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  • Review Article
  • Published:

NAFLD in children: new genes, new diagnostic modalities and new drugs

Nature Reviews Gastroenterology & Hepatology volume 16, pages 517–530 (2019)Cite this article

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Abstract

Nonalcoholic fatty liver disease (NAFLD) has rapidly become the most common form of chronic liver disease in children and adolescents. Over the past 5 years, developments have revolutionized our understanding of the genetic factors, natural history, diagnostic modalities and therapeutic targets for this disease. New polymorphisms, such as those in PNPLA3, TM6SF2, MBOAT7 and GCKR, have been identified and used to predict the development and severity of NAFLD in both adults and children, and their interaction with environmental factors has been elucidated. Studies have demonstrated the true burden of paediatric NAFLD and its progression to end-stage liver disease in adulthood. In particular, nonalcoholic steatohepatitis can progress to advanced fibrosis and cirrhosis, emphasizing the importance of early diagnosis. Non-invasive imaging tests, such as transient elastography, will probably replace liver biopsy for the diagnosis of nonalcoholic steatohepatitis and the assessment of fibrosis severity in the near future. The therapeutic landscape is also expanding rapidly with the development of drugs that can modify liver steatosis, inflammation and fibrosis, indicating that pharmacotherapy for NAFLD will become available in the future. In this Review, we summarize current knowledge and new advances related to the pathogenesis and management of paediatric NAFLD.

Key points

  • Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the obesity and metabolic syndrome epidemics, is now the most common form of chronic liver disease in children and adolescents.

  • Knowledge on the pathogenic role of genetic and epigenetic factors in NAFLD has expanded tremendously over the past decade.

  • The most important risk factors for NAFLD in children are insulin resistance and central obesity.

  • New clinical practice guidelines for the management of NAFLD, published in 2017, provide some guidance to clinicians on how to screen, diagnose and treat NAFLD in children.

  • The landscape of therapeutic developments in paediatric NAFLD is expanding, bringing the identification of safe and effective treatments closer.

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Fig. 1: Mapping the prevalence of paediatric NAFLD.
Fig. 2: Interaction between inherited and environmental factors in the pathogenesis of NAFL and NASH.
Fig. 3: Typical histological appearance of paediatric NAFLD.
Fig. 4: Schematic representation of current pharmacological interventions and new promising therapies.

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References

  1. Nobili, V., Alisi, A., Newton, K. P. & Schwimmer, J. B. Comparison of the phenotype and approach to pediatric versus adult patients with nonalcoholic fatty liver disease. Gastroenterology 150, 1798–1810 (2016).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  3. Goyal, N. P. & Schwimmer, B. J. The progression and natural history of pediatric nonalcoholic fatty liver disease. Clin. Liver Dis. 20, 325–338 (2016).

    Article  PubMed  Google Scholar 

  4. Conjeevaram Selvakumar, P. K., Kabbany, M. N. & Alkhouri, N. Nonalcoholic fatty liver disease in children: not a small matter. Paediatr. Drugs 20, 315–329 (2018).

    Article  PubMed  Google Scholar 

  5. 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 

  6. Manco, M. et al. Waist circumference correlates with liver fibrosis in children with non-alcoholic steatohepatitis. Gut 57, 1283–1287 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Silveira, L. S. et al. Intra-abdominal fat is related to metabolic syndrome and non-alcoholic fat liver disease in obese youth. BMC Pediatr. 13, 115 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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  PubMed  PubMed Central  CAS  Google Scholar 

  9. Patton, H. M. et al. Association between metabolic syndrome and liver histology among children with nonalcoholic fatty liver disease. Am. J. Gastroenterol. 105, 2093–2102 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mencin, A. A. & Lavine, J. E. Advances in pediatric nonalcoholic fatty liver disease. Pediatr. Clin. North Am. 58, 1375–1392 (2011).

    Article  PubMed  Google Scholar 

  11. Vajro, P. et al. Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J. Pediatr. Gastroenterol. Nutr. 54, 700–713 (2012).

