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Review

Pediatric NAFLD: an overview and recent developments in diagnostics and treatment

, &
Pages 447-461 | Received 30 Oct 2018, Accepted 12 Mar 2019, Published online: 04 Apr 2019

References

  • 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):700–713.
  • Anderson EL, Howe LD, Jones HE, et al. The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis. PLoS One. 2015;10(10):e0140908.
  • Miele L, Targher G. Understanding the association between developing a fatty liver and subsequent cardio-metabolic complications. Expert Rev Gastroenterol Hepatol. 2015;9(10):1243–1245.
  • Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547–555.
  • Younossi ZM, Tampi R, Priyadarshini M, et al. Burden of illness and economic model for patients with Non-Alcoholic Steatohepatitis (NASH) in the United States. Hepatology. 2019;69(2):564-572.
  • Mencin AA, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Pediatr Clin North Am. 2011;58(6):1375–1392.
  • Schwimmer JB, Deutsch R, Kahen T, et al. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118(4):1388–1393.
  • Schwimmer JB, Newton KP, Awai HI, et al. Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2013;38(10):1267–1277.
  • Nobili V, Reale A, Alisi A, et al. Elevated serum ALT in children presenting to the emergency unit: relationship with NAFLD. Dig Liver Dis. 2009;41(10):749–752.
  • Patton HM, Yates K, Unalp-Arida A, et al. Association between metabolic syndrome and liver histology among children with nonalcoholic Fatty liver disease. Am J Gastroenterol. 2010;105(9):2093–2102.
  • Armstrong MJ, Adams LA, Canbay A, et al. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology. 2014;59(3):1174–1197.
  • Newton KP, Hou J, Crimmins NA, et al. Prevalence of prediabetes and Type 2 diabetes in children with nonalcoholic fatty liver disease. JAMA Pediatr. 2016;170(10):e161971.
  • Suzuki A, Abdelmalek MF, Schwimmer JB, et al. Association between puberty and features of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012;10(7):786–794.
  • Barshop NJ, Sirlin CB, Schwimmer JB, et al. Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;28(1):1188–1198.
  • Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):794–799.
  • Benedict M, Zhang X. Non-alcoholic fatty liver disease: an expanded review. World J Hepatol. 2017;9(16):715.
  • Nobili V, Cutrera R, Liccardo D, et al. Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance. Am J Respir Crit Care Med. 2014;189(1):666–673.
  • Yuan X, Waterworth D, Perry JR, et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet. 2008;83(4):520–528.
  • He S, McPhaul C, Li JZ, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010;285(9):6706–6715.
  • Kumari M, Schoiswohl G, Chitraju C, et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab. 2012;15(5):691–702.
  • Uygun A, Ozturk K, Demirci H, et al. The association of nonalcoholic fatty liver disease with genetic polymorphisms: a multicenter study. Eur J Gastroenterol Hepatol. 2017;29(4):441–447.
  • Sookoian S, Pirola CJ. 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. 2011;53(6):1883–1894.
  • Liu YL, Reeves HL, Burt AD, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:4309
  • Grandone A, Cozzolino D, Marzuillo P, et al. TM6SF2 Glu167Lys polymorphism is associated with low levels of LDL-cholesterol and increased liver injury in obese children. Pediatr Obes. 2016;11(2):115–119.
  • Santoro N, Zhang CK, Zhao H, et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology. 2012;55(3):781–789.
  • 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(4):869–874.
  • Petta S, Miele L, Bugianesi E, et al. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLoS One. 2014;9(2):e87523.
  • Umano GR, Caprio S, Di Sessa A, et al. The rs626283 variant in the MBOAT7 gene is associated with insulin resistance and fatty liver in Caucasian Obese Youth. Am J Gastroenterol. 2018;113(3):376-383.
  • Dongiovanni P, Valenti L, Rametta R, 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. 2010;59(2):267–273.
  • Miele L, Beale G, Patman G, et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology. 2008;135(1):282–291.e1.
  • Al-Serri A, Anstee QM, Valenti L, et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies. J Hepatol. 2012;56(2):448–454.
  • Dai D, Wen F, Zhou S, et al. Association of MTTP gene variants with pediatric NAFLD: a candidate-gene-based analysis of single nucleotide variations in obese children. PLoS One. 2017;12(9):e0185396.
