Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation

This practice guideline has been approved by the American Association for the Study of Liver Diseases and the American Society of Transplantation. These recommendations provide a data-supported approach to management of adult patients who have successfully undergone liver transplantation. They are based on the following: (1) a formal review and analysis of recently published world literature on the topic (via a MEDLINE search); (2) A Manual for Assessing Health Practices and Designing Practice Guidelines (American College of Physicians)1; (3) guideline policies,2 including the American Association for the Study of Liver Diseases policy on the development and use of practice guidelines and the American Gastroenterological Association policy statement on guidelines3; and (4) the experience of the authors in the specified topic. Intended for use by physicians and health care providers working with adult recipients of liver transplantation (LT), 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 American Association for the Study of Liver Diseases Practice Guidelines Committee has adopted the classification used by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1).4 In the GRADE system, the strength of a recommendation is classified as (1) strong or (2) weak. The quality of evidence supporting a strong or weak recommendation is designated by 1 of 3 levels: (A) high, (B) moderate, or (C) low. AIH, autoimmune hepatitis; ALD, alcoholic liver disease; BMD, bone mineral density; CKD, chronic kidney disease; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CUC, chronic ulcerative colitis; DM, diabetes mellitus; EBV, Epstein-Barr virus; ESRD, end-stage renal disease; FDA, Food and Drug Administration; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; HAART, highly active antiretroviral therapy; HbA1c, hemoglobin A1c; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; LT, liver transplantation; mTOR, mammalian target of rapamycin; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NODM, new-onset diabetes mellitus; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; PTLD, posttransplant lymphoproliferative disorder; TB, tuberculosis. LT is the treatment of choice for patients with decompensated cirrhosis, acute liver failure, small hepatocellular carcinomas (HCCs), or acute liver failure. The success of LT has meant that there is a growing cohort of LT recipients throughout the world. From 1985 through 2011, approximately 100,000 persons in the United States underwent LT. On December 30, 2011, there were 30,000 LT recipients who were alive and had survived at least 5 years, and there were more than 16,000 recipients with 10 or more years' survival. These long-term survivors are at risk of early death and increased morbidity. The purpose of this guideline is to assist in the management of adult recipients of LT, identify the barriers to maintaining their health, and make recommendations on the ways to best prevent or ameliorate these barriers. This guideline focuses on management beyond the first 90 days after transplantation. The greatest proportion of deaths or retransplants after LT occur soon after transplantation. The causes of death and graft loss vary according to the interval from transplantation, with infection and intraoperative and perioperative causes accounting for nearly 60% of deaths and graft losses in the first posttransplant year. After the first year, death due to acute infections declines, whereas malignancies and cardiovascular causes account for a greater proportion of deaths. The recurrence of the pretransplant condition, especially hepatitis C virus (HCV) or autoimmune liver disease, is an increasingly important cause of graft loss the longer the patient survives transplantation for these etiologies. Today, death (or a need for retransplantation) attributable to acute or chronic allograft rejection is uncommon throughout the first 10 years after transplantation. The transplanted liver becomes partially tolerant of immune-mediated injury, so the requirement for immunosuppression declines after the first 90 days. Although some LT recipients may eventually achieve operational tolerance (ie, maintenance without immunosuppressant medications), this is rare. Most patients receive immunosuppression throughout the life of the allograft.5 The continued use of immunosuppression carries inevitable consequences: an increased risk of bacterial, viral, and fungal infections, which can be recurrent or newly acquired; metabolic complications such as hypertension, diabetes mellitus (DM), hyperlipidemia, obesity, and gout; and hepatobiliary or extrahepatic de novo cancers [including posttransplant lymphoproliferative disorder (PTLD)]. The combination of the complications of immunosuppression and the recurrence of the underlying liver