Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the american association for the study of liver diseases, american society of transplantation and the north american society for pediatric gastroenterology, hepatolo
Authors: Robert H. Squires, Vicky Ng, Rene Romero, Udeme Ekong, Winita Hardikar, Sukru Emre, George V. Mazariegos
Journal: Hepatology (2014)

This practice guideline has been approved by the American Association for the Study of Liver Diseases, the American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Current American Association for the Study of Liver Diseases (AASLD) liver transplant evaluation guidelines include both adult and pediatric patients.1 While pediatric liver transplants account for ∼7.8% of all liver transplants in the United States, sufficient differences between pediatric and adult patients seeking liver transplantation (LT) now require independent, yet complementary documents. This document will focus on pediatric issues at each level of the evaluation process. Disease categories suitable for referral to a pediatric LT program are similar to adults: acute liver failure, autoimmune, cholestasis, metabolic or genetic, oncologic, vascular, and infectious. However, specific etiologies and outcomes differ widely from adult patients, justifying independent pediatric guidelines. Data supporting our recommendations are based on a Medline search of the English language literature from 1997 to the present. 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. Each Association appointed at least one author to serve on the writing group. The Chair of the writing group was appointed by the AASLD. Members of the writing group were not compensated for their work and served as volunteers throughout the process from concept design through final publication. Writing group members had no financial conflict of interest or financial relationship with commercial entities relevant to the article. Topics relevant to liver transplant evaluation in the pediatric patients were identified through a conference call with all members of the writing group on July 11, 2012 and assignments were distributed among the members based on their particular expertise and interest. 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. Data supporting our recommendations are based on a MEDLINE search of the English language literature from 1973 to the present. Primary search terms included: liver transplant evaluation, liver transplant, child, pediatric, and liver transplant outcome. In addition, each assessment (e.g., anesthesia, hepatology, renal, etc.); diagnosis (e.g., biliary atresia, organic acidemia, maple syrup urine disease, ductal plate malformation, etc.) and complication (e.g., hepatopulmonary syndrome, malignancy, etc.) was searched in the context of the primary search terms as well as individually when relevant clinical background information was needed. 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. Children have distinct diseases, clinical susceptibilities, physiological responses, as well as neurocognitive and neurodevelopmental features that distinguish them from adults. In fact, even within the pediatric age group differences can be found between newborns, infants, children, and adolescents. Given the intra-abdominal anatomical variations associated with biliary atresia, the most common indication for pediatric LT, as well as the restricted abdominal cavity and small size of blood vessels in infants and young children, surgical teams with exhaustive pediatric experience will benefit the pediatric recipient of an LT. Members of the pediatric LT team (Table 2) use their expertise to tailor the LT evaluation plan (Table 3) to the unique needs of the child. The end product of the evaluation will ensure the elements for an informed decision to proceed to LT are met.2 1. A multidisciplinary pediatric LT evaluation team should be skilled in pediatric conditions and properly communicate with the family and the child, when appropriate, the processes, risks, and benefits associated with LT. (2-B) Based on the United States Organ Procurement and Transplantation Network (OTPN) from January 1, 2011, through May 31, 2013, indications for LT include biliary atresia (32%), metabolic/genetic conditions (22%), acute liver failure (11%), cirrhosis (9%), liver tumor (9%), immune-mediated liver and biliary injury (4%), and other miscellaneous conditions (13%) (Fig. 1). Within these broad categories rest many rare conditions with myriad presentations. As timing for referral varies depending on the child's clinical circumstances, referral for LT may be emergent, urgent, or anticipatory. Acute liver failure (ALF) or an acute decompensation of an established liver disease may have