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Nonalcoholic Fatty Liver Disease in Children: Not a Small Matter

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Abstract

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased substantially in the past two decades and NAFLD has now become the most common cause of chronic liver disease in children and adolescents. NAFLD is a broad clinicopathologic spectrum ranging from simple steatosis to varying degrees of necroinflammation called nonalcoholic steatohepatitis (NASH), leading to fibrosis and subsequently to cirrhosis. Despite the increasing prevalence and progressive nature of NAFLD even among children, therapy for NAFLD in both adults and children are limited. Weight loss remains the only consistently effective therapy for NAFLD. Pharmacologic options are even more limited in children than in adults with NAFLD. Vitamin E has been shown to be effective in improving histology in children with NASH. Few pharmacologic options such as metformin, probiotics, omega-3 fatty acids, and cysteamine bitartrate have been studied in children, with limited beneficial effects. However, these studies are limited by small sample size and heterogeneity of outcome assessment after treatment. Recent studies show promising results with bariatric surgery with regards to weight loss and improvement in liver histology in adolescents with NAFLD. In this review article, we discuss epidemiology, pathophysiology, and extrahepatic comorbidities of pediatric NAFLD and review existing therapeutic options for children with NAFLD. We also review novel therapeutic strategies studied in adults that could potentially be studied in children in the future.

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References

  1. Moran JR, Ghishan FK, Halter SA, Greene HL. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol. 1983;78:374–7.

    PubMed  CAS  Google Scholar 

  2. Brown GT, Kleiner DE. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism. 2016;65:1080–6. https://doi.org/10.1016/j.metabol.2015.11.008.

    Article  PubMed  CAS  Google Scholar 

  3. Kleiner DE, Makhlouf HR. Histology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children. Clin Liver Dis. 2016;20:293–312. https://doi.org/10.1016/j.cld.2015.10.011.

    Article  PubMed  Google Scholar 

  4. 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;58:1538–44. https://doi.org/10.1136/gut.2008.171280.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118:1388–93. https://doi.org/10.1542/peds.2006-1212.

    Article  PubMed  Google Scholar 

  6. Loomba R, Sirlin CB, Schwimmer JB, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Hepatology. 2009;50:1282–93. https://doi.org/10.1002/hep.23119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Skinner AC, Ravanbakht SN, Skelton JA, Perrin EM, Armstrong SC. Prevalence of obesity and severe obesity in US Children, 1999-2016. Pediatrics. 2018;141:e20173459. https://doi.org/10.1542/peds.2017-3459.

    Article  Google Scholar 

  8. Fraser A, Longnecker MP, Lawlor DA. Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999-2004. Gastroenterology. 2007;133:1814–20. https://doi.org/10.1053/j.gastro.2007.08.077.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. J Pediatr. 2013;162(496–500):e1. https://doi.org/10.1016/j.jpeds.2012.08.043.

    Article  Google Scholar 

  10. Lawlor DA, Callaway M, Macdonald-Wallis C, Anderson E, Fraser A, Howe LD, et al. Nonalcoholic fatty liver disease, liver fibrosis, and cardiometabolic risk factors in adolescence: a cross-sectional study of 1874 general population adolescents. J Clin Endocrinol Metab. 2014;99:E410–7. https://doi.org/10.1210/jc.2013-3612.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Anderson EL, Howe LD, Jones HE, Higgins JPT, Lawlor DA, Fraser A, et al. The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis. PLoS One. 2015;10:e0140908. https://doi.org/10.1371/journal.pone.0140908.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Nobili V, Alisi A, Newton KP, Schwimmer JB. Comparison of the phenotype and approach to pediatric vs adult patients with nonalcoholic fatty liver disease. 2016. https://doi.org/10.1053/j.gastro.2016.03.009.

  13. 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(5):e561–5.

    Article  PubMed  Google Scholar 

  14. Angulo P. Long-term mortality in nonalcoholic fatty liver disease: Is liver histology of any prognostic significance? Hepatology. 2010;51:373–5. https://doi.org/10.1002/hep.23521.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, 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(389–97):e10. https://doi.org/10.1053/j.gastro.2015.04.043.