    Article  PubMed  Google Scholar 

  12. Panera, N. et al. A review of the pathogenic and therapeutic role of nutrition in pediatric nonalcoholic fatty liver disease. Nutr. Res. 58, 1–16 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Mollard, R. C. et al. Dietary determinants of hepatic steatosis and visceral adiposity in overweight and obese youth at risk of type 2 diabetes. Am. J. Clin. Nutr. 99, 804–812 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Mann, J. P., Valenti, L., Scorletti, E., Byrne, C. D. & Nobili, V. Nonalcoholic fatty liver disease in children. Semin. Liver Dis. 38, 1–13 (2018).

    Article  PubMed  Google Scholar 

  15. Anderson, E. L. et al. The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis. PLOS ONE 10, e0140908 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Marzuillo, P., Miraglia del Giudice, E. & Santoro, N. Pediatric fatty liver disease: role of ethnicity and genetics. World J. Gastroenterol. 20, 7347–7355 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Palmer, N. D. et al. Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent. Hepatology 58, 966–975 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. 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. 34, 1468–1474 (2010).

    Article  CAS  Google Scholar 

  19. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) & European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol. 64, 1388–1402 (2016).

    Google Scholar 

  20. 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 

  21. Park, H. S., Han, J. H., Choi, K. M. & Kim, S. M. Relation between elevated serum alanine aminotransferase and metabolic syndrome in Korean adolescents. Am. J. Clin. Nutr. 82, 1046–1051 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Song, P. et al. Prevalence and correlates of suspected nonalcoholic fatty liver disease in Chinese children. Int. J. Environ. Res. Public Health 14, 465 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  24. Das, M. K. et al. Prevalence of nonalcoholic fatty liver disease in normal-weight and overweight preadolescent children in Haryana, India. Indian Pediatr. 54, 1012–1016 (2017).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  26. Booth, M. L. et al. The population prevalence of adverse concentrations and associations with adiposity of liver tests among Australian adolescents. J. Paediatr. Child Health 44, 686–691 (2008).

    Article  PubMed  Google Scholar 

  27. Ayonrinde, O. T. et al. Gender-specific differences in adipose distribution and adipocytokines influence adolescent nonalcoholic fatty liver disease. Hepatology 53, 800–809 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Younossi, Z. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11–20 (2018).

    Article  PubMed  Google Scholar 

  29. Zimmermann, E. et al. Body mass index in school-aged children and the risk of routinely diagnosed non-alcoholic fatty liver disease in adulthood: a prospective study based on the Copenhagen School Health Records Register. BMJ Open 5, e006998 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  30. de Onis, M., Blössner, M. & Borghi, E. Global prevalence and trends of overweight and obesity among preschool children. Am. J. Clin. Nutr. 92, 1257–1264 (2010).

    Article  PubMed  CAS  Google Scholar 

  31. Ogden, C. L., Carroll, M. D., Kit, B. K. & Flegal, K. M. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010. JAMA 307, 483–490 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hagström, H., Stål, P., Hultcrantz, R., Hemmingsson, T. & Andreasson, A. Overweight in late adolescence predicts development of severe liver disease later in life: a 39 years follow-up study. J. Hepatol. 65, 363–368 (2016).

    Article  PubMed  Google Scholar 

  33. Berentzen, T. L., Gamborg, M., Holst, C., Sørensen, T. I. & Baker, J. L. Body mass index in childhood and adult risk of primary liver cancer. J. Hepatol. 60, 325–330 (2014).

    Article  PubMed  Google Scholar 

  34. Goldberg, D. et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology 152, 1090–1099 (2017).

    Article  PubMed  Google Scholar 

  35. Piscaglia, F. et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology 63, 827–838 (2016).

    Article  PubMed  Google Scholar 

  36. Noureddin, M. et al. NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances. Am. J. Gastroenterol. 113, 1649–1659 (2018).

    Article  PubMed  Google Scholar 

  37. Blachier, M., Leleu, H., Peck-Radosavljevic, M., Valla, D.-C. & Roudot-Thoraval, F. The burden of liver disease in Europe: a review of available epidemiological data. J. Hepatol. 58, 593–608 (2013).

    Article  PubMed  Google Scholar 

  38. Estes, C., Razavi, H., Loomba, R., Younossi, Z. & Sanyal, A. J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67, 123–133 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Estes, C. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J. Hepatol. 69, 896–904 (2018).

