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Pediatric acute liver failure is a rare process that results from many different diseases including toxin ingestion and drug overdose, infections, metabolic and genetic disorders, immune-mediated diseases, and ischemia. Up to 50% of children with acute liver failure will never have an underlying cause found. Early identification, supportive care, and disease-directed therapy are critical. For some children liver transplantation is needed for survival, but many children will recover with appropriate therapy, without the need for transplantation. Nonetheless, overall survival is approximately 50% without liver transplantation. Opportunities for improvement in the care of children with acute liver failure still exist.

OBJECTIVE: Increased mortality risk because of severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) infection in adults with native liver disease (LD) and liver transplant (LT) is associated with advanced age and comorbid conditions. We aim to report outcomes for children with LD and LT enrolled in the NASPGHAN/SPLIT SARS-CoV2 registry. METHODS: In this multicenter observational cohort study, we collected data from 91 patients

Neonatal acute liver failure (NALF) is a rare disease with a few known primary causes: gestational alloimmune liver disease (GALD), viral infections, metabolic diseases, and ischemic injury. Many cases still do not have a known cause. Laboratory evaluation may suggest a diagnosis. Most of the known causes have disease-specific treatments that improve outcomes. Survival is improving with better knowledge about and treatment options for GALD; however, overall mortality for NALF is still 24%. Liver transplant remains an important option for neonates with an indeterminate cause of NALF and those who do not respond to established treatments.

Background and Aims Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. Approach and Results We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). Conclusions The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal illness characterized by impaired natural killer (NK) cell and cytotoxic T-cell function. Patients develop systemic inflammation, multisystem organ dysfunction, and if untreated, death. Patients who present in the neonatal period often have atypical presentations with evidence of liver dysfunction and cholestasis; this has a broad differential diagnosis including neonatal infection, congenital liver defects, or other causes of liver dysfunction, such as neonatal hemochromatosis. Here, we present an infant whose diagnosis of familial HLH was confounded by the history of a stillborn sibling with suspected neonatal hemochromatosis, ultimately delaying diagnosis and initiation of curative treatment. This highlights the need to maintain a low threshold for sending HLH work-up concurrently with evaluation of liver diseases in infants with liver dysfunction, to ensure timely diagnosis and initiation of treatment. Clinicians should maintain a high index of suspicion for HLH and be aware that HLH may mimic the findings on liver biopsy seen in neonatal hemochromatosis.

Objectives To evaluate the prevalence and clinical significance of autoantibodies in children with overweight and obesity with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) compared with those with autoimmune liver disease (ALD). Study design This was a retrospective, cross-sectional study of children with a biopsy-proven diagnosis of NAFL, NASH, autoimmune hepatitis (AIH), or primary sclerosing cholangitis (PSC) and a body mass index (BMI) >85th percentile treated between 2007 and 2016. Results A total of 181 patients were identified, including 31 (17%) with NAFL, 121 (67%) with NASH, 12 (6.6%) with ALD (AIH, PSC, or overlap), and 17 (9.4%) with combined ALD and NAFLD. Antinuclear antibody (ANA), anti-actin antibody, and anti–liver kidney microsomal (LKM) antibody were positive in 16.1%, 13.8%, and 0%, respectively, of the patients with NAFL and in 32.8%, 15.5%, and 0%, respectively, of those with NASH. Total immunoglobulin G (IgG) was elevated in 27.3% of the patients with NAFL and in 47.7% of those with NASH, but in 100% of those with ALD. The positive predictive value of LKM was 100% for ALD but only 29% for ANA and 46% for anti-actin antibody. Conclusions False-positive rates of autoantibodies were higher in pediatric patients with overweight and obesity with NAFLD compared with the general adult population. Positive LKM had the highest specificity and positive predictive value, and elevated IgG level had the highest sensitivity for ALD. The presence of autoantibodies does not signal more severe NAFLD in children. BMI >98th percentile seems to be an important breakpoint above which ALD is less likely.

