Advances in pediatric nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common cause of pediatric liver disease in the developed world. Children have a form of NAFLD that is pathologically distinct from adults. Although NAFLD remains a pathologic diagnosis, biomarkers and imaging studies hold promise as noninvasive means of both establishing the diagnosis and following the disease course. Significant advancements have recently been made in genetics, pathophysiology, and the treatment of NAFLD. The purpose of this article is to provide a clinically relevant review of pediatric NAFLD with an emphasis on recent developments in the field.

[1]  W. Rosenberg,et al.  Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. , 2009, Gastroenterology.

[2]  C. Maffeis,et al.  Biochemical Parameters and Anthropometry Predict NAFLD in Obese Children , 2011, Journal of pediatric gastroenterology and nutrition.

[3]  S. Sookoian,et al.  Meta‐analysis of the influence of I148M variant of patatin‐like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease , 2011, Hepatology.

[4]  S. McCall,et al.  Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis , 2007, Hepatology.

[5]  K. Widhalm,et al.  Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16 390 overweight or obese children and adolescents , 2010, International Journal of Obesity.

[6]  Udo Hoffmann,et al.  Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits , 2011, PLoS genetics.

[7]  J. Schwimmer,et al.  Symptoms and quality of life in obese children and adolescents with non‐alcoholic fatty liver disease , 2010, Alimentary pharmacology & therapeutics.

[8]  M. Matsuda,et al.  Adipose Tissue Hypoxia in Obesity and Its Impact on Adipocytokine Dysregulation , 2007, Diabetes.

[9]  Shelby Sullivan Implications of diet on nonalcoholic fatty liver disease , 2010, Current opinion in gastroenterology.

[10]  G. Musso,et al.  A meta‐analysis of randomized trials for the treatment of nonalcoholic fatty liver disease , 2010, Hepatology.

[11]  İ. Kırbaş,et al.  Influence of Obstructive Sleep Apnea on Fatty Liver Disease: Role of Chronic Intermittent Hypoxia , 2012, Respiratory Care.

[12]  G. Bedogni,et al.  Prolonged n‐3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non‐alcoholic fatty liver disease: a pilot study , 2006, Alimentary pharmacology & therapeutics.

[13]  Elizabeth M. Brunt,et al.  Pathology of nonalcoholic fatty liver disease , 2010, Nature Reviews Gastroenterology &Hepatology.

[14]  S. Woods,et al.  High‐fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis , 2010, Hepatology.

[15]  Jonathan C. Cohen,et al.  Human Fatty Liver Disease: Old Questions and New Insights , 2011, Science.

[16]  Frank B. Hu,et al.  Sugar-sweetened beverages and risk of obesity and type 2 diabetes: Epidemiologic evidence , 2010, Physiology & Behavior.

[17]  An-fang Cui,et al.  Mouse patatin‐like phospholipase domain‐containing 3 influences systemic lipid and glucose homeostasis , 2011, Hepatology.

[18]  Hongyu Zhao,et al.  A common variant in the patatin‐like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents , 2010, Hepatology.

[19]  C. Ji The prevalence of childhood overweight/obesity and the epidemic changes in 1985–2000 for Chinese school‐age children and adolescents , 2008, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[20]  B. Neuschwander‐Tetri,et al.  Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[21]  K. Flegal,et al.  Prevalence of high body mass index in US children and adolescents, 2007-2008. , 2010, JAMA.

[22]  P. Mandal,et al.  Molecular Mechanism for Adiponectin-dependent M2 Macrophage Polarization , 2011, The Journal of Biological Chemistry.

[23]  G. Bedogni,et al.  A combination of the pediatric NAFLD fibrosis index and enhanced liver fibrosis test identifies children with fibrosis. , 2011, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[24]  A. Feldstein,et al.  Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: Present and future , 2007, Hepatology.

[25]  A. Koçyiğit,et al.  Intima-Media Thickness of Carotid Artery and Susceptibility to Atherosclerosis in Obese Children With Nonalcoholic Fatty Liver Disease , 2008, Journal of pediatric gastroenterology and nutrition.

[26]  D. Torres,et al.  Diagnosis and therapy of nonalcoholic steatohepatitis. , 2008, Gastroenterology.

[27]  Robert V Farese,et al.  Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. , 2007, Cell metabolism.

[28]  Y. Tamura,et al.  Effects of diet-induced moderate weight reduction on intrahepatic and intramyocellular triglycerides and glucose metabolism in obese subjects. , 2007, The Journal of clinical endocrinology and metabolism.

