Advertisement

Pediatric Non-alcoholic Fatty Liver Disease

  • Vikas Uppal
  • Sana Mansoor
  • Katryn N. Furuya
Pediatric Gastroenterology (SR Orenstein, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pediatric Gastroenterology

Abstract

Childhood obesity has reached epidemic proportions, and by 2012, more than one third of American children were overweight or obese. As a result, increasingly, children are developing complications of obesity including liver disease. In fact, non-alcoholic fatty liver disease is the most common form of chronic liver disease seen in children today. Recently, there has been a burgeoning literature examining the pathogenesis, genetic markers, and role of the microbiome in this disease. On the clinical front, new modalities of diagnosing hepatic steatosis and hepatic fibrosis are being developed to provide non-invasive methods of surveillance in children. Lastly, the mainstay of treatment of pediatric non-alcoholic fatty liver disease (NAFLD) has been largely through lifestyle interventions, namely, dieting and exercise. Currently, there are a number of clinical trials examining novel lifestyle and drug therapies for NAFLD that are registered with the US National Institutes of Health ClinicalTrials.gov website.

Keywords

Childhood obesity Pediatric Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis Hepatic fibrosis Cirrhosis 

Notes

Compliance with Ethical Standards

Conflict of Interest

VU and SM declare that they have no conflicts of interest. KNF reports personal fees from Alexion Pharmaceuticals, outside the submitted work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with animal or human subjects performed by authors VU and KNF. With regard to author SM’s research cited in this paper, all procedures in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58(11):1538–44.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Marzuillo P, Grandone A, Perrone L, et al. Understanding the pathophysiological mechanisms in the pediatric nonalcoholic fatty liver disease: the role of genetics. World J Gastroenterol. 2015;7(11):1439–43.Google Scholar
  3. 3.
    Marzuillo P, Del Giudice EM, Santoro N. Pediatric non-alcoholic fatty liver disease: new insights and future directions. World J Gastroenterol. 2014;6(4):217–25.Google Scholar
  4. 4.
    Marzuillo P, Del Giudice EM, Santoro N. Pediatric fatty liver disease: role of ethnicity and genetics. World J Gastroenterol. 2014;20(23):7347–55.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to fibrosing steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62(5):1148–55.PubMedCrossRefGoogle Scholar
  6. 6.
    Preiss D, Sattar N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci. 2008;115(5):141–50.PubMedCrossRefGoogle Scholar
  7. 7.
    Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53(6):1874–82.PubMedCrossRefGoogle Scholar
  8. 8.
    Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42(3):641–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Molleston JP, White F, Teckman J, et al. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol. 2002;97(9):2460–2.PubMedCrossRefGoogle Scholar
  10. 10.•
    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(2):389–97. Retrospective study demonstrating that hepatic fibrosis is the single most important prognostic marker in NAFLD.Google Scholar
  11. 11.
    Xanthakos S, Miles L, Bucuvalas J, et al. Histologic spectrum of nonalcoholic fatty liver disease in morbidly obese adolescents. Clin Gastroenterol Hepatol. 2006;4(2):226–32.PubMedCrossRefGoogle Scholar
  12. 12.
    Loomba R, Sirlin CB, Schwimmer JB, et al. Advances in pediatric nonalcoholic fatty liver disease. Hepatology. 2009;50(4):1282–93.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Schwimmer JB, McGreal N, Deutsch R, et al. Influence of gender, race, and ethnicity of suspected fatty liver in obese adolescents. Pediatrics. 2005;115(5):e561–656.PubMedCrossRefGoogle Scholar
  14. 14.
    Schwimmer JB, Deutsch R, Kahen T, et al. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118(4):1388–93.PubMedCrossRefGoogle Scholar
  15. 15.
    Nomura H, Kashiwagi S, Hayashi J, et al. Prevalence of fatty liver in a general population of Okinawa. Jpn Jpn J Med. 1988;27(2):142–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Park HS, Han JS, Choi KM, et al. Relation between elevated serum alanine aminotransferase and metabolic syndrome in Korean adolescents. Am J Clin Nutr. 2005;82(5):1046–51.PubMedGoogle Scholar
  17. 17.
    Kahali B, Halligan B, Spelitoes E. Insights from genome-wide association analyses of nonalcoholic fatty liver disease. Semin Liver Dis. 2015;35(4):375–91.PubMedCrossRefGoogle Scholar
  18. 18.
    Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114(4):842–5.PubMedCrossRefGoogle Scholar
  19. 19.