    Article  Google Scholar 

  16. Ekstedt M, Hagström H, Nasr P, Fredrikson M, Stål P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61:1547–54. https://doi.org/10.1002/hep.27368.

    Article  PubMed  CAS  Google Scholar 

  17. Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7:234–8. https://doi.org/10.1016/j.cgh.2008.11.005.

    Article  PubMed  Google Scholar 

  18. Alkhouri N, Sedki E, Alisi A, Lopez R, Pinzani M, Feldstein AE, et al. Combined paediatric NAFLD fibrosis index and transient elastography to predict clinically significant fibrosis in children with fatty liver disease. Liver Int. 2013;33:79–85. https://doi.org/10.1111/liv.12024.

    Article  PubMed  Google Scholar 

  19. Carter-Kent C, Brunt EM, Yerian LM, Alkhouri N, Angulo P, Kohli R, et al. Relations of steatosis type, grade, and zonality to histological features in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2011;52:190–7. https://doi.org/10.1097/MPG.0b013e3181fb47d3.

    Article  PubMed  Google Scholar 

  20. Mansoor S, Yerian L, Kohli R, Xanthakos S, Angulo P, Ling S, et al. The evaluation of hepatic fibrosis scores in children with nonalcoholic fatty liver disease. Dig Dis Sci. 2015;60:1440–7. https://doi.org/10.1007/s10620-014-3494-7.

    Article  PubMed  Google Scholar 

  21. Eng K, Lopez R, Liccardo D, Nobili V, Alkhouri N. A non-invasive prediction model for non-alcoholic steatohepatitis in paediatric patients with non-alcoholic fatty liver disease. Dig Liver Dis. 2014. https://doi.org/10.1016/j.dld.2014.07.016.

    Article  PubMed  Google Scholar 

  22. Alkhouri N, Mansoor S, Giammaria P, Liccardo D, Lopez R, Nobili V. The development of the Pediatric NAFLD Fibrosis Score (PNFS) to predict the presence of advanced fibrosis in children with nonalcoholic fatty liver disease. PLoS One 2014; 9. https://doi.org/10.1371/journal.pone.0104558.

  23. Kabbany MN, Selvakumar PKC, Watt K, Lopez R, Akras Z, Zein N, et al. Prevalence of nonalcoholic steatohepatitis-associated cirrhosis in the united states: an analysis of national health and nutrition examination survey data. Am J Gastroenterol. 2017;112:581–7. https://doi.org/10.1038/ajg.2017.5.

    Article  PubMed  Google Scholar 

  24. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the united states. Gastroenterology. 2015;148:547–55. https://doi.org/10.1053/j.gastro.2014.11.039.

    Article  PubMed  Google Scholar 

  25. Alkhouri N, Hanouneh IA, Zein NN, Lopez R, Kelly D, Eghtesad B, et al. Liver transplantation for nonalcoholic steatohepatitis in young patients. Transpl Int. 2016;29:418–24. https://doi.org/10.1111/tri.12694.

    Article  PubMed  CAS  Google Scholar 

  26. Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology. 2014;59:1174–97. https://doi.org/10.1002/hep.26717.

    Article  PubMed  CAS  Google Scholar 

  27. Selvakumar PKC, Kabbany MN, Nobili V, Alkhouri N. Nonalcoholic fatty liver disease in children. Pediatr Clin North Am. 2017;64:659–75. https://doi.org/10.1016/j.pcl.2017.01.008.

    Article  PubMed  Google Scholar 

  28. Alkhouri N, Selvakumar PKC, Kabbany MN, Lopez R, Mosca A, Della Corte C, et al. Extrahepatic complications are extremely common in children with nonalcoholic fatty liver disease (NAFLD) and their frequency correlates with NAFLD histologic severity. Gastroenterology. 2016;150:S1172. https://doi.org/10.1016/S0016-5085(16)33961-0.

    Article  Google Scholar 

  29. Koskinen J, Magnussen CG, Kähönen M, Loo B-M, Marniemi J, Jula A, et al. Association of liver enzymes with metabolic syndrome and carotid atherosclerosis in young adults. The Cardiovascular Risk in Young Finns Study. Ann Med. 2012;44:187–95. https://doi.org/10.3109/07853890.2010.532152.

