which scant original data are available. In such cases it may be necessary to rely on less qualified references with a low grading. Due to the important changes in the treatment of complications of cirrhosis (renal failure, infections, variceal bleeding), studies performed more than 30 years ago have generally not been considered for these guidelines. The funding for the development of this Practice Guideline was provided by the American Association for the Study of Liver Diseases. Liver disease is the twelfth commonest cause of mortality in adults in the United States, resulting in 34,000 deaths annually from cirrhosis.7 In addition, the rising incidence of HCC in the United States is reflected in an increasing number of deaths from HCC. Access to LT, however, has profoundly altered the management of advanced liver disease. Management of decompensated cirrhosis and acute liver failure before the advent of LT was limited to attempts to ameliorate complications. In contrast, successful LT extends life expectancy and enhances quality of life.6 The term orthotopic liver transplantation (OLT) refers to placement of the new organ in the same location as the explanted liver. Although most LT recipients receive a whole organ from a deceased donor, an organ can be "split," with a pediatric recipient receiving a left lateral segment and an adult recipient the larger right lobe. Live donor transplant using the left hepatic lobe initially introduced for pediatric recipients has been extended into adult recipients using the donor's right lobe. Although live donor transplant is widely employed, it remains controversial, with continuing concern about potential risks to the donor, especially when right lobe resection is required for an adult recipient.8-10 Recipients of live donor transplant have reduced waiting list mortality compared to potential recipients of deceased donor organs.11 Live donor transplant should only be contemplated when LT with a deceased donor is unlikely to occur within a reasonable time frame given the severity of the potential candidate's liver disease. Irrespective of the source of the graft, deceased or live, LT is a surgically challenging procedure with dissection and removal of a diseased liver from an abdominal cavity with extensive venous collaterals due to portal hypertension with subsequent implantation of the graft and creation of vascular and biliary anastomoses. Reflecting the complexity of surgery in recipients who are often debilitated because of their advanced liver disease, a number of technical complications can occur as well as a variety of adverse effects from therapeutic immunosuppression. Despite these concerns, however, LT has revolutionized the management of severe liver disease. The United Network for Organ Sharing (UNOS) facilitates organ allocation in the United States and also records graft and recipient outcomes. The UNOS database allows critical evaluation of center- and disease-specific recipient outcomes with LT as well as guiding organ allocation policies. Analogous organizations are involved in organ allocation and data collection in other regions of the world. The greatest challenge in LT remains the inadequate supply of donor organs, limiting access to LT for many potential recipients. LT is indicated for severe acute or advanced chronic liver disease when the limits of medical therapy have been reached (see Table 2). Recognition of cirrhosis per se does not imply a need for LT. Many patients with cirrhosis in the absence of an index complication such as ascites or variceal hemorrhage will not develop hepatic decompensation, although patients with cirrhosis have diminished survival compared to the population as a whole.12, 13 Occurrence of a major complication is an important predictor of decreased survival and should prompt discussion about a possible role for LT.14 However, in many types of liver disease there is the potential for improvement even when major complications have already occurred. A patient with cirrhosis who has suffered a variceal hemorrhage may develop additional complications such as ascites following vigorous fluid resuscitation but with control of bleeding and diuretic therapy the patient's condition may dramatically improve. Similarly, an alcoholic patient with florid hepatic decompensation may have resolution of jaundice and other signs of advanced liver disease with protracted alcohol abstinence. Thus, even in a patient with marked hepatic decompensation LT may be deferred or even avoided if medical therapy is effective. Examples of specific therapies, which may markedly improve hepatocellular function, include oral antiviral agents for hepatitis B infection or corticosteroids for autoimmune hepatitis. However, even if there is a potentially reversible component to hepatic decompensation, LT evaluation should not be deferred if otherwise indicated, as improvement is not invariable even with specific therapy. For certain diseases, notably primary biliary cirrhosis and primary sclerosing cholangitis, prognostic models are available which incorporate readily available clinical and biochemical parameters. For cirrhosis of other etiologies, the Child-Pugh Score had been used to assess prognosis but has been increasingly