    D’Adamo E, Cali AM, Weiss R, et al. Central role of fatty liver in the pathogenesis of insulin resistance in obese adolescents. Diabetes Care. 2010;33(8):1817–22.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Cali AM, De Oliveira AM, Kim H, et al. Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link? Hepatology. 2009;49(6):1896–903.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Giorgio V, Prono F, Graziano F, et al. Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets. BMC Pediatr. 2013;13(40):1–10.Google Scholar
  22. 22.
    Zhu L, Baker RD, Baker SS. From multiple hits to multiple therapeutic targets of non-alcoholic fatty liver disease. Curr Drug Targets. 2015;16(12):1272–3.PubMedCrossRefGoogle Scholar
  23. 23.
    Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–46.PubMedCrossRefGoogle Scholar
  24. 24.
    Schwimmer JB, Celedone MA, Lavine JE, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136(5):1585–92.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Loomba R, Schork N, Chen CH, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015;149(7):1784–93.PubMedCrossRefGoogle Scholar
  26. 26.•
    Marchesini G, Petta S, Dalle Grave R. Diet, weight loss, and liver health in nonalcoholic fatty liver disease: pathophysiology, evidence, and practice. Hepatology. 2015. doi: 10.1002/hep28392. Important review article highlighting the importance of dietary and life style modifications which lead to weight loss and improvement in NAFLD.
  27. 27.
    Huang Y, He S, Li JZ, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A. 2010;107(17):7892–7.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    He S, McPhaul C, Li JZ, et al. A sequence variation (l148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010;285(9):6706–15.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Pirazzi C, Adiels M, Burza MA, et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) l148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol. 2012;57(6):1276–82.PubMedCrossRefGoogle Scholar
  30. 30.
    Kozlitina J, Smargris 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(4):352–6.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.•
    Goffredo M, Caprio S, Feldstein AE, et al. Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: a multiethnic study. Hepatology. 2016;63(1):117–25. The role of the single nucleotide polymorphism, rs58542926 in the TM6SF2 gene in pediatric NAFLD.Google Scholar
  32. 32.
    Arslan N. Obesity, fatty liver disease and intestinal microbiota. World J Gastroenterol. 2014;20(44):16452–63.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457(7228):480–4.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143(4):913–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55–60.PubMedCrossRefGoogle Scholar
  36. 36.•
    Boursier J, Mueller O, Barret M, et al. The severity of NAFLD is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology. 2015. doi: 10.1002/hep28356. This study examines the role of intestinal dysbiosis in NAFLD.
  37. 37.
    Schwimmer JB, Deutsch R, Rauch JB, et al. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr. 2003;143(4):500–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Lavine JE, Schwimmer JB. Nonalcoholic fatty liver disease in the pediatric population. Clin Liver Dis. 2004;8(3):549–58.PubMedCrossRefGoogle Scholar
  39. 39.
    Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2000;30(1):48–53.PubMedCrossRefGoogle Scholar
  40. 40.
    Alkhouri N, De Vito R, Alisi A, et al. Development and validation of a new histological score for pediatric non-alcoholic fatty liver disease. J Hepatol. 2012;57(6):1312–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Barlow SE, Expert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120(S4):S164–S92.PubMedCrossRefGoogle Scholar
  42. 42.
    Schwimmer JB, Dunn W, Norman GJ, et al. SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. Gastroenterology. 2010;138(4):1357–64.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Molleston JP, Schwimmer JB, Yates KP, et al. Histologic abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr. 2014;164(4):707–13.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Kim H, Taksali SE, Dufour S, et al. Comparative MR study of hepatic fat quantification using single-voxel proton spectroscopy, two-point dixon and three-point IDEAL. Magn Reson Med. 2008;59(3):521–7.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Shannon A, Alkhouri N, Carter-Kent C, et al. Ultrasonographic quantitative estimation of hepatic steatosis in children with nonalcoholic fatty liver disease (NAFLD). J Pediatr Gastroenterol Nutr. 2011;53(2):190–5.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010;5:145–71.PubMedCrossRefGoogle Scholar
  47. 47.
    Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7(4):195–203.PubMedCrossRefGoogle Scholar
  48. 48.