    Article  PubMed  CAS  Google Scholar 

  30. Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;30:1212–8. https://doi.org/10.2337/dc06-2247.

    Article  PubMed  Google Scholar 

  31. Schwimmer JB, Pardee PE, Lavine JE, Blumkin AK, Cook S. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation. 2008;118:277–83. https://doi.org/10.1161/CIRCULATIONAHA.107.739920.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Nobili V, Alkhouri N, Bartuli A, Manco M, Lopez R, Alisi A, et al. Severity of liver injury and atherogenic lipid profile in children with nonalcoholic fatty liver disease. Pediatr Res. 2010;67:665–70. https://doi.org/10.1203/PDR.0b013e3181da4798.

    Article  PubMed  CAS  Google Scholar 

  33. Corey KE, Vuppalanchi R, Vos M, Kohli R, Molleston JP, Wilson L, et al. Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2015;60:360–7. https://doi.org/10.1097/MPG.0000000000000584.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Schwimmer JB, Zepeda A, Newton KP, Xanthakos SA, Behling C, Hallinan EK, et al. Longitudinal assessment of high blood pressure in children with nonalcoholic fatty liver disease. PLoS ONE. 2014;9:e112569. https://doi.org/10.1371/journal.pone.0112569.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Sert A, Pirgon O, Aypar E, Yilmaz H, Odabas D. Relationship between left ventricular mass and carotid intima media thickness in obese adolescents with non-alcoholic fatty liver disease. J Pediatr Endocrinol Metab. 2012;25:927–34. https://doi.org/10.1515/jpem-2012-0187.

    Article  PubMed  CAS  Google Scholar 

  36. Pacifico L, Di Martino M, De Merulis A, Bezzi M, Osborn JF, Catalano C, et al. Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease. Hepatology. 2014;59:461–70. https://doi.org/10.1002/hep.26610.

    Article  PubMed  CAS  Google Scholar 

  37. Fintini D, Chinali M, Cafiero G, Esposito C, Giordano U, Turchetta A, et al. Early left ventricular abnormality/dysfunction in obese children affected by NAFLD. Nutr Metab Cardiovasc Dis. 2014;24:72–4. https://doi.org/10.1016/j.numecd.2013.06.005.

    Article  PubMed  CAS  Google Scholar 

  38. Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;30:1212–8. https://doi.org/10.2337/dc06-2247.

    Article  PubMed  Google Scholar 

  39. Williamson RM, Price JF, Glancy S, Perry E, Nee LD, Hayes PC, et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: the edinburgh type 2 diabetes study. Diabetes Care. 2011;34:1139–44. https://doi.org/10.2337/dc10-2229.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Carter-Kent C, Yerian LM, Brunt EM, Angulo P, Kohli R, Ling SC, et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology. 2009;50:1113–20. https://doi.org/10.1002/hep.23133.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr. 2003;143:500–5. https://doi.org/10.1067/S0022-3476(03)00325-1.

    Article  PubMed  Google Scholar 

  42. Newton KP, Hou J, Crimmins NA, Lavine JE, Barlow SE, Xanthakos SA, et al. Prevalence of prediabetes and type 2 diabetes in children with nonalcoholic fatty liver disease. JAMA Pediatr 2016; p. e161971. https://doi.org/10.1001/jamapediatrics.2016.1971.

  43. Narang I, Mathew JL. Childhood obesity and obstructive sleep apnea. J Nutr Metab. 2012;2012:134202. https://doi.org/10.1155/2012/134202.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Romero-Corral A, Caples SM, Lopez-Jimenez F, Somers VK. Interactions between obesity and obstructive sleep apnea: implications for treatment. Chest. 2010;137:711–9. https://doi.org/10.1378/chest.09-0360.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Musso G, Cassader M, Olivetti C, Rosina F, Carbone G, Gambino R. Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis. Obes Rev. 2013;14:417–31. https://doi.org/10.1111/obr.12020.

    Article  PubMed  CAS  Google Scholar 

  46. Sundaram SS, Sokol RJ, Capocelli KE, Pan Z, Sullivan JS, Robbins K, et al. Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in pediatric nonalcoholic fatty liver disease. J Pediatr. 2014;164(699–706):e1. https://doi.org/10.1016/j.jpeds.2013.10.072.

