Shikha S. Sundaram

Sugar, Uric Acid, and the Etiology of Diabetes and Obesity

The intake of added sugars, such as from table sugar (sucrose) and high-fructose corn syrup has increased dramatically in the last hundred years and correlates closely with the rise in obesity, metabolic syndrome, and diabetes. Fructose is a major component of added sugars and is distinct from other sugars in its ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid. In this article, we revisit the hypothesis that it is this unique aspect of fructose metabolism that accounts for why fructose intake increases the risk for metabolic syndrome. Recent studies show that fructose-induced uric acid generation causes mitochondrial oxidative stress that stimulates fat accumulation independent of excessive caloric intake. These studies challenge the long-standing dogma that “a calorie is just a calorie” and suggest that the metabolic effects of food may matter as much as its energy content. The discovery that fructose-mediated generation of uric acid may have a causal role in diabetes and obesity provides new insights into pathogenesis and therapies for this important disease.

Characterization and Outcomes of Young Infants with Acute Liver Failure

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.

The metabolic syndrome and nonalcoholic fatty liver disease in children.

Purpose of review Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in pediatric-age individuals, in parallel with increasing obesity, and can lead to liver inflammation, fibrosis, and even cirrhosis. NAFLD appears tightly linked with features of the metabolic syndrome (MetS). This review aims to reconsider the clinical presentation, laboratory and pathologic assessment, and treatment of NAFLD, with a focus on its relationship with the MetS. Recent findings NAFLD occurs with a high prevalence and severity in obese, insulin-resistant adolescents, especially Hispanic males. Pediatric NAFLD may improve with lifestyle therapy and agents that improve insulin sensitivity. In youth, NAFLD appears tightly correlated with components of the MetS, especially visceral fat, which appears to predict fibrosis as well as liver fat. In addition, noninvasive techniques such as transient elastography may help provide data on fibrosis in youth with NAFLD and avoid biopsy. Summary The close association between NAFLD and the MetS supports screening for other comorbidities associated with the MetS. Further research is urgently required to best identify effective therapies to prevent and treat NAFLD, but its close association with MetS argues for a focus on strategies designed to improve insulin resistance and components of the MetS.

Mechanisms of Disease: inborn errors of bile acid synthesis

Inborn errors of bile acid synthesis are rare genetic disorders that can present as neonatal cholestasis, neurologic disease or fat-soluble-vitamin deficiencies. There are nine known defects of bile acid synthesis, including oxysterol 7α-hydroxylase deficiency, Δ4-3-oxosteroid-5β-reductase deficiency, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, cerebrotendinous xanthomatosis (also known as sterol 27-hydroxylase deficiency), α-methylacyl-CoA racemase deficiency, and Zellweger syndrome (also known as cerebrohepatorenal syndrome). These diseases are characterized by a failure to produce normal bile acids and an accumulation of unusual bile acids and bile acid intermediaries. Individuals with inborn errors of bile acid synthesis generally present with the hallmark features of normal or low serum bile acid concentrations, normal γ-glutamyl transpeptidase concentrations and the absence of pruritus. Failure to diagnose any of these conditions can result in liver failure or progressive chronic liver disease. If recognized early, many patients can have a remarkable clinical response to oral bile acid therapy.

Naspghan Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on Nafld (econ) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (naspghan)

ABSTRACT 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.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 (ECON) reviewed and summarized the available literature, formulating recommendations to guide screening and clinical care of children with NAFLD.