    Caldwell S, Ikura Y, Dias D, et al. Hepatocellular ballooning in NASH. J Hepatol. 2010;53(4):719–23.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Lavine JE, Schwimmer JB, Van Natta ML, et al. 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):1659–68.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Sanyal AJ, Chalasani N, Kowdley KV, et al. Piogrlitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–85.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Carter-Kent C, Yerian LM, Brunt EM, et al. Nonalcoholic steatohepatitis in children: a mutlicenter clinicopathological study. Hepatology. 2009;50(4):1113–20.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis:a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94(9):2467–74.PubMedCrossRefGoogle Scholar
  53. 53.
    Kleiner DE, Brunt EM, Van Natta ML, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.PubMedCrossRefGoogle Scholar
  54. 54.
    Dezsofi A, Baumann U, Dhawan A, et al. Liver biopsy in children: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr. 2015;60:408–20.Google Scholar
  55. 55.•
    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(5):700–13. Most updated position statement on the screening and diagnosis of pediatric NAFLD.Google Scholar
  56. 56.
    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;45:846–54.Google Scholar
  57. 57.
    Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–25.PubMedCrossRefGoogle Scholar
  58. 58.
    Yang HR, Kim HR, Kim MJ, et al. Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease. World J Gastroenterol. 2012;18(13):1525–30.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Mansoor S, Yerian L, Kohli R, et al. The evaluation of hepatic fibrosis scores in children with nonalcoholic fatty liver disease. Dig Dis Sci. 2015;60(5):1440–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Nobili V, Alisi A, Vania A, et al. The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease. BMC Med. 2009;7:21.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Feldstein AE, Alkhouri N, De Vito R, et al. Serum cytokeratin-18 fragment levels are useful biomarkers for nonalcoholic steatohepatitis in children. Am J Gastroenterol. 2013;108:1526–31.PubMedCrossRefGoogle Scholar
  62. 62.
    Feldstein AE, Wieckowska A, Lopez R, et al. Cytokeratin-18 fragment levels as noninvasive biomarker for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology. 2009;50(4):1072–8.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Mandelia C, Collyer E, Mansoor S, et al. Plasma Cytokeratin-18 level as a novel biomarker for liver fibrosis in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2016.Google Scholar
  64. 64.
    Nobili V, Alisi A, Torre G, et al. Hyaluronic acid predicts hepatic fibrosis in children with nonalcoholic fatty liver disease. Transl Res. 2010;156(4):229–34.PubMedCrossRefGoogle Scholar
  65. 65.
    Guha IN, Parkes J, Roderick P, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47(2):455–60.PubMedCrossRefGoogle Scholar
  66. 66.
    Nobili V, Parkes J, Bottazzo G, et al. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology. 2009;136(1):160–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Alkhouri N, Carter-Kent C, Lopez R, et al. A combination of the pediatric NAFLD fibrosis index and enhanced liver fibrosis test identifies children with fibrosis. Clin Gastroenterol Hepatol. 2011;9(2):150–5.PubMedCrossRefGoogle Scholar
  68. 68.
    Stibbe KJ, Verveer C, Francke J, et al. Comparison of non-invasive assessment to diagnose liver fibrosis in chronic hepatitis B and C patients. Scan J Gastroenterol. 2011;46(7–8):962–72.CrossRefGoogle Scholar
  69. 69.
    deLedinghen V, Le Bail B, Rebouissoux L, et al. Liver stiffness measurement in children using FibroScan: feasibility study and comparison with Fibrotest, aspartate transaminase to platelets ratio index, and liver biopsy. J Pediatr Gastroenterol Nutr. 2007;45(4):443–50.CrossRefGoogle Scholar
  70. 70.
    Goldschmidt I, Streckenbach C, Dingemann C, et al. Application and limitations of transient liver elastography in children. J Pediatr Gastroenterol Nutr. 2013;57(1):109–13.PubMedCrossRefGoogle Scholar
  71. 71.
    Petta S, Di Marco V, Camma C, et al. Reliability of liver stiffness measurement in non-alcoholic fatty liver disease: the effects of body mass index. Aliment Pharmacol Ther. 2011;33(12):1350–60.PubMedCrossRefGoogle Scholar
  72. 72.
    Koh H, Kim S, Kim MJ, et al. Hepatic fat quantification magnetic resonance for monitoring treatment response in pediatric nonalcoholic steatohepatitis. World J Gastroenterol. 2015;21(33):3741–8.CrossRefGoogle Scholar
  73. 73.
    Idilman IS, Keskin O, Celik A, et al. A comparison of liver fat content as determined by magnetic resonance imaging-proton density fat fraction and MRS versus liver histology in non-alcoholic fatty liver disease. Acta Radiol. 2015.Google Scholar
  74. 74.
    Permutt Z, Le TA, Peterson MR, et al. Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease - MRI accurately quantifies hepatic steatosis in NAFLD. Aliment Pharmacol Ther. 2012;36(1):22–9.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Schwimmer JB, Middleton MS, Behling C, et al. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology. 2015;61(6):1887–95.PubMedCrossRefGoogle Scholar
