OBJECTIVES:To assess for myopenia in adolescents with overweight/obesity (OO), and to evaluate relationships between skeletal muscle mass, hepatic steatosis and insulin sensitivity/glycemia. STUDY DESIGN:Secondary analysis of data collected across seven metabolic studies in adolescents with BMI ranging from OO to healthy weight (HW). Appendicular lean mass (ALM) was measured from previously obtained dual energy x-ray absorptiometry (DXA) scans and used to calculate ALM index (ALM (kg)/weight (kg) × 100). Metabolic outcomes included MRI-based fat distribution (hepatic fat fraction [HFF], visceral and subcutaneous fat mass), fasting and glucose-stimulated laboratory assessments of insulin sensitivity, secretion, and glycemia, as obtained in the parent studies. The relationships between ALM index and metabolic outcomes were studied using multivariable linear regression. RESULTS:ALM was calculated in 304 adolescents-228 with OO (mean age 15.2 ± 2.4 years, Tanner stage 4.5 ± 1.1, 88.2% female) and 76 HW (13.7 ± 2.6 years, Tanner stage 3.4 ± 1.2, 59.2% female). Mean ALM index was significantly lower in OO than HW (23.7% ± 2.9% vs. 31.8% ± 4.5%, p < 0.01). ALM index had a significant association with square-root-transformed HFF (β = -0.09, SE = 0.03, t-value = -2.92, p < 0.01). ALM index was negatively associated with fasting C-peptide (p < 0.01) but not with other markers of insulin sensitivity/glycemia. CONCLUSION:Low ALM index had a significant association with hepatic steatosis in adolescents with OO, bringing attention to the interplay between muscle mass and hepatic steatosis in this population. This finding has potential implications for optimal management of metabolic dysfunction-associated steatotic liver disease (MASLD), while the relationship between muscle mass and insulin sensitivity/glycemia requires further attention. TRAIL REGISTRATION:ClinicalTrials.gov identifiers: NCT03717935 (https://clinicaltrials.gov/study/NCT03717935), NCT03041129 (https://clinicaltrials.gov/study/NCT03041129), NCT02157974 (https://clinicaltrials.gov/study/NCT02157974), NCT01775813 (https://clinicaltrials.gov/study/NCT01775813) and NCT03919929 (https://clinicaltrials.gov/study/NCT03919929).

OBJECTIVE:To compare isolated liver transplantation (LT) for cystic fibrosis (CF) versus other indications and versus combined liver-lung transplantation (CLLT) for CF in children and identify factors associated with survival. METHODS:We compared clinical and survival data after first isolated LT for CF versus other indications and versus CLLT for CF in children (<18 years) using United Network for Organ Sharing data (02/2002-12/2024). RESULTS:A total of 157 pediatric CF transplant recipients were included (LT: 145; CLLT: 12). Isolated CF LT recipients had higher total bilirubin (TB) than CLLT (median 1.6 vs. 0.7 mg/dL, p = 0.02). A higher proportion of CF transplant recipients with high TB levels (≥1.5 mg/dL) had ascites, encephalopathy, and required life support compared to those with low TB levels (<1.5 mg/dL). CF LT demonstrated superior patient survival versus CF CLLT (log-rank test, p = 0.02; 5-year: 89.1% vs. 72.2%), but inferior versus non-CF LT (log-rank test, p < 0.001; 5-year: 91.5%). Multivariable Cox regression showed increased risk of patient mortality and liver graft loss in CF CLLT recipients compared to isolated CF LT recipients (hazard ratio [HR] = 2.92, 95% confidence interval [95% CI]: 1.20-7.07, p = 0.02 and HR = 2.56, 95% CI: 1.09-5.98, p = 0.03, respectively) and recipients with higher TB levels (HR = 1.05, 95% CI: 1.01-1.10, p = 0.008 and HR = 1.05, 95% CI: 1.01-1.09, p = 0.008, respectively), when adjusting for recipient age, albumin and international normalized ratio (INR) at time of LT, ICU status, and liver graft type. Multivariable Cox regression of isolated LT recipients showed increased risk of patient mortality (HR = 2.03, 95% CI: 1.41-2.93, p < 0.001) and liver graft loss (HR = 1.54, 95% CI: 1.13-2.11, p = 0.006) for CF compared to non-CF etiologies, when adjusting for recipient age, albumin, INR, and TB at time of LT, ICU status, and liver graft type. CONCLUSION:Isolated LT for CF was associated with superior survival compared to CLLT for CF, but inferior survival compared to LT for non-CF indications. Higher TB in CF may be a marker of inferior outcomes post-LT.