    Article  CAS  Google Scholar 

  47. Nobili V, Cutrera R, Liccardo D, Pavone M, Devito R, Giorgio V, et al. Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance. Am J Respir Crit Care Med. 2014;189:66–76. https://doi.org/10.1164/rccm.201307-1339OC.

    Article  PubMed  CAS  Google Scholar 

  48. Pacifico L, Bezzi M, Lombardo CV, Romaggioli S, Ferraro F, Bascetta S, et al. Adipokines and C-reactive protein in relation to bone mineralization in pediatric nonalcoholic fatty liver disease. World J Gastroenterol. 2013;19:4007–14. https://doi.org/10.3748/wjg.v19.i25.4007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Pardee PE, Dunn W, Schwimmer JB. Non-alcoholic fatty liver disease is associated with low bone mineral density in obese children. Aliment Pharmacol Ther. 2012;35:248–54. https://doi.org/10.1111/j.1365-2036.2011.04924.x.

    Article  PubMed  CAS  Google Scholar 

  50. Pirgon O, Bilgin H, Tolu I, Odabas D. Correlation of insulin sensitivity with bone mineral status in obese adolescents with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf). 2011;75:189–95. https://doi.org/10.1111/j.1365-2265.2011.04038.x.

    Article  CAS  Google Scholar 

  51. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–46. https://doi.org/10.1002/hep.24001.

    Article  PubMed  CAS  Google Scholar 

  52. Musso G, Paschetta E, Gambino R, Cassader M, Molinaro F. Interactions among bone, liver, and adipose tissue predisposing to diabesity and fatty liver. Trends Mol Med. 2013;19:522–35. https://doi.org/10.1016/j.molmed.2013.05.006.

    Article  PubMed  CAS  Google Scholar 

  53. Koot BGP, Van Der Baan-Slootweg OH, Bohte AE, Nederveen AJ, Van Werven JR, Tamminga-Smeulders CLJ, et al. Accuracy of prediction scores and novel biomarkers for predicting nonalcoholic fatty liver disease in obese children. Obesity. 2013;21:583–90. https://doi.org/10.1002/oby.20173.

    Article  PubMed  CAS  Google Scholar 

  54. Fitzpatrick E, Dew TK, Quaglia A, Sherwood RA, Mitry RR, Dhawan A. Analysis of adipokine concentrations in paediatric non-alcoholic fatty liver disease. Pediatr Obes. 2012;7:471–9. https://doi.org/10.1111/j.2047-6310.2012.00082.x.

    Article  PubMed  CAS  Google Scholar 

  55. Lebensztejn DM, Wojtkowska M, Skiba E, Werpachowska I, Tobolczyk J, Kaczmarski M. Serum concentration of adiponectin, leptin and resistin in obese children with non-alcoholic fatty liver disease. Adv Med Sci. 2009;54:177–82. https://doi.org/10.2478/v10039-009-0047-y.

    Article  PubMed  CAS  Google Scholar 

  56. Poeta M, Pierri L, Vajro P. Gut-liver axis derangement in non-alcoholic fatty liver disease. Children. 2017;4:66. https://doi.org/10.3390/children4080066.

    Article  PubMed Central  Google Scholar 

  57. Mehal WZ. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10:637–44. https://doi.org/10.1038/nrgastro.2013.146.

    Article  PubMed  Google Scholar 

  58. Miura K, Ohnishi H. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20:7381–91. https://doi.org/10.3748/wjg.v20.i23.7381.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Nakamoto N, Kanai T. Role of Toll-like receptors in immune activation and tolerance in the liver. Front Immunol. 2014;5:1–8. https://doi.org/10.3389/fimmu.2014.00221.

    Article  CAS  Google Scholar 

  60. Krawczyk M, Rau M, Schattenberg JM, Bantel H, Pathil A, Demir M, et al. Combined effects of the TM6SF2 rs58542926, PNPLA3 rs738409 and MBOAT7 rs641738 variants on NAFLD severity: multicentre biopsy-based study. J Lipid Res 2016; 58. https://doi.org/10.1194/jlr.p067454.