OBJECTIVES A quality improvement approach was used to increase pediatric liver transplant recipient live and inactive vaccination rates by assessing titers and recommending vaccinations. METHODS A new screening and immunization process for both live and inactive vaccines was discussed with families at their annual visit. Antibody titers for varicella, measles, mumps, rubella, Haemophilus influenzae type B, hepatitis A, and hepatitis B were obtained. Specific criteria were developed for live virus vaccination candidacy. Vaccines were recommended based on patient titers and vaccination candidacy criteria. Surveillance for adverse effects to live vaccines was performed. Repeat titers were obtained approximately 1-month post-vaccine administration. RESULTS After PDSA cycle 1, 99% (71/72) of pediatric liver transplant patients had titers obtained. Live vaccines were recommended for 32 patients and 16 (50%) were vaccinated. Inactive vaccines were recommended to 64 patients, and 31 (48%) were vaccinated. Eight of 13 (62%) patients with follow-up titers achieved immunity for inactive vaccines. Zero patients had an adverse reaction to any live vaccine. Ten of 12 (83%) patients with follow-up titers achieved immunity from live vaccines. The most common barriers to receive live vaccines included not scheduling appointment with primary care provider (n = 3) and "non-vaccinators" (n = 3). CONCLUSIONS Administering live and inactive vaccines to select pediatric liver transplant patients appears to be safe and effective in our studied population. For PDSA cycle 2, we will continue our current practice and consider offering vaccines in transplant clinic, since this was a barrier to vaccination identified during PDSA cycle 1.

Background and aims Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. Approach and results We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. Conclusions We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.

Background and Aims: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. Approach and Results: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of

Background Smartphone apps have been successfully used to help adults prepare for colonoscopies. However, no study to date has investigated the effect of a smartphone app on pediatric colonoscopy preparation. Objective The aim of this study is to determine if an app (SB Colonoscopy Prep) designed to educate and guide patients through their colonoscopy preparation will yield benefits over paper-based instructions and information. Methods In total, 46 patients aged 5-18 years received either app-based or written material with instructions on how to take their prep medications as well as information about the colonoscopy procedure. Prep quality, the number of calls to the gastroenterology service, and patient arrival time were recorded. After the procedure, a questionnaire was given to each patient through which they graded their knowledge of the procedure both before and after receiving the app or written material. Results App users had higher mean Boston scores versus control subjects receiving written instructions (7.2 vs 5.9, P=.02), indicating better colonoscopy preps. In total, 75% (15/20) of app users and 41% (9/22) of written instruction users had preps categorized as “excellent” on the Boston scale. We found no significant differences in knowledge about the procedure (app users: 10/20 [50%], written instruction users 8/22 [36%]; P=.37), phone calls to the gastroenterology clinic (n=6 vs n=2; P=.27), or arrival times at the endoscopy suite (44 min vs 46 min before the scheduled procedure time; P=.56). Conclusions Smartphone app use was associated with an increased number of colonoscopy preps classified as “excellent” on the Boston scale. There was no significant difference between app users and the control group regarding the number of calls to the gastroenterology clinic, patient arrival time, or patient knowledge about the procedure. Trial Registration ClinicalTrials.gov NCT04590105; https://clinicaltrials.gov/ct2/show/NCT04590105

Background Variation in IS exists among pediatric liver transplant centers. While individual centers may publish their practice paradigms, current data on practices as a whole are lacking. This study sought to ascertain the IS protocols of pediatric liver transplant centers within the SPLIT to better understand variability and similarities among peer institutions. Methods A 27-item questionnaire was developed within the SPLIT Quality Improvement and Clinical Care Committee. The survey collected data regarding center demographics, IS practices, and treatment of acute cellular rejection. Results Twenty-eight (64%) SPLIT centers responded with 22 (79%) centers performing more than 10 transplants per year and 17 (61%) following more than 100 post-transplant recipients. All centers use a written protocol, and 25 (89%) have a dedicated transplant pharmacist/PharmD. Twenty-five (89%) centers use steroids for induction alone or in combination with thymoglobulin/interleukin-2 antibodies. All centers use tacrolimus for initial maintenance therapy. Most centers have specialized protocols for ABO-incompatible transplants, recipients with renal dysfunction, autoimmune liver diseases, and liver tumors. Treatment of rejection varied but was associated with escalation in IS. Conclusion IS practices among pediatric liver transplant centers are similar including the use of written protocols, pharmacy involvement, steroids for induction, tacrolimus as initial IS, tacrolimus reduction/delay for renal dysfunction, and escalation of IS with rejection severity. However, other IS practices show wide variability including treatment for ABO-incompatible grafts and presumed rejection. This study serves as a foundation to guide prospective research linking IS practice to outcomes to determine best practice.

