Introduction: Pediatricians are encouraged to promote behavior modification to reduce childhood obesity and its co-morbidities, yet the effectiveness of office counseling is unclear. We aimed to evaluate if a low-intensity intervention (action-oriented counseling) in a clinic setting results in weight stabilization, and if the effect is modified by a diagnosis of non-alcoholic fatty liver disease (NAFLD). We hypothesized that patients with NAFLD would be more motivated to adhere to the lifestyle goals set in clinic, due to the diagnosis of an obesity-related condition; and, would therefore achieve greater weight reduction compared to similarly overweight and obese patients without a diagnosis of NAFLD. Methods: A retrospective chart review was conducted on 73 (35 male, 38 female) overweight and obese patients (BMI ≥ 85th percentile) attending a pediatric GI clinic between January 2006 and October 2011. Analysis was conducted to determine if lifestyle goals discussed with the patient at each clinic visit were associated with improved BMI, BMI z-score, and liver enzymes. Treatment outcomes among NAFLD patients and similarly obese patients without NAFLD were compared using t-tests and chi-square tests. Results: Of the children evaluated, 74.0% achieved a reduction or stabilization in BMI z-score after 3 months of follow-up. Among NAFLD patients, liver enzymes improved in 72% of those who were able to stabilize or reduce their BMI and among 43% of those who gained weight. Treatment outcome did not significantly differ based on having a diagnosis of NAFLD, although there was a trend towards greater improvements. Conclusion: Our study suggests that action oriented counseling including goal-setting in a low intensity, clinic based approach is effective in improving patient BMI, in the presence or absence of an obesity-related co-morbidity, such as NAFLD. Further, we demonstrated that lifestyle modification led to improvement of liver enzymes in NAFLD patients and may result in other clinically relevant improvements. Longer studies will be needed to determine if the improvements are sustained.
Background: Nonalcoholic fatty liver disease (NAFLD) has emerged as the major pediatric chronic liver disease, and it is estimated to affect more than one third of obese children in the U.S. Cardiovascular complications are a leading cause of increased mortality in adults with NAFLD and many adolescents with NAFLD already manifest signs of subclinical atherosclerosis including increased carotid intima-media thickness. Methods: Volume of intrahepatic fat was assessed in 50 Hispanic-American, overweight adolescents, using Magnetic Resonance Spectroscopy. Lipoprotein compositions were measured using Nuclear Magnetic Resonance. Results: Plasma triglycerides (TG) (p∈=∈0.003), TG/HDL ratio (p∈=∈0.006), TG/apoB ratio (p∈=∈0.011), large VLDL concentration (p∈=∈0.019), VLDL particle size (p∈=∈0.012), as well as small dense LDL concentration (p∈=∈0.026) progressively increased across higher levels of hepatic fat severity, while large HDL concentration progressively declined (p∈=∈0.043). This pattern of associations remained even after controlling for gender, BMI, visceral fat, and insulin resistance. Conclusions: Our findings suggest that increased hepatic fat is strongly associated with peripheral dyslipidemia and the amount of fat in the liver may influence cardiovascular risk. Further studies are needed to longitudinally monitor dyslipidemia in children with NAFLD and to examine whether the reduction of hepatic fat would attenuate their long-term CVD risk.
Fructose-sweetened liquid consumption is associated with fatty liver and oxidative stress. In rodent models of fructose-mediated fatty liver, protein consumption is decreased. Additionally, decreased sulfur amino acid intake is known to cause oxidative stress. Studies were designed to test whether oxidative stress in fructose-sweetened liquid-induced fatty liver is caused by decreased ad libitum solid food intake with associated inadequate sulfur amino acid intake. C57BL6 mice were grouped as: control (ad libitum water), fructose (ad libitum 30% fructose-sweetened liquid), glucose (ad libitum 30% glucose-sweetened water) and pair-fed (ad libitum water and sulfur amino acid intake same as the fructose group). Hepatic and plasma thiol-disulfide antioxidant status were analyzed after five weeks. Fructose- and glucose-fed mice developed fatty liver. The mitochondrial antioxidant protein, thioredoxin-2, displayed decreased abundance in the liver of fructose and glucose-fed mice compared to controls. Glutathione/glutathione disulfide redox potential (E hGSSG) and abundance of the cytoplasmic antioxidant protein, peroxiredoxin-2, were similar among groups. We conclude that both fructose and glucose-sweetened liquid consumption results in fatty liver and upregulated thioredoxin-2 expression, consistent with mitochondrial oxidative stress; however, inadequate sulfur amino acid intake was not the cause of this oxidative stress.
by
Jeffrey B. Schwimmer;
Joel E. Lavine;
Laura A. Wilson;
Brent A. Neuschwander-Tetri;
Stavra A. Xanthakos;
Rohit Kohli;
Sarah E. Barlow;
Miriam Vos;
Saul Karpen;
Jean P. Molleston;
Peter F. Whitington;
Philip Rosenthal;
Ajay K. Jain;
Karen F. Murray;
Elizabeth M. Brunt;
David E. Kleiner;
Mark L. Van Natta;
Jeanne M. Clark;
James Tonascia;
Edward Doo
Background & Aims No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. Methods We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing > 65 to 80 kg, and 450 mg for patients weighing > 80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran–Mantel–Haenszel analysis. Results There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8–2.1; P =.34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P =.02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P =.008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P =.03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3–12.3; P =.005). Conclusions In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.