disease translates into a heavy burden of ill heath for many LT recipients. An analysis of a longitudinal US database of 36,847 LT recipients indicated that the prevalence of kidney failure [defined as a glomerular filtration rate of 29 mL/minute/1.73 m2 of body surface area or less or the development of end-stage renal disease (ESRD)] was 18% at 5 years and 25% at 10 years.6 LT recipients have at-risk cardiovascular profiles with a high prevalence of hypertension requiring antihypertensive medications, recurrent DM and new-onset diabetes mellitus (NODM), and hyperlipidemia requiring lipid-lowering agents. Cardiovascular disease and renal failure are the leading nonhepatic causes of morbidity and mortality late after LT (Table 2). The recurrence of the original disease, such as a chronic HCV infection, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), or HCC, can cause ongoing morbidity and mortality. Many of the patients undergoing LT have a past or present history of addictions, especially to alcohol, cigarettes, or both, which may also persist with harmful effects on patients' health, often by interacting with other risk factors already mentioned. An assessment of the quality of life after LT has shown that although quality measures improve in LT patients in most domains in comparison with their status before transplantation, LT recipients continue to have many deficits in comparison with age-matched control populations; these are manifested as worsening physical symptoms, fatigue, and a greater sense of being unwell.7 Through the reduction of cardiovascular risks, the suppression or eradication of specific infections, improved surveillance for cancer, and the prevention or treatment of recurrent liver diseases, both the quantity and the quality of post-LT life can be improved. In these guidelines, we show how a concentrated effort to moderate immunosuppression, manage recurrent disease, and ameliorate metabolic complications of immunosuppression is required to convert short-term success into sustained success for an extended healthy life. Typically, clinical features of liver failure and portal hypertension resolve rapidly after LT, and they are not usual after the first 3 months. The exception is splenomegaly, which may persist for years. Variceal hemorrhage is very unusual unless the patient has an occluded portal vein. The late emergence of hepatic encephalopathy in a patient with a functioning liver allograft suggests the development of clandestine cirrhosis or a persistent portosystemic shunt. Late-onset ascites or peripheral edema may indicate stenosis of the inferior vena cava or portal vein anastomosis. Persistent late ascites in a patient with a recurrent HCV infection is a poor prognostic sign. Liver tests are routinely monitored after LT. When liver tests are elevated for a healthy recipient, the course of action will depend on the severity and type of abnormality (cholestatic, hepatitic, or other). Clinical challenges arise when liver tests are normal in the presence of graft damage or conversely abnormal in an asymptomatic LT recipient. The many causes of liver test abnormalities in the asymptomatic recipient are shown in Table 3. More than 1 cause may coexist in the same patient. When abnormal liver tests are recognized in a healthy, asymptomatic LT recipient, it is reasonable to repeat the tests in 1 to 2 weeks. A decision to investigate further should be based on the persistence and severity of the liver test abnormalities. Investigations should include a thorough history and examination, appropriate laboratory tests, and Doppler ultrasound of the liver. It should not be assumed without appropriate histological confirmation that abnormal liver tests represent immune-mediated damage. Elevated alkaline phosphatase, total bilirubin, and aminotransferase levels may arise from the late appearance of biliary anastomotic strictures due to thrombosis or stenosis of the hepatic artery or to recurrent PSC or PBC. Appropriate biliary imaging includes endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, and/or ultrasound. Biliary cast syndrome refers to a severe form of intrahepatic bile duct ischemic injury unique to post-LT patients,8 and it is associated with hepatic artery thrombosis and the use of a split liver, including partial grafts derived from living donors and, more commonly, from donation after cardiac death donors. Biliary cast syndrome may resolve with repeated clearance of bile duct debris either percutaneously or endoscopically. The frequency of monitoring with liver tests should be individualized by the transplant center according to the time from LT, the complications from LT, the stability of serial test results, and the underlying cause (grade 1, level A). Depending on the pattern of liver tests, magnetic resonance imaging, computed tomography, endoscopic retrograde