Long-term medical management of the pediatric patient after liver transplantation: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation

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Abstract

These recommendations provide a data-supported approach to establishing guidelines. They are based on the following: (1) a formal review and analysis of recently published world literature on the topic (via a PubMed/MEDLINE search from 1996 to July 2011 limited to the English language, human studies, and children 0-18 years old); (2) A Manual for Assessing Health Practices and Designing Practice Guidelines from the American College of Physicians1; (3) guideline policies, 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 the use of medical practice guidelines2; and (4) the experience of the authors in managing children undergoing liver transplantation (LT). Intended for use by pediatricians and 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 quality of the evidence supporting the recommendations, the Practice Guidelines Committee of the American Association for the Study of Liver Diseases requires a class (reflecting the benefit versus the risk) and level of evidence (assessing the strength or certainty) to be assigned to and reported with each recommendation. To more fully characterize the available evidence supporting the recommendations, the Practice Guidelines Committee has adopted the classification used by the Grading of Recommendations, Assessment, Development, and Evaluation workgroup with minor modifications3, 4 (Table 1). In the Grading of Recommendations, Assessment, Development, and Evaluation system, the strength of recommendations is classified as (1) strong or (2) weak. The quality of evidence supporting strong or weak recommendations is designated by 1 of 3 levels: (A) high, (B) moderate, or (C) low. Pediatric LT has dramatically changed the prognosis for many infants and children with liver failure and metabolic disease. As survival increases, long-term maintenance resources exceed perioperative care requirements. The commonest indication for LT is biliary atresia, which accounts for 50% of children requiring transplantation in the United States5 and for 74% in Europe.6 Most early deaths occur within 3 months after transplantation. The main causes of graft loss in the first week include primary nonfunction, hepatic artery thrombosis (HAT) or portal vein thrombosis (PVT), systemic sepsis, and multiorgan failure (90% for chronic liver disease and 89% for metabolic liver disease.18, 19 Vital to survival are improved selection (prioritization and management of candidates with the Pediatric End-Stage Liver Disease score), better preoperative management of hepatic complications and nutritional support, innovative surgical techniques for expanding the donor pool, and improved postoperative immunosuppression and management.7, 20, 21 As the emphasis moves from immediate survival and the prevention and management of early postoperative complications, attention has become focused on long-term outcomes and quality of life. Most studies have demonstrated improved nutrition, bone metabolism, endocrine function, and psychosocial development after successful transplantation, with recent studies documenting cognitive function, educational achievement, and patient and family perceptions of quality of life. Long-term issues include recurrent disease, adverse effects of immunosuppression (especially chronic kidney disease), hypertension, hyperlipidemia, the development of malignancies (eg, posttransplant lymphoproliferative disease), and the management of adolescents' transition to adult care. Although they undergo transplantation at specialized centers, recipients receive care from local providers, who must recognize potential long-term care challenges. This document provides an expert consensus on managing children from 3 months after LT. It focuses on preventing and diagnosing complications, preventing chronic infections, reducing the adverse effects of immunosuppression, ensuring a good quality of life, and managing the transition from childhood to adolescence and adulthood. Physical measurements include height, weight, and lean muscle mass. Few pediatric LT studies have measured muscle mass, but weight gain appears to recover fully in patients with adequate graft function despite previous malnutrition. Linear growth failure is common in children with cirrhosis because of malnutrition secondary to fat malabsorption, abnormal nitrogen metabolism, and increased energy expenditure and possibly growth hormone resistance.22 After successful LT and nutritional restitution, growth hormone and insulin-like growth factor 1 levels return to normal, and linear growth improves.23 Catch-up growth is dependent on steroid usage and may not occur until the second year24,25; this plateaus after 2 to 3 years, and up to 25% of patients have heights less than 5% for their age over the long term. The Studies of Pediatric Liver Transplantation (SPLIT) registry reveals that linear growth impairment ( 10 degrees. Males were predominantly affected.56 Low muscle mass, found in many children with liver disease, leads to low bone mass. The only relevant study showed a moderately reduced ratio of the bone mineral content to the lean tissue mass.49 Hepatic protein synthesis, including insulin-like growth factor 1 production, improves after LT48 and spurs moderate catch-up growth. Vitamin D (25-hydroxyvitamin D) levels in children are low before and immediately after OLT45, 46, 48 but improve during the first year.48 Routine vitamin D (3-10 times the recommended daily allowance37) is recommended for cholestatic liver disease but is not yet routine after OLT. Monitoring includes measurements of calcium, phosphate, vitamin D, and parathyroid hormone levels at least twice a year. Vitamin D should be given as cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2).57 An appropriate intake of calcium and phosphate should be ensured, especially in children on immunosuppressants such as tacrolimus, which can cause phosphate loss.58 Children with pretransplant osteopenia should be monitored for scoliosis, and children older than 5 years should be monitored for fractures. Dual-energy