  • Marzuillo P, Grandone A, Conte M, et al. Novel association between a nonsynonymous variant (R270H) of the G-protein-coupled receptor 120 and liver injury in children and adolescents with obesity. J Pediatr Gastroenterol Nutr. 2014;59(4):472–475.
  • 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):1538–1544.
  • Molleston JP, White F, Teckman J, et al. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol. 2002;97(9):752–755.
  • Alkhouri N, Hanouneh IA, Zein NN, et al. Liver transplantation for nonalcoholic steatohepatitis in young patients. Transpl Int. 2016;29(4):418–424.
  • Nobili V, Alisi A, Grimaldi C, et al. Non-alcoholic fatty liver disease and hepatocellular carcinoma in a 7-year-old obese boy: coincidence or comorbidity? Pediatr Obes. 2014;9(5):e99-e102.
  • Mann JP, Vreugdenhil A, Socha P, et al. European paediatric non-alcoholic fatty liver disease registry (EU-PNAFLD): design and rationale. Contemp Clin Trials. 2018;75:67–71.
  • Barritt AST, Gitlin N, Klein S, et al. Design and rationale for a real-world observational cohort of patients with nonalcoholic fatty liver disease: the TARGET-NASH study. Contemp Clin Trials. 2017;61:33–38.
  • Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011;332(6037):173–174.
  • Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology. 2006;131(3):934–945.
  • Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology. 2016;150(8):1769–1777.
  • Puri P, Mirshahi F, Cheung O, et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology. 2008;134(2):2059–2069.
  • Ajith TA. Role of mitochondria and mitochondria-targeted agents in non-alcoholic fatty liver disease. Clin Exp Pharmacol Physiol. 2018;45(5):413-421.
  • Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol. 2018;68(2):280–295.
  • Bria A, Marda J, Zhou J, et al. Hepatic progenitor cell activation in liver repair. Liver Res. 2017;1(2):81–87.
  • Jensen T, Abdelmalek MF, Sullivan S, et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68:1063–1075.
  • Savard C, Tartaglione EV, Kuver R, et al. Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis. Hepatology. 2013;57(1):81–92.
  • Zhu L, Baker RD, Baker SS. Gut microbiome and nonalcoholic fatty liver diseases. Pediatr Res. 2015;77(1–2):245–251.
  • Marzuillo P, Grandone A, Perrone L, et al. Understanding the pathophysiological mechanisms in the pediatric non-alcoholic fatty liver disease: the role of genetics. World J Hepatol. 2015;7(11):1439.
  • Brunt EM, Tiniakos DG. Histopathology of nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16(42):5286.
  • Mahmood S, Inada N, Izumi A, et al. Wilson’s disease masquerading as nonalcoholic steatohepatitis. N Am J Med Sci. 2009;1(2):74-76.
  • Angulo P, Lindor KD. Non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2002;17(Suppl):S186-S190.
  • Molleston JP, Schwimmer JB, Yates KP, et al. Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr. 2014;164(4):807–810.
  • 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):1440–1447.
  • Carter-Kent C, Yerian LM, Brunt EM, et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology. 2009;50(4):1113–1120.
  • Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42(3):641–649.
  • 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):745–753.
  • Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898–1906.
  • Fukusato T, Fukushima J, Shiga J, et al. Interobserver variation in the histopathological assessment of nonalcoholic steatohepatitis. Hepatol Res. 2005;33(2):122–127.
  • Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology. 2009;49(3):1017–1044.
  • Rehm JL, Connor EL, Wolfgram PM, et al. Predicting hepatic steatosis in a racially and ethnically diverse cohort of adolescent girls. J Pediatr. 2014;165(2):1230–1235.e5.
  • Radetti G, Kleon W, Stuefer J, et al. Non-alcoholic fatty liver disease in obese children evaluated by magnetic resonance imaging. Acta Paediatr. 2006;95(7):833–837.
  • Burgert TS, Taksali SE, Dziura J, et al. Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab. 2006;91(11):4287–4294.
  • Koot BGP, Nobili V. Screening for non-alcoholic fatty liver disease in children: do guidelines provide enough guidance? Obes Rev. 2017;18:1050–1060.