    Article  PubMed  Google Scholar 

  40. Makkonen, J., Pietilainen, K. H., Rissanen, A., Kaprio, J. & Yki-Jarvinen, H. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J. Hepatol. 50, 1035–1042 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Loomba, R. et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology 149, 1784–1793 (2015).

    Article  PubMed  Google Scholar 

  42. Guerrero, R., Vega, G. L., Grundy, S. M. & Browning, J. D. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology 49, 791–801 (2009).

    Article  PubMed  Google Scholar 

  43. Fernandes, D. M. Pediatric nonalcoholic fatty liver disease in New York City: an autopsy study. J. Pediatr. 200, 174–180 (2018).

    Article  PubMed  Google Scholar 

  44. Caussy, C. et al. Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. J. Clin. Invest. 127, 2697–2704 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dongiovanni, P. et al. PNPLA3 I148M polymorphism and progressive liver disease. World J. Gastroenterol. 19, 6969–6978 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Valenti, L. et al. I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 52, 1274–1280 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Sookoian, S. & Pirola, C. J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 53, 1883–1894 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Nobili, V. et al. Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents. Genes Nutr. 9, 392 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Mitsche, M. A., Hobbs, H. H. & Cohen, J. C. Phospholipase domain-containing protein 3 promotes transfers of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J. Biol. Chem. 293, 9232 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. BasuRay, S., Smagris, E., Cohen, J. & Hobbs, H. H. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 66, 1111–1124 (2017).

    Article  CAS  PubMed  Google Scholar 

  52. Donati, B. et al. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology 63, 787–798 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Mondul, A. et al. PNPLA3 1148M variant influences circulating retinol in adults with nonalcoholic fatty liver disease or obesity. J. Nutr. 145, 1687–1691 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pirazzi, C. et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum. Mol. Genet. 23, 4077–4085 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pingitore, P. et al. PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis. Hum. Mol. Genet. 25, 5212–5222 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kozlitina, J. et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46, 352–356 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dongiovanni, P. et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506–514 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Liu, Y. L. et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 5, 4309 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Mancina, R. M. et al. Variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 150, 1219–1230 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Speliotes, E. K. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLOS Genet. 7, e1001324 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Santoro, N. et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55, 781–789 (2011).

    Article  PubMed  CAS  Google Scholar 

  62. Mancina, R. M. et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 150, 1219–1230 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Dongiovanni, P. et al. Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease. Hepatol. Commun. 2, 666–675 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dongiovanni, P. et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J. Intern. Med. 283, 356–370 (2018).

    Article  CAS  PubMed  Google Scholar 

  65. Petta, S. et al. IFNL4 rs368234815 δG>TT variant is associated with histological liver damage in patients with non-alcoholic fatty liver disease. Hepatology 66, 1885–1893 (2017).

    Article  CAS  PubMed  Google Scholar 

  66. Petta, S. et al. MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 64, 682–690 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Abul-Husn, N. S. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J. Med. 378, 1096–1106 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wattacheril, J. et al. Genome-wide associations related to hepatic histology in nonalcoholic fatty liver disease in Hispanic boys. J. Pediatr. 190, 100–107 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Di Filippo, M. et al. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J. Hepatol. 61, 891–902 (2014).

    Article  PubMed  CAS  Google Scholar 

  70. Donati, B. & Valenti, L. Telomeres, NAFLD and chronic liver disease. Int. J. Mol. Sci. 17, 383 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Donati, B. et al. Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. Cancer Med. 6, 1930–1940 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Calado, R. T. et al. A spectrum of severe familial liver disorders associate with telomerase mutations. PLOS ONE 4, e7926 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Pericleous, M., Kelly, C., Wang, T., Livingstone, C. & Ala, A. Wolman’s disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol. Hepatol. 2, 670–679 (2017).

    Article  PubMed  Google Scholar 

  74. Eslam, M., Valenti, L. & Romeo, S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J. Hepatol. 68, 268–279 (2018).

    Article  CAS  PubMed  Google Scholar 

  75. Bruce, K. D. et al. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression. Hepatology 50, 1796–1808 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Bugianesi, E. et al. Low birthweight increases the likelihood of severe steatosis in pediatric non-alcoholic fatty liver disease. Am. J. Gastroenterol. 112, 1277–1286 (2017).