X-ray absorptiometry scanning at LT and 12 and 24 months afterward may help with appropriate size correction59-62 and lateral thoracic spine X-rays. Bisphosphonates should be considered for low bone mass with a vertebral fracture, a lower extremity fracture, or 2 upper limb fractures.63 Studies suggest that pediatric LT patients have lower physical and psychosocial function.64-68 A multicenter study of more than 800 recipients found psychosocial function more compromised than physical function, and psychosocial health was affected by school function, particularly if there was cognitive impairment or significant school absence. A large survey of children included in the SPLIT registry revealed that one-third missed more than 10 days of school in the previous year, and 18% missed more than 20 days. Absence was likelier for older participants and children with shorter intervals from LT.69 Programs caring for pediatric LT recipients might consider routine follow-up clinics for older children at times not interfering with school attendance. Up to 16% of adolescents reported symptoms consistent with posttraumatic stress disorder.70 Parents also reported symptoms of posttraumatic stress disorder and significant stress and anxiety related to the child's medical condition.71, 72 Medication concerns and treatment anxiety were significant among pediatric recipients.73 Children reported that medications changed their physical appearance and that parents nagged them about adherence. Nonadherence has been associated with lower physical quality of life, limitations in social and school activities, increased parental emotional distress, and decreased family cohesion.74 The onset of liver disease in infancy impairs neurodevelopment.69, 75-83 Infants with metabolic diseases (eg, urea cycle defects and tyrosinemia) may suffer significant neurological damage that may be alleviated by early therapy, which can include LT.84 Liver disease in infancy is commonly caused by biliary atresia or other biliary cirrhosis. These infants typically experience advanced malnutrition, growth arrest, and profound muscle weakness. Although many maintain low-average mental and motor development before transplantation, their function drops significantly during the transplant process.85 Recovery and delayed developmental catch-up in these infants have been associated with prolonged hospitalization, an older age at transplant, and malnutrition before transplantation. Studies comparing neurocognitive function before and after LT have noted that many patients' delays persist after physical rehabilitation.64, 69, 79, 80, 86, 87 Various groups have demonstrated severely impaired intellectual ability in 10% to 15% of recipients; newer studies have reported slightly better outcomes. Several studies have suggested differential impairment of language and verbal skills80; nearly 15% lose some hearing, and this is especially true for children who receive ototoxic medications before transplantation (eg, children with hepatoblastoma).88 Approximately 30% require special education after transplantation.64 Early results of a longitudinal, multicenter study measuring intelligence, academic achievement, and executive function in recipients who received a transplant at less than 5 years of age indicated that a cognitive delay could be identified at 5 to 7 years.87 A mild to moderate delay was demonstrated in 28% of the members of this cohort, with little improvement 2 years later. Executive functions (organizational skills, multitasking, and behavior regulation) were also delayed in this group. The results of the 6-question Pediatric Quality of Life Inventory Cognitive Function Scale correlated well with formal testing of intelligence and executive function.89 Immunosuppression is essential for graft survival, and adherence to the prescribed regimen is essential to ensure adequate immunosuppression. Nonadherence could cause allograft rejection90-93 and death.94 Measurement of adherence is difficult because different assessments yield different results.95, 96 Methods are subjective (self-reports and interviews) or objective (patient observation, medication blood levels, electronic monitoring, pill counts, and refill rates). Objective methods (especially direct measurements of ingestion) are preferred.91 One direct measure is the calculation of the standard deviation of consecutive immunosuppressant (tacrolimus) blood levels.96 A higher standard deviation denotes more variability (less consistent ingestion). A fluctuation exceeding 2 or 2.5 standard deviations predicts clinically significant nonadherence.96 Many reviews discuss the psychosocial factors that predict nonadherence,97-99 such as psychological symptoms of the patient or the caretaker, family interactions, barriers to adherent behavior, health beliefs (including responsibility shifts between the caretaker and the child), the disease process (eg, the time since transplantation), care factors (prescription pattern and clinic makeup), and socioeconomic status. Strategies for improving adherence include simplifying treatment regimens, addressing risk factors, using interventions such as reminders (eg, text messaging100), and following up patients more intensively.101 Successful pediatric LT is associated with improved quality of life12 and normal liver function. Survival rates are 70% to 90%.7, 13, 14, 21 Two reviews summarize operative techniques.102, 103 The transplant center should summarize surgical details such as the type of allograft implanted (whole versus partial and living donor versus split), the type of biliary reconstruction employed (duct-to-duct reconstruction versus Roux-en Y choledochojejunostomy), and the type of abdominal wall closure used (primary fascial versus prosthetic reconstruction). Major complications (HAT, PVT, biliary strictures, and biliary leaks) should be communicated. A thorough physical examination, standard laboratory parameters, and ultrasound examinations of the liver, spleen, and kidneys generally define vascular patency and biliary complications. Most series have reported HAT rates between 3% and 10%.8 Early HAT commonly leads to early graft failure, retransplantation, or death. Collateralized arterial flow into the