  • Vos MB, Abrams SH, Barlow SE, et al. NASPGHAN clinical practice guideline for the diagnosis and treatment of nonalcoholic fatty liver disease in children. J Pediatr Gastroenterol Nutr. 2017;64(2):319-334.
  • Hh AK, Henderson J, Vanhoesen K, et al. Nonalcoholic fatty liver disease in children: a single center experience. Clin Gastroenterol Hepatol. 2008;6(7):799-802.
  • Manco M, Marcellini M, Devito R, et al. Metabolic syndrome and liver histology in paediatric non-alcoholic steatohepatitis. Int J Obes (Lond). 2008;32(2):381–387.
  • Patton HM, Lavine JE, Van Natta ML, et al. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology. 2008;135(6):1961–1971.e2.
  • He L, Deng L, Zhang Q, 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;2017:1–12.
  • Neuman MG, Cohen LB, Nanau RM. Biomarkers in nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol. 2014;28(11):e1-4.
  • Polyzos SA, Toulis KA, Goulis DG, et al. Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Metabolism. 2011;60(3):313–326.
  • Lebensztejn DM, Wierzbicka A, Socha P, et al. Cytokeratin-18 and hyaluronic acid levels predict liver fibrosis in children with non-alcoholic fatty liver disease. Acta Biochim Pol. 2011;58(4).
  • 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):181–187.
  • Manco M, Marcellini M, Giannone G, et al. Correlation of serum TNF-alpha levels and histologic liver injury scores in pediatric nonalcoholic fatty liver disease. Am J Clin Pathol. 2007;127(6):954–960.
  • Shi HB, Fu JF, Wang CL. Clinical value of hepatic fibrosis parameters and serum ferritin in obese children with nonalcoholic fatty liver disease. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2008;37(3):245-249.
  • Li YW, Zhu CL, Gao RT, et al. Determination and clinical significance of tissue inhibitors of metalloproteinase-1 and −2 in serum of children with nonalcoholic fatty liver disease. Zhongguo Dang Dai Er Ke Za Zhi. 2010;12(6):462–467.
  • Abdelaziz R, Elbasel M, Esmat S, et al. Tissue inhibitors of metalloproteinase-1 and 2 and obesity related non-alcoholic fatty liver disease: is there a relationship. Digestion. 2015;92(3):130–137.
  • 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):229–234.
  • Fitzpatrick E, Dew TK, Quaglia A, et al. Analysis of adipokine concentrations in paediatric non-alcoholic fatty liver disease. Pediatr Obes. 2012;7(6):471–479.
  • LITMUS. [cited 2018 Nov 17]. Available from: https://litmus-project.eu/about/.
  • Poynard T, Ratziu V, Naveau S, et al. The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis. Comp Hepatol. 2005;4:10.
  • Kotronen A, Peltonen M, Hakkarainen A, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137(3):865–872.
  • Lee JH, Kim D, Kim HJ, et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis. 2010;42(7):503–508.
  • Maffeis C, Banzato C, Rigotti F, et al. Biochemical parameters and anthropometry predict NAFLD in obese children. J.Pediatr.Gastroenterol.Nutr. 2011;53(6):590-593.
  • Koot BG, van der Baan-Slootweg OH, Bohte AE, et al. Accuracy of prediction scores and novel biomarkers for predicting nonalcoholic fatty liver disease in obese children. Obesity (Silver Spring). 2013;21(3):583–590.
  • Alkhouri N, McCullough AJ. Noninvasive diagnosis of NASH and liver fibrosis within the spectrum of NAFLD. Gastroenterol Hepatol. 2012;8(10):661-668.
  • Eng K, Lopez R, Liccardo D, et al. A non-invasive prediction model for non-alcoholic steatohepatitis in paediatric patients with non-alcoholic fatty liver disease. Dig Liver Dis. 2014;46(11):1008–1013.
  • Kumar R, Rastogi A, Sharma MK, et al. Liver stiffness measurements in patients with different stages of nonalcoholic fatty liver disease: diagnostic performance and clinicopathological correlation. Dig Dis Sci. 2013;58(1):265–274.
  • 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):150–155.e1.