cholangiopancreatography, and sonography may be appropriate (grade 1, level A). Liver histology should be obtained when parenchymal injury is suspected as the cause of abnormal liver tests (grade 1, level A). intrahepatic non-anastomotic strictures and/or sterile or infected fluid collections within the liver, sometimes referred to as bilomas, ischemic cholangiopathy or biliary cast syndrome. Bilomas and biliary cast syndrome should be managed in a center with expertise in LT medicine, radiology, and biliary endoscopy (grade 1, level A). Hepatic artery thrombosis or stenosis is most readily assessed initially by Doppler ultrasound, but angiography is usually required to confirm the diagnosis and plan therapy (grade 1, level B). Indication for transplantation: the choice of immunosuppression may affect disease recurrence (eg, HCV, malignancy, or autoimmune disease). Comorbidities. Drug side effects: calcineurin inhibitors (CNIs) may cause renal impairment. Likelihood of pregnancy: mycophenolate and mammalian target of rapamycin (mTOR) inhibitors such as sirolimus are potential teratogens. History of severe or recurrent rejection. Prior experience with the various immunosuppressive agents. History of or risk for cancers. History of or risk for infections. There is no reliable marker for determining the effective level of immunosuppression; therefore, the choice of the agent (or agents) and doses given will be determined by the clinical, laboratory, and histological response. The CNI dose is generally determined by the drug level; the target levels after 3 months are 5 to 10 ng/mL for tacrolimus and 100 to 150 ng/mL for cyclosporine (both are whole blood trough levels). The target whole blood trough level for sirolimus is 5 ng/mL. The need for therapeutic drug monitoring for mycophenolate is uncertain. Table 4 describes drug-drug interactions involving the commonly used immunosuppressant medications. Common side effects of immunosuppressants are presented in Table 5. The majority of LT recipients need lifelong immunosuppression to maintain graft function. A very small number of LT recipients develop operational tolerance to the allograft and do not require long-term immunosuppression.5 Late rejection is defined as rejection that has its onset more than 90 days after transplantation. Traditionally, 2 forms have been recognized: cellular rejection (also known as acute cellular rejection and late-onset rejection) and ductopenic rejection (also known as vanishing bile duct syndrome). Both forms of rejection are, until the late stages, asymptomatic, and the diagnosis is made through the investigation of abnormal liver tests; the diagnosis can be confirmed only on the basis of histology. For both cellular rejection and ductopenic rejection, the Banff criteria have been adopted to define the nature and severity.10 Liver tests in patients with late-onset cellular rejection show nonspecific abnormalities with a rise in serum bilirubin and aminotransferases. Histologically, cellular rejection is characterized by the triad of inflammatory bile duct damage, subendothelial inflammation of the portal, central, or perivenular veins, and a predominantly lymphocytic portal inflammatory infiltrate with neutrophils and eosinophils in addition. The focus of inflammation may be portal, central, or both, but the central component is more prominent and frequently occurs as pure centrilobular necroinflammation (isolated central perivenulitis). Late acute rejection differs from early acute cellular rejection by having fewer classic histological features. Reduction of immunosuppression (whether iatrogenic or due to noncompliance). Pre-LT autoimmune liver disease. Concurrent administration of interferon (for HCV treatment). The differential diagnosis includes infection, recurrent and de novo autoimmune disease, and drug toxicity; it may sometimes be difficult to distinguish cellular rejection from HCV infection, and indeed, the two often coexist. In mild cases of cellular rejection, an increase in maintenance levels of immunosuppression may be sufficient, whereas in histologically moderate or severe cases, the treatment should be a short course of increased immunosuppression (eg, methyl prednisone at 500 mg/day or prednisolone at 200 mg/day for 3 days) followed by an increase in the baseline immunosuppression. A full response (defined as a return to normal liver tests) is seen in only approximately half of patients, with approximately 25% developing a further episode of cellular rejection and 25% developing ductopenic rejection. Ductopenic rejection is seen most commonly in the first year but may occur at any time. Recent data suggest that humoral alloreactivity mediated by antibodies against donor human leukocyte antigen (HLA) molecules, acting in concert with cellular mechanisms, may play a role in the development of ductopenia (a