    Article  PubMed  Google Scholar 

  77. Nobili, V. et al. Intrauterine growth retardation, insulin resistance, and nonalcoholic fatty liver disease in children. Diabetes Care 30, 2638–2640 (2007).

    Article  PubMed  Google Scholar 

  78. Suomela, E. et al. Childhood predictors of adult fatty liver. The Cardiovascular Risk in Young Finns Study. J. Hepatol. 65, 784–790 (2016).

    Article  PubMed  Google Scholar 

  79. Valenti, L. & Romeo, S. Destined to develop NAFLD? The predictors of fatty liver from birth to adulthood. J. Hepatol. 65, 668–670 (2016).

    Article  PubMed  Google Scholar 

  80. Murphy, S. K. et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 145, 1076–1087 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Kitamoto, T. et al. Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with non-alcoholic fatty liver disease. J. Hepatol. 63, 494–502 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Cheung, O. et al. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 48, 1810–1820 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Hsu, S. H. et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J. Clin. Invest. 122, 2871–2883 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Csak, T. et al. microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. Liver. Int. 35, 532–541 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Pirola, C. J. et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 64, 800–812 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Brandt, S. et al. Circulating levels of miR-122 and nonalcoholic fatty liver disease in pre-pubertal obese children. Pediatr. Obes. 13, 175–182 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Liu, C. H. et al. mi-RNAs in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis. J. Hepatol. 69, 1335–1348 (2018).

    Article  CAS  PubMed  Google Scholar 

  88. Valenti, L. & Dongiovanni, P. Mutant PNPLA3 I148M protein as pharmacological target for liver disease. Hepatology 66, 1026–1028 (2017).

    Article  CAS  PubMed  Google Scholar 

  89. Vos, M. B. 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. 64, 319–334 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2018).

    Article  PubMed  Google Scholar 

  91. Vuppalanchi, R. et al. Effects of liver biopsy sample length and number of readings on sampling variability in nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 7, 481–486 (2009).

    Article  PubMed  Google Scholar 

  92. Younossi, Z. M. et al. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. Mod. Pathol. 11, 560–565 (1998).

    CAS  PubMed  Google Scholar 

  93. 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 

  94. Berardis, S. & Sokal, E. Pediatric non-alcoholic fatty liver disease: an increasing public health issue. Eur. J. Pediatr. 173, 131–139 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  96. Kleiner, D. E. & Makhlouf, H. R. Histology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children. Clin. Liver Dis. 20, 293–312 (2016).

    Article  PubMed  Google Scholar 

  97. 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 

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

    Article  PubMed  Google Scholar 

  99. Swiderska-Syn, M. et al. Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology 57, 1814–1825 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. 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 

  101. 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 

  102. Alkhouri, N. et al. Development and validation of a new histological score for pediatric non-alcoholic fatty liver disease. J. Hepatol. 57, 1312–1318 (2012).

    Article  PubMed  Google Scholar 

  103. 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  PubMed  PubMed Central  CAS  Google Scholar 

  104. 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 

  105. Feldstein, A. E. et al. Hepatocyte apoptosis and Fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125, 437–443 (2003).

    Article  PubMed  Google Scholar 

  106. 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 

  107. Vuppalanchi, R. et al. Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 12, 2121–2130 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lei, H. et al. Diagnostic value of CK-18, FGF-21, and related biomarker panel in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Biomed. Res. Int. 2017, 9729107 (2017).

    Google Scholar 

  109. Perito, E. R. et al. Association between cytokines and liver histology in children with nonalcoholic fatty liver disease. Hepatol. Commun. 1, 609–622 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Fain, J. N. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm. 2010, 513948 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Hernaez, R. et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 54, 1082–1090 (2011).

    Article  PubMed  Google Scholar 

  112. Shannon, A. et al. Ultrasonographic quantitative estimation of hepatic steatosis in children with NAFLD. J. Pediatr. Gastroenterol. Nutr. 53, 190–195 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Akcam, M., Boyaci, A., Pirgon, O., Koroglu, M. & Dundar, B. N. Importance of the liver ultrasound scores in pubertal obese children with nonalcoholic fatty liver disease. Clin. Imaging 37, 504–508 (2013).