Living donor (LD) liver transplant (LT) is associated with improved outcomes compared with deceased donor (DD) LT, including shorter waitlist times, decreased pre-LT mortality, and improved post-LT survival. However, the cost difference between LDLT and DDLT remains unknown. In this study, we used the linked Pediatric Health Information System and Scientific Registry of Transplant Recipients data sets to compare pre-LT, LT, and 1-year post-LT hospitalization costs and resource utilization between children with biliary atresia aged <2 years who received LDLT or DDLT between January 1, 2010, and December 31, 2020. For all children (N = 819), the median cost for transplant hospitalization was less for LDLT ($179 965; interquartile range [IQR]: $130 238-$275 951) than for DDLT recipients ($224 851; IQR: $163 724-$336 550, P < .001), and fewer LDLT (4%) than DDLT recipients (10%, P = .01) required dialysis during transplant hospitalization. In a subanalysis of recipients of a technical variant graft (TVG) (n = 471), transplant hospitalization costs were lower for LDLT ($179 965; IQR: $130 238-$275 951) than for deceased TVG ($249 371; IQR: $171 678-$363 664, P < .001), and fewer LDLT than deceased TVG recipients required dialysis (4% vs 9%, P = .045) and total parenteral nutrition (63% vs 74%, P = .007). In conclusion, LDLT offers an opportunity to decrease costs and should be considered for children in need of LT.

Sarcopenia has been increasingly recognized as a risk factor for worse outcomes in liver transplantation; however, the data remain limited on pediatric-specific outcomes. These gaps in knowledge are in part due to the lack of a standardized definition, challenges inherent to functional assessments in children, and overlapping features with other nutritional states. It is important to understand the differences between malnutrition, frailty, and sarcopenia to best apply nutritional assessments to our clinical practice and advance our understanding of how sarcopenia impacts patient outcomes. In the present review, we highlight areas of unmet need in identifying, evaluating, and treating sarcopenia in children with cholestatic liver disease peri-transplant. We review what is known and what remains unknown about the disease mechanism of sarcopenia in pediatric versus adult patients with chronic liver disease and identify future research priorities in the field.

Childhood is an essential period for growth and development during which time chronic liver disease can have compounding negative effects on patient health. Aggressive screening and nutritional intervention strategies are key for improving patient outcomes and should involve a multidisciplinary approach with support from a skilled dietitian.

Infection is a leading cause of short-term morbidity and mortality in pediatric patients after liver transplant (LT). Diagnosing infection in this population can be challenging, requiring consideration of laboratory results and clinical context. The prevalence and significance of post-operative leukocytosis has not yet been explored in children after LT. Our goals were to characterize post-transplant leukocytosis in pediatric patients after LT for biliary atresia (BA) and evaluate the relationship between post-LT leukocytosis and infection. Retrospective review of patients aged 0-18 years who underwent LT between 2012-2022 for BA. Clinical data were extracted from electronic medical records. Infectious outcomes were characterized as organism-confirmed infection (OCI), presumed infection, and no apparent infection. Differences between groups were assessed using two-sample t-tests and Fisher’s Exact tests. 60 children met criteria for inclusion (mean age at LT 33.7 ± 50.9 months; 65% female). Forty-four (73.3%) had leukocytosis in the 14 days after transplant. There was no association between leukocytosis in general and OCI (p = 0.67) or presumed (p = 0.71) infection. Only leukocytosis >30,000/µL was associated with OCI (p = 0.008). Leukocytosis after LT for BA is common, although only white blood cell (WBC) count >30,000/µL was associated with organism-confirmed infection. This study is the first to describe the prevalence of leukocytosis in children after LT and emphasizes the importance of considering the multifactorial nature of leukocytosis when evaluating for and treating infections in this population.

OBJECTIVES:To investigate potential mechanisms of muscle wasting in children with chronic cholestatic liver disease (CCLD). METHODS:This is a cross-sectional study comparing estimated skeletal muscle mass (eSMM) z-score, assessed by whole body dual energy X-ray absorptiometry (DXA), in children with CCLD versus healthy controls. Relationships between eSMM z-score and serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), myostatin, and ammonia were analyzed by Spearman correlation and multiple linear regression. Myopenia was defined as eSMM z-score ≤ -2. RESULTS:DXA was obtained in 15 children with CCLD (eight biliary atresia, four Alagille syndrome, one alpha-1-antitrypsin deficiency, one bile salt export protein deficiency, one idiopathic cirrhosis; mean age 12.1 ± 3.9 years) and 19 controls (mean age 11.5 ± 3.9 years). Although growth and muscle mass (eSMM z-score) were similar between CCLD and controls, children with CCLD had significantly higher GH levels (2.7 ± 4.0 ng/mL vs. 0.5 ± 0.6 ng/mL, p = 0.04) and lower IGF-1 z-score (-0.9 ± 0.8 vs. 0.0 ± 0.5, p < 0.01), indicating GH resistance in CCLD. Children with CCLD and myopenia had significantly higher GH levels than those without myopenia (median 7.9 [0.5-13.0] ng/mL vs. 0.3 [0.0-4.6] ng/mL, p = 0.04), with a trend toward a moderate inverse correlation between GH and eSMM z-score in CCLD (rho = -0.48, p = 0.07). CONCLUSIONS:GH resistance is prevalent in CCLD, even in older children with relatively mild liver disease severity and preserved growth. The relationship between eSMM z-score and GH indicates a potential role for GH resistance in the development of myopenia in CCLD.