a rapid and unpredictable course progressing to death or irreversible neurological damage.3 Children with metabolic liver disease, such as urea cycle defects or maple syrup urine disease, can suffer significant neurological sequelae as a consequence of metabolic crises.4 Primary and secondary liver tumors are rare in children, with hepatoblastoma (HB) and hepatocellular carcinoma (HCC) being the most common. Survival for children with HB is dependent on response to initial chemotherapy and complete surgical resection.5 Screening for HCC is imperfect, but an elevated or rising alpha-fetoprotein identifies a heightened risk for HCC.6 Only 16% of children with biliary atresia survive to 2 years with their native liver if the total serum bilirubin measured 3 months following hepatoportoenterostomy (Kasai Procedure) is over 6 mg/dL, compared to 84% for those with a total bilirubin less than 2 mg/dL.7 For some children with Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC) types 1, 2, and 3, pruritus and/or deforming xanthomas can severely impact the child's quality of life despite relatively preserved liver function.8 Sequelae associated with endstage liver disease place children at risk for life-threatening events. 2. Immediate contact with a pediatric LT center should be initiated for children with acute liver failure or acute decompensation of an established liver disease; emergent referral for LT evaluation may be required. (1-A) 3. Children with liver-based metabolic crises refractory to medical and/or surgical therapy (1-B), unresectable hepatoblastoma (1-B), or evidence of hepatocellular unresectable carcinoma (1-B) should be referred urgently for LT evaluation. 4. Biliary atresia (BA) patients who are post-hepatoportoenterostomy (HPE) should be promptly referred for LT evaluation if the total bilirubin is greater than 6 mg/dL beyond 3 months from HPE (1-B); liver transplant evaluation should be considered in BA patients whose total bilirubin remains between 2-6 mg/dL. (1-B) 5. Referral for LT evaluation should be anticipated for children with chronic liver disease and evidence of deteriorating liver function characterized by poor weight gain, growth failure, variceal hemorrhage, intractable ascites, recurrent cholangitis, or episodes of spontaneous bacterial peritonitis, pruritus, advancing encephalopathy, and/or uncorrectable coagulopathy. (1-B) The child's diagnostic evaluation as it relates to their primary disease, associated comorbidities, subspecialty consultations, and management strategies should be documented and provided by the primary pediatric specialist responsible for management of the child's liver disease. These documents should include clinical assessments, results of laboratory and diagnostic studies, medical and nutritional management, surgical procedures, pathology reports and slides, as well as radiographic reports and copies of the radiographs. Personal communication between a member of the LT evaluation team and the child's physician will identify clinical, social, and psychological factors that may not be apparent in the medical record. New or worsening comorbidities may be identified during the LT evaluation.9 6. A review of the local records by the LT team prior to the LT evaluation will inform the evaluation schedule and enable affirmation of the primary diagnosis, assessment of comorbidities, and identify technical challenges related to LT. (2-B) 7. In collaboration with the local primary pediatric specialist, management of the primary disease and comorbidities should be reviewed and optimized. (2-B) Complications associated with endstage liver disease include ascites, pruritus, portal hypertension, malnutrition, vitamin deficiencies, and delayed growth and development.10 In cirrhosis patients, accumulation of ascites is a result of portal hypertension, vasodilatation, and hyperaldosteronism.11 Hypoalbuminemia is an additional risk factor for ascites. Ultrasonography is sensitive enough to detect as little as an ounce of intra-abdominal fluid, while significantly more is required for it to be detected on physical examination. Decisions to initiate diuretic therapy to manage ascites are ill-defined. Abdominal distension alone does not reliably predict ascites, as organomegaly and vascular congestion of the bowel may also contribute to distension. Fluid that is easily palpated between the abdominal wall and the surface of the liver ("ballotable fluid") would suggest sufficient ascites to warrant therapy; its presence can be used to judge response to therapy. Initial treatment includes spironolactone and a "no-added" salt diet. Loop-diuretics should be used with caution as overaggressive diuresis can precipitate hepatorenal syndrome. For hospitalized