transplanted liver may minimize late HAT. Mild abnormalities (1.5-2 times normal levels) in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) are common but may indicate vascular problems. Because the blood supply to transplanted bile ducts is derived solely from the hepatic artery, HAT is frequently associated with biliary pathology. Serum total bilirubin, alkaline phosphatase, and gamma-glutamyltransferase (GGT) levels are sensitive indicators of late HAT. The first-line imaging test is usually a Doppler ultrasound examination of the liver. Although it is >90% sensitive for detecting early HAT,104 its utility for late HAT is poor. A definitive diagnosis of late HAT requires more advanced imaging [computed tomography (CT), magnetic resonance (MR), or standard angiographies105]. Treatment may not be required if the patient is stable and the liver receives adequate blood flow through arterial collaterals or the portal vein. If treatment is required, thrombolysis and anticoagulation are rarely effective, and surgical reconstruction is contraindicated. Radiological treatment of biliary strictures is indicated if necessary, and drainage of intrahepatic abscesses/bilomas is required. For late HAT with hepatic or biliary is frequently required. is generally reported at rates of and most are Early frequently leads to graft failure, retransplantation, or death. flow the transplanted liver with is common and may for for vein strictures that develop in reduced or have also been Children with or portal vein strictures a liver and an abdominal wall or may be may develop with the severe portal hypertension associated with of may also occur in advanced because has been associated with and syndrome and with testing provides evidence of and levels typically may be normal to slightly abnormal (1.5-2 times normal Serum bilirubin, alkaline phosphatase, and levels are typically The usually is low because of is common and is related to or and imaging with Doppler hepatic ultrasound is usually The liver is typically or because is associated with The portal vein is more and thrombosis can commonly be and can be with this with or standard define the of the within the portal vein as well as its into such as the or vein. for detecting and may late The treatment is to that for portal hypertension in the treatment of can also prevent or intrahepatic have because of thrombosis of the portal vein. systemic and are but may be vein or with and is and with and The diagnosis is with Doppler ultrasound and hepatic The of a may be The rates for biliary strictures after pediatric LT from 5% to In contrast to biliary which are an early biliary biliary strictures late after LT. The main cause of late biliary strictures is graft HAT can be with definitive biliary strictures are frequently and affect aspects of the biliary In biliary strictures are usually associated with the surgical These strictures are more common with than The physical examination may be strictures with and testing is in and levels are normal or The are alkaline and 5 to 10 times normal This can be with hepatic or magnetic resonance imaging A definitive diagnosis is with contrast or with to the hepatic The most test is and the of a biliary the biliary is only in patients who have received a Treatment of late biliary strictures is successful if the hepatic artery is and if there is an or is usually for patients for has is usually required for and biliary strictures and particularly for associated with late should be An occurs in 5% to 18% of The is after primary fascial and this is followed by the in patients with a prosthetic This can be with a physical An of and their is A requires an surgical most only require The preoperative should include an of the liver or may a The for liver in patients with normal liver function is to document the history of the rejection or graft or the withdrawal of immunosuppression, and biliary disease or other recurrent are but to 5% of children may have a significant complication assessments of with of or are being in children with or liver has been in adults at 7 to 21 at and 10 years, or to or or recurrent A pediatric have liver after transplantation to Most found that 1-year from children with normal liver function were normal in and they not provide on graft However, examinations of and from children have increased graft and In children underwent liver was and at and 10 years, < also and at and 10 years, < 10 years, 15% had to cirrhosis. was identified in there was evidence of a viral was a for and 10% of children with normal results at 5 and 10 years, and for and of with chronic at 5 and 10 years, < children the for 2 were It is not these a of due to the immunosuppression or because the graft improved with increased An in graft but not graft was also reported after transplantation by that noted from to = from 1 year after LT to 5 was increased of at 10 years = but the proportion of patients with severe increased from 10% at 5 years to The was not related to chronic or but may have or occurs in 5% to 10% of children after This syndrome is by and from in patients undergoing transplantation for other than It is by evidence of chronic associated with and muscle an of (particularly and allograft The cause may be a of and may be related to or of The increased in children may be related to a of normal Most respond to increased or studies have identified graft in adults for or are not available for for and every year for 5 years and testing for and and may or viral infections and the for may decreased damage from or a to chronic is during the first 10 to 15 years after An analysis of the found that malignancies for 12% of pediatric posttransplant In a study that solid organ transplant patients than 18 years between and = to the 2 of were recipients should be on and The following is from the Diseases of Practice and the American of Routine should be given before transplantation; these include diseases, A and and (Table are generally after transplantation. is not recommended in children long-term One found the to be with the of may be given to family are with with lower levels of immunosuppression. particularly for should be up to physical including

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