OBJECTIVES: Most patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). The liver and colon express MAdCAM-1, a target of lymphocyte homing integrins. Vedolizumab (VDZ) is an α4β7 integrin antibody used to treat IBD. We investigated liver outcomes in children with PSC-IBD treated with VDZ. METHODS: Patients were identified within the Pediatric PSC Consortium, a multicenter research registry. Retrospective demographic, phenotypic, biochemical, radiological, histopathologic and IBD data for up to 1 year of VDZ therapy were collected. Liver biochemical and IBD responses were defined as: a 75% or greater reduction in initial γ-glutamyltransferase (GGT), or a GGT that fell to

BACKGROUND Smartphone apps have been successfully used to help adults prepare for colonoscopies. However, no study to date has investigated the effect of a smartphone app on pediatric colonoscopy preparation. OBJECTIVE The aim of this study is to determine if an app (SB Colonoscopy Prep) designed to educate and guide patients through their colonoscopy preparation will yield benefits over paper-based instructions and information. METHODS In total, 46 patients aged 5-18 years received either app-based or written material with instructions on how to take their prep medications as well as information about the colonoscopy procedure. Prep quality, the number of calls to the gastroenterology service, and patient arrival time were recorded. After the procedure, a questionnaire was given to each patient through which they graded their knowledge of the procedure both before and after receiving the app or written material. RESULTS App users had higher mean Boston scores versus control subjects receiving written instructions (7.2 vs 5.9, P=.02), indicating better colonoscopy preps. In total, 75% (15/20) of app users and 41% (9/22) of written instruction users had preps categorized as “excellent” on the Boston scale. We found no significant differences in knowledge about the procedure (app users: 10/20 [50%], written instruction users 8/22 [36%]; P=.37), phone calls to the gastroenterology clinic (n=6 vs n=2; P=.27), or arrival times at the endoscopy suite (44 min vs 46 min before the scheduled procedure time; P=.56). CONCLUSIONS Smartphone app use was associated with an increased number of colonoscopy preps classified as “excellent” on the Boston scale. There was no significant difference between app users and the control group regarding the number of calls to the gastroenterology clinic, patient arrival time, or patient knowledge about the procedure.

Primary hepatic functional paraganglioma is a rare form of extra-adrenal catecholamine-secreting tumor. Definitive treatment of functioning paraganglioma is challenging because of the critical location of the tumor frequently in close proximity to vital structures and risk of excessive catecholamine release during operative manipulation. We report the multidisciplinary management approach for a case of unresectable primary hepatic functional paraganglioma with invasion into the hepatic veins and suprahepatic vena cava. To our knowledge, this is the first report showing that orthotopic liver transplantation is curative for patients with unresectable primary hepatic paraganglioma. For locally advanced unresectable hepatic paraganglioma that involves the intrapericardial vena cava, a meticulous pre- and intraoperative medical management and transabdominal intrapericardial vascular control of the suprahepatic vena cava during orthotopic liver transplantation allows for complete extirpation of the tumor and achieves optimal outcome.

Background: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC. Methods: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic. Results: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy. Conclusions: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

Post-operative ileus is common after abdominal surgeries. Children undergoing liver transplant are at increased risk of ileus for various reasons including multiple abdominal procedures and use of narcotic medications. Ileus can lead to abdominal compartment syndrome and compromise the integrity of the liver graft. In some of these patients, ileus is resistant to standard therapies including stool softeners, bowel stimulants, enemas, and even methylnaltrexone. Neostigmine has been shown in pediatric case series to be efficacious in some children for refractory post-operative ileus. We report three children (9 months, 3 years, and 12 years old) who developed refractory ileus after liver transplant, with one of them developing abdominal compartment syndrome, who were treated successfully with continuous infusions of neostigmine. Clinical responses included passage of flatus and stool and improvement in abdominal distension. All patients tolerated the infusion without serious adverse effects such as bradycardia or bronchospasm. Neostigmine was used safely in our patients and may be safe and efficacious for the treatment of refractory ileus in pediatric patients after liver transplantation. Neostigmine should be considered early in the treatment of these patients.

