Biliary atresia (BA) is a progressive, fibro‐obliterative disorder of the intrahepatic and extrahepatic bile ducts in infancy. The majority of affected children will eventually develop end‐stage ...liver disease and require liver transplantation (LT). Indications for LT in BA include failed Kasai portoenterostomy, significant and recalcitrant malnutrition, recurrent cholangitis, and the progressive manifestations of portal hypertension. Extrahepatic complications of this disease, such as hepatopulmonary syndrome and portopulmonary hypertension, are also indications for LT. Optimal pretransplant management of these potentially life‐threatening complications and maximizing nutrition and growth require the expertise of a multidisciplinary team with experience caring for BA. The timing of transplant for BA requires careful consideration of the potential risk of transplant versus the survival benefit at any given stage of disease. Children with BA often experience long wait times for transplant unless exception points are granted to reflect severity of disease. Family preparedness for this arduous process is therefore critical. Liver Transplantation 23:96–109 2017 AASLD.
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that occurs in the setting of insulin resistance and increased adiposity. It has rapidly evolved into the most ...common liver disease seen in the pediatric population and is a management challenge for general pediatric practitioners, subspecialists, and for health systems. In this guideline, the expert committee on NAFLD reviewed and summarized the available literature, formulating recommendations to guide screening and clinical care of children with NAFLD.
Background and Aims
Tolerance is transplantation’s holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long‐term pediatric ...liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance.
Approach and Results
We conducted a multicenter, single‐arm trial of immunosuppression withdrawal over 36‐48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3‐4). For‐cause biopsies were done at investigators’ discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval CI 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial‐entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects.
Conclusions
Immunosuppression withdrawal showed that 37.5% of selected pediatric liver‐transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.
Little is known about the impact of sarcopenia (reduced muscle mass and function) in pediatric chronic liver disease. We compared psoas muscle surface area (PMSA), measured at the 4th lumbar ...vertebrae, in children listed for liver transplantation (LT) to that of healthy controls and studied the impact of sarcopenia on transplant‐associated outcomes. The effect of PMSA (raw value and z score) on survival was studied using multivariable proportional hazards, whereas the impact of PMSA on other transplant‐associated outcomes was assessed by multivariable linear or logistic regression. The correlation of PMSA with anthropometric values and markers of disease severity was studied using Spearman’s rank‐order correlation. Mean PMSA was significantly lower in LT candidates (n = 57, 699.4 ± 591.9 mm2 mean ± SD) than controls (n = 53, 1052.9 ± 960.7 mm2; P = 0.02). For LT candidates, there was an increased risk of death (either while on the waiting list or following transplantation) with lower PMSA (hazard ratio HR, 1.6 per 100 mm2 P = 0.03; 95% confidence interval CI, 1.1‐2.8), amounting to a 4.9 times higher risk of death for every 1 unit decrease in PMSA z score (HR, 4.9 P = 0.05, 95% CI, 1.2‐34.5), adjusting for age and sex. PMSA did not correlate with posttransplant length of intubation, hospital length of stay, or perioperative complications. PMSA also did not correlate with calculated (r = 0.10, P = 0.60) or appealed Model for End‐Stage Liver Disease/Pediatric End‐Stage Liver Disease scores (r = 0.10, P = 0.69). Pediatric LT candidates have a significant reduction in muscle compared with controls. LT candidates with lower PMSA experience significant increases in mortality. As such, sarcopenia may provide a novel indicator of disease severity in children with chronic liver disease.
To develop neonate-specific prediction models for survival with native liver (SNL) in neonatal acute liver failure (ALF) and to determine if these prediction models have superior accuracy to existing ...models for older children with ALF.
A single-center, retrospective chart review was conducted on neonates ≤ 30 days of life between 2005 and 2022 with ALF (international normalized ratio ≥ 2 or prothrombin time ≥ 20s and liver dysfunction). Statistical analysis included comparison of patients by outcome of SNL and generalized linear modeling to derive prediction models. The predictive accuracy of variables was evaluated by receiver operating characteristic (ROC) analysis and Kaplan-Meier survival analysis.