superseded by the Model for Endstage Liver Disease (MELD).15 The MELD score was initially devised to evaluate 3-month prognosis in patients with cirrhosis undergoing a transjugular intrahepatic portosystemic shunt (TIPS) procedure.16, 17 It is a mathematical model that incorporates serum creatinine and bilirubin levels with the international normalized ratio (INR) of prothrombin time. The MELD score is on a continuous scale from 6 to 40 that corresponded to a 3-month survival of 90% to 7%, respectively. The MELD score is now used to assess prognosis in cirrhosis in a variety of settings, including organ allocation for LT, and can be calculated for individual patients at online sites, including www.UNOS.org. As discussed in the AASLD Pediatric Guidelines, an analogous formula has been validated for children with liver disease omitting serum creatinine but additionally incorporating age, serum albumin, and growth failure. Application of the MELD score has determined that the risk of deceased donor LT in patients with a MELD <15 outweighs its benefits in most circumstances.18 Development of hyponatremia in cirrhosis is a marker of increased waiting list mortality,19 as well as neurological dysfunction post-LT.20 Incorporation of serum sodium into the MELD score has been proposed to increase priority for organ allocation to candidates with hyponatremia to reduce waiting list deaths (www.UNOS.org). Once hepatic decompensation develops, the course of a patient with cirrhosis can be rapidly downhill, as additional complications including Hepatorenal Syndrome Type 1 or sepsis supervene.17 If a determination has been made that LT is indicated, evaluation should be prompt, as most potential recipients face at least several months on the waiting list before receiving a donor organ. An important indication for LT is liver graft failure. In the immediate postoperative period primary nonfunction and hepatic artery thrombosis are the most frequent causes of graft failure, whereas more remotely from LT, other important causes are recurrent disease (especially hepatitis C virus [HCV]) and chronic rejection. Results of retransplantation are generally inferior to initial transplant. A candidate for retransplantation for late graft failure needs to complete a similar formal evaluation process as for initial transplant, with weight given to the likelihood of a successful outcome, for instance, if the first graft has failed due to recurrent disease.21 1. Evaluation for LT should be considered once a patient with cirrhosis has experienced an index complication such as ascites, hepatic encephalopathy, or variceal hemorrhage or hepatocellular dysfunction results in a MELD Score ≥15 (1-A). 2. In a liver transplant candidate potentially treatable etiologies and components of hepatic decompensation such as ascites, hepatic encephalopathy, or variceal hemorrhage should be treated (1-B). 3. Potential liver transplant candidates with worsening renal dysfunction or other evidence of rapid hepatic decompensation should have prompt evaluation for liver transplant (2-B). The transplant candidate is seen and examined by a hepatologist and transplant surgeon. Key aspects of the patient's history are reviewed including duration, severity, and complications as well as establishing that options for medical management have been exhausted. Attention is paid to comorbidities with the potential to diminish the likelihood of a good outcome. Issues related to drug and alcohol use are also discussed. In addition, the impact of liver disease on the patient's functional level as well as degree of available social support are reviewed. Insurance coverage for LT and immunosuppressive medications is confirmed. Physical examination in addition to confirming signs of advanced liver disease is also an opportunity to record other clinical signs that may impact LT, including loss of muscle mass and debility. The hepatology consult is an opportunity to identify interventions such as prophylaxis of variceal hemorrhage or vaccination against hepatitis A and B that are appropriate in any patient with advanced liver disease, as well as discussions regarding recurrent disease after transplantation, and possible HCV antiviral therapies pre- or posttransplantation. The surgical evaluation, in addition to addressing the patient's history and manifestations of liver disease, also identifies additional factors that may complicate the transplant operation including prior abdominal surgery, obesity, as well as the candidate's general robustness and ability to undergo a major surgical procedure. The surgical consultation facilitates education of the patient and family about the spectrum of donor and graft types, the complexity of the proposed surgery, potential complications, rejection rates, and other aspects of LT including long-term immunosuppression and its side effects. Evaluation for LT frequently uncovers unsuspected medical conditions such as cardiac disease or highlights other disorders such as obesity. In addition, increasingly older patients who frequently harbor associated comorbidities are now under consideration for LT. Obesity is on the rise in the general population22 and this translates to an increase in the number of LT candidates