BACKGROUND:Liver transplantation (LT) is the only potentially curative option for children with unresectable hepatoblastoma (HBL). Although post-transplant outcomes have improved in the contemporary era, the impact of donor graft type on survival remains unclear. METHODS:Using the United Network for Organ Sharing database (02/2002-06/2021), demographics, clinical characteristics, and patient and graft survival were analyzed in children (<18 years) who underwent LT for HBL according to donor graft type. The Kaplan-Meier method, log-rank tests, and Cox regression modeling were used to evaluate the effect of whole, partial, and split deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT) on patient and graft survival. RESULTS:A total of 590 pediatric HBL LT recipients (344 whole graft DDLT; 62 partial graft DDLT; 139 split graft DDLT; 45 LDLT) were included. During 2012-2021 the proportion of LDLTs for HBL decreased to about 5% compared with about 11% during 2002-2011. No significant differences were identified by donor graft type in either patient survival (log-rank test, p = .45) or graft survival (log-rank test, p = .69). The results remained similar during the 2002-2011 era, while during the 2012-2021 era, split graft DDLT was associated with decreased graft loss risk versus whole graft DDLT (hazard ratio: 0.48, 95% confidence interval: 0.23-0.99, p = .046) without any other significant between-group differences. CONCLUSIONS:Utilizing non-whole liver grafts can increase access to LT in children with unresectable HBL while ensuring favorable outcomes. LDLT is underutilized in children with HBL in the United States, and efforts to explore LDLT options should be undertaken.

1University of Colorado, Pediatrics; Children’s Hospital Colorado, Pediatric Gastroenterology, Hepatology, and Nutrition, Aurora, Colorado, USA 2Children’s Hospital Colorado, University of Colorado, School of Medicine, Pediatrics, Aurora, Colorado USA Abbreviation: TSMI, total skeletal muscle index. Correspondence Shikha S. Sundaram, Children’s Hospital Colorado, University of Colorado School of Medicine, 13123 East 16th Ave, B290, Aurora, CO 80045. Email: [email protected]

BACKGROUND:Hepatic undifferentiated embryonal sarcoma (HUES) is the third most common primary hepatic malignancy in children. If unresectable, liver transplantation (LT) is the only curative option. Historically, HUES LT outcomes were not favorable; however, modern-era data are lacking. We aimed to describe LT outcomes in children with HUES and compared with LT outcomes in children transplanted for hepatoblastoma (HBL) and non-malignancy indications. METHODS:Children 18 years or younger with HUES who underwent LT from 1987 to 2021 were identified from the Scientific Registry of Transplant Recipients database. Graft and patient survival were studied in HUES and LT recipients with HBL and non-malignancy indications using Kaplan-Meier analysis. Cox regression was used to compare patient and graft survival among groups, controlling for confounders. RESULTS:Twenty-one children with HUES underwent LT during the study period with a median age at LT of 10 years (IQR: 8-12 years). One and five-year patient survival for HUES recipients was not significantly different from that of recipients with HBL (p = .3) or non-malignancy diagnoses (p = .6). There were no deaths due to HUES recurrence. In multivariable Cox regression, HUES did not increase risk of either patient or graft loss as compared to HBL (HR 2.36, p = .2) or non-malignancy indications (HR 0.74, p = .7). CONCLUSION:LT outcomes are more favorable in patients with HUES than historically described, and similar to LT outcomes of patients with HBL and non-malignancy indications. Transplant should be considered for HUES patients with unresectable localized tumors.

As of June 15, 2022, the Centers for Disease Control and Prevention has reported 296 pediatric patients under investigation for hepatitis of unknown etiology in the United States; the World Health Organization has reported 650 probable cases worldwide. One of the leading hypotheses for this cluster of cases is adenovirus, a virus that commonly causes respiratory or gastrointestinal symptoms in healthy children but rarely causes severe hepatitis or acute liver failure in immunocompetent children. The other leading hypothesis is that prior infection with SARS-CoV-2 may predispose children to developing liver injury from a normally innocuous agent. We describe a case of a previously healthy child presenting with acute liver failure who had detectable adenovirus DNA in his stool, whole blood, and in liver explant tissue, suggesting adenovirus as the likely etiology for the liver failure. He had no evidence of prior or current SARS-CoV-2 infection, nor had he received COVID vaccination, suggesting that SARS-CoV-2 did not play a role. Additionally, we report on the ability to provide rapid evaluation of a living donor within 72 hours and successfully perform a lifesaving, left-lobe, living donor liver transplant.