process known as antibody-mediated rejection).11 The onset of ductopenia is usually insidious, with a progressive rise in liver tests with a cholestatic picture (a rise in alkaline phosphatase and gamma-glutamyl transpeptidase followed by a progressive rise in serum bilirubin). In late cases, the recipient may complain of pruritus and jaundice. A liver biopsy sample with at least 10 portal tracts is advisable in order to establish with confidence that injury to and loss of bile ducts have occurred. In the early stages of ductopenic rejection, there may be a cellular infiltrate, but more commonly, the characteristic features include the progressive loss of bile ducts from the portal tracts and cholestasis; in late stages, foamy macrophages may be seen. Recurrent and unresponsive cellular rejection. Transplantation for autoimmune disease. Exposure to interferon. Loss of a previous graft to ductopenic rejection. The differential diagnosis includes recurrent disease (PBC or PSC) and drug toxicity. The treatment of ductopenic rejection is increased immunosuppression, and an increase in or switch to tacrolimus may be effective in some early cases. Conversely, especially when fewer than 50% of the portal tracts contain bile ducts, the condition progresses to graft failure. Immunosuppressive drugs for LT recipients should be prescribed and monitored only by those with knowledge and expertise in that area. The choice of agents will depend on many factors, and no one regimen can be recommended for any patient (grade 2, level A). Every patient's immunosuppressive regimen should be reviewed at least every 6 months and modified as required with the goal of minimizing long-term toxicities (grade 1, level B). Rejection can be reliably diagnosed only on the basis of liver histology; a biopsy sample should be taken before treatment initiation and classified according to the Banff criteria (grade 1, level A). Although the long-term withdrawal of all immunosuppression can be achieved in a small number of patients, this should be undertaken only with select recipients and under close supervision (grade 2, level C). Frequent handwashing reduces the risk of infection with pathogens acquired by direct contact, including Clostridium difficile, community-acquired viral infections, and pathogens found in soil (grade 1, level A). Shoes, socks, long-sleeve shirts, and long pants should be worn for activities that will involve soil exposure and tick exposure and also to avoid unnecessary sun exposure (grade 1, level A). During periods of maximal immunosuppression, LT recipients should avoid crowds to minimize exposures to respiratory illnesses (grade 1, level A). Work in high-risk areas, such as construction, animal care settings, gardening, landscaping, and farming, should be reviewed with the transplant team to develop appropriate strategies for the prevention of high-risk exposures (grade 2, level A). LT recipients should avoid the consumption of water from lakes and rivers (grade 1, level A). LT recipients should avoid unpasteurized milk products and raw and undercooked eggs and meats (particularly uncooked pork, poultry, fish, and seafood; grade 1, level A). LT recipients should avoid high-risk pets, which include rodents, reptiles, chicks, ducklings, and birds (grade 1, level A). Travel by LT recipients, especially to developing countries, should be reviewed with the transplant team a minimum of 2 months before departure to determine optimal strategies for the reduction of travel-related risks (grade 1, level A). LT recipients should take precautions to prevent vector (including mosquito) -borne diseases. These include avoiding going out during peak mosquito feeding times (dawn and dusk) and using N,N-diethyl-meta-toluamide–containing insect repellants (grade 1, level A). LT recipients should undertake a thorough review of hobbies to assess potential infectious disease risks, particularly those associated with outdoor hobbies (grade 2, level A). All LT recipients should be educated about the importance of sun avoidance and sun protection through the use of a sun block with a sun protection factor of at least 15 and protective clothing. They should be encouraged to examine their skin on a regular basis and report any suspicious or concerning lesions to their physicians (grade 1, level A). Because of the strong association of lung, head, and neck cancers with smoking, the sustained cessation of smoking is the most important preventative intervention (grade 1, level A). For female LT recipients of a child-bearing age, preconception counseling about contraception and the risks and outcomes of pregnancy should start in the pretransplant period and should be reinforced after transplantation (grade 1, level A). Bone loss and fracturing are seen with 2 distinct phases after LT. In the first 4 postoperative months, there is accelerated bone