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Nonalcoholic Fatty Liver Disease and Steatohepatitis in Children

  • Antonella MoscaEmail author
  • Silvio Veraldi
  • Andrea Dellostrologo
  • Mariateresa Sanseviero
  • Valerio Nobili
Chapter

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children, especially in Western countries, with a worldwide prevalence estimated between 3 and 12% in the general pediatric population, with peaks of 70% in obese children. NAFLD pathogenesis is not fully understood, but it is known that many risk factors, both environmental and genetic, contribute to the development and progression of liver injury, which can eventually lead to cirrhosis and hepatocellular carcinoma. The only treatment approved is weight loss through diet and physical activity, but it is very difficult to obtain an optimal compliance by children and their families. Some different pharmacological approaches, such as insulin sensitizers, omega-3 fatty acids, and vitamin D, have been studied, but the results are not univocal, and their applicability is actually limited in the pediatric population. Many other therapeutic strands are currently under investigation, especially in view of the new pathogenetic findings.

Keywords

NAFLD NASH Obesity Fatty liver Insulin resistance Liver biopsy Omega-3 

References

  1. 1.
    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;54:700–13.CrossRefGoogle Scholar
  2. 2.
    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;58:1218–29.CrossRefGoogle Scholar
  3. 3.
    Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014;2:901–10.CrossRefGoogle Scholar
  4. 4.
    Sayin O, Tokgoz Y, Arslan N. Investigation of adropin and leptin levels in pediatric obesity-related nonalcoholic fatty liver disease. J Pediatr Endocrinol Metab. 2014;27:479–84.CrossRefGoogle Scholar
  5. 5.
    Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7:195–203.CrossRefGoogle Scholar
  6. 6.
    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;58:1538–44.CrossRefGoogle Scholar
  7. 7.
    Brunt EM, Wong VW, Nobili V, et al. Nonalcoholic fatty liver disease. Nat Rev Dis Primers. 2015;1:15080.CrossRefGoogle Scholar
  8. 8.
    Brunt EM, Kleiner DE, Wilson LA, et al. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53(3):810–20.CrossRefGoogle Scholar
  9. 9.
    Nobili V, Putignani L, Mosca A, et al. Bifidobacteria and lactobacilli in the gut microbiome of children with non-alcoholic fatty liver disease: which strains act as health players? Arch Med Sci. 2018;14(1):81–7.CrossRefGoogle Scholar
  10. 10.
    Li ZZ, Berk M, McIntyre TM, et al. Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-CoA desaturase. J Biol Chem. 2009;284(9):5637–44.CrossRefGoogle Scholar
  11. 11.
    Lin YC, Chang PF, Chang MH, et al. Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals. Am J Clin Nutr. 2014;99:869–74.CrossRefGoogle Scholar
  12. 12.
    Fessler MB, Rudel LL, Brown JM. Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome. Curr Opin Lipidol. 2009;20(5):379–85.CrossRefGoogle Scholar
  13. 13.
    Pappachan JM, Babu S, Krishnan B, et al. Non-alcoholic fatty liver disease: a clinical update. J Clin Transl Hepatol. 2017;5(4):384–93.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Selvakumar PKC, Kabbany MN, Nobili V, et al. Nonalcoholic fatty liver disease in children: hepatic and Extrahepatic complications. Pediatr Clin N Am. 2017;64(3):659–75.CrossRefGoogle Scholar
  15. 15.
    Mann JP, Raponi M, Nobili V. Clinical implications of understanding the association between oxidative stress and pediatric NAFLD. Expert Rev Gastroenterol Hepatol. 2017;11(4):371–82.CrossRefGoogle Scholar
  16. 16.