OBJECTIVE: To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. STUDY DESIGN: We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level ≥50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level

Introduction Biliary complications after pediatric orthotopic liver transplantation remain causes of significant patient morbidity. Staged operative approach in complex hepatobiliary surgery has improved postoperative outcomes but has not been evaluated in pediatric orthotopic liver transplantation. We sought to analyze the outcomes of staged biliary reconstruction after orthotopic liver transplantation in high acuity patients. Methods A retrospective analysis of 43 pediatric orthotopic liver transplantations at our center (January 2013 through December 2017). Median follow-up was 25 months. Variables were compared for group I: 1-stage orthotopic liver transplantation with biliary anastomosis (n = 6) versus group II: staged biliary reconstruction orthotopic liver transplantation (n = 37). Results Comparing groups I and II, median age (7.3 vs 4.8 years), weight (27 vs 19 kg), proportion of urgent orthotopic liver transplantation (50% vs 65%), partial graft orthotopic liver transplantation (33% vs 35%), and intraoperative red blood cell transfusion volume (11 vs 21 mL/kg) were comparable. Roux-en-Y hepaticojejunostomy was performed in 67% (group I) and 49% (group II). There was no biliary complication in both groups. For groups I and II, 3-year survival rates for graft (100% vs 92%, P = .477) and patient (100% vs 97%, P = .679) were comparable. Conclusion Our study showed excellent outcomes with staged biliary reconstruction orthotopic liver transplantation in high acuity pediatric transplant recipients. This is the first report showing clinical applicability of staged biliary reconstruction orthotopic liver transplantation in children.

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long-term outcomes in pediatric PSC patients. We evaluated GGT normalization (75% versus 75% by 1 year after PSC diagnosis predicts favorable 5-year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC–inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome. Conclusion: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC–inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518–527).

Objective The aims of this study were to assess the opportunities for therapeutic endoscopy, liver biopsies, and percutaneous endoscopic gastrostomy (PEG) placements available to fellows during a 3-year pediatric gastroenterology fellowship, and to evaluate access to ancillary procedural-training opportunities. Methods Data were collected from 12 pediatric gastroenterology fellowship programs in the United States. Procedures completed in the years 2009-2011 were queried using CPT codes and endoscopy databases. The maximal opportunity for procedures was based on the total procedures performed by the institution in 3 years divided by the total number of fellows in the program. The centers completed a questionnaire regarding ancillary opportunities for endoscopic training. Results There is significant variability in pediatric endoscopic training opportunities in specialized gastrointestinal (GI) procedures. Under the 1999 guidelines, no centers were able to meet the thresholds for polypectomy and control of nonvariceal bleeding. The 2013 guidelines allowed the number of programs reaching polypectomy thresholds to increase by 67% but made no difference for control of bleeding despite a decrease in the threshold. Training in PEG placement was not available in 42% of the surveyed centers. Elective ancillary procedural training is offered by 92% of the surveyed centers. Conclusions Most training programs do not have the volume of therapeutic endoscopy procedures for all of the fellows to meet the training guidelines. Training in therapeutic endoscopy, PEG placement, and liver biopsy in pediatric GI fellowships should be supplemented using all of the possible options including rotations with adult GI providers and hands-on endoscopy courses. A shift toward evaluating competency via quality measures may be more appropriate.