Children transplanted for ALF urgently require an optimal graft and have lower post-transplant survival compared with children transplanted for chronic liver disease. Over 10 yr, 33 consecutive children transplanted for ALF were followed. Demographics, encephalopathy, intubation, dialysis, laboratory values, graft type ABOI, XL (GRWR > 5%), DDSLT, LDLT and WLT were evaluated. Complications and survival were determined. ALF accounted for 33/201 (16.4%) of transplants during this period. Twelve of 33 received ABOI, five XL grafts, 18 DDSLT, and three LDLT. Waiting time pretransplant was 2.1 days. One- and three-yr patient survival in the ALF group was 93.4% and 88.9%, and graft survivals were 86.4% and 77.7%. Median follow-up was 1452 days. ABOI one- and three yr patient and graft survival in the ALF was 91.6% and 78.6%. No difference in graft or patient survival was noted in the ALF and chronic liver disease group or the ABOI and the ABO compatible group. A combination of ABO incompatible donor livers, XL grafts, DDSLT, LDLT and WLT led to a short wait time and subsequent graft and patient survival comparable to patients with non-acute disease.
In preclinical studies of fructose-induced NAFLD, endotoxin appears to play an important role. We retrospectively examined samples from three pediatric cohorts (1) to investigate whether endotoxemia is associated with the presence of hepatic steatosis; (2) to evaluate postprandial endotoxin levels in response to fructose beverage in an acute 24-hour feeding challenge, and (3) to determine the change of fasting endotoxin amounts in a 4-week randomized controlled trial comparing fructose to glucose beverages in NAFLD. We found that adolescents with hepatic steatosis had elevated endotoxin levels compared to obese controls and that the endotoxin level correlated with insulin resistance and several inflammatory cytokines. In a 24-hour feeding study, endotoxin levels in NAFLD adolescents increased after fructose beverages (consumed with meals) as compared to healthy children. Similarly, endotoxin was significantly increased after adolescents consumed fructose beverages for 2 weeks and remained high although not significantly at 4 weeks. In conclusion, these data provide support for the concept of low level endotoxemia contributing to pediatric NAFLD and the possible role of fructose in this process. Further studies are needed to determine if manipulation of the microbiome or other methods of endotoxin reduction would be useful as a therapy for pediatric NAFLD.
Introduction. Given the high prevalence of childhood obesity in the United States, we aimed to investigate youth's understanding of obesity and to investigate gaps between their nutritional knowledge, dietary habits, and perceived susceptibility to obesity and its co-morbidities. Methods. A marketing firm contracted by Children's Healthcare of Atlanta facilitated a series of focus group discussions (FGD) to test potential concepts and sample ads for the development of an obesity awareness campaign. Data were collected in August and September of 2010 with both overweight and healthy weight 4th-5th grade and 7th-8th grade students. We conducted a secondary analysis of the qualitative FGD transcripts using inductive thematic coding to identify key themes related to youth reports of family eating habits (including food preparation, meal frequency, and eating environment), perceived facilitators and barriers of healthy diet, and knowledge about obesity and its complications. Results. Across focus group discussions, mixed attitudes about healthy eating, low perceived risk of being or becoming obese, and limited knowledge about the health consequences of obesity may contribute to the rising prevalence of obesity among youth in Georgia. Most youth were aware that obesity was a problem; yet most overweight youth felt that their weight was healthy and attributed overweight to genetics or slow metabolism. Conclusions. Our analysis suggests that urban youth in Georgia commonly recognize obesity as a problem, but there is less understanding of the link to lifestyle choices or the connection to future morbidities, suggesting a need for education to connect lifestyle behaviors to development of obesity.
Nonalcoholic fatty liver disease (NAFLD) is now thought to be the most common liver disease worldwide. Cardiovascular complications are a leading cause of mortality in NAFLD. Fructose, a common nutrient in the westernized diet, has been reported to be associated with increased cardiovascular risk, but its impact on adolescents with NAFLD is not well understood. We designed a 4-week randomized, controlled, double-blinded beverage intervention study. Twenty-four overweight Hispanic-American adolescents who had hepatic fat >8% on imaging and who were regular consumers of sweet beverages were enrolled and randomized to calorie-matched study-provided fructose only or glucose only beverages. After 4 weeks, there was no significant change in hepatic fat or body weight in either group. In the glucose beverage group there was significantly improved adipose insulin sensitivity, high sensitivity C-reactive protein (hs-CRP), and low-density lipoprotein (LDL) oxidation. These findings demonstrate that reduction of fructose improves several important factors related to cardiovascular disease despite a lack of measurable improvement in hepatic steatosis. Reducing dietary fructose may be an effective intervention to blunt atherosclerosis progression among NAFLD patients and should be evaluated in longer term clinical trials.
by
Kathryn E. Harlow;
Jonathan A. Africa;
Alan Wells;
Patricia H. Belt;
Cynthia A. Behling;
Ajay K. Jain;
Jean P. Molleston;
Kimberly P. Newton ;
Philip Rosenthal;
Miriam Vos;
Stavra A Xanthakos;
Joel E. Lavine;
Jeffrey B. Schwimmer
Objective: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. Study design: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. Results: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. Conclusions: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management.