  61. Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, et al. Chronic overexpression of PNPLA3I148 M in mouse liver causes hepatic steatosis. J Clin Invest. 2012;122:4130–44. https://doi.org/10.1172/JCI65179.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Goffredo M, Caprio S, Feldstein AE, D’Adamo E, Shaw MM, Pierpont B, et al. Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: a multiethnic study. Hepatology. 2016;63:117–25. https://doi.org/10.1002/hep.28283.

    Article  PubMed  CAS  Google Scholar 

  63. Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, et al. The MBOAT7-TMC4 Variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016;150:1219e6–1230e6. https://doi.org/10.1053/j.gastro.2016.01.032.

    Article  CAS  Google Scholar 

  64. Gijón MA, Riekhof WR, Zarini S, Murphy RC, Voelker DR. Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J Biol Chem. 2008;283:30235–45. https://doi.org/10.1074/jbc.M806194200.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Akazawa Y, Nakao K. To die or not to die: death signaling in nonalcoholic fatty liver disease. J Gastroenterol. 2018. https://doi.org/10.1007/s00535-018-1451-5.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Nobili V, Manco M, Devito R, Di Ciommo V, Comparcola D, Sartorelli MR, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: A randomized, controlled trial. Hepatology. 2008;48:119–28. https://doi.org/10.1002/hep.22336.

    Article  PubMed  CAS  Google Scholar 

  67. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149(367–378):e5. https://doi.org/10.1053/j.gastro.2015.04.005.

    Article  Google Scholar 

  68. Marchesini G, Petta S, Dalle Grave R. Diet, weight loss, and liver health in nonalcoholic fatty liver disease: pathophysiology, evidence, and practice. Hepatology. 2016;63:2032–43. https://doi.org/10.1002/hep.28392.

    Article  PubMed  Google Scholar 

  69. de Ruyter JC, Olthof MR, Seidell JC, Katan MB. A trial of sugar-free or sugar-sweetened beverages and body weight in children. N Engl J Med. 2012;367:1397–406. https://doi.org/10.1056/NEJMoa1203034.

    Article  PubMed  CAS  Google Scholar 

  70. Ebbeling CB, Feldman HA, Chomitz VR, Antonelli TA, Gortmaker SL, Osganian SK, et al. A randomized trial of sugar-sweetened beverages and adolescent body weight. N Engl J Med. 2012;367:1407–16. https://doi.org/10.1056/NEJMoa1203388.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Lee S, Bacha F, Hannon T, Kuk JL, Boesch C, Arslanian S. Effects of aerobic versus resistance exercise without caloric restriction on abdominal fat, intrahepatic lipid, and insulin sensitivity in obese adolescent boys: a randomized, controlled trial. Diabetes. 2012;61:2787–95. https://doi.org/10.2337/db12-0214.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. van der Heijden G-J, Wang ZJ, Chu ZD, Sauer PJJ, Haymond MW, Rodriguez LM, et al. A 12-week aerobic exercise program reduces hepatic fat accumulation and insulin resistance in obese. Hispanic Adolescents. Obesity. 2010;18:384–90. https://doi.org/10.1038/oby.2009.274.

    Article  PubMed  Google Scholar 

  73. DeVore S, Kohli R, Lake K, Nicholas L, Dietrich K, Balistreri WF, et al. A multidisciplinary clinical program is effective in stabilizing BMI and reducing transaminase levels in pediatric patients with NAFLD. J Pediatr Gastroenterol Nutr. 2013;57:119–23. https://doi.org/10.1097/MPG.0b013e318290d138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149:379–88. https://doi.org/10.1053/j.gastro.2015.04.014.

    Article  PubMed  Google Scholar 

  75. Inge TH, Courcoulas AP, Jenkins TM, Michalsky MP, Helmrath MA, Brandt ML, et al. Weight loss and health status 3 years after bariatric surgery in adolescents. N Engl J Med. 2016;374:113–23. https://doi.org/10.1056/NEJMoa1506699.

    Article  PubMed  CAS  Google Scholar 

  76. Manco M, Mosca A, De Peppo F, Caccamo R, Cutrera R, Giordano U, et al. The benefit of sleeve gastrectomy in obese adolescents on nonalcoholic steatohepatitis and hepatic fibrosis. J Pediatr. 2017;180(31–37):e2. https://doi.org/10.1016/j.jpeds.2016.08.101.