Despite continued advancements in perioperative care for pediatric liver transplant (LT), graft-threatening vascular occlusion events including hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT) remain a source of significant morbidity and mortality. Perioperative anticoagulation is commonly used for the prevention of HAT and PVT, but evidence-based guidelines are lacking. The goals of this survey were to determine the frequency of use of an anticoagulation protocol and to describe variation in anticoagulation practices among pediatric LT centers. The study consisted of an online survey distributed to members of SPLIT. The survey focused on institutional anticoagulation practices employed to reduce the incidence of graft and life-threatening vascular occlusion events. Responses were received from 31 of 39 SPLIT centers. All respondents report using anticoagulation after pediatric LT, and approximately 90% have institutional anticoagulation protocols. Subgroup analysis of high volume pediatric LT centers revealed similar variability in anticoagulation patterns. All participating SPLIT centers reported the use of post-transplant anticoagulation and nearly all use a protocol. However, there is marked variability in the type and dose of anticoagulation as well as the timing of initiation and duration of therapy across centers.

Obesity in adolescents is associated with metabolic risk factors for type 2 diabetes, particularly insulin resistance and excessive accumulation of intrahepatic triglyceride (IHTG). The purpose of this study was to evaluate the effect of moderate weight loss on IHTG content and insulin sensitivity in obese adolescents who had normal oral glucose tolerance. Insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp technique in conjunction with stable isotopically labeled tracer infusion, and IHTG content, assessed by using magnetic resonance spectroscopy, were evaluated in eight obese adolescents (BMI >or=95th percentile for age and sex; age 15.3 +/- 0.6 years) before and after moderate diet-induced weight loss (8.2 +/- 2.0% of initial body weight). Weight loss caused a 61.6 +/- 8.5% decrease in IHTG content (P = 0.01), and improved both hepatic (56 +/- 18% increase in hepatic insulin sensitivity index, P = 0.01) and skeletal muscle (97 +/- 45% increase in insulin-mediated glucose disposal, P = 0.01) insulin sensitivity. Moderate diet-induced weight loss decreases IHTG content and improves insulin sensitivity in the liver and skeletal muscle in obese adolescents who have normal glucose tolerance. These results support the benefits of weight loss therapy in obese adolescents who do not have evidence of obesity-related metabolic complications during a standard medical evaluation.

Nonalcoholic fatty liver disease (NAFLD) and insulin resistance are common in overweight adolescents.The purpose of this study was to determine the relation between NAFLD and insulin sensitivity in liver and skeletal muscle by studying overweight adolescents with a normal or high intrahepatic triglyceride (IHTG) content, who were matched for age, sex, body mass index (BMI; in kg/m(2)), and Tanner stage.Stable-isotope-labeled tracer infusion and the hyperinsulinemic-euglycemic clamp procedure were used to assess skeletal muscle and hepatic insulin sensitivity, and magnetic resonance spectroscopy was used to assess the IHTG content in 10 overweight (BMI = 35.9 +/- 1.3) adolescents with NAFLD (IHTG = 28.4 +/- 3.4%) and 10 overweight (BMI = 36.6 +/- 1.5) adolescents with a normal IHTG content (3.3 +/- 0.5%).The baseline plasma glucose concentration and the rate of appearance of glucose in plasma were the same in subjects with a normal (87.1 +/- 1.2 mg/dL, 16.2 +/- 1.1 micromol . kg fat-free mass(-1) . min(-1)) or high (89.2 +/- 2.5 mg/dL, 16.3 +/- 1.2 micromol . kg fat-free mass(-1) . min(-1)) IHTG content. However, compared with subjects who had a normal IHTG content, subjects with NAFLD had a lower hepatic insulin sensitivity index, based on baseline glucose kinetics and insulin concentrations (4.0 +/- 0.5 compared with 2.4 +/- 0.4; P0.05) and an impaired increase in glucose uptake during insulin infusion (169 +/- 28.1% compared with 67 +/- 9.6% above baseline; P0.01). In addition, the plasma triglyceride concentration was greater and the plasma HDL-cholesterol concentration was lower in subjects with NAFLD than in those with a normal IHTG content.An elevated IHTG content in overweight adolescents is associated with dyslipidemia and with insulin-resistant glucose metabolism in both liver and skeletal muscle.