with obesity. Concerns for LT in this group of patients include the impact of the other associated components of the metabolic syndrome and increased risk of complications and poorer outcomes following LT.23, 24 The World Health Organization defines a body mass index (BMI) from 25-29.9 as overweight, class 1 obesity 30-34.9, class 2 35-39.9, and class 3 ≥40. Consequences of obesity in LT recipients have included an increased risk of perioperative complications and reduced long-term survival,25 although when corrected for ascites the obesity category was reduced in up to 20% of candidates.14 However, in this study for each liter of ascites removed the mortality risk increased 7%, suggesting that the severity of the underlying liver disease increased risk rather than obesity per se. Unequivocally, severe obesity (BMI ≥40) is implicated in a variety of adverse outcomes post-LT.15 Weight reduction in obese LT candidates can be attempted under the supervision of a dietician. Decompensated cirrhosis is a contraindication to bariatric surgery. However, there may be a role for innovative approaches such as a gastric sleeve operation for morbid obesity simultaneous with LT,26 although evidence of reduction in risk with successful weight loss is lacking. 4. Obese patients (WHO class 1 and greater) require dietary counseling prior to LT (1-C). 5. Class 3 obesity (BMI ≥40) is a relative contraindication to LT (2-B). The purpose of cardiac evaluation pre-LT is to assess perioperative risk and to exclude concomitant cardiopulmonary disorders that would preclude a good long-term outcome.27 Although the hemodynamic state typical of advanced liver disease results in a low prevalence of systemic hypertension and impaired hepatic production of lipids may reduce serum cholesterol levels, coronary artery disease (CAD) is at least as frequent in LT candidates as in the general population and is influenced by typical cardiovascular risk factors.28 Therefore, noninvasive testing with echocardiography is indicated for all adult LT candidates.21 Patients with advanced liver disease may be unable to achieve the target heart rate during a standard exercise test. These patients should undergo pharmacological stress with adenosine, dipyridamole, or dobutamine, used to screen for cardiac disease with subsequent cardiac catheterization if CAD cannot be confidently excluded. Dobutamine stress echocardiography is frequently used as the initial screening test. Cardiac catheterization in a patient with cirrhosis is more likely to result in vascular complications such as bleeding compared to controls without liver disease.29 In addition, many decompensated patients with cirrhosis have tenuous renal function, increasing the risk of contrast-induced nephropathy. If significant coronary artery stenosis (>70% stenosis) is detected, revascularization may be attempted prior to LT, although rigorous proof of benefit in asymptomatic recipients is lacking. Cardiac surgery carries an increased risk in patients with cirrhosis, especially with more decompensated disease.16 Coronary artery stenting is increasingly performed prior to LT. Bare metal stents are favored to avoid the need for dual antiplatelet therapy (clopidogrel plus aspirin rather than the latter alone), although the requirement for antiplatelet agents to prevent stent occlusion may delay LT.30 Of note, recent data demonstrates superior outcomes in patients who have undergone cardiac stenting with single vessel disease compared to outcomes for patients with prior CABG for multivessel disease.30 The cardiac evaluation may also need to address other entities including valvular heart disease and ventricular dysfunction, which may be of such severity to preclude LT. Anecdotally, aortic valve replacement has been performed simultaneously with LT; however, current medical therapies may sufficiently improve ventricular function to permit safe LT.31 Unsuspected pulmonary hypertension as discussed subsequently may be initially detected by echocardiography during the LT evaluation. 6. Cardiac evaluation needs to include assessment of cardiac risk factors with stress echocardiography as an initial screening test with cardiac catheterization as clinically indicated (1-B). 7. Cardiac revascularization should be considered in LT candidates with significant coronary artery stenosis prior to transplant (2-C). Physiological, not chronological, age determines whether an older patient can be accepted for LT, with careful attention to comorbidities and functional status.32 Overall outcomes are acceptable in recipients >70 years of age, although they are inferior to those in younger age groups.33 8. In the absence of significant comorbidities, older recipient age (>70 years) is not a contraindication to LT (2-B). Pulmonary hypertension, an elevation of the mean pulmonary artery pressure (MPAP) ≥25 mmHg, occurring in the presence of portal hypertension, is referred to as portopulmonary hypertension (POPH).34, 35 It is not correlated with the severity of or etiology of portal hypertension. POPH is detected in 4-8% of LT candidates.36 Mild POPH, MPAP <35 mmHg, is not of major concern but moderate (MPAP ≥35 mmHg) and severe POPH (MPAP ≥45 mmHg) are predictors of increased mortality