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Semin Liver Dis 2018; 38(01): 001-013
DOI: 10.1055/s-0038-1627456
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Nonalcoholic Fatty Liver Disease in Children

Jake P. Mann
1   Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom
,
Luca Valenti
2   Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Università degli Studi di Milano, Milan, Italy
,
Eleonora Scorletti
3   Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
,
Christopher D. Byrne
3   Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
4   National Institute for Health Research Southampton Biomedical Research Centre (in Nutrition), University of Southampton and University Hospital Southampton National Health Service (NHS) Foundation Trust, Southampton, United Kingdom
5   Respiratory Biomedical Research Unit, University of Southampton and University Hospital Southampton National Health Service (NHS) Foundation Trust, Southampton, United Kingdom
,
Valerio Nobili
6   Hepatometabolic Disease Unit, Bambino Gesù Children's Hospital, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy
7   Department of Pediatrics, University “La Sapienza,” Rome, Italy
› Author Affiliations Funding No external funding supported the research described in this manuscript. This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Further Information

Publication History

Publication Date:
22 February 2018 (online)

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Abstract

Nonalcoholic steatohepatitis, a progressive form of nonalcoholic fatty liver disease (NAFLD), is one of the most common hepatic diseases in children who present with particular risk factors including obesity, sedentary lifestyle, and/or a predisposing genetic background. The worldwide prevalence of NAFLD in children is a worrying phenomenon because this disease is closely associated with the development of both cirrhosis and cardiometabolic syndrome in adulthood. To date, the etiopathogenesis of primary NAFLD in children is unknown. Understanding the pathogenetic mechanisms provides the basis to characterize early predictors of the disease and noninvasive diagnostic tools and to design novel specific treatments and possible management strategies. Despite a few clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD, no treatment exists for children with NAFLD. In this review, the authors provide an overview of current concepts in epidemiology, histological features, etiopathogenesis, diagnosis, and treatment of NAFLD in pediatric population.

Keywords

NAFLD - obesity - children - NASH

Authors' Contribution

All authors equally participated to the manuscript, approved the final version as submitted, and agreed to be accountable for all aspects of the work.


 

  • References

  • 1 Nobili V, Svegliati-Baroni G, Alisi A, Miele L, Valenti L, Vajro P. A 360-degree overview of paediatric NAFLD: recent insights. J Hepatol 2013; 58 (06) 1218-1229
    CrossrefPubMedSearch in Google Scholar
  • 2 Mencin AA, Lavine JE. Nonalcoholic fatty liver disease in children. Curr Opin Clin Nutr Metab Care 2011; 14 (02) 151-157
    PubMedSearch in Google Scholar
  • 3 Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006; 118 (04) 1388-1393
    CrossrefPubMedSearch in Google Scholar
  • 4 Pacifico L, Poggiogalle E, Cantisani V. , et al. Pediatric nonalcoholic fatty liver disease: a clinical and laboratory challenge. World J Hepatol 2010; 2 (07) 275-288
    CrossrefPubMedSearch in Google Scholar
  • 5 Anderson EL, Howe LD, Jones HE, Higgins JP, Lawlor DA, Fraser A. The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis. PLoS One 2015; 10 (10) e0140908
    CrossrefPubMedSearch in Google Scholar