Among infants, almost half of acute liver failure cases are classified as indeterminate, whereas only a small number of cases show a documented viral infection. We present the first reported case of isolated acute hepatic failure in an infant in the setting of a human parechovirus (HPeV) infection. HPeV also may have been contributory to the posttransplant complication of 2 intussusceptions. This is a 10-month-old girl who presented with only symptoms of fussiness and was noted to have progressive decline in synthetic liver function as well as worsening coagulopathy requiring a liver transplant. The acute liver failure was in the setting of a positive serum RNA HPeV, subtype 3 (HPeV-3), after extensive diagnostic testing with genetic, autoimmune, and infectious causes otherwise negative. After liver transplantation, the postoperative course was complicated by both an ileal-ileal intussusception as well as a jejunal intussusception. Viral testing in pediatric acute liver failure is often performed, but the workup is frequently incomplete. This case report would support more extensive viral testing in this population of patients. In the setting of HPeV, clinicians could be alerted to the possibility of delayed gastrointestinal pathology in the posttransplant phase. Wider use of routine HPeV testing may more clearly define the variable clinical presentations and outcomes.

To determine the association among nonalcoholic fatty liver disease (NAFLD), metabolic function, and cardiac function in obese adolescents.Intrahepatic triglyceride (IHTG) content (magnetic resonance spectroscopy), insulin sensitivity and β-cell function (5-hour oral glucose tolerance test with mathematical modeling), and left ventricular function (speckle tracking echocardiography) were determined in 3 groups of age, sex, and Tanner matched adolescents: (1) lean (n=14, body mass index [BMI]=20±2 kg/m2); (2) obese with normal (2.5%) IHTG content (n=15, BMI=35±3 kg/m2); and (3) obese with increased (8.7%) IHTG content (n=15, BMI=37±6 kg/m2).The disposition index (β-cell function) and insulin sensitivity index were ∼45% and ∼70% lower, respectively, and whole body insulin resistance, calculated by homeostasis model of assessment-insulin resistance (HOMA-IR), was ∼60% greater, in obese than in lean subjects, and ∼30% and ∼50% lower and ∼150% greater, respectively, in obese subjects with NAFLD than those without NAFLD (P.05 for all). Left ventricular global longitudinal systolic strain and early diastolic strain rates were significantly decreased in obese than in lean subjects, and in obese subjects with NAFLD than those without NAFLD (P.05 for all), and were independently associated with HOMA-IR (β=0.634). IHTG content was the only significant independent determinant of insulin sensitivity index (β=-0.770), disposition index (β=-0.651), and HOMA-IR (β=0.738).These findings demonstrate that the presence of NAFLD in otherwise asymptomatic obese adolescents is an early marker of cardiac dysfunction.

Objective: It has been hypothesized that excessive fatty acid availability contributes to steatosis and the metabolic abnormalities associated with nonalcoholic fatty liver disease (NAFLD). The purpose of this study was to evaluate whether adipose tissue lipolytic activity and the rate of fatty acid release into plasma are increased in obese adolescents with NAFLD. Methods: Palmitate kinetics were determined in obese adolescents with normal (n = 9; BMI = 37 ± 2 kg/m2; intrahepatic triglyceride (IHTG) ≤5.5% of liver volume) and increased (n = 9; BMI = 36 ± 2 kg/m2; IHTG ≥ 10% of liver volume) IHTG content during the basal state (postabsorptive condition) and during physiological hyperinsulinemia (postprandial condition). Both groups were matched on body weight, BMI, percent body fat, age, sex, and Tanner stage. The hyperinsulinemic-euglycemic clamp procedure, in conjunction with a deuterated palmitate tracer infusion, was used to determine free-fatty acid (FFA) kinetics, and magnetic resonance spectroscopy was used to determine IHTG content. Results: The rate of whole-body palmitate release into plasma was greater in subjects with NAFLD than those with normal IHTG content during basal conditions, (87 ± 7 vs. 127 ± 13 µmol/min; P < 0.01) and during physiological hyperinsulinemia, (24 ± 2 vs. 44 ± 8 µmol/min; P < 0.01). Discussion: These results demonstrate that adipose tissue lipolytic activity is increased in obese adolescents with NAFLD and results in an increase in the rate of fatty acid release into plasma throughout the day. This continual excess in fatty acid flux supports the hypothesis that adipose insulin resistance is involved in the pathogenesis of steatosis and contributes to the metabolic complications associated with NAFLD.