    Article  PubMed  Google Scholar 

  114. Schwimmer, J. B. et al. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology 61, 1887–1895 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Middleton, M. S. et al. Diagnostic accuracy of magnetic resonance imaging hepatic proton density fat fraction in pediatric nonalcoholic fatty liver disease. Hepatology 67, 858–872 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Mikolasevic, I. et al. Transient elastography (FibroScan®) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease — where do we stand? World J. Gastroenterol. 22, 7236–7251 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Kumar, R. et al. Liver stiffness measurements in patients with different stages of nonalcoholic fatty liver disease: diagnostic performance and clinicopathological correlation. Dig. Dis. Sci. 58, 265–274 (2013).

    Article  PubMed  Google Scholar 

  118. 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 

  119. Cho, Y. et al. Transient elastography-based liver profiles in a hospital-based pediatric population in Japan. PLOS ONE 10, e0137239 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Schwimmer, J. B. et al. Magnetic resonance elastography measured shear stiffness as a biomarker of fibrosis in pediatric nonalcoholic fatty liver disease. Hepatology 66, 1474–1485 (2017).

    Article  CAS  PubMed  Google Scholar 

  121. Mansoor, S., Collyer, E. & Alkhouri, N. A comprehensive review of noninvasive liver fibrosis tests in pediatric nonalcoholic fatty liver disease. Curr. Gastroenterol. Rep. 17, 23 (2015).

    Article  PubMed  Google Scholar 

  122. Nobili, V. et al. 360-degree overview of paediatric NAFLD: recent insights. J. Hepatol. 58, 1218–1229 (2013).

    Article  PubMed  Google Scholar 

  123. Hannah, W. N. Jr. & Harrison, S. A. Effect of weight loss, diet, exercise, and bariatric surgery on nonalcoholic fatty liver disease. Clin. Liver Dis. 20, 339–350 (2016).

    Article  PubMed  Google Scholar 

  124. Prokopowicz, Z., Malecka-Tendera, E. & Matusik, P. Predictive value of adiposity level, metabolic syndrome, and insulin resistance for the risk of nonalcoholic fatty liver disease diagnosis in obese children. Can. J. Gastroenterol. Hepatol. 2018, 9465784 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  125. DeVore, S. et al. A multidisciplinary clinical program is effective in stabilizing BMI and reducing transaminase levels in pediatric patients with NAFLD. J. Pediatr. Gastroenterol. Nutr. 57, 119–123 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Vilar-Gomez, E. et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149, 367–378 (2015).

    Article  PubMed  Google Scholar 

  127. Nobili, V. et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 48, 119–128 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Mameli, C. et al. Effects of a multidisciplinary weight loss intervention in overweight and obese children and adolescents: 11 years of experience. PLOS ONE 12, e0181095 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. van der Heijden, L. B., Feskens, E. J. M. & Janse, A. Maintenance interventions for overweight or obesity in children: a systematic review and meta-analysis. J. Obes. Rev. 19, 798–809 (2018).

    Article  Google Scholar 

  130. Anania, C., Perla, F. M., Olivero, F., Pacifico, L. & Chiesa, C. Mediterranean diet and nonalcoholic fatty liver disease. World J. Gastroenterol. 24, 2083–2094 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Michalsky, M. et al. ASMBS pediatric committee best practice guidelines. Surg. Obes. Relat. Dis. 8, 1–7 (2012).

    Article  PubMed  Google Scholar 

  132. Inge, T. H. et al. Perioperative outcomes of adolescents undergoing bariatric surgery: the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. JAMA Pediatr. 168, 47–53 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Manco, M. et al. The benefit of sleeve gastrectomy in obese adolescents on nonalcoholic steatohepatitis and hepatic fibrosis. J. Pediatr. 180, 31–37 (2017).

    Article  PubMed  Google Scholar 

  134. 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 

  135. Klein, E. A. et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306, 1549–1556 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Miller, E. R. et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann. Intern. Med. 142, 37–46 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. 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 

  138. Nobili, V. et al. Docosahexaenoic acid for the treatment of fatty liver: randomised controlled trial in children. Nutrition, metabolism, and cardiovascular diseases. Nutr. Metab. Cardiovasc. Dis. 23, 1066–1070 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Pacifico, L. 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. 25, 734–741 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. Janczyk, W. et al. Omega-3 fatty acids therapy in children with nonalcoholic fatty liver disease: a randomized controlled trial. J. Pediatr. 166, 1358–1363 (2015).