Background: Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes.Methods: Estimated skeletal muscle mass (eSMM) was calculated on dual-energy x-ray absorptiometry obtained in a Childhood Liver Disease Research Network study of children with bile acid synthesis disorders(BASD) alpha-1 antitrypsin deficiency (a1ATd), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Relationships between eSMM, liver disease, and transplant-free survival were assessed.Results: eSMM was calculated in 127 participants (5-18 y): 12 BASD, 41 a1ATd, 33 CIC, and 41 ALGS. eSMM z-score was lower in CIC (-1.6 +/- 1.3) and ALGS (-2.1 +/- 1.0) than BASD (-0.1 +/- 1.1) and a1ATd (-0.5 +/- 0.8, p < 0.001). Sarcopenia (defined as eSMM z-score <=- 2) was present in 33.3% of CIC and 41.5% of ALGS participants. eSMM correlated with bone mineral density in the 4 disease groups (r=0.52-0.55, p < 0.001-0.07), but not serum bile acids, bilirubin, aspartate aminotransferase/platelet ratio index, or clinically evident portal hypertension. Of the 2 patients who died (1 with sarcopenia) and 18 who underwent liver transplant (LT, 4 with sarcopenia), eSMM z-score did not predict transplant-free survival. eSMM z-score correlated with the Physical Pediatric Quality of Life Inventory score (r=0.38-0.53, p = 0.007-0.04) in CIC and a1ATd.Conclusion: Severe sarcopenia occurs in some children with ALGS and CIC. The lack of correlation between eSMM and biochemical cholestasis suggests mechanisms beyond cholestasis contribute to sarcopenia. While sarcopenia did not predict transplant-free survival, LT and death were infrequent events. Future studies may define mechanisms of sarcopenia in genetic intrahepatic cholestasis.

Congenital portosystemic shunts (CPSS) are rare developmental anomalies resulting in diversion of portal flow to the systemic circulation. These shunts allow intestinal blood to reach the systemic circulation directly, and if persistent or large, may lead to long-term complications. CPSS can have a variety of clinical presentations that depend on the substrate that is bypassing hepatic metabolism or the degree of hypoperfusion of the liver. Many intrahepatic shunts spontaneously close by 1 year of age, but extrahepatic and persistent intrahepatic shunts require intervention by a single session or staged closure with a multidisciplinary approach. Early detection and appropriate management are important for a good prognosis. The aim of this case series is to describe the varied clinical presentations, treatment approaches, and outcomes of 5 children with CPSS at our institution. Management of these patients should involve a multidisciplinary team, including interventional radiology, surgery, hepatology, and other medical services as the patient's clinical presentation warrants. Regardless of clinical presentation, if a CPSS persists past 1-2 years of age, closure is recommended.

Abstract Vibration controlled transient elastography (FibroScan) is used to predict the severity of liver fibrosis and steatosis. In pediatrics, few studies have been performed directly comparing liver histologic features with FibroScan liver stiffness measurements (LSMs) and controlled attenuation parameters (CAPs). The FibroScan–aspartate aminotransferase (FAST) score, which predicts liver disease severity in adult nonalcoholic fatty liver disease (NAFLD), has not been analyzed in children. The aims of this study were to determine if LSM and CAP correlated with liver histologic fibrosis stage and steatosis grade, respectively, and to determine the predictive capacity of FAST in pediatric NAFLD. Research participants (n = 216) included those with FibroScan within 90 days of a liver biopsy. The ability of LSM, CAP, and FAST to predict severity of liver disease was analyzed by Spearman correlation, linear regression, and receiver operating characteristic and C statistic. Significant correlations were identified between LSM and Ishak fibrosis stages, with the strongest correlation occurring in the non‐NAFLD group (Spearman r = 0.47, p < 0.0001). LSM adequately predicted Ishak stages F0–2 versus F3–F6 (area under the receiver operating characteristic curve [AUROC], 0.73 for all; 0.77 for non‐NAFLD). CAP strongly predicted histologic steatosis grade (r = 0.84; p < 0.0001; AUROC, 0.98). FAST had acceptable discriminatory ability for significant liver disease (AUROC, 0.75). A FAST cutoff ≥0.67 had a sensitivity of 89% but a specificity of only 62% at determining significant liver disease. This study encompasses one of the largest pediatric cohorts describing the accuracy of FibroScan LSM and CAP to predict liver histologic fibrosis stage and steatosis grade, respectively. In order to determine specific LSM, CAP, and FAST cut‐off values for fibrosis stages, steatosis grades, and significant liver disease, respectively, a much larger cohort is necessary and will likely entail the need for multicentered studies.