  • 6 Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A. Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 2013; 5 (05) 1544-1560
    CrossrefPubMedSearch in Google Scholar
  • 7 Valenti L, Bugianesi E, Pajvani U, Targher G. Nonalcoholic fatty liver disease: cause or consequence of type 2 diabetes?. Liver Int 2016; 36 (11) 1563-1579
    CrossrefPubMedSearch in Google Scholar
  • 8 Nobili V, Liccardo D, Bedogni G. , et al. Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents. Genes Nutr 2014; 9 (03) 392
    CrossrefPubMedSearch in Google Scholar
  • 9 Dongiovanni P, Valenti L. Genetics of nonalcoholic fatty liver disease. Metabolism 2016; 65 (08) 1026-1037
    CrossrefPubMedSearch in Google Scholar
  • 10 Dongiovanni P, Lanti C, Riso P, Valenti L. Nutritional therapy for nonalcoholic fatty liver disease. J Nutr Biochem 2016; 29: 1-11
    CrossrefPubMedSearch in Google Scholar
  • 11 Vos MB, Lavine JE. Dietary fructose in nonalcoholic fatty liver disease. Hepatology 2013; 57 (06) 2525-2531
    CrossrefPubMedSearch in Google Scholar
  • 12 Schwarz JM, Noworolski SM, Erkin-Cakmak A. , et al. Effects of dietary fructose restriction on liver fat, de novo lipogenesis, and insulin kinetics in children with obesity. Gastroenterology 2017; 153 (03) 743-752
    CrossrefPubMedSearch in Google Scholar
  • 13 Mosca A, Nobili V, De Vito R. , et al. Serum uric acid concentrations and fructose consumption are independently associated with NASH in children and adolescents. J Hepatol 2017; 66 (05) 1031-1036
    CrossrefPubMedSearch in Google Scholar
  • 14 Santoro N, Savoye M, Kim G. , et al. Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake. PLoS One 2012; 7 (05) e37827
    CrossrefPubMedSearch in Google Scholar
  • 15 Romeo S, Kozlitina J, Xing C. , et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40 (12) 1461-1465
    CrossrefPubMedSearch in Google Scholar
  • 16 Kozlitina J, Smagris E, Stender S. , et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014; 46 (04) 352-356
    CrossrefPubMedSearch in Google Scholar
  • 17 Mancina RM, Dongiovanni P, Petta S. , et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 2016; 150 (05) 1219-1230.e6
    CrossrefPubMedSearch in Google Scholar
  • 18 Schwimmer JB, McGreal N, Deutsch R, Finegold MJ, Lavine JE. Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents. Pediatrics 2005; 115 (05) e561-e565
    CrossrefPubMedSearch in Google Scholar
  • 19 Dongiovanni P, Romeo S, Valenti L. Genetic factors in the pathogenesis of nonalcoholic fatty liver and steatohepatitis. BioMed Res Int 2015; 2015: 460190
    PubMedSearch in Google Scholar
  • 20 Dongiovanni P, Donati B, Fares R. , et al. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol 2013; 19 (41) 6969-6978
    CrossrefPubMedSearch in Google Scholar
  • 21 Dongiovanni P, Petta S, Maglio C. , et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015; 61 (02) 506-514
    CrossrefPubMedSearch in Google Scholar
  • 22 Santoro N, Zhang CK, Zhao H. , et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 2012; 55 (03) 781-789
    CrossrefPubMedSearch in Google Scholar
  • 23 Suomela E, Oikonen M, Pitkänen N. , et al. Childhood predictors of adult fatty liver. The Cardiovascular Risk in Young Finns Study. J Hepatol 2016; 65 (04) 784-790
    CrossrefPubMedSearch in Google Scholar
  • 24 Sun C, Fan JG, Qiao L. Potential epigenetic mechanism in non-alcoholic Fatty liver disease. Int J Mol Sci 2015; 16 (03) 5161-5179
    CrossrefPubMedSearch in Google Scholar
  • 25 Nobili V, Marcellini M, Marchesini G. , et al. Intrauterine growth retardation, insulin resistance, and nonalcoholic fatty liver disease in children. Diabetes Care 2007; 30 (10) 2638-2640
