Abstract

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 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 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 50% from baseline, or a rise in serum creatinine of ≥26.4 μmol/L (≥0.3 mg/dL) in 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 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