  • 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):26–31.
  • Alkhouri N, Mansoor S, Giammaria P, et al. The development of the pediatric NAFLD fibrosis score (PNFS) to predict the presence of advanced fibrosis in children with nonalcoholic fatty liver disease. PLoS One. 2014;9(8):e104558.
  • 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.
  • Jackson JA, Konomi JV, Mendoza MV, et al. Performance of fibrosis prediction scores in paediatric non-alcoholic fatty liver disease. J Paediatr Child Health. 2018;54(2):172–176.
  • 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.
  • Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J (Clin Res Ed). 1986;292(6512):13–15.
  • Bohte AE, Koot BG, van der Baan-Slootweg OH, et al. US cannot be used to predict the presence or severity of hepatic steatosis in severely obese adolescents. Radiology. 2011;262(1):327-334.
  • Pacifico L, Celestre M, Anania C, et al. MRI and ultrasound for hepatic fat quantification: relationshipsto clinical and metabolic characteristics of pediatric nonalcoholic fatty liver disease. Acta Paediatr. 2007;96(4):542–547.
  • Pozzato C, Radaelli G, Dall’Asta C, et al. MRI in identifying hepatic steatosis in obese children and relation to ultrasonography and metabolic findings. J Pediatr Gastroenterol Nutr. 2008;47(4):493–499.
  • Draijer LG, Feddouli S, Bohte AE, et al. Comparison of diagnostic accuracy of screening tests ALT and ultrasound for pediatric non-alcoholic fatty liver disease. Eur J Pediatr. 2019. [Epub ahead of print].
  • Shannon A, Alkhouri N, Carter-Kent C, et al. Ultrasonographic quantitative estimation of hepatic steatosis in children With NAFLD. J Pediatr Gastroenterol Nutr. 2011;53(2):190–195.
  • Strauss S, Gavish E, Gottlieb P, et al. Interobserver and intraobserver variability in the sonographic assessment of fatty liver. AJR Am J Roentgenol. 2007;189(6):W320–W323.
  • Karlas T, Petroff D, Garnov N, et al. Non-invasive assessment of hepatic steatosis in patients with NAFLD using controlled attenuation parameter and 1H-MR spectroscopy. PLoS One. 2014;9(3):e91987.
  • Chan WK, Nik Mustapha NR, Mahadeva S. Controlled attenuation parameter for the detection and quantification of hepatic steatosis in nonalcoholic fatty liver disease. J Gastroenterol Hepatol. 2014;29(7):1470–1476.
  • Desai NK, Harney S, Raza R, et al. Comparison of controlled attenuation parameter and liver biopsy to assess hepatic steatosis in pediatric patients. J Pediatr. 2016;173:160–164.e1.
  • Noureddin M, Lam J, Peterson MR, et al. Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology. 2013;58(6):1930–1940.
  • Bohte AE, van Werven JR, Bipat S, et al. The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis. Eur Radiol. 2011;21(1):87–97.
  • Awai HI, Newton KP, Sirlin CB, et al. Evidence and recommendations for imaging liver fat in children, based on systematic review. Clin Gastroenterol Hepatol. 2014;12(5):765–773.
  • 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):8314–8321.
  • 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):1887–1895.
  • Rehm JL, Wolfgram PM, Hernando D, et al. Proton density fat-fraction is an accurate biomarker of hepatic steatosis in adolescent girls and young women. Eur Radiol. 2015;25(10):2921–2930.
  • Middleton MS, Van Natta ML, Heba ER, et al. Diagnostic accuracy of magnetic resonance imaging hepatic proton density fat fraction in pediatric nonalcoholic fatty liver disease. Hepatology. 2018;67(3):858–872.
  • Pavlides M, Banerjee R, Tunnicliffe EM, et al. Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. Liver Int. 2017;37(7):1788–1795.
  • Afdhal NH. Fibroscan (transient elastography) for the measurement of liver fibrosis. Gastroenterol Hepatol. 2012;8(9).605-607
  • Fitzpatrick E, Quaglia A, Vimalesvaran S, et al. Transient elastography is a useful noninvasive tool for the evaluation of fibrosis in paediatric chronic liver disease. J Pediatr Gastroenterol Nutr. 2013;56(1):72–76.
