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  • Review Article
  • Published:

Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach

Nature Reviews Gastroenterology & Hepatology volume 9, pages 152–161 (2012)Cite this article

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a multifactorial condition, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis. NAFLD affects both adults and children who present with particular risk factors, including obesity, sedentary lifestyle and/or a predisposing genetic background. The escalation of the prevalence of NAFLD in children worldwide is a worrying phenomenon because this disease is closely associated with the development of both cirrhosis and cardiometabolic syndrome in adulthood. The etiopathogenesis of primary NAFLD in children is unknown; however, considerable knowledge about the mechanisms of liver damage that occur during disease progression has been gathered over the past 30 years. Understanding the pathogenetic mechanisms, together with the histological pattern, provide the basis to characterize potential early predictors of the disease, suitable noninvasive diagnostic tools and design novel specific treatments and possible management strategies. Despite a few clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD that showed encouraging results, to date, no treatment guidelines exist for children with NAFLD. In this Review, we provide an overview of current concepts in epidemiology, histological features, etiopathogenesis, diagnosis and treatment of NAFLD in children and adolescents.

Key Points

  • Risk factors for pediatric NAFLD include obesity, insulin resistance, type 2 diabetes mellitus and the metabolic syndrome

  • In susceptible individuals, pediatric NAFLD can evolve to cirrhosis and eventually hepatocellular carcinoma

  • Knowledge of the pathology and pathogenesis of pediatric NAFLD drives current approaches in diagnosis and treatment

  • Noninvasive tools could be useful in the diagnosis of NAFLD in children, greatly reducing the need for liver biopsy

  • A multitarget and multidisciplinary approach is preferable, both in diagnosis of and therapy for pediatric NAFLD

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Figure 1: Schematic representation of the complex crosstalk between multiple factors and organs during NAFLD pathogenesis.
Figure 2: Liver histology of a child with NAFLD.
Figure 3: Management algorithm for children affected by primary NAFLD.

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References

  1. Day, C. P. Non-alcoholic fatty liver disease: a massive problem. Clin. Med. 11, 176–178 (2011).

    Article  Google Scholar 

  2. Vernon, G., Baranova, A. & Younossi, Z. M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. 34, 274–285 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Alisi, A., Manco, M., Vania, A. & Nobili, V. Pediatric nonalcoholic fatty liver disease in 2009. J. Pediatr. 155, 469–474 (2009).

    Article  PubMed  Google Scholar 

  4. Flegal, K. M., Carroll, M. D., Ogden, C. L. & Johnson, C. L. Prevalance and trends in obesity among US adults, 1999–2000. JAMA 288, 1723–1727 (2002).

    Article  PubMed  Google Scholar 

  5. Mencin, A. A. & Lavine, J. E. Nonalcoholic fatty liver disease in children. Curr. Opin. Clin. Nutr. Metab. Care 14, 151–157 (2011).

    CAS  PubMed  Google Scholar 

  6. Obesity and overweight. World Health Organisation [online], (2011).

  7. Drewnowski, A. & Darmon, N. The economics of obesity: dietary energy density and energy cost. Am. J. Clin. Nutr. 82 (Suppl. 1), 265S–273S (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Brunt, E. M. Pathology of nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 7, 195–203 (2010).

    Article  PubMed  Google Scholar 

  9. Alisi, A., Locatelli, M. & Nobili, V. Nonalcoholic fatty liver disease in children. Curr. Opin. Clin. Nutr. Metab. Care 13, 397–402 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Schwimmer, J. B. et al. Prevalence of fatty liver in children and adolescents. Pediatrics 118, 1388–1393 (2006).

    Article  PubMed  Google Scholar 

  11. Feldstein, A. E. et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 58, 1538–1544 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Alisi, A., Manco, M., Panera, N. & Nobili, V. Association between type two diabetes and non-alcoholic fatty liver disease in youth. Ann. Hepatol. 8 (Suppl. 1), S44–S50 (2009).

    PubMed  Google Scholar 

  13. Schwimmer, J. B., Pardee, P. E., Lavine, J. E., Blumkin, A. K. & Cook, S. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation 118, 277–283 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kelishadi, R. et al. Association of the components of the metabolic syndrome with non-alcoholic fatty liver disease among normal-weight, overweight and obese children and adolescents. Diabetol. Metab. Syndr. 1, 29 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Day, C. P. Genetic and environmental susceptibility to non-alcoholic fatty liver disease. Dig. Dis. 28, 255–260 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Loomba, R., Sirlin, C. B., Schwimmer, J. B. & Lavine, J. E. Advances in pediatric nonalcoholic fatty liver disease. Hepatology 50, 1282–1293 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Nobili, V. et al. Elevated serum ALT in children presenting to the emergency unit: relationship with NAFLD. Dig. Liver Dis. 41, 749–752 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Rodríguez, G., Gallego, S., Breidenassel, C., Moreno, L. A. & Gottrand, F. Is liver transaminases assessment an appropriate tool for the screening of non-alcoholic fatty liver disease in at risk obese children and adolescents? Nutr. Hosp. 25, 712–717 (2010).