Outcomes after liver transplantation in young infants

Background: Liver transplantation in infants younger than 90 days is increasingly common. These infants typically arrive for transplantation in fragile medical condition. It is commonly assumed that they may experience high complication rates, difficult postoperative courses, and poor graft and patient survival. Objectives: We sought to understand whether graft and patient survival rates in these young infants were lower than in older children, these patients experienced more complications than older children, and health care resource utilization was higher in this population. Patients and Methods: Data queried from the Study of Pediatric Liver Transplantation (SPLIT) database were limited to infants ages 0 to 90 days who had received their primary liver transplant between February 1996 and May 2004. Patients older than 90 days registered in the SPLIT database were used for comparison. Results: Thirty-eight patients, ages 0 to 90 days, were included in the analysis. Their severity of illness was reflected by a median calculated Pediatric Endstage Liver Disease score of 34.8 at transplant. A majority (89.5%) of infants received cadaveric liver grafts, of which 47% were reduced organs. The infants experienced prolonged hospitalizations, spending an average of 50.9 ± 7.6 days in the hospital after transplant. Long stays in the intensive care unit (average 22.1 ± 1.5 days) and need for mechanical ventilation (average 16.2 ± 2.7 days) also occurred. Length of hospitalization, intensive care, and mechanical ventilation were significantly higher than in older children (P < 0.0001). The reoperation rate (60.5%) was high and significantly greater than in older children (P = 0.007), with 10 patients (26.3%) needing 3 or more early reoperations. Reoperations occurred for bleeding, wound complications, biliary complications, and sepsis. There was no difference in vascular or biliary tract complications compared with older children. Bacterial infections were also common (52.6%) and were seen with greater frequency than in older children (P < 0.04). This infant cohort had an overall graft survival of 76.1% and overall patient survival of 87.8% at 1 year, with median follow-up of 12.5 months (range 0.6–84.0 months). Graft and patient survival in infants younger than 90 days was similar to that in older infants and children (P = NS). Conclusions: Young infants experience graft and patient survival similar to that in older cohorts of liver transplant recipients. Posttransplant complication rates, including the reoperation rate, were higher in this younger group, and the duration of hospitalization and intensive support were significantly longer. Future studies to better examine the factors, including age, that may contribute to the need for reoperation in children are warranted. Recognition and further analysis of the cost of care in this age group is also needed.

Growth impairment in children with extrahepatic portal vein obstruction is improved by mesenterico-left portal vein bypass

BACKGROUND Extrahepatic portal vein obstruction (EHPVO) has been associated with growth impairment in children. We hypothesized that growth parameters improve after reversal of portal hypertension and restoration of mesenteric venous blood flow to the liver by the mesenterico-left portal vein bypass (MLPVB). METHODS A retrospective review of 45 children with idiopathic EHPVO who underwent MLPVB between 1997 and 2007 and had follow-up data for analysis was carried out. Growth was assessed using SD scores (z scores) for height, weight, and body mass index (BMI) at the time of operation and at early (5-12 months) and late (13-24 months) follow-up. RESULTS The mean height and weight of children with EHPVO was significantly lower than the general population before surgery. Mean BMI was also lower, although statistically insignificant. All parameters increased significantly after MLPVB as follows: height from -0.42 before surgery to -0.12 (P = .027) at 5 to 12 months and -0.14 (P = .026) at 13 to 24 months; weight from -0.49 before surgery to 0.03 (P < .001) at 5 to 12 months and 0.35 (P < .001) at 13 to 24 months; and BMI from -0.22 before surgery to 0.17 (P = .001) at 5 to 12 months and 0.48 (P < .001) at 13 to 24 months. CONCLUSION Restoration of portal blood flow to the liver by MLPVB improves growth in children with EHPVO.

Health Related Quality of Life in Patients with Biliary Atresia Surviving with their Native Liver

OBJECTIVES To quantify health related quality of life (HRQOL) of patients with biliary atresia with their native livers and compare them with healthy children and patients with biliary atresia post-liver transplant (LT) and to examine the relationship between HRQOL and medical variables. STUDY DESIGN A cross-sectional HRQOL study of patients with biliary atresia with their native livers (ages 2-25 years) was conducted and compared with healthy and post-LT biliary atresia samples using Pediatric Quality of Life Inventory 4.0 child self and parent proxy reports, a validated measure of physical/psychosocial functioning. RESULTS 221 patients with biliary atresia with native livers (54% female, 67% white) were studied. Patient self and parent proxy reports showed significantly poorer HRQOL than healthy children across all domains (P < .001), particularly in emotional and psychosocial functioning. Child self and parent proxy HRQOL scores from patients with biliary atresia with their native livers and post-LT biliary atresia were similar across all domains (P = not significant). Child self and parent proxy reports showed moderate agreement across all scales, except social functioning (poor to fair agreement). On multivariate regression analysis, black race and elevated total bilirubin were associated with lower Total and Psychosocial HRQOL summary scores. CONCLUSIONS HRQOL in patients with biliary atresia with their native livers is significantly poorer than healthy children and similar to children with post-LT biliary atresia. These findings identify significant opportunities to optimize the overall health of patients with biliary atresia.

Biliary atresia: Indications and timing of liver transplantation and optimization of pretransplant care

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.

The SPLIT research agenda 2013.

This review focuses on active clinical research in pediatric liver transplantation with special emphasis on areas that could benefit from studies utilizing the SPLIT infrastructure and data repository. Ideas were solicited by members of the SPLIT Research Committee and sections were drafted by members of the committee with expertise in those given areas. This review is intended to highlight priorities for clinical research that could successfully be conducted through the SPLIT collaborative and would have significant impact in pediatric liver transplantation.