    Article  CAS  PubMed  Google Scholar 

  141. 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 16, 957–960 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Vajro, P. et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J. Pediatr. Gastroenterol. Nutr. 52, 740–743 (2011).

    Article  PubMed  Google Scholar 

  143. Alisi, A. et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 39, 1276–1285 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 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. 64, 413–417 (2017).

    Article  CAS  PubMed  Google Scholar 

  145. Ratziu, V. et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147–1159 (2016).

    Article  CAS  PubMed  Google Scholar 

  146. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02704403 (2019).

  147. Alawad, A. S. & Levy, C. FXR agonists: from bench to bedside, a guide for clinicians. Dig. Dis. Sci. 61, 3395–3404 (2016).

    Article  PubMed  Google Scholar 

  148. Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).

    Article  CAS  PubMed  Google Scholar 

  149. Kefala, G. & Tziomalos, K. Apoptosis signal-regulating kinase-1 as a therapeutic target in nonalcoholic fatty liver disease. Expert. Rev. Gastroenterol. Hepatol. 13, 189–191 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03053050 (2019).

  151. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03053063 (2019).

  152. Gilead Sciences. Gilead announces topline data from phase 3 STELLAR-4 study of selonsertib in compensated cirrhosis (F4) due to nonalcoholic steatohepatitis (NASH). GILEAD https://www.gilead.com/news-and-press/press-room/press-releases/2019/2/gilead-announces-topline-data-from-phase-3-stellar4-study-of-selonsertib-in-compensated-cirrhosis-f4-due-to-nonalcoholic-steatohepatitis-nash (2019).

  153. Gilead Sciences. Gilead announces topline data from phase 3 STELLAR-3 study of selonsertib in bridging fibrosis (F3) due to nonalcoholic steatohepatitis (NASH). GILEAD https://www.gilead.com/news-and-press/press-room/press-releases/2019/4/gilead-announces-topline-data-from-phase-3-stellar3-study-of-selonsertib-in-bridging-fibrosis-f3-due-to-nonalcoholic-steatohepatitis-nash (2019).

  154. Seki, E. et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 50, 185–197 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. Friedman, S. L. et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 67, 1754–1767 (2018).

    Article  CAS  PubMed  Google Scholar 

  156. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03028740 (2019).

  157. Safadi, R. et al. The fatty acid-bile acid conjugate aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 12, 2085–2091 (2014).

    Article  CAS  PubMed  Google Scholar 

  158. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02279524 (2018).

  159. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03467217 (2019).

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Author notes

  1. Deceased: Valerio Nobili.

Authors and Affiliations

  1. Hepato-Gastroenterology Disease Unit, “Bambino Gesù’’ Children’s Hospital IRCCS, Rome, Italy

    Valerio Nobili

  2. Department of Pediatrics, University “La Sapienza”, Rome, Italy

    Valerio Nobili

  3. Research Unit of Molecular Genetics of Complex Phenotypes, “Bambino Gesù” Children’s Hospital IRCCS, Rome, Italy

    Anna Alisi

  4. Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS C’a Granda Ospedale Maggiore Policlinico, Milan, Italy

    Luca Valenti

  5. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

    Luca Valenti

  6. Area Medicina Interna, Gastroenterologia e Oncologia Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

    Luca Miele

  7. Department of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy

    Luca Miele

  8. Department of Pediatrics, University of California, San Diego, CA, USA

    Ariel E. Feldstein

  9. Texas Liver Institute, UT Health San Antonio, San Antonio, TX, USA

    Naim Alkhouri

Authors
  1. Valerio Nobili
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  2. Anna Alisi
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All authors contributed equally to this article.

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Correspondence to Anna Alisi.

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Dedication

We wish to dedicate this article to the memory of Valerio Nobili, who died prematurely and unexpectedly after its acceptance, and to whom we are all profoundly indebted, not only for conceiving this manuscript, but most importantly for his significant personal contribution to the recent advancements in the field that are here described and for his friendship.

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Nobili, V., Alisi, A., Valenti, L. et al. NAFLD in children: new genes, new diagnostic modalities and new drugs. Nat Rev Gastroenterol Hepatol 16, 517–530 (2019). https://doi.org/10.1038/s41575-019-0169-z

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