    CrossrefPubMedSearch in Google Scholar
  • 26 Kleiner DE, Brunt EM, Van Natta M. , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41 (06) 1313-1321
    CrossrefPubMedSearch in Google Scholar
  • 27 Dongiovanni P, Fracanzani AL, Fargion S, Valenti L. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. J Hepatol 2011; 55 (04) 920-932
    CrossrefPubMedSearch in Google Scholar
  • 28 Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015; 13 (04) 643-54.e1 , 9, quiz e39–e40
    CrossrefPubMedSearch in Google Scholar
  • 29 Angulo P, Kleiner DE, Dam-Larsen S. , et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015; 149 (02) 389-97.e10
    CrossrefPubMedSearch in Google Scholar
  • 30 Ekstedt M, Hagström H, Nasr P. , et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61 (05) 1547-1554
    CrossrefPubMedSearch in Google Scholar
  • 31 Dulai PS, Singh S, Patel J. , et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 2017; 65 (05) 1557-1565
    CrossrefPubMedSearch in Google Scholar
  • 32 Hagström H, Nasr P, Ekstedt M. , et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol 2017; 67 (06) 1265-1273
    CrossrefPubMedSearch in Google Scholar
  • 33 Schwimmer JB, Behling C, Newbury R. , et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 2005; 42 (03) 641-649
    CrossrefPubMedSearch in Google Scholar
  • 34 Ko JS, Yoon JM, Yang HR. , et al. Clinical and histological features of nonalcoholic fatty liver disease in children. Dig Dis Sci 2009; 54 (10) 2225-2230
    CrossrefPubMedSearch in Google Scholar
  • 35 Takahashi Y, Inui A, Fujisawa T, Takikawa H, Fukusato T. Histopathological characteristics of non-alcoholic fatty liver disease in children: comparison with adult cases. Hepatol Res 2011; 41 (11) 1066-1074
    CrossrefPubMedSearch in Google Scholar
  • 36 Skoien R, Richardson MM, Jonsson JR. , et al. Heterogeneity of fibrosis patterns in non-alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways. Liver Int 2013; 33 (04) 624-632
    CrossrefPubMedSearch in Google Scholar
  • 37 Brunt EM, Kleiner DE, Wilson LA. , et al; NASH Clinical Research NetworkA list of members of the Nonalcoholic Steatohepatitis Clinical Research Network can be found in the Appendix. Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Hepatology 2009; 49 (03) 809-820
    CrossrefPubMedSearch in Google Scholar
  • 38 Mann JP, De Vito R, Mosca A. , et al. Portal inflammation is independently associated with fibrosis and metabolic syndrome in pediatric nonalcoholic fatty liver disease. Hepatology 2016; 63 (03) 745-753
    CrossrefPubMedSearch in Google Scholar
  • 39 Scorletti E, Calder PC, Byrne CD. Non-alcoholic fatty liver disease and cardiovascular risk: metabolic aspects and novel treatments. Endocrine 2011; 40 (03) 332-343
    CrossrefPubMedSearch in Google Scholar
  • 40 Byrne CD. Ectopic fat, insulin resistance and non-alcoholic fatty liver disease. Proc Nutr Soc 2013; 72 (04) 412-419
    CrossrefPubMedSearch in Google Scholar
  • 41 Angulo P, Hui JM, Marchesini G. , et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45 (04) 846-854
    CrossrefPubMedSearch in Google Scholar
  • 42 Byrne CD, Olufadi R, Bruce KD, Cagampang FR, Ahmed MH. Metabolic disturbances in non-alcoholic fatty liver disease. Clin Sci (Lond) 2009; 116 (07) 539-564
    CrossrefPubMedSearch in Google Scholar
  • 43 Kong L, Lu Y, Zhang S, Nan Y, Qiao L. Role of nutrition, gene polymorphism, and gut microbiota in non-alcoholic fatty liver disease. Discov Med 2017; 24 (131) 95-106
    PubMedSearch in Google Scholar
  • 44 Modi N, Murgasova D, Ruager-Martin R. , et al. The influence of maternal body mass index on infant adiposity and hepatic lipid content. Pediatr Res 2011; 70 (03) 287-291