    PubMed  Google Scholar 

  19. Hesham A-Kader, H. Nonalcoholic fatty liver disease in children living in the obeseogenic society. World J. Pediatr. 5, 245–254 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Pacifico, L. et al. Pediatric nonalcoholic fatty liver disease: A clinical and laboratory challenge. World J. Hepatol. 2, 275–288 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tominaga, K. et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig. Dis. Sci. 40, 2002–2009 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Franzese, A. et al. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig. Dis. Sci. 42, 1428–1432 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Strauss, R. S., Barlow, S. E. & Dietz, W. H. Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents. J. Pediatr. 136, 727–733 (2000).

    CAS  PubMed  Google Scholar 

  24. Chan, D. F. et al. Hepatic steatosis in obese Chinese children. Int. J. Obes. Relat. Metab. Disord. 28, 1257–1263 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Widhalm, K. & Ghods, E. Nonalcoholic fatty liver disease: a challenge for pediatricians. Int. J. Obes. (Lond.) 34, 1451–1467 (2010).

    Article  CAS  Google Scholar 

  26. Nadeau, K. J., Klingensmith, G. & Zeitler, P. Type 2 diabetes in children is frequently associated with elevated alanine aminotransferase. J. Pediatr. Gastroenterol. Nutr. 41, 94–98 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Manco, M. et al. Metabolic syndrome and liver histology in paediatric non-alcoholic steatohepatitis. Int. J. Obes. (Lond.) 32, 381–387 (2008).

    Article  CAS  Google Scholar 

  28. Barshop, N. J., Francis, C. S., Schwimmer, J. B. & Lavine, J. E. Nonalcoholic fatty liver disease as a comorbidity of childhood obesity. Ped. Health 3, 271–281 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sundaram, S. S., Zeitler, P. & Nadeau, K. The metabolic syndrome and nonalcoholic fatty liver disease in children. Curr. Opin. Pediatr. 21, 529–535 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Barshop, N. J., Sirlin, C. B., Schwimmer, J. B. & Lavine, J. E. Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 28, 13–24 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Schwimmer, J. B., McGreal, N., Deutsch, R., Finegold, M. J. & Lavine, J. E. Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents. Pediatrics 115, e561–e565 (2005).

    Article  PubMed  Google Scholar 

  32. Wiegand, S. et al. Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16,390 overweight or obese children and adolescents. Int. J. Obes. (Lond.) 34, 1468–1474 (2010).

    Article  CAS  Google Scholar 

  33. Poustchi, H. et al. Gender differences in healthy ranges for serum alanine aminotransferase levels in adolescence. PLoS ONE 6, e21178 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Graham, R. C., Burke, A. & Stettler, N. Ethnic and sex differences in the association between metabolic syndrome and suspected nonalcoholic fatty liver disease in a nationally representative sample of US adolescents. J. Pediatr. Gastroenterol. Nutr. 49, 442–449 (2009).

    Article  PubMed  Google Scholar 

  35. Imhof, A. et al. Prevalence of non-alcoholic fatty liver and characteristics in overweight adolescents in the general population. Eur. J. Epidemiol. 22, 889–897 (2007).

    Article  PubMed  Google Scholar 

  36. Fraser, A., Longnecker, M. P. & Lawlor, D. A. Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999–2004. Gastroenterology 133, 1814–1820 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Carrillo-Iregui, A. et al. Relationship between aminotransferases levels and components of the metabolic syndrome among multiethnic adolescents. J. Pediatr. Endocrinol. Metab. 23, 1253–1261 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. de Alwis, N. M. & Day, C. P. Non-alcoholic fatty liver disease: the mist gradually clears. J. Hepatol. 48 (Suppl. 1), S104–S112 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Day, C. P. Genetic and environmental susceptibility to non-alcoholic fatty liver disease. Dig. Dis. 28, 255–260 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Bruce, K. D. & Cagampang, F. R. Epigenetic priming of the metabolic syndrome. Toxicol. Mech. Methods 21, 353–361 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Alisi, A., Cianfarani, S., Manco, M., Agostoni, C. & Nobili, V. Non-alcoholic fatty liver disease and metabolic syndrome in adolescents: pathogenetic role of genetic background and intrauterine environment. Ann. Med. http://dx.doi.org/10.3109/07853890.2010.547869.