[29]  F. Marra,et al.  Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis , 2008, Hepatology.

[30]  M. Pagliassotti,et al.  Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. , 2006, Endocrinology.

[31]  Y. Kondo,et al.  Possible involvement and the mechanisms of excess trans-fatty acid consumption in severe NAFLD in mice. , 2010, Journal of hepatology.

[32]  M. Funaki Saturated fatty acids and insulin resistance. , 2009, The journal of medical investigation : JMI.

[33]  G. Farrell,et al.  A fresh look at NASH pathogenesis. Part 1: The metabolic movers , 2010, Journal of gastroenterology and hepatology.

[34]  Wei Zhang,et al.  Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. , 2009, The Journal of clinical investigation.

[35]  K. Petersen,et al.  Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. , 2010, The New England journal of medicine.

[36]  C. Buechler,et al.  Adiponectin, a key adipokine in obesity related liver diseases. , 2011, World journal of gastroenterology.

[37]  M. Zappa,et al.  The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver. , 2011, Journal of hepatology.

[38]  H. Tilg The Role of Cytokines in Non-Alcoholic Fatty Liver Disease , 2010, Digestive Diseases.

[39]  I. Guha,et al.  Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers , 2007, Hepatology.

[40]  C. Ker,et al.  Leptin in hepatocellular carcinoma. , 2010, World journal of gastroenterology.

[41]  S. Caldwell,et al.  Epidemiology and natural history of non-alcoholic steatohepatitis. , 2009, Clinics in liver disease.

[42]  M. Thompson,et al.  Regulation of the promoter region of the human adiponutrin/PNPLA3 gene by glucose and insulin. , 2010, Biochemical and biophysical research communications.

[43]  Jaimie N. Davis,et al.  Effects of PNPLA3 on Liver Fat and Metabolic Profile in Hispanic Children and Adolescents , 2010, Diabetes.

[44]  H. Tilg,et al.  Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis , 2010, Hepatology.

[45]  T. Liang,et al.  The association of genetic variability in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease , 2010, Hepatology.

[46]  A. Abid,et al.  Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. , 2009, Journal of hepatology.

[47]  Cameron S. Francis,et al.  Nonalcoholic fatty liver disease as a comorbidity of childhood obesity. , 2009, Pediatric health.

[48]  Vito Cantisani,et al.  Functional and morphological vascular changes in pediatric nonalcoholic fatty liver disease , 2010, Hepatology.

[49]  E. Trolle,et al.  Prevalence and trends in overweight and obesity among children and adolescents in Denmark , 2008, Scandinavian journal of public health.

[50]  A. Suzuki,et al.  Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease , 2010, Hepatology.

[51]  Jonathan C. Cohen,et al.  A feed-forward loop amplifies nutritional regulation of PNPLA3 , 2010, Proceedings of the National Academy of Sciences.

[52]  E. Tsochatzis,et al.  Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy , 2009, Mediators of inflammation.

[53]  S. Harrison,et al.  Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection , 2010, Hepatology.

[54]  C. McClain,et al.  Decreased Prevalence of Nonalcoholic Fatty Liver Disease in Black Obese Children , 2005, Journal of pediatric gastroenterology and nutrition.

[55]  R. Deutsch,et al.  Influence of Gender, Race, and Ethnicity on Suspected Fatty Liver in Obese Adolescents , 2005, Pediatrics.

[56]  K. Choi,et al.  Relation between elevated serum alanine aminotransferase and metabolic syndrome in Korean adolescents. , 2005, The American journal of clinical nutrition.

[57]  A. Feldstein,et al.  Nonalcoholic steatohepatitis in children: A multicenter clinicopathological study , 2009, Hepatology.

[58]  Jeffrey B. Schwimmer,et al.  Prevalence of Fatty Liver in Children and Adolescents , 2006, Pediatrics.

[59]  P. Katzmarzyk,et al.  Comparison of overweight and obesity prevalence in school‐aged youth from 34 countries and their relationships with physical activity and dietary patterns , 2005, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[60]  G. Norman,et al.  SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. , 2010, Gastroenterology.

[61]  Vincent Wai-Sun Wong,et al.  Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years , 2010, Gut.

[62]  S. Grundy,et al.  Metabolic correlates of nonalcoholic fatty liver in women and men , 2007, Hepatology.

[63]  G. Bedogni,et al.  Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial , 2011, Archives of Disease in Childhood.

[64]  I. Wanless,et al.  The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis. , 2004, Seminars in liver disease.

[65]  Laura E Nagy,et al.  Obesity, diabetes mellitus, and liver fibrosis. , 2011, American journal of physiology. Gastrointestinal and liver physiology.