    Article  Google Scholar 

  77. Nobili V, Vajro P, Dezsofi A, Fischler B, Hadzic N, Jahnel J, 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;60:550–61. https://doi.org/10.1097/MPG.0000000000000715.

    Article  PubMed  Google Scholar 

  78. Schwimmer JB, Middleton MS, Deutsch R, Lavine JE. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2005;21:871–9. https://doi.org/10.1111/j.1365-2036.2005.02420.x.

    Article  PubMed  CAS  Google Scholar 

  79. 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;10:5–13. https://doi.org/10.1111/j.1399-5448.2008.00450.x.

    Article  PubMed  CAS  Google Scholar 

  80. Nobili V, Manco M, Ciampalini P, Alisi A, Devito R, Bugianesi E, et al. Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Ther. 2008;30:1168–76. https://doi.org/10.1016/j.clinthera.2008.06.012.

    Article  PubMed  CAS  Google Scholar 

  81. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents. JAMA. 2011;305:1659. https://doi.org/10.1001/jama.2011.520.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, Vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85. https://doi.org/10.1056/NEJMoa0907929.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000;136:734–8.

    Article  PubMed  CAS  Google Scholar 

  84. Vajro P, Mandato C, Franzese A, Ciccimarra E, Lucariello S, Savoia M, et al. Vitamin E treatment in pediatric obesity-related liver disease: a randomized study. J Pediatr Gastroenterol Nutr. 2004;38:48–55.

    Article  PubMed  CAS  Google Scholar 

  85. Nobili V, Manco M, Devito R, Ciampalini P, Piemonte F, Marcellini M. Effect of vitamin E on aminotransferase levels and insulin resistance in children with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2006;24:1553–61. https://doi.org/10.1111/j.1365-2036.2006.03161.x.

    Article  PubMed  CAS  Google Scholar 

  86. Bjelakovic G, Nikolova D, Gluud C. Meta-regression analyses, meta-analyses, and trial sequential analyses of the effects of supplementation with beta-carotene, vitamin a, and vitamin e singly or in different combinations on all-cause mortality: do we have evidence for lack of Harm? PLoS One. 2013;8:e74558. https://doi.org/10.1371/journal.pone.0074558.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. In: Bjelakovic G, editor. Cochrane Database Syst. Rev. Chichester: Wiley; 2012. p. CD007176. https://doi.org/10.1002/14651858.cd007176.pub2.

    Chapter  Google Scholar 

  88. Nobili V, Bedogni G, Alisi A, Pietrobattista A, Risé P, Galli C, et al. Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial. Arch Dis Child. 2011;96:350–3. https://doi.org/10.1136/adc.2010.192401.

    Article  PubMed  Google Scholar 

  89. Nobili V, Alisi A, Della Corte C, Risé P, Galli C, Agostoni C, et al. Docosahexaenoic acid for the treatment of fatty liver: randomised controlled trial in children. Nutr Metab Cardiovasc Dis. 2013;23:1066–70. https://doi.org/10.1016/j.numecd.2012.10.010.

    Article  PubMed  CAS  Google Scholar 

  90. Nobili V, Carpino G, Alisi A, De Vito R, Franchitto A, Alpini G, et al. Role of docosahexaenoic acid treatment in improving liver histology in pediatric nonalcoholic fatty liver disease. PLoS One. 2014;9:e88005. https://doi.org/10.1371/journal.pone.0088005.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Pacifico L, Bonci E, Di Martino M, Versacci P, Andreoli G, Silvestri LM, 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;25:734–41. https://doi.org/10.1016/j.numecd.2015.04.003.

    Article  PubMed  CAS  Google Scholar 

  92. Janczyk W, Lebensztejn D, Wierzbicka-Rucińska A, Mazur A, Neuhoff-Murawska J, Matusik P, et al. Omega-3 fatty acids therapy in children with nonalcoholic fatty liver disease: a randomized controlled trial. J Pediatr. 2015;166(1358–1363):e3. https://doi.org/10.1016/j.jpeds.2015.01.056.

    Article  CAS  Google Scholar 

  93. Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M, EPE-A Study Group. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology. 2014;147(377–84):e1. https://doi.org/10.1053/j.gastro.2014.04.046.