  42. Song, J. et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J. 19, 1266–1271 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Miele, L. et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology 135, 282–291e1 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Lin, Y. C. et al. Variants in the UGT1A1 gene and the risk of pediatric nonalcoholic fatty liver disease. Pediatrics 124, e1221–e1227 (2009).

    Article  PubMed  Google Scholar 

  45. Valenti, L. et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51, 1209–1217 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Dongiovanni, P. et al. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut 59, 267–273 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Al-Serri, A. et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case–control and intra-familial allele association studies. J. Hepatol. http://dx.doi.org/10.1016/j.jhep.2011.05.029.

  48. Povel, C. M., Boer, J. M., Reiling, E. & Feskens, E. J. Genetic variants and the metabolic syndrome: a systematic review. Obes. Rev. 12, 952–967 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Cazanave, S. C. & Gores, G. J. Mechanisms and clinical implications of hepatocyte lipoapoptosis. Clin. Lipidol. 5, 71–85 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Byrne, C. D. Fatty liver: role of inflammation and fatty acid nutrition. Prostaglandins Leukot. Essent. Fatty Acids 82, 265–271 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Musso, G., Gambino, R. & Cassader, M. Gut microbiota as a regulator of energy homeostasis and ectopic fat deposition: mechanisms and implications for metabolic disorders. Curr. Opin. Lipidol. 21, 76–83 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Sakaguchi, S., Takahashi, S., Sasaki, T., Kumagai, T. & Nagata, K. Progression of alcoholic and non-alcoholic steatohepatitis: common metabolic aspects of innate immune system and oxidative stress. Drug Metab. Pharmacokinet. 26, 30–46 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Fabbrini, E., Sullivan, S. & Klein, S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51, 679–689 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Larter, C. Z., Chitturi, S., Heydet, D. & Farrell, G. C. A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J. Gastroenterol. Hepatol. 25, 672–690 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Cohen, J. C., Horton, J. D. & Hobbs, H. H. Human fatty liver disease: old questions and new insights. Science 332, 1519–1523 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Perseghin, G. Lipids in the wrong place: visceral fat and nonalcoholic steatohepatitis. Diabetes Care 34 (Suppl. 2), S367–S370 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tiniakos, D. G., Vos, M. B. & Brunt, E. M. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu. Rev. Pathol. 5, 145–171 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. Hübscher, S. G. Histological assessment of non-alcoholic fatty liver disease. Histopathology 49, 450–465 (2006).

    Article  PubMed  Google Scholar 

  59. Burt, A. D., Mutton, A. & Day, C. P. Diagnosis and interpretation of steatosis and steatohepatitis. Semin. Diagn. Pathol. 15, 246–258 (1998).

    CAS  PubMed  Google Scholar 

  60. Brunt, E. M. & Tiniakos, D. G. Histopathology of nonalcoholic fatty liver disease. World J. Gastroenterol. 16, 5286–5296 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Brunt, E. M. et al. Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Mod. Pathol. 16, 49–56 (2003).

    Article  PubMed  Google Scholar 

  62. Lavine, J. E. & Schwimmer, J. B. Nonalcoholic fatty liver disease in the pediatric population. Clin. Liver Dis. 8, 549–558 (2004).

    Article  PubMed  Google Scholar 

  63. Matteoni, C. A. et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116, 1413–1419 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Tajiri, K., Shimizu, Y., Tsuneyama, K. & Sugiyama, T. Role of liver infiltrating CD3+CD56+ natural killer T cells in the pathogenesis of non-alcoholic fatty liver disease. Eur. J. Gastroenterol. Hepatol. 21, 673–680 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Syn, W. K. et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51, 1998–2007 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Brunt, E. M. Nonalcoholic steatohepatitis: definition and pathology. Semin. Liver Dis. 21, 3–16 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Brunt, E. M. Alcoholic and nonalcoholic steatohepatitis. Clin. Liver Dis. 6, 399–420 (2002).

    Article  PubMed  Google Scholar 

  68. Brunt, E. M. et al. 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 49, 809–820 (2009).

    Article  PubMed  Google Scholar 

  69. Alisi, A., Devito, R. & Nobili, V. Portal inflammation as index of steatohepatitis in children with nonalcoholic fatty liver disease. Hepatology 50, 659 (2009).