    PubMedSearch in Google Scholar
  • 45 Brumbaugh DE, Tearse P, Cree-Green M. , et al. Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes. J Pediatr 2013; 162 (05) 930-6.e1
    CrossrefPubMedSearch in Google Scholar
  • 46 Brumbaugh DE, Friedman JE. Developmental origins of nonalcoholic fatty liver disease. Pediatr Res 2014; 75 (1–2): 140-147
    CrossrefPubMedSearch in Google Scholar
  • 47 Holland ML, Lowe R, Caton PW. , et al. Early-life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice. Science 2016; 353 (6298): 495-498
    CrossrefPubMedSearch in Google Scholar
  • 48 Tarry-Adkins JL, Fernandez-Twinn DS, Hargreaves IP. , et al. Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth. Am J Clin Nutr 2016; 103 (02) 579-588
    CrossrefPubMedSearch in Google Scholar
  • 49 Alfaradhi MZ, Kusinski LC, Fernandez-Twinn DS. , et al. Maternal obesity in pregnancy developmentally programs adipose tissue inflammation in young, lean male mice offspring. Endocrinology 2016; 157 (11) 4246-4256
    CrossrefPubMedSearch in Google Scholar
  • 50 Fernandez-Twinn DS, Gascoin G, Musial B. , et al. Exercise rescues obese mothers' insulin sensitivity, placental hypoxia and male offspring insulin sensitivity. Sci Rep 2017; 7: 44650
    CrossrefPubMedSearch in Google Scholar
  • 51 Sutton EF, Gilmore LA, Dunger DB. , et al. Developmental programming: state-of-the-science and future directions-Summary from a Pennington Biomedical symposium. Obesity (Silver Spring) 2016; 24 (05) 1018-1026
    CrossrefPubMedSearch in Google Scholar
  • 52 Wesolowski SR, Kasmi KC, Jonscher KR, Friedman JE. Developmental origins of NAFLD: a womb with a clue. Nat Rev Gastroenterol Hepatol 2017; 14 (02) 81-96
    CrossrefPubMedSearch in Google Scholar
  • 53 Mouralidarane A, Soeda J, Visconti-Pugmire C. , et al. Maternal obesity programs offspring nonalcoholic fatty liver disease by innate immune dysfunction in mice. Hepatology 2013; 58 (01) 128-138
    CrossrefPubMedSearch in Google Scholar
  • 54 Li M, Reynolds CM, Segovia SA, Gray C, Vickers MH. Developmental programming of nonalcoholic fatty liver disease: the effect of early life nutrition on susceptibility and disease severity in later life. BioMed Res Int 2015; 2015: 437107
    PubMedSearch in Google Scholar
  • 55 Herrera E, Amusquivar E. Lipid metabolism in the fetus and the newborn. Diabetes Metab Res Rev 2000; 16 (03) 202-210
    CrossrefPubMedSearch in Google Scholar
  • 56 Bruce KD, Cagampang FR, Argenton M. , et al. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression. Hepatology 2009; 50 (06) 1796-1808
    CrossrefPubMedSearch in Google Scholar
  • 57 Hales CN, Barker DJP. The thrifty phenotype hypothesis. Br Med Bull 2001; 60: 5-20
    CrossrefPubMedSearch in Google Scholar
  • 58 Bugianesi E, Bizzarri C, Rosso C. , et al. Low birthweight increases the likelihood of severe steatosis in pediatric non-alcoholic fatty liver disease. Am J Gastroenterol 2017; 112 (08) 1277-1286
    CrossrefPubMedSearch in Google Scholar
  • 59 Clària J, González-Périz A, López-Vicario C, Rius B, Titos E. New insights into the role of macrophages in adipose tissue inflammation and fatty liver disease: modulation by endogenous omega-3 fatty Acid-derived lipid mediators. Front Immunol 2011; 2: 49
    CrossrefPubMedSearch in Google Scholar
  • 60 Rius B, López-Vicario C, González-Périz A. , et al. Resolution of inflammation in obesity-induced liver disease. Front Immunol 2012; 3: 257
    PubMedSearch in Google Scholar
  • 61 Moran A, Jacobs Jr DR, Steinberger J. , et al. Insulin resistance during puberty: results from clamp studies in 357 children. Diabetes 1999; 48 (10) 2039-2044