patients with significant ascites, intravenous albumin, with or without an accompanying diuretic, can improve diuresis and response to diuretics.12 Tense ascites can compromise respiratory function and renal perfusion, heighten the risk for infection, and contribute to a poor quality of life.13 Large-volume paracentesis14 and transjugular intrahepatic portosystemic shunt (TIPS)15 are effective if ascites is compromising the child's respiratory effort and is not responsive to medical therapy. Rapid accumulation of ascites should raise concern for obstruction of the portal or hepatic vein or bacterial peritonitis. Evaluation and management of esophageal varices in children varies widely among practitioners.16, 17 In the absence of data supporting primary prophylactic therapy for esophageal varices in children, screening endoscopy for esophageal varicies has not been recommended.18 Inflammatory bowel disease (IBD), particularly ulcerative colitis, is a notable comorbidity of children with primary sclerosing cholangitis (PSC). Following LT, some patients with autoimmune hepatitis and bile salt excretory pump disease are at risk for recurrence of their primary liver disease19, 20; those with PSC may also be at increased risk for colon cancer.21, 22 8. Clinically detectable ascites can be managed initially with an aldosterone antagonist (2-B); more aggressive removal of ascitic fluid using paracentesis or transjugular intrahepatic portosystemic shunt or surgical shunt should be reserved for ascites that compromises respiratory effort or severely affects quality of life. (2-B) 9. Patients with conditions such as autoimmune hepatitis, PSC, and bile salt excretory pump disease should be informed that liver disease can recur post-LT. (2-B) 10. Patients at risk for extrahepatic complications such as IBD should be informed of the need for scheduled monitoring for evidence of IBD, including colonoscopy, for colon cancer surveillance. (2-B) Children with chronic liver disease are at risk for malnutrition as they require 20%-80% more calories than normal children to achieve adequate growth.23-25 Increased caloric requirements result from a hypermetabolic state coupled with malabsorption. Aggressive nutritional support prior to LT improves patient and graft survival as well as neurodevelopmental outcome.26, 27 Serial triceps skin fold and mid-arm circumference are the most reliable anthropometric assessments to judge nutritional status, as reliance on weight alone may overestimate nutritional adequacy in children with chronic liver disease.24, 25, 28 Fat soluble vitamin (FSV) deficiency is common and dosing and monitoring recommendations to prevent FSV deficiency are available.24, 25, 29, 30 Enteral formulas that contain medium chain triglycerides (MCT) are preferred in cholestatic patients, but excessive administration of MCT can lead to essential fatty acid deficiency.31 Protein intake should not be restricted in the absence of hyperammonemia.32 When oral intake is not sufficient, initiation of nasogastric (NG) tube feeding improves body composition in children with chronic liver disease.33 Parenteral nutrition may help reverse poor weight gain and growth in malnourished children with BA.34 Less than 15% of children receiving a liver transplant are obese.35 Patients with body mass index (BMI) z-scores ≥3 have similar short-term survival as normal-weight counterparts, but had increased late (>12 years) mortality and are more likely to experience posttransplant obesity.36 Metabolic syndrome occurs frequently in obese adult liver transplant recipients, but the rate in obese pediatric recipients is not known.37, 38 11. Complete nutritional assessment should include serial triceps skin fold thickness and mid-arm circumference measurements (2-B); identification of nutritional goals to maximize health; fat soluble vitamin supplementation and monitoring (2-B); and in cholestatic infants, use of medium-chain triglyceride-containing formulas with normal protein administration (2-4 g/kg/day). (2-B) 12. Aggressive nutritional support for children awaiting LT should be initiated to optimize outcomes (1-B); NG tube feedings and parenteral nutrition may be needed in some circumstances. (2-B) Structural cardiac disease can be seen in children with BA and Alagille syndrome.39 Cirrhotic cardiomyopathy (CC), characterized by increased cardiac output, impaired diastolic relaxation, myocardial hypertrophy, and repolarization abnormalities, carries a high risk of post-LT mortality in adults. Evidence of cardiomyopathy, as determined by two-dimensional echocardiography (2-DE), can also be found in children with cirrhosis as well as those with cardiomyopathy associated with glycogen storage disease or systemic