    Article  PubMed  Google Scholar 

  70. Alisi, A. et al. Relationship between portal chronic inflammation and disease severity in paediatric non-alcoholic fatty liver disease. Dig. Liver Dis. 43, 143–146 (2011).

    Article  PubMed  Google Scholar 

  71. Burt, A. D., Mutton, A. & Day, C. P. Diagnosis and interpretation of steatosis and steatohepatitis. Semin. Diagn. Pathol. 15, 246–258 (1998).

    CAS  PubMed  Google Scholar 

  72. Caldwell, S. H. et al. Enlarged hepatocytes in NAFLD examined with osmium fixation: does microsteatosis underlie cellular ballooning in NASH? Am. J. Gastroenterol. 101, 1677–1678 (2006).

    Article  PubMed  Google Scholar 

  73. Brunt, E. M. Nonalcoholic steatohepatitis: pathologic features and differential diagnosis. Semin. Diagn. Pathol. 22, 330–338 (2005).

    Article  PubMed  Google Scholar 

  74. Lackner, C. et al. Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis. J. Hepatol. 48, 821–828 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005).

    Article  PubMed  Google Scholar 

  76. Richardson, M. M. et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology 133, 80–90 (2007).

    Article  PubMed  Google Scholar 

  77. Schwimmer, J. B. et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 42, 641–649 (2005).

    Article  PubMed  Google Scholar 

  78. Nobili, V. et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology 44, 458–465 (2006).

    Article  PubMed  Google Scholar 

  79. Carter-Kent, C. et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology 50, 1113–1120 (2009).

    Article  PubMed  Google Scholar 

  80. Patton, H. M. et al. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology 135, 1961–1971 (2008).

    Article  PubMed  Google Scholar 

  81. Brunt, E. M., Janney, C. G., Di Bisceglie, A. M., Neuschwander-Tetri, B. A. & Bacon, B. R. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am. J. Gastroenterol. 94, 2467–2474 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Wieckowska, A. & Feldstein, A. E. Nonalcoholic fatty liver disease in the pediatric population: a review. Curr. Opin. Pediatr. 17, 636–641 (2005).

    Article  PubMed  Google Scholar 

  83. Straub, B. K. & Schirmacher, P. Pathology and biopsy assessment of non-alcoholic fatty liver disease. Dig. Dis. 28, 197–202 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Angulo, P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 346, 1221–1231 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Mofrad, P. et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 37, 1286–1292 (2003).

    Article  PubMed  Google Scholar 

  86. Alkhouri, N. et al. The inflamed liver and atherosclerosis: a link between histologic severity of nonalcoholic fatty liver disease and increased cardiovascular risk. Dig. Dis. Sci. 55, 2644–2650 (2009).

    Article  PubMed  Google Scholar 

  87. Adams, L. A., Lindor, K. D. & Angulo, P. The prevalence of autoantibodies and autoimmune hepatitis in patients with nonalcoholic fatty liver disease. Am. J. Gastroenterol. 99, 1316–1320 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Wieckowska, A., McCullough, A. J. & Feldstein, A. E. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology 46, 582–589 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Nobili, V. et al. The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease. BMC Med. 7, 21 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Alkhouri, N. et al. A combination of the pediatric NAFLD fibrosis index and enhanced liver fibrosis test identifies children with fibrosis. Clin. Gastroenterol. Hepatol. 9, 150–155 (2011).

    Article  PubMed  Google Scholar 

  91. Alkhouri, N., Carter-Kent, C. & Feldstein, A. E. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev. Gastroenterol. Hepatol. 5, 201–212 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Vos, M. B. et al. Cytokeratin 18, a marker of cell death, is increased in children with suspected nonalcoholic fatty liver disease. J. Pediatr. Gastroenterol. Nutr. 47, 481–485 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fitzpatrick, E. et al. Serum levels of CK18 M30 and leptin are useful predictors of steatohepatitis and fibrosis in paediatric NAFLD. J. Pediatr. Gastroenterol. Nutr. 51, 500–506 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Feldstein, A. E. & Nobili, V. Biomarkers in nonalcoholic fatty liver disease: a new era in diagnosis and staging of disease in children. J. Pediatr. Gastroenterol. Nutr. 51, 378–379 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Adams, L. A. & Feldstein, A. E. Nonalcoholic steatohepatitis: risk factors and diagnosis. Expert Rev. Gastroenterol. Hepatol. 4, 623–635 (2010).