    Article  CAS  Google Scholar 

  94. Dasarathy S, Dasarathy J, Khiyami A, Yerian L, Hawkins C, Sargent R, et al. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J Clin Gastroenterol. 2015;49:137–44. https://doi.org/10.1097/MCG.0000000000000099.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Nobili V, Bedogni G, Donati B, Alisi A, Valenti L. The I148M variant of PNPLA3 reduces the response to docosahexaenoic acid in children with non-alcoholic fatty liver disease. J Med Food. 2013;16:957–60. https://doi.org/10.1089/jmf.2013.0043.

    Article  PubMed  CAS  Google Scholar 

  96. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–131. https://doi.org/10.1038/nature05414.

    Article  PubMed  Google Scholar 

  97. Vajro P, Mandato C, Licenziati MR, Franzese A, Vitale DF, Lenta S, et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr. 2011;52:740–3. https://doi.org/10.1097/MPG.0b013e31821f9b85.

    Article  PubMed  Google Scholar 

  98. Alisi A, Bedogni G, Baviera G, Giorgio V, Porro E, Paris C, et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2014;39:1276–85. https://doi.org/10.1111/apt.12758.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. 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;64:413–7. https://doi.org/10.1097/MPG.0000000000001422.

    Article  PubMed  CAS  Google Scholar 

  100. Videla LA, Rodrigo R, Orellana M, Fernandez V, Tapia G, Quiñones L, et al. Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin Sci. 2004;106:261–8. https://doi.org/10.1042/CS20030285.

    Article  PubMed  CAS  Google Scholar 

  101. Dohil R, Cabrera BL, Gangoiti JA, Barshop BA, Rioux P. Pharmacokinetics of cysteamine bitartrate following intraduodenal delivery. Fundam Clin Pharmacol. 2014;28:136–43. https://doi.org/10.1111/fcp.12009.

    Article  PubMed  CAS  Google Scholar 

  102. Dohil R, Schmeltzer S, Cabrera BL, Wang T, Durelle J, Duke KB, et al. Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2011;33:1036–44. https://doi.org/10.1111/j.1365-2036.2011.04626.x.

    Article  PubMed  CAS  Google Scholar 

  103. Schwimmer JB, Lavine JE, Wilson LA, Neuschwander-Tetri BA, Xanthakos SA, Kohli R, et al. In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores. Gastroenterology. 2016;151(1141–1154):e9. https://doi.org/10.1053/j.gastro.2016.08.027.

    Article  CAS  Google Scholar 

  104. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36:525–31. https://doi.org/10.1053/jhep.2002.36088.

    Article  PubMed  CAS  Google Scholar 

  105. Orlando R, Azzalini L, Orando S, Lirussi F. Bile acids for non-alcoholic fatty liver disease and/or steatohepatitis. In: Orlando R, editor. Cochrane Database Syst. Rev. Chichester: Wiley; 2007. p. CD005160. https://doi.org/10.1002/14651858.cd005160.pub2.

    Chapter  Google Scholar 

  106. Vajro P, Franzese A, Valerio G, Iannucci MP, Aragione N. Lack of efficacy of ursodeoxycholic acid for the treatment of liver abnormalities in obese children. J Pediatr. 2000;136:739–43. https://doi.org/10.1016/S0022-3476(00)26774-7.

    Article  PubMed  CAS  Google Scholar 

  107. Ray K. NAFLD: obeticholic acid for the treatment of fatty liver disease—NASH no more? Nat Rev Gastroenterol Hepatol. 2014;12:1–1. https://doi.org/10.1038/nrgastro.2014.203.

    Article  PubMed  Google Scholar 

  108. Cariou B, Van Harmelen K, Duran-Sandoval D, Van Dijk TH, Grefhorst A, Abdelkarim M, et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem. 2006;281:11039–49. https://doi.org/10.1074/jbc.M510258200.

    Article  PubMed  CAS  Google Scholar 

  109. Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51:771–84. https://doi.org/10.1194/jlr.M001602.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–65. https://doi.org/10.1016/S0140-6736(14)61933-4.