    CrossrefPubMedSearch in Google Scholar
  • 62 Moran A, Jacobs Jr DR, Steinberger J. , et al. Changes in insulin resistance and cardiovascular risk during adolescence: establishment of differential risk in males and females. Circulation 2008; 117 (18) 2361-2368
    CrossrefPubMedSearch in Google Scholar
  • 63 Vos MB, Kimmons JE, Gillespie C, Welsh J, Blanck HM. Dietary fructose consumption among US children and adults: the Third National Health and Nutrition Examination Survey. Medscape J Med 2008; 10 (07) 160
    PubMedSearch in Google Scholar
  • 64 Softic S, Gupta MK, Wang GX. , et al. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest 2017; 127 (11) 4059-4074
    CrossrefPubMedSearch in Google Scholar
  • 65 Geisler CE, Renquist BJ. Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones. J Endocrinol 2017; 234 (01) R1-R21
    CrossrefPubMedSearch in Google Scholar
  • 66 Solinas G, Borén J, Dulloo AG. De novo lipogenesis in metabolic homeostasis: more friend than foe?. Mol Metab 2015; 4 (05) 367-377
    CrossrefPubMedSearch in Google Scholar
  • 67 Bode JC, Zelder O, Rumpelt HJ, Wittkamp U. Depletion of liver adenosine phosphates and metabolic effects of intravenous infusion of fructose or sorbitol in man and in the rat. Eur J Clin Invest 1973; 3 (05) 436-441
    CrossrefPubMedSearch in Google Scholar
  • 68 Crescenzo R, Bianco F, Falcone I, Coppola P, Liverini G, Iossa S. Increased hepatic de novo lipogenesis and mitochondrial efficiency in a model of obesity induced by diets rich in fructose. Eur J Nutr 2013; 52 (02) 537-545
    CrossrefPubMedSearch in Google Scholar
  • 69 Softic S, Cohen DE, Kahn CR. Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig Dis Sci 2016; 61 (05) 1282-1293
    CrossrefPubMedSearch in Google Scholar
  • 70 Diggle CP, Shires M, Leitch D. , et al. Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme. J Histochem Cytochem 2009; 57 (08) 763-774
    CrossrefPubMedSearch in Google Scholar
  • 71 Petrie JL, Patman GL, Sinha I, Alexander TD, Reeves HL, Agius L. The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis. Am J Physiol Endocrinol Metab 2013; 305 (10) E1255-E1265
    CrossrefPubMedSearch in Google Scholar
  • 72 Serdula MK, Ivery D, Coates RJ, Freedman DS, Williamson DF, Byers T. Do obese children become obese adults? A review of the literature. Prev Med 1993; 22 (02) 167-177
    CrossrefPubMedSearch in Google Scholar
  • 73 Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 2009; 58 (11) 1538-1544
    CrossrefPubMedSearch in Google Scholar
  • 74 Molleston JP, White F, Teckman J, Fitzgerald JF. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol 2002; 97 (09) 2460-2462
    CrossrefPubMedSearch in Google Scholar
  • 75 Vajro P, Lenta S, Socha P. , et al. Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr 2012; 54 (05) 700-713
    CrossrefPubMedSearch in Google Scholar
  • 76 Adams LA, Feldstein A, Lindor KD, Angulo P. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology 2004; 39 (04) 909-914
    CrossrefPubMedSearch in Google Scholar
  • 77 Unalp-Arida A, Ruhl CE. Liver fibrosis scores predict liver disease mortality in the United States population. Hepatology 2017; 66 (01) 84-95
    CrossrefPubMedSearch in Google Scholar
  • 78 Nobili V, Alisi A, Vania A, Tiribelli C, Pietrobattista A, Bedogni G. The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease. BMC Med 2009; 7: 21
    CrossrefPubMedSearch in Google Scholar
  • 79 Lavine JE, Schwimmer JB, Van Natta ML. , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011; 305 (16) 1659-1668
    CrossrefPubMedSearch in Google Scholar
  • 80 Nobili V, Manco M, Devito R. , et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 2008; 48 (01) 119-128