mitochondrial disease. In one study, 70% of children with BA had evidence of CC.40 While those with CC experienced a longer ICU and hospital stay, there were no differences in the 2-DE between those who died awaiting LT versus those who survived to LT. Hepatopulmonary syndrome (HPS) and porto-pulmonary hypertension (PPHN), both described in more detail below, are potentially life-threatening conditions that develop as a consequence of portosystemic shunting regardless of the severity of the liver disease.41, 42 Nonspecific clinical findings include digital clubbing, facial telangiectasia, dyspnea, wheezing, and syncope. Screening for HPS is performed by pulse oximetry detection of oxygen desaturation when in the sitting or standing position; pulse oximetry less than 97% on room air should be considered for further evaluation.43 HPS is confirmed with 2-DE during infusion of agitated saline with the appearance of saline bubbles in the left atrium within 3-6 cardiac cycles. A 99mTechnetium-macroaggregated albumin (MAA) perfusion lung scan can be used to quantify and follow the degree of intrapulmonary shunting; an MAA shunt fraction of 27.8% was highly specific for intrapulmonary shunting associated with hypoxia.44, 45 Unlike HPS, screening procedures for PPHN are imperfect. While the chest radiograph and electrocardiogram may reveal a prominent pulmonary artery and right ventricular hypertrophy, but both may be normal.46 In addition, 2-DE with Doppler may show elevations in right ventricular systolic pressures which should be confirmed by cardiac catheterization to exclude other causes of pulmonary hypertension such as increased central volume and high cardiac output due to a hyperdynamic cardiac physiology.47 Patients with cystic fibrosis (CF) referred for LT present a unique challenge. In addition to being at risk for development of HPS and PPHN, the severity of CF-related lung disease can impact outcome. The forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) have been used in a model to predict survival.48 FEV1 was found to be lower in CF patients with liver disease who subsequently receive LT than those who do not undergo LT and is used to monitor improvement following LT.49 13. Screening transcutaneous oxygen saturation with the patient in the upright position should be performed in all patients with possible portosystemic shunting. (2-B) 14. Two-dimensional echocardiography (2-DE) with Doppler should be performed in all patients at the time of liver transplant evaluation (2-B); if the right ventricular systolic pressure is over 50 mmHg by 2-DE, a right-heart cardiac catheterization is necessary to establish the diagnosis of porto-pulmonary hypertension. (2-B) 15. Pulmonary function tests, including forced expiratory volume in one second and forced vital capacity should be performed in patients with cystic fibrosis evaluated for liver transplant. (2-B) Glomerular filtration rate (GFR) is the most practical measure of kidney function.50 Direct measurement of GFR using an exogenous filtration marker, such as iohexol plasma clearance, is impractical in the routine clinical setting.51 Endogenous filtration markers, such as creatinine clearance, are hampered by the imperfections of timed urinary collections. Static measurements of naturally filtered molecules, such as creatinine, are affected by muscle mass, age, and gender as well as renal tubular absorption and secretion. At best, only an estimate of the GFR can be achieved. Serum creatinine, while imperfect, is most often used to screen individuals for evidence of renal insufficiency, but cannot be used to estimate GFR independently. The recently revised Schwartz Formula utilizes the serum creatinine (sCr), patient height, and a "constant" to derive an estimated creatinine clearance (eCCL) and is easily used at the bedside.51 The formula is 0.413 × [sCr (mg/dL) / height (cm)] = GFR (mL/min/1.73 m2). Cystatin C is a low molecular weight protein that is almost completely filtered by the glomerulus, is not excreted or absorbed by the renal tubules, and is not affected by muscle mass, age, or gender.52 Normal values for cystatin C are high in infants but approach normal adult levels (0.51-0.98 mg/L) by 1 year of age.53 A cystatin C level of 1.06 mg/L predicted a GFR <80 mL/min/1.73 m2 with a sensitivity and specificity of 91% and 81%, respectively, in a pediatric cohort of 62 children with a median age of 3.1 years (range 0.6-18.7 years) that included both pre- and post-LT patients.52 For children with acute renal injury, the pediatric modified RIFLE (Risk for renal dysfunction, Injury to the kidney, Failure of the kidney, Loss of kidney function, and Endstage renal disease) criteria utilizes a combination of the eCCL by the Schwartz