    Article  PubMed  CAS  Google Scholar 

  111. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and safety of the farnesoid x receptor agonist Obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(574–582):e1. https://doi.org/10.1053/j.gastro.2013.05.042.

    Article  CAS  Google Scholar 

  112. Derosa G, Sahebkar A, Maffioli P. The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. J Cell Physiol. 2018;233:153–61. https://doi.org/10.1002/jcp.25804.

    Article  PubMed  CAS  Google Scholar 

  113. Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015;62:720–33. https://doi.org/10.1016/j.jhep.2014.10.039.

    Article  PubMed  CAS  Google Scholar 

  114. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(1147–1159):e5. https://doi.org/10.1053/j.gastro.2016.01.038.

    Article  CAS  Google Scholar 

  115. Phase 2 Data for Selonsertib in Nonalcoholic Steatohepatitis (NASH) Presented at The Liver Meeting® 2016. Gilead Website 2016; pp 1:4–6.

  116. Bertola A, Bonnafous S, Anty R, Patouraux S, Saint-Paul MC, Iannelli A, et al. Hepatic expression patterns of inflammatory and immune response genes associated with obesity and nash in morbidly obese patients. PLoS One 2010; 5. https://doi.org/10.1371/journal.pone.0013577.

  117. Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One. 2016;11:1–19. https://doi.org/10.1371/journal.pone.0158156.

    Article  CAS  Google Scholar 

  118. Friedman S, Sanyal A, Goodman Z, Lefebvre E, Gottwald M, Fischer L, et al. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: cENTAUR Phase 2b study design. Contemp Clin Trials. 2016;47:356–65. https://doi.org/10.1016/j.cct.2016.02.012.

    Article  PubMed  Google Scholar 

  119. Lefebvre E, Gottwald M, Lasseter K, Chang W, Willett M, Smith PF, et al. Pharmacokinetics, safety, and CCR2/CCR5 antagonist activity of cenicriviroc in participants with mild or moderate hepatic impairment. Clin Transl Sci. 2016;9:139–48. https://doi.org/10.1111/cts.12397.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Dobrzyn A, Ntambi JM. Stearoyl-CoA desaturase as a new drug target for obesity treatment. Obes Rev. 2005;6(2):169–74. https://doi.org/10.1111/j.1467-789X.2005.00177.x.

    Article  PubMed  CAS  Google Scholar 

  121. Dobrzyn A, Ntambi JM. The role of stearoyl-CoA desaturase in the control of metabolism. Prostaglandins Leukot Essent Fat Acids. 2005;73:35–41. https://doi.org/10.1016/j.plefa.2005.04.011.

    Article  CAS  Google Scholar 

  122. Leikin-Frenkel A, Goldiner I, Leikin-Gobbi D, Rosenberg R, Bonen H, Litvak A, et al. Treatment of preestablished diet-induced fatty liver by oral fatty acid–bile acid conjugates in rodents. Eur J Gastroenterol Hepatol 2008; 1. https://doi.org/10.1097/meg.0b013e3282fc9743.

  123. Gilat T, Leikin-Frenkel A, Goldiner I, Juhel C, Lafont H, Gobbi D, et al. Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC). Hepatology. 2003;38:436–42. https://doi.org/10.1053/jhep.2003.50348.

    Article  PubMed  CAS  Google Scholar 

  124. Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, et al. The fatty acid-bile acid conjugate aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12:2085–91. https://doi.org/10.1016/j.cgh.2014.04.038.

    Article  PubMed  CAS  Google Scholar 

  125. Armstrong MJ, Hull D, Guo K, Barton D, Hazlehurst JM, Gathercole LL, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64:399–408. https://doi.org/10.1016/j.jhep.2015.08.038.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679–90. https://doi.org/10.1016/S0140-6736(15)00803-X.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA

    Praveen Kumar Conjeevaram Selvakumar & Mohammad Nasser Kabbany

  2. Texas Liver Institute, 607 Camden Street, San Antonio, TX, 78215, USA

    Naim Alkhouri

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Conjeevaram Selvakumar, P.K., Kabbany, M.N. & Alkhouri, N. Nonalcoholic Fatty Liver Disease in Children: Not a Small Matter. Pediatr Drugs 20, 315–329 (2018). https://doi.org/10.1007/s40272-018-0292-2

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