    CrossrefPubMedSearch in Google Scholar
  • 81 Barritt IV AS, Gitlin N, Klein S. , et al. Design and rationale for a real-world observational cohort of patients with nonalcoholic fatty liver disease: the TARGET-NASH study. Contemp Clin Trials 2017; 61: 33-38
    CrossrefPubMedSearch in Google Scholar
  • 82 Mann J. , et al. European Paediatric NAFLD Registry (EU-PNAFLD). 2017. . Project ID: 174534 (UK)
    Search in Google Scholar
  • 83 Feldman A, Eder SK, Felder TK. , et al. Clinical and metabolic characterization of lean Caucasian subjects with non-alcoholic fatty liver. Am J Gastroenterol 2017; 112 (01) 102-110
    CrossrefPubMedSearch in Google Scholar
  • 84 Parker VE, Semple RK. Genetics in endocrinology: genetic forms of severe insulin resistance: what endocrinologists should know. Eur J Endocrinol 2013; 169 (04) R71-R80
    CrossrefPubMedSearch in Google Scholar
  • 85 Mak CM, Lam CW, Tam S. Diagnostic accuracy of serum ceruloplasmin in Wilson disease: determination of sensitivity and specificity by ROC curve analysis among ATP7B-genotyped subjects. Clin Chem 2008; 54 (08) 1356-1362
    CrossrefPubMedSearch in Google Scholar
  • 86 European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012; 56 (03) 671-685
    CrossrefPubMedSearch in Google Scholar
  • 87 Burton BK, Deegan PB, Enns GM. , et al. Clinical features of lysosomal acid lipase deficiency. J Pediatr Gastroenterol Nutr 2015; 61 (06) 619-625
    CrossrefPubMedSearch in Google Scholar
  • 88 Burton BK, Balwani M, Feillet F. , et al. A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. N Engl J Med 2015; 373 (11) 1010-1020
    CrossrefPubMedSearch in Google Scholar
  • 89 Selvakumar PK, Kabbany MN, Lopez R. , et al. Reduced lysosomal acid lipase activity - a potential role in the pathogenesis of non alcoholic fatty liver disease in pediatric patients. Dig Liver Dis 2016; 48 (08) 909-913
    CrossrefPubMedSearch in Google Scholar
  • 90 Molleston JP, Schwimmer JB, Yates KP. , et al; NASH Clinical Research Network. Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr 2014; 164 (04) 707-713.e3
    CrossrefPubMedSearch in Google Scholar
  • 91 Burgert TS, Taksali SE, Dziura J. , et al. Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab 2006; 91 (11) 4287-4294
    CrossrefPubMedSearch in Google Scholar
  • 92 Chalasani N, Younossi Z, Lavine JE. , et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67 (01) 328-357
    CrossrefPubMedSearch in Google Scholar
  • 93 Vajro P, Mandato C, Franzese A. , et al. Vitamin E treatment in pediatric obesity-related liver disease: a randomized study. J Pediatr Gastroenterol Nutr 2004; 38 (01) 48-55
    CrossrefPubMedSearch in Google Scholar
  • 94 Boyraz M, Pirgon Ö, Dündar B, Çekmez F, Hatipoğlu N. Long-term treatment with n-3 polyunsaturated fatty acids as a monotherapy in children with nonalcoholic fatty liver disease. J Clin Res Pediatr Endocrinol 2015; 7 (02) 121-127
    CrossrefPubMedSearch in Google Scholar
  • 95 Gibson PS, Lang S, Dhawan A. , et al. Systematic review: nutrition and physical activity in the management of paediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2017; 65 (02) 141-149
    CrossrefPubMedSearch in Google Scholar
  • 96 Ramon-Krauel M, Salsberg SL, Ebbeling CB. , et al. A low-glycemic-load versus low-fat diet in the treatment of fatty liver in obese children. Child Obes 2013; 9 (03) 252-260
    PubMedSearch in Google Scholar
  • 97 Vos MB, Weber MB, Welsh J. , et al. Fructose and oxidized low-density lipoprotein in pediatric nonalcoholic fatty liver disease: a pilot study. Arch Pediatr Adolesc Med 2009; 163 (07) 674-675
    CrossrefPubMedSearch in Google Scholar