A total of 51 patients met inclusion criteria. The most common causes of neonatal ALF included ischemia (22%), infection (20%), and gestational alloimmune liver disease (16%). Overall SNL rate was 43% (n = 22). Alpha fetoprotein levels were higher in SNL patients (P = .034) and differed more significantly by SNL status among nongestational alloimmune liver disease patients (n = 21, P = .001). An alpha fetoprotein < 4775 ng/mL had 75% sensitivity and 100% specificity to predict death or transplant in nongestational alloimmune liver disease patients with an area under the ROC curve of 0.81. A neonate-specific admission model (international normalized ratio and ammonia) and peak model (prothrombin time and ammonia) also predicted SNL with good accuracy (area under the ROC curve = 0.73 and 0.82, respectively).
We identified neonate-specific prognostic variables for SNL in ALF. Findings from our study may help early risk stratification to guide medical decision-making and consideration for liver transplantation.
Objective To characterize infants aged ≤90 days enrolled in an international, multicenter, prospective registry of children aged <18 years with acute liver failure (ALF). Study design The Pediatric ...Acute Liver Failure (PALF) Study Group collects prospective data on children from birth to 18 years. We analyzed data from infants aged ≤90 days enrolled in the PALF Study before May 18, 2009. Results A total of 148 infants were identified in the PALF registry (median age, 18 days). Common etiologies of ALF were indeterminate (38%), neonatal hemochromatosis (13.6%), and herpes simplex virus (12.8%). Spontaneous survival occurred in 60% of the infants, 16% underwent liver transplantation, and 24% died without undergoing liver trsansplantation. Infants with indeterminate ALF were more likely to undergo liver transplantation than those with viral-induced ALF ( P = .0002). The cumulative incidence of death without liver transplantation was higher in infants with viral ALF (64%) compared with those with neonatal hemochromatosis (16%) or indeterminate ALF (14%) ( P = .0007). Conclusion ALF in young infants presents unique diagnostic considerations. Spontaneous survival is better than previously thought. Liver transplantation provides an additional option for care.
While dietary changes are recommended to treat pediatric non-alcoholic fatty liver disease (NAFLD), the role of specific nutrients in disease progression is unclear. The objective of this study is to ...(1) assess the macronutrient and micronutrient intake in adolescents with liver biopsy proven NAFLD with and without non-alcoholic steatohepatitis (NASH) and lean controls; (2) determine nutritional predictors of disease severity amongst these groups.
Adolescents with biopsy-proven NAFLD and lean controls completed the Harvard Food Frequency Questionnaire.
Twenty-eight NAFLD and 15 lean controls were studied. NAFLD with (n = 20) and without NASH (n = 8) had similar total calorie, protein, fat, and carbohydrate intake. Subjects with NASH had higher total sugar (122.3 ± 48.3 vs 83.1 ± 38.8 g), glucose (24.3 ± 9.3 vs 15.2 ± 7.5 g), sucrose (42.3 ± 16.9 vs 28.8 ± 11.7 g), and fructose (29.4 ± 12.5 vs 18.1 ± 8.0 g) intake than those with NAFLD but without NASH ( P < 0.05). Both NAFLD groups had similar micronutrient intake. Alanine aminotransferase (ALT) correlated with total caloric intake ( ρ = 0.4; P = 0.04). Total carbohydrate calories correlated with a higher NAS summary score ( ρ = 0.38; P = 0.04) and lobular inflammation ( ρ = 0.50; P = 0.007). Percent calories from added sugar and glucose correlated with worsening NAS summary score ( ρ = 0.44, P = 0.02; ρ = 0.48, P = 0.009) and lobular inflammation ( ρ = 0.51, P = 0.006; ρ = 0.53, P = 0.004). Percent calories from fructose correlated with lobular inflammation ( ρ = 0.56; P = 0.002). Total daily calories, protein, fat, carbohydrate, and micronutrient intake were similar between NAFLD and lean controls.
NASH patients consume similar total calories, protein, and fat as those without NASH, but have significantly higher sugar intake. NAFLD and lean children, however, have similar macro/micronutrient intake. Histologic disease severity correlates with total carbohydrate and added sugar intake, supporting a role for simple sugar intake in NAFLD progression.
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