[66]  Julien Vergniol,et al.  Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease , 2010, Hepatology.

[67]  Heidi M. Blanck,et al.  Vital signs: state-specific obesity prevalence among adults --- United States, 2009. , 2010, MMWR. Morbidity and mortality weekly report.

[68]  A. Krasinskas,et al.  Surgically-Induced Weight Loss Significantly Improves Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome , 2005, Annals of Surgery.

[69]  J. Jessurun,et al.  Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. , 2005, The Journal of clinical investigation.

[70]  S. Piro,et al.  Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. , 2008, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[71]  D. Lawlor,et al.  Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999-2004. , 2007, Gastroenterology.

[72]  T Nakamura,et al.  Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. , 1999, Biochemical and biophysical research communications.

[73]  Michael Krawczak,et al.  Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians , 2010, Hepatology.

[74]  J. Benson,et al.  The natural history of non-alcoholic fatty liver disease , 2006 .

[75]  H. Grønbæk,et al.  Effect of a 10-week Weight Loss Camp on Fatty Liver Disease and Insulin Sensitivity in Obese Danish Children , 2012, Journal of pediatric gastroenterology and nutrition.

[76]  V. Wong,et al.  Nonalcoholic fatty liver in Asia: Firmly entrenched and rapidly gaining ground , 2011, Journal of gastroenterology and hepatology.

[77]  Jianping Ye,et al.  Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. , 2007, American journal of physiology. Endocrinology and metabolism.

[78]  V. Cantisani,et al.  Nonalcoholic Fatty Liver Disease and Carotid Atherosclerosis in Children , 2008, Pediatric Research.

[79]  B. Neuschwander‐Tetri,et al.  Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. , 2010, The New England journal of medicine.

[80]  M. Romero-Gómez,et al.  APOC3 polymorphisms and non-alcoholic fatty liver disease: resolving some doubts and raising others. , 2011, Journal of hepatology.

[81]  S. Harrison,et al.  Non-Alcoholic Steatohepatitis: Effect of Roux-en-Y Gastric Bypass Surgery , 2006, The American Journal of Gastroenterology.

[82]  Rocio Lopez,et al.  The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis , 2010, Hepatology.

[83]  Jonathan C. Cohen,et al.  Dissociation Between APOC3 Variants, Hepatic Triglyceride Content and Insulin Resistance , 2011, Hepatology.

[84]  G. Karaca,et al.  Leptin Promotes the Myofibroblastic Phenotype in Hepatic Stellate Cells by Activating the Hedgehog Pathway , 2010, The Journal of Biological Chemistry.

[85]  F. Gottrand,et al.  Is liver transaminases assessment an appropriate tool for the screening of non-alcoholic fatty liver disease in at risk obese children and adolescents? , 2010, Nutricion hospitalaria.

[86]  Vanessa S Teaberry,et al.  Pan‐caspase inhibitor VX‐166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis , 2009, Hepatology.

[87]  P. Angulo,et al.  Nonalcoholic fatty liver disease. , 2002, Revista de gastroenterologia de Mexico.

[88]  A. Diehl,et al.  Hepatic triglyceride synthesis and nonalcoholic fatty liver disease , 2008, Current opinion in lipidology.

[89]  Claudio Cobelli,et al.  Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men , 2006, Proceedings of the National Academy of Sciences.

[90]  S. Commans,et al.  Characterization of the human patatin-like phospholipase familys⃞ Published, JLR Papers in Press, June 25, 2006. , 2006, Journal of Lipid Research.

[91]  C. Caserta,et al.  Cardiovascular risk factors, nonalcoholic fatty liver disease, and carotid artery intima-media thickness in an adolescent population in southern Italy. , 2010, American journal of epidemiology.

[92]  J. Kountouras,et al.  The role of adiponectin in the pathogenesis and treatment of non‐alcoholic fatty liver disease , 2010, Diabetes, obesity & metabolism.

[93]  R. Weiner Surgical Treatment of Non-Alcoholic Steatohepatitis and Non-Alcoholic Fatty Liver Disease , 2010, Digestive Diseases.

[94]  A. Sanyal,et al.  Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. , 2009, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[95]  J. Dillon,et al.  Systematic review of performance of non‐invasive biomarkers in the evaluation of non‐alcoholic fatty liver disease , 2011, Liver international : official journal of the International Association for the Study of the Liver.

[96]  D. Mozaffarian,et al.  Trans fatty acids: effects on metabolic syndrome, heart disease and diabetes , 2009, Nature Reviews Endocrinology.