  • 98 Goss A. A Carbohydrate-Restricted Diet to Reverse Fatty Liver in Adolescents with Obesity. Birmingham, AL: University of Alabama at Birmingham; 2017
    Search in Google Scholar
  • 99 O'Connor EA, Evans CV, Burda BU, Walsh ES, Eder M, Lozano P. Screening for obesity and intervention for weight management in children and adolescents: evidence report and systematic review for the US Preventive Services Task Force. JAMA 2017; 317 (23) 2427-2444
    CrossrefPubMedSearch in Google Scholar
  • 100 Schwimmer JB. Clinical advances in pediatric nonalcoholic fatty liver disease. Hepatology 2016; 63 (05) 1718-1725
    CrossrefPubMedSearch in Google Scholar
  • 101 Akcam M, Boyaci A, Pirgon O, Kaya S, Uysal S, Dundar BN. Therapeutic effect of metformin and vitamin E versus prescriptive diet in obese adolescents with fatty liver. Int J Vitam Nutr Res 2011; 81 (06) 398-406
    CrossrefPubMedSearch in Google Scholar
  • 102 Zöhrer E, Alisi A, Jahnel J. , et al. Efficacy of docosahexaenoic acid-choline-vitamin E in paediatric NASH: a randomized controlled clinical trial. Appl Physiol Nutr Metab 2017; 42 (09) 948-954
    CrossrefPubMedSearch in Google Scholar
  • 103 Wang CL, Liang L, Fu JF. , et al. Effect of lifestyle intervention on non-alcoholic fatty liver disease in Chinese obese children. World J Gastroenterol 2008; 14 (10) 1598-1602
    CrossrefPubMedSearch in Google Scholar
  • 104 Schwimmer JB, Lavine JE, Wilson LA. , et al; NASH CRN. In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores. Gastroenterology 2016; 151 (06) 1141-1154.e9
    CrossrefPubMedSearch in Google Scholar
  • 105 Shiasi Arani K, Taghavi Ardakani A, Moazami Goudarzi R. , et al. Effect of vitamin E and metformin on fatty liver disease in obese children- randomized clinical trial. Iran J Public Health 2014; 43 (10) 1417-1423
    PubMedSearch in Google Scholar
  • 106 Nadeau KJ, Ehlers LB, Zeitler PS, Love-Osborne K. Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. Pediatr Diabetes 2009; 10 (01) 5-13
    CrossrefPubMedSearch in Google Scholar
  • 107 Pastor-Villaescusa B, Cañete MD, Caballero-Villarraso J. , et al. Metformin for obesity in prepubertal and pubertal children: a randomized controlled trial. Pediatrics 2017; 140 (01) e20164285
    CrossrefPubMedSearch in Google Scholar
  • 108 Nobili V, Alisi A, Della Corte C. , et al. Docosahexaenoic acid for the treatment of fatty liver: randomised controlled trial in children. Nutr Metab Cardiovasc Dis 2013; 23 (11) 1066-1070
    CrossrefPubMedSearch in Google Scholar
  • 109 Pacifico L, Bonci E, Di Martino M. , et al. A double-blind, placebo-controlled randomized trial to evaluate the efficacy of docosahexaenoic acid supplementation on hepatic fat and associated cardiovascular risk factors in overweight children with nonalcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2015; 25 (08) 734-741
    CrossrefPubMedSearch in Google Scholar
  • 110 Alisi A, Bedogni G, Baviera G. , et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2014; 39 (11) 1276-1285
    CrossrefPubMedSearch in Google Scholar
  • 111 Famouri F, Shariat Z, Hashemipour M, Keikha M, Kelishadi R. Effects of probiotics on nonalcoholic fatty liver disease in obese children and adolescents. J Pediatr Gastroenterol Nutr 2017; 64 (03) 413-417
    CrossrefPubMedSearch in Google Scholar
  • 112 Henao-Mejia J, Elinav E, Jin C. , et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482 (7384): 179-185
    CrossrefPubMedSearch in Google Scholar
  • 113 Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014; 146 (06) 1513-1524
    CrossrefPubMedSearch in Google Scholar
  • 114 Leung DH, Yimlamai D. The intestinal microbiome and paediatric liver disease. Lancet Gastroenterol Hepatol 2017; 2 (06) 446-455