following LT. In a report from the Mayo Clinic mortality was 50% with MPAP >35 mmHg and 100% with MPAP >50 mmHg.37 Other causes of pulmonary hypertension need to be excluded, including left heart failure, recurrent pulmonary emboli, and sleep apnea. Contrast enhanced echocardiography is the initial screening test to estimate right ventricular systolic pressure (RVSP), with right heart catheterization as the gold standard confirmatory definitive test. In addition to demonstrating an elevated MPAP >35 mmHg, it should also confirm an elevated pulmonary vascular resistance (PVR) ≥240-dynes.s.cm−5 and a pulmonary wedge pressure ≤15 mmHg. Milder degrees of POPH do not adversely affect outcome of LT, but mortality rate climbs with more pronounced degrees.37 However, if MPAP can be reduced by vasodilator therapy to less than 35 mmHg and PVR <400 dynes.s.cm −5 LT is possible, with acceptable short-term outcomes.38-40 POPH can potentially improve with LT and vasodilator therapy can ultimately be discontinued in a subset of recipients. 9. POPH should be excluded in LT candidates by routine echocardiography. For RVSP ≥45 mm Hg right heart cardiac catheterization is indicated. (1-B). 10. Potential recipients with POPH should be evaluated by a pulmonary or cardiac specialist for vasodilator therapy (1-A). 11. LT can be offered to potential recipients with POPH, which responds to medical therapy with an MPAP ≤35 mmHg (1-B). Hepatopulmonary syndrome (HPS) resulting from intrapulmonary microvascular dilation in the setting of chronic liver disease and/or portal hypertension leads to arterial deoxygenation.41 Intrapulmonary shunting can be demonstrated by contrast echocardiography or by 99mTC macro aggregated albumin (MAA) lung-brain perfusion scanning. HPS is found in 5-32% of adult liver transplant candidates. LT offers a survival benefit in HPS, with 76% of LT recipients at the Mayo Clinic surviving 5 years compared to 26% of matched patients with equivalent severity of hypoxemia and liver disease who were not transplanted.42 LT reverses HPS in almost all patients who survive more than 6 months,35 although perioperative mortality appears to be high in those with severe HPS,35 with a preoperative PaO2 <50 mmHg alone or in combination with an MAA shunt scan of greater than 20% predictors of increased mortality after LT. More recent experience indicates that more severe hypoxemia predicts the need for longer-term supplemental oxygen and a longer recovery rather than increased mortality post-LT.43-46 Current Organ Procurement Transplant Network/UNOS policy assigns a MELD exception score of 22 for patients with evidence of portal hypertension, intrapulmonary shunting, and a room air PaO2 <60 mmHg, with a 10% mortality equivalent increase in points every 3 months if the PaO2 remains <60 mmHg. Screening of LT candidates by pulse oximetry is indicated to detect HPS patients with a PaO2 <70 mmHg, using a threshold value of SPO2 <96% at sea level to trigger complete evaluation.47 Preoperative evaluation of patients suspected of having HPS should include a room air arterial blood gas, transthoracic contrast echocardiography, and an evaluation to exclude alternate causes for arterial deoxygenation including chest x-ray (CXR), pulmonary function tests (PFTs), and chest computed tomography (CT) scanning. Arterial response to administration of 100% oxygen (performed with a nose clip and mouth piece) may be used to gauge the ability to provide adequate oxygenation in the perioperative period but does not appear to influence outcome.35, 48 12. HPS is relatively common in patients evaluated for LT and should be screened for by pulse oximetry (1-A). 13. The presence of severe HPS is associated with increased mortality and affected individuals should undergo expedited LT evaluation (1-B) The recognition of renal dysfunction in a patient with cirrhosis has a dramatic effect on prognosis, with a substantial increase in the risk of mortality. In a recent meta-analysis the risk of death increased 7-fold in patients with renal dysfunction, with 50% of patients with cirrhosis dying within a month of the onset of renal dysfunction.17 The differential diagnosis of renal failure in patients with cirrhosis is broad and includes intercurrent sepsis, hypovolemia, parenchymal renal disease, and, most commonly, hepatorenal syndrome (HRS).49 A recent working group has proposed the following definitions of renal dysfunction complicating liver disease: acute kidney injury that includes all causes of acute deterioration of renal function with an increase in serum creatinine of >50% from baseline, or a rise in serum creatinine of ≥26.4 μmol/L (≥0.3 mg/dL) in <48 hours. Chronic renal disease is defined as an estimated glomerular filtration rate (GFR) of <60 mL/min calculated using the Modification of Diet in Renal Disease 6 (MDRD6) formula.49 Evaluation of renal dysfunction in patients with decompensated cirrhosis should include an accurate calculation of the true glomerular filtration rate (GFR) and determination of the precise etiology as it impacts prognosis both with and without LT. In a recent study of 463 patients with cirrhosis and renal dysfunction, survival was significantly worse in patients with HRS versus those without HRS.50 