method and urine output to inform the severity of renal injury.54 Renal insufficiency that would necessitate combined liver and kidney transplant (CLKT) is less common in children than adults.55 Renal dysfunction among children with chronic liver disease can be quite variable. For example, children with biliary atresia tend to have good renal function prior to and following liver transplant,56, 57 while those with tyrosinemia may have a glomerular filtration rate of less than 55 mL/min/1.73 m2.58 Significant renal disease can be associated with primary hyperoxaluria, congenital hepatic fibrosis, and methylmalonic acidemia. Renal dysfunction prior to LT can be exacerbated following LT, particularly in children with inborn errors of metabolism, alpha-1-antitrypsin deficiency (A1ATD), and Alagille syndrome (AGS).59-62 Increased susceptibility to renal toxicity caused by calcineurin inhibitors may be attributed to associated genetic polymorphisms in the ABCB1 gene.63 16. Renal function should be assessed in all patients, with special emphasis on those with metabolic liver diseases associated with renal dysfunction (1-B) and those at increased risk for calcineurin inhibitor toxicity. (2-B) 17. Serum creatinine alone should not be used to assess renal function (1-B); either cystatin C (2-B) or the revised Schwartz Formula (2-C) should be used to estimate the glomerular filtration rate in children with chronic liver disease. 18. The modified Risk for Renal Dysfunction, Injury, Failure, Loss, and Endstage renal disease could be used to assess the degree of acute renal injury. (2-B) Dental caries due to frequent and prolonged bottle-feeding occur in children with endstage liver disease.64, 65 A survey of transplant centers in the United States noted that a dental infection prior to transplantation resulted in cancellation or postponement of LT (38% of responding sites) and post-LT sepsis from a suspected dental source (27% of sites).66 Preventive oral health care strategies are important in this patient population.66, 67 19. Children with endstage liver disease should receive a careful oral examination looking for evidence of dental caries, gingival disease, or dental abscess; referral to a pediatric dentist should occur if abnormalities are identified. (2-B) General anesthesiology assessment should include determination of venous access, review of cardiovascular, respiratory, gastrointestinal, renal, central nervous system, hepatic, and hematological systems.68 Pathophysiological changes associated with these systems will impact method of induction, intraoperative fluid management, drug dosing, and ventilatory requirements.68, 69 Risk factors that require careful assessment include patient age and weight, nutritional status, hypoalbuminemia, hepatopulmonary syndrome, and cardiomyopathy associated with cirrhosis.69, 70 Pediatric conditions and their associated comorbidities that may heighten anesthetic risk include Alagille syndrome (cardiac disease, vascular and renal abnormalities, and moyamoya), biliary atresia with splenic malformation (complex heart disease, interrupted inferior vena cava), and primary hyperoxaluria (renal and cardiac dysfunction).69 A specialized LT anesthesia team has been associated with more favorable patient outcomes in adults, although pediatric centers were excluded from this study.71 The United Network for Organ Sharing (UNOS) has recently modified policy to require liver transplant programs to designate a Director of Liver Transplant Anesthesia who has expertise in the area of perioperative care of liver transplant patients and can serve as an advisor to other members of the team. 20. An anesthesiologist familiar with pediatric indications for LT and associated comorbidities should ensure the LT evaluation includes appropriate disease-specific assessments to minimize intraoperative and postoperative anesthetic risk. (2-B) Children with chronic liver disease are often not fully immunized prior to LT.72, 73 Development of a vaccine preventable disease (VPD) either before or after LT will increase morbidity and mortality and heightened the risk of graft injury or loss.74, 75 Timing of immunization administration in the LT candidate is important, as vaccines are more immunogenic before the development of endstage liver disease and more immunogenic before than after LT. Humoral immunity to rubella, measles, and varicella vaccines is significantly decreased in children with biliary atresia compared to healthy controls.76 VPD can develop in immunized children with chronic liver disease when antibody titers are low.77 There is a paucity of data related to influenza vaccine in patients with chronic liver disease.78 Hepatic decompensation has been reported with