[97]  M. Manco,et al.  Metabolic syndrome and liver histology in paediatric non-alcoholic steatohepatitis , 2008, International Journal of Obesity.

[98]  K. Kotoh,et al.  Liver X receptor in cooperation with SREBP‐1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease , 2008, Hepatology research : the official journal of the Japan Society of Hepatology.

[99]  S. Barlow,et al.  Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. , 2007, Pediatrics.

[100]  Y. Kesäniemi,et al.  Plasma adiponectin--an independent indicator of liver fat accumulation. , 2011, Metabolism: clinical and experimental.

[101]  A. Sanyal,et al.  Population-based risk factors and resource utilization for HCC: US perspective , 2010, Current medical research and opinion.

[102]  B. Neuschwander‐Tetri Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites , 2010, Hepatology.

[103]  J. Schwimmer,et al.  Diagnosis and treatment of pediatric nonalcoholic steatohepatitis and the implications for bariatric surgery. , 2009, Seminars in pediatric surgery.

[104]  C. Day,et al.  Steatohepatitis: a tale of two "hits"? , 1998, Gastroenterology.

[105]  Alexander Pertsemlidis,et al.  Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease , 2008, Nature Genetics.

[106]  P. Rosenthal,et al.  Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. , 2011, JAMA.

[107]  A. Feldstein,et al.  Cytokeratin‐18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: A multicenter validation study , 2009, Hepatology.

[108]  J. Schwimmer,et al.  Cardiovascular Risk Factors and the Metabolic Syndrome in Pediatric Nonalcoholic Fatty Liver Disease , 2008, Circulation.

[109]  Yu Wang,et al.  The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. , 2003, The Journal of clinical investigation.

[110]  P. Ciampalini,et al.  NAFLD in children: A prospective clinical‐pathological study and effect of lifestyle advice , 2006, Hepatology.

[111]  J. Olefsky,et al.  Insulin sensitivity: modulation by nutrients and inflammation. , 2008, The Journal of clinical investigation.

[112]  K. Kaestner,et al.  Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling. , 2011, The Journal of clinical investigation.

[113]  B. Popkin,et al.  Changes in beverage intake between 1977 and 2001. , 2004, American journal of preventive medicine.

[114]  H. Kirikoshi,et al.  Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). , 2008, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[115]  J. Kountouras,et al.  The potential adverse role of leptin resistance in nonalcoholic fatty liver disease: a hypothesis based on critical review of the literature. , 2011, Journal of clinical gastroenterology.

[116]  W. Nseir,et al.  Soft drink consumption linked with fatty liver in the absence of traditional risk factors. , 2008, Canadian journal of gastroenterology = Journal canadien de gastroenterologie.

[117]  V. M. Cambuli,et al.  The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. , 2010, Journal of hepatology.

[118]  S. Caldwell,et al.  Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. , 2009, Journal of hepatology.

[119]  F. Schick,et al.  Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. , 2009, Journal of hepatology.

[120]  D. Franchimont,et al.  Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease. , 2011, Journal of hepatology.

[121]  C. Nievergelt,et al.  Histopathology of pediatric nonalcoholic fatty liver disease , 2005, Hepatology.

[122]  G. Bedogni,et al.  Waist circumference correlates with liver fibrosis in children with non-alcoholic steatohepatitis , 2008, Gut.

[123]  R. Schwabe,et al.  Reduced nicotinamide adenine dinucleotide phosphate oxidase mediates fibrotic and inflammatory effects of leptin on hepatic stellate cells , 2008, Hepatology.

[124]  E. Roberts,et al.  Non-alcoholic fatty liver disease (NAFLD) in children. , 2005, Frontiers in bioscience : a journal and virtual library.

[125]  H. Tilg,et al.  Update on nonalcoholic fatty liver disease: genes involved in nonalcoholic fatty liver disease and associated inflammation , 2010, Current opinion in clinical nutrition and metabolic care.

[126]  R. Ehman,et al.  Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography. , 2011, Radiology.

[127]  N. Schork,et al.  Heritability of nonalcoholic fatty liver disease. , 2009, Gastroenterology.

[128]  P. Rosenthal,et al.  Correlation of Vitamin E, Uric Acid, and Diet Composition With Histologic Features of Pediatric NAFLD , 2012, Journal of pediatric gastroenterology and nutrition.

[129]  J. Sallis,et al.  Physical Activity Recommendations, Exercise Intensity, and Histological Severity of Nonalcoholic Fatty Liver Disease , 2011, The American Journal of Gastroenterology.