Since the introduction of MELD for organ allocation the number of simultaneous liver kidney (SLK) transplants has increased from <3% to nearly 5% in 200951 and continues to rise. Because of concerns surrounding the increased use of renal grafts in LT recipients, a panel of experts convened to evaluate and recommend the most appropriate indications for SLK.52 SLK was sanctioned for (1) endstage renal disease (acute HRS etiology excluded) with cirrhosis; (2) liver failure with chronic kidney disease (CKD) and GFR <30 mL/min, (3) acute kidney injury or HRS with creatinine ≥2.0 mg/dL and dialysis for ≥8 weeks; or (4) liver failure with CKD and renal biopsy demonstrating >30% glomerulosclerosis or >30% fibrosis. These recommendations may evolve with increased experience of SLK.53 14. Renal dysfunction requires vigorous evaluation prior to LT to determine etiology and prognosis (1-A). 15. Simultaneous liver-kidney transplantation is indicated for LT candidates in whom renal failure reflects CKD with GFR <30 mL/min or acute kidney injury with dialysis >8 weeks or if extensive glomerulosclerosis is present (1-B). Cigarette smoking is implicated in a number of adverse outcomes in LT recipients including cardiovascular mortality54 and an increased incidence of hepatic artery thrombosis,55 although the risk of the latter diminishes with smoking cessation, by over two-thirds within 2 years of cessation in one report.44 Oropharyngeal and other neoplasms following LT are also linked to cigarette smoking and can result in significant potentially avoidable long-term mortality.56-58 While tobacco use is common in patients with a history of liver disease, the use of chewing tobacco, which is associated with oropharyngeal malignancies, is not well studied.56 There are compelling reasons to prohibit all tobacco use in LT candidates, and indeed some programs make cigarette cessation a condition for listing for LT and require negative serial nicotine screens for documenting tobacco cessation. 16. Tobacco consumption should be prohibited in LT candidates (1-A). LT recipients are at increased risk of a variety of cancers.59 In an LT recipient with a preexisting malignancy, treatment should have been curative and sufficient time should have elapsed to exclude recurrence. The Israel Penn International Transplant Tumor Registry (www.ipittr.com) has accumulated a large database of outcomes after LT in recipients with a variety of tumors and can guide an appropriate strategy for LT candidates with a history of extrahepatic malignancy. The interval from cancer diagnosis to treatment and subsequent presumed cure, to transplant listing candidacy, varies depending on the type of malignancy and the proposed evidence-based efficacy of treatment. All LT candidates should undergo age-appropriate screening for malignancies including colonoscopy, mammography, and Papanicolaou smear. In candidates with particular risk factors for malignancy, additional screening should be considered such as ENT evaluation and chest imaging in current or prior smokers. 17. LT candidates with a prior extrahepatic malignancy should have received definitive treatment with adequate tumor-free survival prior to listing for LT (1-B). 18. Candidates should undergo age and risk factor-appropriate cancer screening, e.g., colonoscopy, mammography, Papanicolaou smear (1-A). Due to hepatocellular dysfunction, LT candidates are at increased risk of a variety of infections, including spontaneous bacterial peritonitis, aspiration pneumonia, urinary tract, and catheter-associated bloodstream infections.60 Active infection needs to be adequately treated before LT can be attempted. As part of the transplant evaluation, a candidate should be screened serologically for viral infections including HBV, HCV, and HIV, as discussed separately below.61 Hepatitis A and B immunity should be confirmed and vaccination performed if necessary. Serological testing for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) is also indicated. Latent syphilis and tuberculosis (TB) infections should be tested for. Screening for TB can be done by tuberculin skin testing (TST) or interferon-γ release assays such as QuantiFERON (QFT,Cellestis) or T-SPOT.TB (Oxford Immunotec).62 If latent TB is detected, antimicrobial therapy is indicated pre-LT, typically with isoniazid 300 mg daily plus pyridoxine 50 mg daily for 6-9 months, a 3-month regimen of weekly isoniazide and rifapentine, or rifampin 600 mg daily for 4 months. There had been concerns previously about hepatotoxicity with anti-TB regimens but more recent experience with isoniazid has been reassuring in LT candidates with cirrhosis.63, 64 Syphilis, if detected, needs to be treated pre-LT. In areas such as the American Southwest where Coccidiomycosis is endemic, pretransplant screening is indicated; if seropositive for Coccidiomycosis, active infection should be excluded and lifelong prophylaxis with fluconazole posttransplant considered. By contrast, routine screening for histoplasmosis or blastomycosis is not recommended and treatment for a positive result should be discussed with the ID team. Serological screening for Stronglyloides is indicated in candidates with a history of residence in endemic areas; patients who are