loss in almost all liver recipients, regardless of the pretransplant bone mineral density (BMD), that is consistent with the effects of corticosteroids and possibly CNIs.12 After the first 4 postoperative months with normal allograft function, bone metabolism improves, and in the osteopenic patient, there will be a gain in bone mass over the next postoperative years with a gradual reduction in the incidence of fractures.12, 13 In patients with preexisting osteopenia or pretransplant fracturing, this early, rapid bone loss results in a high susceptibility to fracturing, mainly at sites of trabecular bone (vertebrae and ribs), especially in the first year after LT, but there is a smaller but steady cumulative increase in fracturing. Table 6 outlines the evaluation of the metabolic bone status of LT recipients with osteopenia. In the early years after LT, BMD should be measured annually in osteopenic patients and every 2 to 3 years in patients with normal BMD. Later screening depends on risk factors. T-score less than −2.5 or atraumatic fractures. T-score between −1.5 and −2.5 and other risk factors. Oral alendronate at 70 mg weekly is an appropriate starting point, although other oral agents may, however, be equally efficacious. If oral therapy is not tolerated, intravenous zolendronic acid or ibandronate can be used. The optimal duration of therapy is unknown, although oral alendronate has been given with good effect for 10 years for postmenopausal osteoporosis. Hormone replacement therapy is an alternative in postmenopausal women. In the first 5 years after transplantation, screening by BMD should be done yearly for osteopenic patients and every 2 to 3 years for patients with normal BMD; thereafter, screening depends on the progression of BMD and on risk factors (grade 2, level B). If osteopenic bone disease is confirmed or if atraumatic fractures are present, then patients should be assessed for risk factors for bone loss; in particular, this should include an assessment of calcium intake and 25-hydroxyvitamin D levels, an evaluation of gonadal and thyroid function, a full medication history, and thoracolumbar radiography (grade 1, level A). The osteopenic LT recipient should perform regular weight-bearing exercise and receive calcium and vitamin D supplements (grade 1, level A). Bisphosphonate therapy should be considered in LT recipients with osteoporosis or recent fractures (grade 1, level A). The majority of LT recipients who survive the first 6 months develop chronic kidney disease (CKD).6 Predialysis CKD prevalence rates in this population range from 30% to 80%. The wide range of reported incidences is partly due to the different thresholds used to define CKD and the various durations of posttransplant observation. The cumulative risk of ESRD that requires maintenance dialysis therapy or kidney transplantation is 5% to 8% during the first 10 years after LT.6, 14, 15 Furthermore, 1.0% of all kidney transplants currently in the United States are undertaken for LT recipients who subsequently developed ESRD.16 The etiology of CKD in the LT population is multifactorial (Table 2) and includes chronic exposure to CNIs, hypertension, DM, obesity, atherosclerosis, hyperlipidemia, chronic HCV infection, pretransplant renal dysfunction, and perioperative acute kidney injury. CKD is associated with a 4.48 relative risk of death more than 1 year after LT in comparison with recipients without CKD.6, 17 A serum creatinine elevation is a late and insensitive indicator of CKD in this population. An estimating equation that has been shown to have reasonable precision should be routinely used. Both the 4-variable Modification of Diet in Renal Disease equation and the Chronic Kidney Disease Epidemiology Collaboration formula are superior to serum creatinine alone and 24-hour urinary creatinine clearance in estimating renal function.18, 19 Increased proteinuria (spot protein-to-creatinine ratio > 0.3) may be absent even in the presence of advanced CKD because of the antiproteinuric effect of CNIs. Proteinuria is best assessed by the measurement of the concentration ratio of protein to creatinine in a spot urine specimen.20 Aggressive blood pressure control and the use of agents that block the renin-angiotensin-aldosterone system are key foundations of CKD treatment in the nontransplant population and would be expected to have beneficial effects in LT recipients. A reduction in the dosage or a complete withdrawal of CNIs several months to years after LT is a common practice aimed at ameliorating the progression of CKD. These renal-sparing maintenance protocols typically rely on sirolimus or everolimus, often in combination with mycophenolate, to prevent acute rejection; others use steroids and mycophenolate or azathioprine.21-24 Renal function is more likely to be preserved if CNI withdrawal is instituted when the