    PubMedSearch in Google Scholar
  • 115 Olson ML, Maalouf NM, Oden JD, White PC, Hutchison MR. Vitamin D deficiency in obese children and its relationship to glucose homeostasis. J Clin Endocrinol Metab 2012; 97 (01) 279-285
    CrossrefPubMedSearch in Google Scholar
  • 116 Eliades M, Spyrou E, Agrawal N. , et al. Meta-analysis: vitamin D and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2013; 38 (03) 246-254
    CrossrefPubMedSearch in Google Scholar
  • 117 Della Corte C, Carpino G, De Vito R. , et al. Docosahexanoic acid plus vitamin D treatment improves features of NAFLD in children with serum vitamin D deficiency: results from a single centre trial. PLoS One 2016; 11 (12) e0168216
    CrossrefPubMedSearch in Google Scholar
  • 118 Manco M, Mosca A, De Peppo F. , et al. The benefit of sleeve gastrectomy in obese adolescents on nonalcoholic steatohepatitis and hepatic fibrosis. J Pediatr 2017; 180: 31-37.e2
    CrossrefPubMedSearch in Google Scholar
  • 119 Nobili V, Vajro P, Dezsofi A. , et al. Indications and limitations of bariatric intervention in severely obese children and adolescents with and without nonalcoholic steatohepatitis: ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr 2015; 60 (04) 550-561
    CrossrefPubMedSearch in Google Scholar
  • 120 Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev 2010; CD007340 (01) CD007340
    PubMedSearch in Google Scholar
  • 121 Sjöström L, Narbro K, Sjöström CD. , et al; Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357 (08) 741-752
    CrossrefPubMedSearch in Google Scholar
  • 122 Zeller MH, Pendery EC, Reiter-Purtill J. , et al. From adolescence to young adulthood: trajectories of psychosocial health following Roux-en-Y gastric bypass. Surg Obes Relat Dis 2017; 13 (07) 1196-1203
    CrossrefPubMedSearch in Google Scholar
  • 123 Ayonrinde OT, Oddy WH, Adams LA. , et al. Infant nutrition and maternal obesity influence the risk of non-alcoholic fatty liver disease in adolescents. J Hepatol 2017; 67 (03) 568-576
    CrossrefPubMedSearch in Google Scholar
  • 124 Nobili V, Bedogni G, Alisi A. , et al. A protective effect of breastfeeding on the progression of non-alcoholic fatty liver disease. Arch Dis Child 2009; 94 (10) 801-805
    CrossrefPubMedSearch in Google Scholar
  • 125 Breij LM, Kerkhof GF, Hokken-Koelega ACS. Accelerated infant weight gain and risk for nonalcoholic fatty liver disease in early adulthood. J Clin Endocrinol Metab 2014; 99 (04) 1189-1195
    CrossrefPubMedSearch in Google Scholar
  • 126 Sandboge S, Perälä MM, Salonen MK. , et al. Early growth and non-alcoholic fatty liver disease in adulthood-the NAFLD liver fat score and equation applied on the Helsinki Birth Cohort Study. Ann Med 2013; 45 (5–6): 430-437
    CrossrefPubMedSearch in Google Scholar
  • 127 Fraser A, Ebrahim S, Smith GD, Lawlor DA. The associations between birthweight and adult markers of liver damage and function. Paediatr Perinat Epidemiol 2008; 22 (01) 12-21
    PubMedSearch in Google Scholar
  • 128 Jin R, Welsh JA, Le NA. , et al. Dietary fructose reduction improves markers of cardiovascular disease risk in Hispanic-American adolescents with NAFLD. Nutrients 2014; 6 (08) 3187-3201
    CrossrefPubMedSearch in Google Scholar
  • 129 Janczyk W, Lebensztejn D, Wierzbicka-Rucińska A. , et al. Omega-3 fatty acids therapy in children with nonalcoholic fatty liver disease: a randomized controlled trial. J Pediatr 2015; 166 (06) 1358-63.e1 , 3
    CrossrefPubMedSearch in Google Scholar
  • 130 Vajro P, Mandato C, Licenziati MR. , et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr 2011; 52 (06) 740-743
    CrossrefPubMedSearch in Google Scholar