    Article  PubMed  Google Scholar 

  96. Dasarathy, S. et al. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J. Hepatol. 51, 1061–1067 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Mishra, P. & Younossi, Z. M. Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD). Am. J. Gastroenterol. 102, 2716–2717 (2007).

    Article  PubMed  Google Scholar 

  98. Hamaguchi, M. et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am. J. Gastroenterol. 102, 2708–2715 (2007).

    Article  PubMed  Google Scholar 

  99. Shannon, A. et al. Ultrasonographic quantitative estimation of hepatic steatosis in children with nonalcoholic fatty liver disease (NAFLD): a prospective study. J. Pediatr. Gastroenterol. Nutr. 53, 190–195 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Saadeh, S. et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 123, 745–750 (2002).

    Article  PubMed  Google Scholar 

  101. Qayyum, A. et al. Evaluation of diffuse liver steatosis by ultrasound, computed tomography, and magnetic resonance imaging: which modality is best? Clin. Imaging 33, 110–115 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Wong, V. W. & Chan, H. L. Transient elastography. J. Gastroenterol. Hepatol. 25, 1726–1731 (2010).

    Article  PubMed  Google Scholar 

  103. Wong, V. W. et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 51, 454–462 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Nobili, V. et al. Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology 48, 442–448 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Wang, C. L. et al. Effect of lifestyle intervention on non-alcoholic fatty liver disease in Chinese obese children. World J. Gastroenterol. 14, 1598–1602 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nobili, V. et al. Lifestyle intervention and antioxidants in children with non alcoholic fatty liver disease: a randomized controlled trial. Hepatology 48, 119–128 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Reinehr, T., Schmidt, C., Toschke, A. M. & Andler, W. Lifestyle intervention in obese children with non-alcoholic fatty liver disease: 2-year follow-up study. Arch. Dis. Child 94, 437–442 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. van der Heijden, G. J. et al. A 12-week aerobic exercise program reduces hepatic fat accumulation and insuline resistance in obese, Hispanic adolescents. Obesity 18, 384–390 (2010).

    Article  PubMed  Google Scholar 

  109. Zelber-Sagi, S., Ratziu, V. & Oren, R. Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World J. Gastroenterol. 17, 3377–3389 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Nobili, V. et al. Effect of vitamin E on aminotransferase levels and insulin resistance in children with non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 24, 1553–1561 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Nobili, V. et al. Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin. Ther. 30, 1168–1176 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Nadeau, K. J., Ehlers, L. B., Zeitler, P. S. & Love-Osborne, K. Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. Pediatr. Diabetes 10, 5–13 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Nobili, V. 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 96, 350–353 (2011).

    Article  PubMed  Google Scholar 

  114. Lavine, J. E. 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 305, 1659–1668 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Alisi, A. & Nobili, V. Nonalcoholic fatty liver disease: targeted therapy in children—what is the right way? Nat. Rev. Gastroenterol. Hepatol. 8, 425–426 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Nobili, V. & Pinzani, M. Alcoholic and non-alcoholic fatty liver in adolescents: a worrisome convergence. Alcohol Alcohol. 46, 627–629 (2011).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Professor A. Ugazio, the current President of The Italian Society of Pediatrics, for his suggestions and editorial assistance.

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Authors and Affiliations

  1. Liver Research Unit, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Piazza Sant'Onofrio 4, 00165, Rome, Italy

    Anna Alisi & Valerio Nobili

  2. Department of Pediatrics, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Piazza Sant'Onofrio 4, 00165, Rome, Italy

    Alberto Villani

  3. Health Planning Department, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Piazza Sant'Onofrio 4, 00165, Rome, Italy

    Massimiliano Raponi

  4. Division of Pediatric Gastroenterology, Hepatology and Nutrition University of California, San Diego, 9500 Gilman Drive, San Diego, 92093, CA, USA

    Ariel E. Feldstein

Authors
  1. Anna Alisi
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  2. Ariel E. Feldstein
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  3. Alberto Villani
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  4. Massimiliano Raponi
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  5. Valerio Nobili
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Contributions

A. Alisi, A. E. Feldstein, A. Villani and V. Nobili researched data for the article. All authors contributed equally to discussion of content and writing the article. A. Alisi, A. E. Feldstein, M. Raponi and V. Nobili reviewed and edited the manuscript before submission.

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Correspondence to Valerio Nobili.

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The authors declare no competing financial interests.

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Alisi, A., Feldstein, A., Villani, A. et al. Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach. Nat Rev Gastroenterol Hepatol 9, 152–161 (2012). https://doi.org/10.1038/nrgastro.2011.273

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