estimated glomerular filtration rate is between 40 and 50 mL/minute/1.73 m2.25 LT recipients with ESRD who subsequently receive a living or deceased kidney transplant have a 44% to 60% reduction in long-term mortality in comparison with their dialysis-treated counterparts.26, 27 Monitoring of renal function in LT recipients for the detection and management of CKD should use an estimating equation to evaluate the glomerular filtration rate (grade 1, level B). Urinary protein quantification using the concentration ratio of protein to creatinine in a spot urine specimen should be evaluated at least once yearly (grade 1, level B). The reduction or withdrawal of CNI-associated immunosuppression is an appropriate response to the development of CKD in LT recipients (grade 1, level A). Kidney transplantation from deceased or living donors is beneficial in improving survival and should be considered the optimal therapy for LT recipients who develop ESRD (grade 1, level A). The clinical features of metabolic syndrome, either alone or in combination, contribute to post-LT morbidity and mortality. The clinical factors related to LT that exacerbate metabolic syndrome are shown in Table 7. The spectrum of hyperglycemia after LT includes preexisting DM and NODM, some of which is transient in the perioperative period. Insulin-requiring DM that is present at the time of transplantation virtually always persists after LT, and many patients on oral hypoglycemic agents need a conversion to insulin early after LT. In LT recipients followed beyond 1 year, estimates of the prevalence of NODM vary from 5% to 26%. Diabetogenic factors after LT include corticosteroids, CNIs (tacrolimus more than cyclosporine), HCV infection, and metabolic syndrome.28-33 NODM tends to remit over time, especially as corticosteroids are withdrawn and the tacrolimus dosage is reduced, and patients may go from insulin therapy to oral hypoglycemic agents to diet control only over the years. Because stringent glycemic control significantly reduces morbidity and mortality in diabetic patients, it seems reasonable to assume that LT recipients would similarly benefit. The goals of the long-term management of diabetes after LT are not substantially different from the goals for nontransplant patients (Table 8). There is controversy regarding the appropriate target level of hemoglobin A1c (HbA1c), and consequently, our recommendation of a threshold of <7.0% rather than <6.0% reflects the view that the more demanding standard may confer no additional advantage. When insulin requirements are low, oral agents may be substituted if allograft function is normal. Metformin or a sulfonylurea may be used in LT recipients with normal renal function, whereas sulfonylureas such as glipizide and glimepiride are preferable if there is any deterioration in renal function. The safety of thiazolidinediones in LT recipients is unproven. Retrospective data sets and a small prospective study suggest that the conversion of immunosuppression from tacrolimus to cyclosporine improves glycemic control in patients with established DM and NODM.33 The treatment of DM after LT should aim for an HBA1c target goal of <7.0% with a combination of lifestyle modifications and pharmacological agents as appropriate (grade 1, level B). When high-dose corticosteroids are administered, insulin therapy is the most effective and safest agent with which to control hyperglycemia; however, as the interval from LT extends, patients with NODM may experience a decline in insulin requirements, and oral hypoglycemic agents may be appropriate if allograft function is normal (grade 1, level C). Metformin or sulfonylureas may be used in LT recipients with normal renal function, whereas sulfonylureas such as glipizide and glimepiride are preferable if there is any deterioration of renal function (grade 1, level C). Consideration can be given to the conversion of immunosuppression from tacrolimus to cyclosporine in LT recipients with poor glycemic control (grade 2, level B). Hypertension in LT recipients increases the risk of fatal and nonfatal cardiovascular disease events and CKD.15 Although there are no clinical trials of antihypertensive therapy in LT recipients, it is prudent to target a blood pressure treatment goal of 130/80 mm Hg in LT recipients with systemic hypertension.34 For the management of hypertensive LT recipients, immunosuppression leading to hypertension, such as CNIs and corticosteroids, should be minimized under the direction of the transplant center.35 Lifestyle modifications, including weight loss in overweight recipients (see the discussion on obesity) and the restriction of dietary salt intake, are appropriate nonpharmacological interventions.34 Home measurement of blood pressure is encouraged. If lifestyle modification and a reduction of immunosuppression do not achieve the target blood pres