    Doulberis M, Kotronis G, Gialamprinou D, et al. Non-alcoholic fatty liver disease: an update with special focus on the role of gut microbiota. Metabolism. 2017;71:182–97.CrossRefGoogle Scholar
  17. 17.
    Poeta M, Pierri L, Vajro P. Gut-liver axis derangement in non-alcoholic fatty liver disease. Children (Basel). 2017;4(8).CrossRefGoogle Scholar
  18. 18.
    Silva Figueiredo P, Carla Inada A, Marcelino G, et al. Fatty acids consumption: the role metabolic aspects involved in obesity and its associated disorders. Nutrients 2017;9(10).CrossRefGoogle Scholar
  19. 19.
    Del Chierico F, Nobili V, Vernocchi P, et al. Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach. Hepatology. 2017;65(2):451–64.CrossRefGoogle Scholar
  20. 20.
    Della Corte C, Vajro P, Socha P, Nobili V. Pediatric non-alcoholic fatty liver disease: recent advances. Clin Res Hepatol Gastroenterol. 2014;38(4):419–22.CrossRefGoogle Scholar
  21. 21.
    Ramírez-Pérez O, Cruz-Ramón V, Chinchilla-López P, Méndez-Sánchez N. The role of the gut microbiota in bile acid metabolism. Ann Hepatol. 2017;16(Suppl. 1: s3-105):s15–20.  https://doi.org/10.5604/01.3001.0010.5494.CrossRefPubMedGoogle Scholar
  22. 22.
    Molinaro A, Wahlström A, Marschall HU. Role of bile acids in metabolic control. Trends Endocrinol Metab. 2018;29(1):31–41.CrossRefGoogle Scholar
  23. 23.
    Nobili V, Alisi A, Mosca A, et al. Hepatic farnesoid X receptor protein level and circulating fibroblast growth factor 19 concentration in children with NAFLD. Liver Int. 2018;38(2):342–9.CrossRefGoogle Scholar
  24. 24.
    Carpino G, Pastori D, Baratta F, et al. PNPLA3 variant and portal/periportal histological pattern in patients with biopsy-proven non-alcoholic fatty liver disease: a possible role for oxidative stress. Sci Rep. 2017;7(1):15756.CrossRefGoogle Scholar
  25. 25.
    Nobili V, Bedogni G, Donati B, et al. 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.CrossRefGoogle Scholar
  26. 26.
    Mangge H, Baumgartner BG, Zelzer S, et al. Patatin-like phospholipase 3 (rs738409) gene polymorphism is associated with increased liver enzymes in obese adolescents and metabolic syndrome in all ages. Aliment Pharmacol Ther. 2015;42:99–105.CrossRefGoogle Scholar
  27. 27.
    Vos MB, Abrams SH, Barlow SE, et al. NASPGHAN clinical practice guideline for the diagnosis and treatment of nonalcoholic fatty liver disease in children: recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017;64(2):319–34.CrossRefGoogle Scholar
  28. 28.
    Glen J, Floros L, Day C, et al. Non-alcoholic fatty liver disease (NAFLD): summary of NICE guidance. BMJ. 2016;354:i4428.CrossRefGoogle Scholar
  29. 29.
    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;63(2):181–7.CrossRefGoogle Scholar
  30. 30.
    Walenbergh SM, Houben T, Hendrikx T, et al. Plasma cathepsin D levels: a novel tool to predict pediatric hepatic inflammation. Am J Gastroenterol. 2015;110(3):462–70.CrossRefGoogle Scholar
  31. 31.
    Di Martino M, Koryukova K, Bezzi M. Imaging features of non-alcoholic fatty liver disease in children and adolescents. Children (Basel). 2017;4(8).Google Scholar
  32. 32.
    Di Martino M, Pacifico L, Bezzi M, et al. Comparison of magnetic resonance spectroscopy, proton density fat fraction and histological analysis in the quantification of liver steatosis in children and adolescents. World J Gastroenterol. 2016;22(39):8812–9.CrossRefGoogle Scholar
  33. 33.
    Dezsőfi A, Baumann U, Dhawan A, et al. Liver biopsy in children: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr. 2015;60(3):408–20.CrossRefGoogle Scholar
  34. 34.
    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(3):745–53.CrossRefGoogle Scholar
  35. 35.