  • Nobili V, Vizzutti F, Arena U, et al. Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology. 2008;48(2):442–448.
  • Yoneda M, Yoneda M, Mawatari H, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). Dig Liver Dis. 2008;40(5):371–378.
  • Castera L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology. 2010;51(3).828-835
  • Myers RP, Pomier-Layrargues G, Kirsch R, et al. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology. 2012;55(1):199–208.
  • Chartampilas E. Imaging of nonalcoholic fatty liver disease and its clinical utility. Hormones (Athens). 2018;17(1):69–81.
  • Hanquinet S, Rougemont AL, Courvoisier D, et al. Acoustic radiation force impulse (ARFI) elastography for the noninvasive diagnosis of liver fibrosis in children. Pediatr Radiol. 2013;43(5):846–850.
  • Noruegas MJ, Matos H, Goncalves I, et al. Acoustic radiation force impulse-imaging in the assessment of liver fibrosis in children. Pediatr Radiol. 2012;42(2).201-204
  • Yin M, Talwalkar JA, Glaser KJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol. 2007;5(10):1207–1213.e2.
  • Huwart L, Sempoux C, Vicaut E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology. 2008;135(1):32–40.
  • Loomba R, Wolfson T, Ang B, et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology. 2014;60(6):2127–2128.
  • Kim D, Kim WR, Talwalkar JA, et al. Advanced fibrosis in nonalcoholic fatty liver disease: noninvasive assessment with MR elastography. Radiology. 2013;268(2):411–419.
  • Yoon JH, Lee JM, Joo I, et al. Hepatic fibrosis: prospective comparison of MR elastography and US shear-wave elastography for evaluation. Radiology. 2014;273(3):772–782.
  • Xiao G, Zhu S, Xiao X, et al. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis. Hepatology. 2017;66(5):1486–1501.
  • Schwimmer JB, Behling C, Angeles JE, et al. Magnetic resonance elastography measured shear stiffness as a biomarker of fibrosis in pediatric nonalcoholic fatty liver disease. Hepatology. 2017;66(5):1474–1485.
  • 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):807–810.
  • Nasr P, Hilliges A, Thorelius L, et al. Contrast-enhanced ultrasonography could be a non-invasive method for differentiating none or mild from severe fibrosis in patients with biopsy proven non-alcoholic fatty liver disease. Scand J Gastroenterol. 2016;51(9):1126–1132.
  • Smits LP, Coolen BF, Panno MD, et al. Noninvasive differentiation between hepatic steatosis and steatohepatitis with mr imaging enhanced with USPIOs in patients with nonalcoholic fatty liver disease: a proof-of-concept study. Radiology. 2016;278(3):782–791.
  • Bastati N, Feier D, Wibmer A, et al. Noninvasive differentiation of simple steatosis and steatohepatitis by using gadoxetic acid-enhanced MR imaging in patients with nonalcoholic fatty liver disease: a proof-of-concept study. Radiology. 2014;271(3):739–747.
  • Sevastianova K, Hakkarainen A, Kotronen A, et al. Nonalcoholic fatty liver disease: detection of elevated nicotinamide adenine dinucleotide phosphate with in vivo 3.0-T 31P MR spectroscopy with proton decoupling. Radiology. 2010;256(2):466–473.
  • Kawamura Y, Saitoh S, Arase Y, et al. Three-dimensional magnetic resonance imaging for stringent diagnosis of advanced fibrosis associated with nonalcoholic steatohepatitis. Hepatol Int. 2013;7(3):850–858.
  • Koot BG, van der Baan-Slootweg OH, Tamminga-Smeulders CL, et al. Lifestyle intervention for non-alcoholic fatty liver disease: prospective cohort study of its efficacy and factors related to improvement. Arch Dis Child. 2011;96(7):669–674.
  • Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121–129.
  • Reinehr T, Schmidt C, Toschke AM, et al. Lifestyle intervention in obese children with non-alcoholic fatty liver disease: 2-year follow-up study. Arch Dis Child. 2009;94(6):437–442.
  • 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):458–465.
  • Gronbaek H, Lange A, Birkebaek NH, et al. Effect of a 10-week weight loss camp on fatty liver disease and insulin sensitivity in obese Danish children. J Pediatr Gastroenterol Nutr. 2012;54(2):223–228.