influenza,79 and influenza vaccination in adults with cirrhosis significantly reduced the frequency of hepatic decompensation compared to those who did not receive the vaccine.80 Guidelines for vaccination of liver transplant candidates and recipients are published periodically by the American Society of Transplantation.81 Clinical practice guidelines for vaccination of the immunocompromised host were recently published by the Infectious Diseases Society of America.82 Vaccination of household contacts provides additional protection to the child.83 Paralytic polio has been described in household contacts of oral polio vaccine recipients.84 Data suggest that administration of live virus vaccines to household contacts, other than oral polio, poses minimal risk to the child.83 Both Epstein-Barr virus (EBV)-associated lymphoproliferative disease and disseminated cytomegalovirus (CMV) are associated with significant morbidity and mortality in children receiving LT. Children are at highest risk for these conditions if they are immunologically naive to EBV and CMV and receive a liver from a serologically positive donor.85, 86 LT candidates serologically positive for CMV remain at risk for developing post-LT CMV.87 Preventive strategies to reduce EBV and CMV disease post-LT include assessment of EBV and CMV status in the recipient and have significantly improved LT outcomes.86, 87 21. Completion of all age-appropriate vaccinations, for the child and family members, should occur prior to transplantation and ideally before the development of endstage liver disease (1-B); children who have not completed the necessary vaccine schedule can receive vaccinations on an accelerated schedule. (1-B) 22. Seasonal inactivated influenza vaccination should be given for listed patients older than 6 months and their family members, and to family members of infants less than 6 months. (1-A) 23. Family members of children evaluated for LT should be fully immunized using both live and attenuated virus vaccines (1-B); the oral polio vaccine should never be used. (1-A) 24. Evidence of a prior Epstein-Barr virus and cytomegalovirus infection, as determined by virus-specific serological measurements, should be performed on all individuals evaluated for liver transplant, recognizing that for children less than 12-18 months of age, antibodies may have been passively transmitted to the child from the mother. (1-A) Successful LT requires lifelong care and presents unique challenges to families dealing with a child with a serious illness.88 Feelings of guilt, inadequacy, stress, lack of control, uncertainty, anger, and fear by the primary caregiver can have a negative impact on disease management and family structure unless they are identified and addressed. Lack of parental understanding of the child's condition, of housing, and transportation are deleterious to the management of chronic conditions. Engagement of child protective services may be necessary if the principal impediment to successful disease management is the child's social situation.89, 90 Psychosocial factors impact posttransplant outcomes, specifically factors related to treatment adherence.91-93 Risk factors for nonadherence include a history of resistance to taking medications, substance abuse, physical or sexual abuse, school absenteeism, single parent home, and having received public assistance. Psychiatric assessment tools designed for pediatric LT candidates can identify risk factors such as parental psychopathology, substance abuse by the parent/guardian or patient, chaotic family environment, family perceptions, and lack of financial resources suggesting high-risk candidates who would benefit from targeted early intervention, including barriers to adherence.93-96 25. Families should be assessed to ensure social services and psychosocial support systems are adequate for LT-candidates in order to optimize posttransplantation outcomes. (1-B) 26. Patients and families at potential risk for nonadherence should be identified and receive focused psychosocial interventions prior to and following transplantation. (1-B) 27. Members of the transplant team, in conjunction with the child's primary care provider, may need to serve as the child's advocate in situations where support systems are inadequate to the degree that the child's transplant candidacy in impaired or a high risk of noncompliance is identified. (1-B) Cognitive measures have revealed reduced global cognitive functioning in children following LT,97-99 and specific weaknesses in motor skills and receptive language development following LT.100, 101 Poorer nutritional status early in life, reduced head circumference, poor weight gain and growth, and low vitamin E levels correlate with poor cogniti