    Kleiner DE, Makhlouf HR. Histology of NAFLD and NASH in adults and children. Clin Liver Dis. 2016;20(2):293–312.CrossRefGoogle Scholar
  36. 36.
    Strnad P, Zatloukal K, Stumptner C, et al. Mallory-Denk-bodies: lessons from keratin-containing hepatic inclusion bodies. Biochim Biophys Acta. 2008;1782(12):764–74.CrossRefGoogle Scholar
  37. 37.
    Brunt EM, Tiniakos DG. Histopathology of nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16(42):5286–96.CrossRefGoogle Scholar
  38. 38.
    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.CrossRefGoogle Scholar
  39. 39.
    Kleiner DE, Brunt EM, Van Natta M. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.CrossRefGoogle 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.CrossRefGoogle Scholar
  41. 41.
    Nobili V, Donati B, Panera N, et al. A 4-polymorphism risk score predicts steatohepatitis in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2014;58(5):632–6.CrossRefGoogle Scholar
  42. 42.
    Nobili V, Marcellini M, Devito R, et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology. 2006;44(2):458–65.CrossRefGoogle Scholar
  43. 43.
    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.CrossRefGoogle Scholar
  44. 44.
    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.CrossRefGoogle Scholar
  45. 45.
    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;305:1659–68.CrossRefGoogle Scholar
  46. 46.
    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;136:739–43.CrossRefGoogle Scholar
  47. 47.
    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.CrossRefGoogle Scholar
  48. 48.
    Famouri F, Shariat Z, Hashemipour M, et al. Effects of probiotics on non-alcoholic fatty liver disease in obese children and adolescents: a randomized clinical trial. J Pediatr Gastroenterol Nutr. 2017;64:413–7.CrossRefGoogle Scholar
  49. 49.
    Kim S-G, Kim B-K, Kim K, et al. Bile acid nuclear receptor Farnesoid X receptor: therapeutic target for nonalcoholic fatty liver disease. Endocrinol Metab (Seoul). 2016;31(4):500–4.CrossRefGoogle Scholar
  50. 50.
    Armstrong MJ, Gaunt P, Aithal GP, 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(10019):679–90.CrossRefGoogle Scholar
  51. 51.
    Charlotte F, Le Naour G, Bernhardt C, et al. A comparison of the fibrotic potential of nonalcoholic fatty liver disease and chronic hepatitis C. Hum Pathol. 2010;41(8):1178–85.CrossRefGoogle Scholar
  52. 52.
    Shaker M, Tabbaa A, Albeldawi M, et al. Liver transplantation for nonalcoholic fatty liver disease: new challenges and new opportunities. World J Gastroenterol. 2014;20(18):5320–30.CrossRefGoogle Scholar
  53. 53.
    Alkhouri N, Hanouneh IA, Zein NN, et al. Liver transplantation for nonalcoholic steatohepatitis in young patients. Transpl Int. 2016;29(4):418–24.CrossRefGoogle Scholar
  54. 54.
    Zezos P, Renner EL. Liver transplantation and non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20(42):15532–8.CrossRefGoogle Scholar
  55. 55.
    Orman ES, Mayorga ME, Wheeler SB, et al. Declining liver graft quality threatens the future of liver transplantation in the United States. Liver Transpl. 2015;21(8):1040–50.CrossRefGoogle Scholar
  56. 56.
    Pais R, Barritt AS, Calmus Y, et al. NAFLD and liver transplantation: current burden and expected challenges. J Hepatol. 2016;65(6):1245–57.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Antonella Mosca
    • 1
    Email author
  • Silvio Veraldi
    • 1
  • Andrea Dellostrologo
    • 1
  • Mariateresa Sanseviero
    • 1
  • Valerio Nobili
    • 1
    • 2
  1. 1.Hepatology, Gastroenterology and Nutrition Unit“Bambino Gesù” Children’s HospitalRomeItaly
  2. 2.Department of Pediatrics, Facoltà di Medicina e PsicologiaSapienza University of RomeRomeItaly

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