  • de Piano A, Prado WL, Caranti DA, et al. Metabolic and nutritional profile of obese adolescents with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2007;44(4):446–452.
  • Nobili V, Manco M, Devito R, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology. 2008;48(1):119–128.
  • Tock L, Prado WL, Caranti DA, et al. Nonalcoholic fatty liver disease decrease in obese adolescents after multidisciplinary therapy. Eur J Gastroenterol Hepatol. 2006;18(12):483–491.
  • Medrano M, Cadenas-Sanchez C, Alvarez-Bueno C, et al. Evidence-based exercise recommendations to reduce hepatic fat content in youth- a systematic review and meta-analysis. Prog Cardiovasc Dis. 2018;61:222–231.
  • Goldschmidt I, Di Nanni A, Streckenbach C, et al. Improvement of BMI after lifestyle intervention is associated with normalisation of elevated ELF score and liver stiffness in obese children. Biomed Res Int. 2015;2015:1–8.
  • McCurdy LE, Winterbottom KE, Mehta SS, et al. Using nature and outdoor activity to improve children’s health. Curr Probl Pediatr Adolesc Health Care. 2010;40(5).102-117.
  • Gonzalez-Ruiz K, Ramirez-Velez R, Correa-Bautista JE, et al. The effects of exercise on abdominal fat and liver enzymes in pediatric obesity: a systematic review and meta-analysis. Child Obes. 2017;13(4):443–454.
  • Mahady SE, George J. Exercise and diet in the management of nonalcoholic fatty liver disease. Metabolism. 2016;65(8):1172–1182.
  • Younossi ZM, Reyes MJ, Mishra A, et al. Systematic review with meta-analysis: non-alcoholic steatohepatitis – a case for personalised treatment based on pathogenic targets. Aliment Pharmacol Ther. 2014;39(1):3–14.
  • Eckard C, Cole R, Lockwood J, et al. Prospective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial. Therap Adv Gastroenterol. 2013;6(4):249–259.
  • Saha S, Carlsson KS, Gerdtham UG, et al. Are lifestyle interventions in primary care cost-effective? – an analysis based on a Markov model, differences-in-differences approach and the Swedish Bjorknas study. PLoS One. 2013;8(11):e80672.
  • Tsai AG, Wadden TA, Volger S, et al. Cost-effectiveness of a primary care intervention to treat obesity. Int J Obes (Lond). 2013;37(Suppl 1):382–389.
  • 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.
  • Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–1685.
  • Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–357.
  • 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;2013(11).1276-1285.
  • 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):740–743.
  • Dohil R, Schmeltzer S, Cabrera BL, et al. Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2011;33(9):1036–1044.
  • Mitchel EB, Lavine JE. Review article: the management of paediatric nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2014;40(10):123–132.
  • Janczyk W, Lebensztejn 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):531–7.e13.
  • Liyanagedera S, Williams RP, Veraldi S, et al. The pharmacological management of NAFLD in children and adolescents. Expert Rev Clin Pharmacol. 2017;10(11):1225–1237.
  • Nadeau KJ, Ehlers LB, Zeitler PS, et al. Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. Pediatr Diabetes. 2009;10(1):5–13.
  • Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–965.
  • Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(5):1147–1159.e5.
  • Loomba R, Lawitz E, Mantry PS, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology. 2017
  • Neokosmidis G, Tziomalos K. Role of cenicriviroc in the management of nonalcoholic fatty liver disease. World J Gastroenterol. 2018;24(48):5415–5417.
  • Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut. 2017;66(1):180–190.
  • Javor ED, Ghany MG, Cochran EK, et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology. 2005;41(4):753–760.
  • Vos MB, Jin R, Konomi JV, et al. A randomized, controlled, crossover pilot study of losartan for pediatric nonalcoholic fatty liver disease. Pilot Feasibility Stud. 2018;4.
  • Bower G, Toma T, Harling L, et al. Bariatric surgery and non-alcoholic fatty liver disease: a systematic review of liver biochemistry and histology. Obes Surg. 2015;25(12):2280–2289.
  • 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.
  • 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):550–561.

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