  76. 76.
    Achmad E, Yokoo T, Hamilton G, et al. Feasibility of and agreement between MR imaging and spectroscopic estimation of hepatic proton density fat fraction in children with known or suspected nonalcoholic fatty liver disease. Abdom Imaging. 2015;40(8):3084–90.PubMedCrossRefGoogle Scholar
  77. 77.
    Yin M, Talwalkar JA, Glaser KJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol. 2007;5(10):1207–13.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Imajo K, Kessoku T, Honda Y, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology 2015.Google Scholar
  79. 79.
    Cui J, Ang B, Haufe W, et al. Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study. Aliment Pharmacol Ther. 2015;41(12):1271–80.PubMedCrossRefGoogle Scholar
  80. 80.
    Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J Magn Reson Imaging. 2013;37(3):544–55.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Xanthakos SA, Podberesky DJ, Serai SD, et al. Use of magnetic resonance elastography to assess hepatic fibrosis in children with chronic liver disease. J Pediatr. 2014;164(1):186–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Maurantonio M, Ballestri S, Odoardi MR, et al. Treatment of atherogenic liver based on the pathogenesis of nonalcoholic fatty liver disease: a novel approach to reduce cardiovascular risk? Arch Med Res. 2011;42(5):337–53.PubMedCrossRefGoogle Scholar
  83. 83.
    Nobili V, Manco M, De Vito R, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology. 2008;48(1):119–28.PubMedCrossRefGoogle Scholar
  84. 84.
    Gidding SS, Dennison BA, Birch LL, et al. Dietary recommendations for children and adolescents: a guide for practitioners: consensus statement from the American Heart Association. Circulation. 2005;112(13):2061–75.PubMedCrossRefGoogle Scholar
  85. 85.
    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(6):740–3.PubMedCrossRefGoogle Scholar
  86. 86.
    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):1276–85.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Loguercio C, Federico A, Tuccillo C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol. 2005;39(6):540–3.PubMedCrossRefGoogle Scholar
  88. 88.
    Parker HM, Johnson NA, Burdon CA, et al. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012;56(4):944–51.PubMedCrossRefGoogle Scholar
  89. 89.
    Masteron GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids - a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;31(7):679–392.CrossRefGoogle Scholar
  90. 90.
    Nobili V, Bedogni G, Alisi A, 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(4):350–3.PubMedCrossRefGoogle Scholar
  91. 91.
    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):1066–70.PubMedCrossRefGoogle Scholar
  92. 92.
    Janczyk W, Lebensztein D, Wierzbicka-Rucinska A, et al. Omega-3 Fatty acids therapy in children with nonalcoholic Fatty liver disease: a randomized controlled trial. J Pediatr. 2015;166(6):1358–63.PubMedCrossRefGoogle Scholar
  93. 93.
    Janczyk W, Socha P, Lebensztein D, et al. Omega-3 fatty acids for treatment of non-alcoholic fatty liver disease: design and rationale of randomized controlled trial. BMC Pediatr. 2013.Google Scholar
  94. 94.
    Sanyal AJ, Abdelmalek MF, Suzuki A, et al. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology. 2014;147(2):374–87.CrossRefGoogle Scholar
  95. 95.
    Scorletti E, Bhatia L, McCormick KG, et al. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology. 2014;60(4):1211–21.PubMedCrossRefGoogle Scholar
  96. 96.
    Lavine JE. Vitamin E, treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000;136(6):734–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Vajro P, Franzese A, Valerio G, et al. Lack of efficacy of ursodeoxycholic acid for the treatment of liver abnormalities in obese children. J Pediatr. 2000;136(6):739–43.PubMedCrossRefGoogle Scholar
  98. 98.
    Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology. 2008;135(1):100–10.PubMedCrossRefGoogle Scholar
  99. 99.
    Du J, Ma Y, Yu C, et al. Effects of pentoxifylline on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol. 2014;20(2):569–77.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Zein CO, Yerian LM, Gogate P, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. 2011;54(5):1610–9.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Adorini L, Purzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today. 2012;17–18:988–97.CrossRefGoogle Scholar
  102. 102.•
    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(4):550–61. Consensus statement on the role of bariatric surgery in pediatric NASH.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Vikas Uppal
    • 1
    • 2
  • Sana Mansoor
    • 1
    • 2
  • Katryn N. Furuya
    • 1
    • 2
  1. 1.Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of PediatricsAlfred I duPont Hospital for ChildrenWilmingtonUSA
  2. 2.The Sidney Kimmel Medical College at Thomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations