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Advances in Pediatrics

Pediatric Nonalcoholic Fatty Liver Disease: A Comprehensive Review

  • Sarah M. Lindbäck
    Affiliations
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, 200 West Arbor Drive, San Diego, CA 92103-8450, USA
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  • Charles Gabbert
    Affiliations
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, 200 West Arbor Drive, San Diego, CA 92103-8450, USA

    Department of Medicine, University of California, San Diego School of Medicine, 9500 Gilman Drive La Jolla, CA 92093-0671, USA
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  • Benjamin L. Johnson
    Affiliations
    Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, 200 West Arbor Drive San Diego, CA 92103, USA
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  • Emmanuil Smorodinsky
    Affiliations
    Department of Medicine, University of California, San Diego School of Medicine, 9500 Gilman Drive La Jolla, CA 92093-0671, USA

    Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, 200 West Arbor Drive San Diego, CA 92103, USA
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  • Claude B. Sirlin
    Affiliations
    Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, 200 West Arbor Drive San Diego, CA 92103, USA
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  • Natalie Garcia
    Affiliations
    Department of Medicine, University of California, San Diego School of Medicine, 9500 Gilman Drive La Jolla, CA 92093-0671, USA
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  • Perrie E. Pardee
    Affiliations
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, 200 West Arbor Drive, San Diego, CA 92103-8450, USA
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  • Kristin D. Kistler
    Affiliations
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, 200 West Arbor Drive, San Diego, CA 92103-8450, USA
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  • Jeffrey B. Schwimmer
    Correspondence
    Corresponding author. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103-8450.
    Affiliations
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, 200 West Arbor Drive, San Diego, CA 92103-8450, USA

    Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, 200 West Arbor Drive San Diego, CA 92103, USA

    Department of Gastroenterology, Rady Children’s Hospital San Diego, 3020 Children's Way - MC 5030 San Diego, CA 92123, USA
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      Nonalcoholic fatty liver disease (NAFLD) rapidly emerged from a relatively unknown condition to become the most common form of chronic liver disease in the pediatric population. This change was due in large part to the rapid, widespread increase in child and adolescent overweight and obesity. Not only is obesity a major risk factor for NAFLD, but the intensive investigation of obesity advanced the knowledge base for many comorbidities of obesity including NAFLD. The phenotype of NAFLD has both overlapping and nonoverlapping elements with obesity, and these are described in this article. In its progressive form, nonalcoholic steatohepatitis (NASH), some children will develop cirrhosis and end-stage liver disease. NAFLD also is a risk factor for adverse cardiovascular, endocrine, and psychological outcomes. The aim of this review is to provide a comprehensive understanding of the current knowledge on NAFLD in children and adolescents. Increased attention is given to those with the most recent advances in key aspects including diagnosis (histopathology, biomarkers, imaging), epidemiology, pathogenesis, clinical presentation, and treatment. A concise, practical guide to pediatric NAFLD may be found in Box 1.
      Summary of key points as a guide for the general pediatrician
      • Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver pathology ranging from isolated steatosis to steatohepatitis to cirrhosis in the absence of other infectious or autoimmune etiology
      • Signs and Symptoms
        • May be asymptomatic but often will have some level of abdominal pain, irritability, and/or fatigue
        • Quality of life often lower than healthy children
        • Notable physical examination features can include obesity, hepatomegaly, acanthosis nigricans, and hypertension
      • Laboratory Evaluation
        • Initial screening includes alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
      • Differential Diagnosis
        • Viral hepatitis, Wilson disease, α1-antitrypsin deficiency, autoimmune hepatitis, medication toxicity
      • Diagnosis
        • Histology is critically important in making an accurate diagnosis and monitoring disease progression
        • Diagnosis requires at least ≥5% hepatocytes with macrovesicular steatosis and exclusion of other liver diseases
        • Noninvasive tests (biochemistry, imaging) are not sufficient alone or in combination for the diagnosis of NAFLD
      • Screening
        • Expert Committee Guidelines recommend screening AST and ALT for obese children as well as for overweight children with additional risk factors
        • Children diagnosed with NAFLD should be screened for other comorbid disorders including dyslipidemia, diabetes mellitus, hypertension, and obstructive sleep apnea
      • Risk Factors & Outcomes
        • Children with NAFLD may progress to end-stage liver disease and/or hepatocellular carcinoma (HCC)
        • When cirrhosis is present, screening for HCC is recommended and is best done by magnetic resonance imaging (MRI)
        • Children with NAFLD are at increased risk for cardiovascular disease and type 2 diabetes
      • Treatment
        • Lifestyle optimization including healthy diet and adequate physical activity are universally recommended
        • Pharmacologic approaches to treatment are under active investigation
        • Weight loss surgery can be an important element of therapy for some adolescents; however, optimal timing of surgical intervention (age and disease severity) remains to be determined
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      References

        • Brunt E.M.
        Pathology of fatty liver disease.
        Mod Pathol. 2007; 20: S40-S48
        • Matteoni C.A.
        • Younossi Z.M.
        • Gramlich T.
        • et al.
        Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
        Gastroenterology. 1999; 116: 1413-1419
        • Brunt E.M.
        Nonalcoholic steatohepatitis: definition and pathology.
        Semin Liver Dis. 2001; 21: 3-16
        • Brunt E.M.
        • Janney C.G.
        • Di Bisceglie A.M.
        • et al.
        Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.
        Am J Gastroenterol. 1999; 94: 2467-2474
        • Kleiner D.E.
        • Brunt E.M.
        • Van Natta M.
        • et al.
        Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
        Hepatology. 2005; 41: 1313-1321
        • Mendler M.H.
        • Kanel G.
        • Govindarajan S.
        Proposal for a histological scoring and grading system for non-alcoholic fatty liver disease.
        Liver Int. 2005; 25: 294-304
        • Promrat K.
        • Lutchman G.
        • Uwaifo G.I.
        • et al.
        A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis.
        Hepatology. 2004; 39: 188-196
        • Brunt E.M.
        Nonalcoholic steatohepatitis.
        Semin Liver Dis. 2004; 24: 3-20
        • Chalasani N.
        • Wilson L.
        • Kleiner D.E.
        • et al.
        Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease.
        J Hepatol. 2008; 48: 829-834
        • Schaff Z.
        • Lapis K.
        Fine structure of hepatocytes during the etiology of several common pathologies.
        J Electron Microsc Tech. 1990; 14: 179-207
        • Lackner C.
        • Gogg-Kamerer M.
        • Zatloukal K.
        • et al.
        Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis.
        J Hepatol. 2008; 48: 821-828
        • Schwimmer J.B.
        • Behling C.
        • Newbury R.
        • et al.
        Histopathology of pediatric nonalcoholic fatty liver disease.
        Hepatology. 2005; 42: 641-649
        • Nobili V.
        • Marcellini M.
        • Devito R.
        • et al.
        NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice.
        Hepatology. 2006; 44: 458-465
        • Carter-Kent C.
        • Yerian L.M.
        • Brunt E.M.
        • et al.
        Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study.
        Hepatology. 2009; 50: 1113-1120
        • Ko J.S.
        • Yoon J.M.
        • Yang H.R.
        • et al.
        Clinical and histological features of nonalcoholic fatty liver disease in children.
        Dig Dis Sci. 2009; 54: 2225-2230
        • Xanthakos S.
        • Miles L.
        • Bucuvalas J.
        • et al.
        Histologic spectrum of nonalcoholic fatty liver disease in morbidly obese adolescents.
        Clin Gastroenterol Hepatol. 2006; 4: 226-232
        • Brunt E.M.
        • Kleiner D.E.
        • Wilson L.A.
        • 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. 2009; 49: 809-820
        • Adani G.L.
        • Baccarani U.
        • Sainz-Barriga M.
        • et al.
        The role of hepatic biopsy to detect macrovacuolar steatosis during liver procurement.
        Transplant Proc. 2006; 38: 1404-1406
        • Joy D.
        • Thava V.R.
        • Scott B.B.
        Diagnosis of fatty liver disease: is biopsy necessary?.
        Eur J Gastroenterol Hepatol. 2003; 15: 539-543
        • Longo R.
        • Pollesello P.
        • Ricci C.
        • et al.
        Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis.
        J Magn Reson Imaging. 1995; 5: 281-285
        • Lupsor M.
        • Badea R.
        Imaging diagnosis and quantification of hepatic steatosis: is it an accepted alternative to needle biopsy?.
        Rom J Gastroenterol. 2005; 14: 419-425
        • Smith E.H.
        Complications of percutaneous abdominal fine-needle biopsy.
        Radiology. 1991; 178 ([review]): 253-258
        • Schwimmer J.B.
        • Deutsch R.
        • Rauch J.B.
        • et al.
        Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease.
        J Pediatr. 2003; 143: 500-505
        • Nobili V.
        • Manco M.
        • Ciampalini P.
        • et al.
        Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease.
        Eur J Endocrinol. 2006; 155: 735-743
        • Patton H.M.
        • Lavine J.E.
        • Van Natta M.L.
        • et al.
        Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis.
        Gastroenterology. 2008; 135 (e1962): 1961-1971
        • Nobili V.
        • Alkhouri N.
        • Alisi A.
        • et al.
        Retinol-binding protein 4: a promising circulating marker of liver damage in pediatric nonalcoholic fatty liver disease.
        Clin Gastroenterol Hepatol. 2009; 7: 575-579
        • Poynard T.
        • Ratziu V.
        • Charlotte F.
        • et al.
        Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease.
        BMC Gastroenterol. 2006; 6: 34
        • Miele L.
        • Forgione A.
        • La Torre G.
        • et al.
        Serum levels of hyaluronic acid and tissue metalloproteinase inhibitor-1 combined with age predict the presence of nonalcoholic steatohepatitis in a pilot cohort of subjects with nonalcoholic fatty liver disease.
        Transl Res. 2009; 154: 194-201
        • Feldstein A.E.
        • Canbay A.
        • Angulo P.
        • et al.
        Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.
        Gastroenterology. 2003; 125: 437-443
        • Danial N.N.
        • Korsmeyer S.J.
        Cell death: critical control points.
        Cell. 2004; 116: 205-219
        • Wieckowska A.
        • Zein N.N.
        • Yerian L.M.
        • et al.
        In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease.
        Hepatology. 2006; 44: 27-33
        • Feldstein A.E.
        • Wieckowska A.
        • Lopez A.R.
        • et al.
        Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study.
        Hepatology. 2009; 50: 1072-1078
        • Mitry R.R.
        • De Bruyne R.
        • Quaglia A.
        • et al.
        Noninvasive diagnosis of nonalcoholic fatty liver disease using serum biomarkers.
        Hepatology. 2007; 46 (author reply 2048): 2047-2048
        • 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: 160-167
        • Yajima Y.
        • Ohta K.
        • Narui T.
        • et al.
        Ultrasonographical diagnosis of fatty liver: significance of the liver-kidney contrast.
        Tohoku J Exp Med. 1983; 139: 43-50
        • Zwiebel W.J.
        Sonographic diagnosis of diffuse liver disease.
        Semin Ultrasound CT MR. 1995; 16: 8-15
        • Karcaaltincaba M.
        • Akhan O.
        Imaging of hepatic steatosis and fatty sparing.
        Eur J Radiol. 2007; 61: 33-43
        • Saadeh S.
        • Younossi Z.M.
        • Remer E.M.
        • et al.
        The utility of radiological imaging in nonalcoholic fatty liver disease.
        Gastroenterology. 2002; 123: 745-750
        • Pacifico L.
        • Celestre M.
        • Anania C.
        • et al.
        MRI and ultrasound for hepatic fat quantification: relationships to clinical and metabolic characteristics of pediatric nonalcoholic fatty liver disease.
        Acta Paediatr. 2007; 96: 542-547
        • Graif M.
        • Yanuka M.
        • Baraz M.
        • et al.
        Quantitative estimation of attenuation in ultrasound video images: correlation with histology in diffuse liver disease.
        Invest Radiol. 2000; 35: 319-324
        • Joseph A.E.
        • Saverymuttu S.H.
        • al-Sam S.
        • et al.
        Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease.
        Clin Radiol. 1991; 43: 26-31
        • Mathiesen U.L.
        • Franzen L.E.
        • Aselius H.
        • et al.
        Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases.
        Dig Liver Dis. 2002; 34: 516-522
        • Saverymuttu S.H.
        • Joseph A.E.
        • Maxwell J.D.
        Ultrasound scanning in the detection of hepatic fibrosis and steatosis.
        Br Med J (Clin Res Ed). 1986; 292: 13-15
        • Ali R.
        • Cusi K.
        New diagnostic and treatment approaches in non-alcoholic fatty liver disease (NAFLD).
        Ann Med. 2009; 41: 265-278
        • Celle G.
        • Savarino V.
        • Picciotto A.
        • et al.
        Is hepatic ultrasonography a valid alternative tool to liver biopsy? Report on 507 cases studied with both techniques.
        Dig Dis Sci. 1988; 33: 467-471
        • Hepburn M.J.
        • Vos J.A.
        • Fillman E.P.
        • et al.
        The accuracy of the report of hepatic steatosis on ultrasonography in patients infected with hepatitis C in a clinical setting: a retrospective observational study.
        BMC Gastroenterol. 2005; 5: 14
        • Needleman L.
        • Kurtz A.B.
        • Rifkin M.D.
        • et al.
        Sonography of diffuse benign liver disease: accuracy of pattern recognition and grading.
        AJR Am J Roentgenol. 1986; 146: 1011-1015
        • 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: W320-W323
        • Bydder G.M.
        • Chapman R.W.
        • Harry D.
        • et al.
        Computed tomography attenuation values in fatty liver.
        J Comput Tomogr. 1981; 5: 33-35
        • Speliotes E.K.
        • Massaro J.M.
        • Hoffmann U.
        • et al.
        Liver fat is reproducibly measured using computed tomography in the Framingham Heart Study.
        J Gastroenterol Hepatol. 2008; 23: 894-899
        • Limanond P.
        • Raman S.S.
        • Lassman C.
        • et al.
        Macrovesicular hepatic steatosis in living related liver donors: correlation between CT and histologic findings.
        Radiology. 2004; 230: 276-280
        • Lee S.W.
        • Park S.H.
        • Kim K.W.
        • et al.
        Unenhanced CT for assessment of macrovesicular hepatic steatosis in living liver donors: comparison of visual grading with liver attenuation index.
        Radiology. 2007; 244: 479-485
        • Schwimmer J.B.
        Definitive diagnosis and assessment of risk for nonalcoholic fatty liver disease in children and adolescents.
        Semin Liver Dis. 2007; 27: 312-318
        • Hamer O.W.
        • Aguirre D.A.
        • Casola G.
        • et al.
        Fatty liver: imaging patterns and pitfalls.
        Radiographics. 2006; 26: 1637-1653
        • Siegelman E.S.
        • Rosen M.A.
        Imaging of hepatic steatosis.
        Semin Liver Dis. 2001; 21: 71-80
        • Mehta S.R.
        • Thomas E.L.
        • Bell J.D.
        • et al.
        Non-invasive means of measuring hepatic fat content.
        World J Gastroenterol. 2008; 14: 3476-3483
        • Cassidy F.H.
        • Yokoo T.
        • Aganovic L.
        • et al.
        Fatty liver disease: MR imaging techniques for the detection and quantification of liver steatosis.
        Radiographics. 2009; 29: 231-260
        • Longo R.
        • Ricci C.
        • Masutti F.
        • et al.
        Fatty infiltration of the liver. Quantification by 1H localized magnetic resonance spectroscopy and comparison with computed tomography.
        Invest Radiol. 1993; 28: 297-302
        • Thomsen C.
        • Becker U.
        • Winkler K.
        • et al.
        Quantification of liver fat using magnetic resonance spectroscopy.
        Magn Reson Imaging. 1994; 12: 487-495
        • Kim H.
        • Taksali S.E.
        • Dufour S.
        • et al.
        Comparative MR study of hepatic fat quantification using single-voxel proton spectroscopy, two-point Dixon and three-point IDEAL.
        Magn Reson Med. 2008; 59: 521-527
        • Thomas E.L.
        • Hamilton G.
        • Patel N.
        • et al.
        Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study.
        Gut. 2005; 54: 122-127
        • Browning J.D.
        • Szczepaniak L.S.
        • Dobbins R.
        • et al.
        Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.
        Hepatology. 2004; 40: 1387-1395
        • Szczepaniak L.S.
        • Nurenberg P.
        • Leonard D.
        • et al.
        Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population.
        Am J Physiol Endocrinol Metab. 2005; 288: E462-E468
        • Vuppalanchi R.
        • Cummings O.W.
        • Saxena R.
        • et al.
        Relationship among histologic, radiologic, and biochemical assessments of hepatic steatosis: a study of human liver samples.
        J Clin Gastroenterol. 2007; 41: 206-210
        • Bugianesi E.
        • Gentilcore E.
        • Manini R.
        • et al.
        A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease.
        Am J Gastroenterol. 2005; 100: 1082-1090
        • Carey D.G.
        • Cowin G.J.
        • Galloway G.J.
        • et al.
        Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients.
        Obes Res. 2002; 10: 1008-1015
        • Schwimmer J.B.
        • Middleton M.S.
        • Deutsch R.
        • et al.
        A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis.
        Aliment Pharmacol Ther. 2005; 21: 871-879
        • Hamilton G.
        • Middleton M.S.
        • Bydder M.
        • et al.
        Effect of PRESS and STEAM sequences on magnetic resonance spectroscopic liver fat quantification.
        J Magn Reson Imaging. 2009; 30: 145-152
        • Taouli B.
        • Ehman R.L.
        • Reeder S.B.
        Advanced MRI methods for assessment of chronic liver disease.
        AJR Am J Roentgenol. 2009; 193: 14-27
        • Dixon W.T.
        Simple proton spectroscopic imaging.
        Radiology. 1984; 153: 189-194
        • Sirlin C.B.
        Noninvasive imaging biomarkers for steatosis assessment.
        Liver Transpl. 2009; 15: 1389-1391
        • Mazhar S.M.
        • Shiehmorteza M.
        • Sirlin C.B.
        Noninvasive assessment of hepatic steatosis.
        Clin Gastroenterol Hepatol. 2009; 7: 135-140
        • Fishbein M.
        • Castro F.
        • Cheruku S.
        • et al.
        Hepatic MRI for fat quantitation: its relationship to fat morphology, diagnosis, and ultrasound.
        J Clin Gastroenterol. 2005; 39: 619-625
        • Kim S.H.
        • Lee J.M.
        • Han J.K.
        • et al.
        Hepatic macrosteatosis: predicting appropriateness of liver donation by using MR imaging—correlation with histopathologic findings.
        Radiology. 2006; 240: 116-129
        • Qayyum A.
        • Goh J.S.
        • Kakar S.
        • et al.
        Accuracy of liver fat quantification at MR imaging: comparison of out-of-phase gradient-echo and fat-saturated fast spin-echo techniques—initial experience.
        Radiology. 2005; 237: 507-511
        • Borra R.J.
        • Salo S.
        • Dean K.
        • et al.
        Nonalcoholic fatty liver disease: rapid evaluation of liver fat content with in-phase and out-of-phase MR imaging.
        Radiology. 2009; 250: 130-136
        • Fishbein M.H.
        • Gardner K.G.
        • Potter C.J.
        • et al.
        Introduction of fast MR imaging in the assessment of hepatic steatosis.
        Magn Reson Imaging. 1997; 15: 287-293
        • Hussain H.K.
        • Chenevert T.L.
        • Londy F.J.
        • et al.
        Hepatic fat fraction: MR imaging for quantitative measurement and display—early experience.
        Radiology. 2005; 237: 1048-1055
        • Bydder M.
        • Yokoo T.
        • Hamilton G.
        • et al.
        Relaxation effects in the quantification of fat using gradient echo imaging.
        Magn Reson Imaging. 2008; 26: 347-359
        • Liu C.Y.
        • McKenzie C.A.
        • Yu H.
        • et al.
        Fat quantification with IDEAL gradient echo imaging: correction of bias from T(1) and noise.
        Magn Reson Med. 2007; 58: 354-364
        • Yokoo T.
        • Bydder M.
        • Hamilton G.
        • et al.
        Nonalcoholic fatty liver disease: diagnostic and fat-grading accuracy of low-flip-angle multiecho gradient-recalled-echo MR imaging at 1.5 T.
        Radiology. 2009; 251: 67-76
        • Brix G.
        • Heiland S.
        • Bellemann M.E.
        • et al.
        MR imaging of fat-containing tissues: valuation of two quantitative imaging techniques in comparison with localized proton spectroscopy.
        Magn Reson Imaging. 1993; 11: 977-991
        • Reeder S.B.
        • Robson P.M.
        • Yu H.
        • et al.
        Quantification of hepatic steatosis with MRI: the effects of accurate fat spectral modeling.
        J Magn Reson Imaging. 2009; 29: 1332-1339
        • Yu H.
        • Shimakawa A.
        • McKenzie C.A.
        • et al.
        Multiecho water-fat separation and simultaneous R2* estimation with multifrequency fat spectrum modeling.
        Magn Reson Med. 2008; 60: 1122-1134
        • Hines C.D.
        • Yu H.
        • Shimakawa A.
        • et al.
        T1 independent, T2* corrected MRI with accurate spectral modeling for quantification of fat: validation in a fat-water-SPIO phantom.
        J Magn Reson Imaging. 2009; 30: 1215-1222
        • Huwart L.
        • Sempoux C.
        • Vicaut E.
        • et al.
        Magnetic resonance elastography for the noninvasive staging of liver fibrosis.
        Gastroenterology. 2008; 135: 32-40
        • Sandrin L.
        • Fourquet B.
        • Hasquenoph J.M.
        • et al.
        Transient elastography: a new noninvasive method for assessment of hepatic fibrosis.
        Ultrasound Med Biol. 2003; 29: 1705-1713
        • Yeh W.C.
        • Li P.C.
        • Jeng Y.M.
        • et al.
        Elastic modulus measurements of human liver and correlation with pathology.
        Ultrasound Med Biol. 2002; 28: 467-474
        • 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: 371-378
        • 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: 442-448
        • Fraquelli M.
        • Rigamonti C.
        • Casazza G.
        • et al.
        Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.
        Gut. 2007; 56: 968-973
        • Coco B.
        • Oliveri F.
        • Maina A.M.
        • et al.
        Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases.
        J Viral Hepat. 2007; 14: 360-369
        • Lebray P.
        • Varnous S.
        • Charlotte F.
        • et al.
        Liver stiffness is an unreliable marker of liver fibrosis in patients with cardiac insufficiency.
        Hepatology. 2008; 48: 2089
        • Ganne-Carrie N.
        • Ziol M.
        • de Ledinghen V.
        • et al.
        Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases.
        Hepatology. 2006; 44: 1511-1517
        • Ito K.
        • Mitchell D.G.
        • Siegelman E.S.
        Cirrhosis: MR imaging features.
        Magn Reson Imaging Clin N Am. 2002; 10 (vi): 75-92
        • Martin D.R.
        Magnetic resonance imaging of diffuse liver diseases.
        Top Magn Reson Imaging. 2002; 13: 151-163
        • Brancatelli G.
        • Federle M.P.
        • Ambrosini R.
        • et al.
        Cirrhosis: CT and MR imaging evaluation.
        Eur J Radiol. 2007; 61: 57-69
        • Aguirre D.A.
        • Behling C.A.
        • Alpert E.
        • et al.
        Liver fibrosis: noninvasive diagnosis with double contrast material-enhanced MR imaging.
        Radiology. 2006; 239: 425-437
        • Hughes-Cassidy F.
        • Chavez A.D.
        • Schlang A.
        • et al.
        Superparamagnetic iron oxides and low molecular weight gadolinium chelates are synergistic for direct visualization of advanced liver fibrosis.
        J Magn Reson Imaging. 2007; 26: 728-737
        • Faria S.C.
        • Ganesan K.
        • Mwangi I.
        • et al.
        MR imaging of liver fibrosis: current state of the art.
        Radiographics. 2009; 29: 1615-1635
        • Semelka R.C.
        • Chung J.J.
        • Hussain S.M.
        • et al.
        Chronic hepatitis: correlation of early patchy and late linear enhancement patterns on gadolinium-enhanced MR images with histopathology initial experience.
        J Magn Reson Imaging. 2001; 13: 385-391
        • Ide M.
        • Yamate J.
        • Machida Y.
        • et al.
        Emergence of different macrophage populations in hepatic fibrosis following thioacetamide-induced acute hepatocyte injury in rats.
        J Comp Pathol. 2003; 128: 41-51
        • Lieber C.S.
        Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis.
        Alcohol. 2004; 34: 9-19
        • Tanimoto A.
        • Yuasa Y.
        • Shinmoto H.
        • et al.
        Superparamagnetic iron oxide-mediated hepatic signal intensity change in patients with and without cirrhosis: pulse sequence effects and Kupffer cell function.
        Radiology. 2002; 222: 661-666
        • Hanna R.F.
        • Kased N.
        • Kwan S.W.
        • et al.
        Double-contrast MRI for accurate staging of hepatocellular carcinoma in patients with cirrhosis.
        AJR Am J Roentgenol. 2008; 190: 47-57
        • Bensamoun S.F.
        • Wang L.
        • Robert L.
        • et al.
        Measurement of liver stiffness with two imaging techniques: magnetic resonance elastography and ultrasound elastometry.
        J Magn Reson Imaging. 2008; 28: 1287-1292
        • Rouviere O.
        • Yin M.
        • Dresner M.A.
        • et al.
        MR elastography of the liver: preliminary results.
        Radiology. 2006; 240: 440-448
        • Yin M.
        • Talwalkar J.A.
        • Glaser K.J.
        • et al.
        Assessment of hepatic fibrosis with magnetic resonance elastography.
        Clin Gastroenterol Hepatol. 2007; 5 (e1202): 1207-1213
        • Talwalkar J.A.
        • Yin M.
        • Fidler J.L.
        • et al.
        Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications.
        Hepatology. 2008; 47: 332-342
        • Pardee P.E.
        • Lavine J.E.
        • Schwimmer J.B.
        Diagnosis and treatment of pediatric nonalcoholic steatohepatitis and the implications for bariatric surgery.
        Semin Pediatr Surg. 2009; 18: 144-151
        • Kahn C.R.
        • Flier J.S.
        • Bar R.S.
        • et al.
        The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man.
        N Engl J Med. 1976; 294: 739-745
        • Moller D.E.
        • Flier J.S.
        Insulin resistance—mechanisms, syndromes, and implications.
        N Engl J Med. 1991; 325: 938-948
        • Poretsky L.
        • Piper B.
        Insulin resistance, hypersecretion of LH, and a dual-defect hypothesis for the pathogenesis of polycystic ovary syndrome.
        Obstet Gynecol. 1994; 84: 613-621
        • Jeanrenaud B.
        Hyperinsulinemia in obesity syndromes: its metabolic consequences and possible etiology.
        Metabolism. 1978; 27: 1881-1892
        • Barrows B.R.
        • Parks E.J.
        Contributions of different fatty acid sources to very low-density lipoprotein-triacylglycerol in the fasted and fed states.
        J Clin Endocrinol Metab. 2006; 91: 1446-1452
        • Donnelly K.L.
        • Smith C.I.
        • Schwarzenberg S.J.
        • et al.
        Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
        J Clin Invest. 2005; 115: 1343-1351
        • Fabbrini E.
        • deHaseth D.
        • Deivanayagam S.
        • et al.
        Alterations in fatty acid kinetics in obese adolescents with increased intrahepatic triglyceride content.
        Obesity (Silver Spring). 2009; 17: 25-29
        • Boden G.
        • She P.
        • Mozzoli M.
        • et al.
        Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver.
        Diabetes. 2005; 54: 3458-3465
        • Cai D.
        • Yuan M.
        • Frantz D.F.
        • et al.
        Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
        Nat Med. 2005; 11: 183-190
        • Musso G.
        • Gambino R.
        • Cassader M.
        Non-alcoholic fatty liver disease from pathogenesis to management: an update.
        Obes Rev. 2010; 11: 430-445
        • Li Z.
        • Berk M.
        • McIntyre T.M.
        • et al.
        The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity.
        Hepatology. 2008; 47: 1495-1503
        • Connolly M.K.
        • Bedrosian A.S.
        • Mallen-St Clair J.
        • et al.
        In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha.
        J Clin Invest. 2009; 119: 3213-3225
        • Nieto N.
        Oxidative-stress and IL-6 mediate the fibrogenic effects of Kupffer cells on stellate cells.
        Hepatology. 2006; 44: 1487-1501
        • Wang J.
        • Leclercq I.
        • Brymora J.M.
        • et al.
        Kupffer cells mediate leptin-induced liver fibrosis.
        Gastroenterology. 2009; 137: 713-723
        • Louthan M.V.
        • Barve S.
        • McClain C.J.
        • et al.
        Decreased serum adiponectin: an early event in pediatric nonalcoholic fatty liver disease.
        J Pediatr. 2005; 147: 835-838
        • Burgert T.S.
        • Taksali S.E.
        • 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: 4287-4294
        • Asano T.
        • Watanabe K.
        • Kubota N.
        • et al.
        Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis.
        J Gastroenterol Hepatol. 2009; 24: 1669-1676
        • Fukushima J.
        • Kamada Y.
        • Matsumoto H.
        • et al.
        Adiponectin prevents progression of steatohepatitis in mice by regulating oxidative stress and Kupffer cell phenotype polarization.
        Hepatol Res. 2009; 39: 724-738
        • Yamaguchi K.
        • Yang L.
        • McCall S.
        • et al.
        Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis.
        Hepatology. 2007; 45: 1366-1374
        • Rigazio S.
        • Lehto H.R.
        • Tuunanen H.
        • et al.
        The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans.
        Am J Physiol Endocrinol Metab. 2008; 295: E413-E419
        • Bruce K.D.
        • Cagampang F.R.
        • Argenton M.
        • et al.
        Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression.
        Hepatology. 2009; 50: 1796-1808
        • McCurdy C.E.
        • Bishop J.M.
        • Williams S.M.
        • et al.
        Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates.
        J Clin Invest. 2009; 119: 323-335
        • Schwimmer J.B.
        • Deutsch R.
        • Kahen T.
        • et al.
        Prevalence of fatty liver in children and adolescents.
        Pediatrics. 2006; 118: 1388-1393
        • Schwimmer J.B.
        • Celedon M.A.
        • Lavine J.E.
        • et al.
        Heritability of nonalcoholic fatty liver disease.
        Gastroenterology. 2009; 136: 1585-1592
        • Wagenknecht L.E.
        • Scherzinger A.L.
        • Stamm E.R.
        • et al.
        Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort.
        Obesity (Silver Spring). 2009; 17: 1240-1246
        • Romeo S.
        • Kozlitina J.
        • Xing C.
        • et al.
        Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.
        Nat Genet. 2008; 40: 1461-1465
        • Kotronen A.
        • Johansson L.E.
        • Johansson L.M.
        • et al.
        A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans.
        Diabetologia. 2009; 52: 1056-1060
        • Sookoian S.
        • Castano G.O.
        • Burgueno A.L.
        • et al.
        A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity.
        J Lipid Res. 2009; 50: 2111-2116
        • Wilson P.A.
        • Gardner S.D.
        • Lambie N.M.
        • et al.
        Characterization of the human patatin-like phospholipase family.
        J Lipid Res. 2006; 47: 1940-1949
        • Kollerits B.
        • Coassin S.
        • Beckmann N.D.
        • et al.
        Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein B-containing lipoproteins.
        Hum Mol Genet. 2009; 18: 4669-4676
        • Fraser A.
        • Longnecker M.P.
        • Lawlor D.A.
        Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999-2004.
        Gastroenterology. 2007; 133: 1814-1820
        • Kawasaki T.
        • Hashimoto N.
        • Kikuchi T.
        • et al.
        The relationship between fatty liver and hyperinsulinemia in obese Japanese children.
        J Pediatr Gastroenterol Nutr. 1997; 24: 317-321
        • Sagi R.
        • Reif S.
        • Neuman G.
        • et al.
        Nonalcoholic fatty liver disease in overweight children and adolescents.
        Acta Paediatr. 2007; 96: 1209-1213
        • Nadeau K.J.
        • Ehlers L.B.
        • Zeitler P.S.
        • et al.
        Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents.
        Pediatr Diabetes. 2009; 10: 5-13
        • Schwimmer J.B.
        • McGreal N.
        • Deutsch R.
        • et al.
        Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents.
        Pediatrics. 2005; 115: e561-e565
        • Quirós-Tejeira R.E.
        • Rivera C.A.
        • Ziba T.T.
        • et al.
        Risk for nonalcoholic fatty liver disease in Hispanic youth with BMI > or =95th percentile.
        J Pediatr Gastroenterol Nutr. 2007; 44: 228-236
        • Sartorio A.
        • Del Col A.
        • Agosti F.
        • et al.
        Predictors of non-alcoholic fatty liver disease in obese children.
        Eur J Clin Nutr. 2007; 61: 877-883
        • Louthan M.V.
        • Theriot J.A.
        • Zimmerman E.
        • et al.
        Decreased prevalence of nonalcoholic fatty liver disease in black obese children.
        J Pediatr Gastroenterol Nutr. 2005; 41: 426-429
        • Kistler K.D.
        • Molleston J.
        • Unalp A.
        • et al.
        Symptoms and quality of life in obese children and adolescents with nonalcoholic fatty liver disease.
        Aliment Pharmacol Ther. 2009; 31: 396-406
        • Hh A.K.
        • Henderson J.
        • Vanhoesen K.
        • et al.
        Nonalcoholic fatty liver disease in children: a single center experience.
        Clin Gastroenterol Hepatol. 2008; 6: 799-802
        • Rhee H.
        • Miles M.S.
        • Halpern C.T.
        • et al.
        Prevalence of recurrent physical symptoms in U.S. adolescents.
        Pediatr Nurs. 2005; 31 (350): 314-319
        • Riley M.R.
        • Bass N.M.
        • Rosenthal P.
        • et al.
        Underdiagnosis of pediatric obesity and underscreening for fatty liver disease and metabolic syndrome by pediatricians and pediatric subspecialists.
        J Pediatr. 2005; 147: 839-842
        • Barlow S.E.
        Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report.
        Pediatrics. 2007; 120: S164-S192
        • Schwimmer J.B.
        • Dunn W.
        • Norman G.J.
        • et al.
        SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease.
        Gastroenterology. 2010; 138: 1357-1364
        • Manco M.
        • Bedogni G.
        • Marcellini M.
        • et al.
        Waist circumference correlates with liver fibrosis in children with non-alcoholic steatohepatitis.
        Gut. 2008; 57: 1283-1287
      1. Anthropometry procedures manual. National Health and Nutrition Examination Survey. Center for Disease Control; 2000. Available at: http://www.cdc.gov/nchs/data/nhanes/bm.pdf. Accessed September 12, 2009.

        • Rashid M.
        • Roberts E.A.
        Nonalcoholic steatohepatitis in children.
        J Pediatr Gastroenterol Nutr. 2000; 30: 48-53
        • Burke J.P.
        • Hale D.E.
        • Hazuda H.P.
        • et al.
        A quantitative scale of acanthosis nigricans.
        Diabetes Care. 1999; 22: 1655-1659
        • Schwimmer J.B.
        • Pardee P.E.
        • Lavine J.E.
        • et al.
        Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease.
        Circulation. 2008; 118: 277-283
        • Moreno M.
        • Bataller R.
        Cytokines and renin-angiotensin system signaling in hepatic fibrosis.
        Clin Liver Dis. 2008; 12 (ix): 825-852
        • Puri M.
        • Flynn J.T.
        Management of hypertension in children and adolescents with the metabolic syndrome.
        J Cardiometab Syndr. 2006; 1: 259-268
        • Ogden C.L.
        • Carroll M.D.
        • Curtin L.R.
        • et al.
        Prevalence of overweight and obesity in the United States, 1999–2004.
        JAMA. 2006; 295: 1549-1555
        • Guzzaloni G.
        • Grugni G.
        • Minocci A.
        • et al.
        Liver steatosis in juvenile obesity: correlations with lipid profile, hepatic biochemical parameters and glycemic and insulinemic responses to an oral glucose tolerance test.
        Int J Obes Relat Metab Disord. 2000; 24: 772-776
        • Manton N.D.
        • Lipsett J.
        • Moore D.J.
        • et al.
        Non-alcoholic steatohepatitis in children and adolescents.
        Med J Aust. 2000; 173: 476-479
        • Harrison S.A.
        • Torgerson S.
        • Hayashi P.H.
        The natural history of nonalcoholic fatty liver disease: a clinical histopathological study.
        Am J Gastroenterol. 2003; 98: 2042-2047
        • Lindor K.D.
        • Kowdley K.V.
        • Heathcote E.J.
        • et al.
        Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.
        Hepatology. 2004; 39: 770-778
        • Adams L.A.
        • Feldstein A.
        • Lindor K.D.
        • et al.
        Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction.
        Hepatology. 2004; 39: 909-914
        • Evans H.M.
        • Shaikh M.G.
        • McKiernan P.J.
        • et al.
        Acute fatty liver disease after suprasellar tumor resection.
        J Pediatr Gastroenterol Nutr. 2004; 39: 288-291
        • Nakajima K.
        • Hashimoto E.
        • Kaneda H.
        • et al.
        Pediatric nonalcoholic steatohepatitis associated with hypopituitarism.
        J Gastroenterol. 2005; 40: 312-315
        • Bugianesi E.
        Non-alcoholic steatohepatitis and cancer.
        Clin Liver Dis. 2007; 11 (x–xi): 191-207
        • Cuadrado A.
        • Orive A.
        • Garcia-Suarez C.
        • et al.
        Non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma.
        Obes Surg. 2005; 15: 442-446
        • Hashizume H.
        • Sato K.
        • Takagi H.
        • et al.
        Primary liver cancers with nonalcoholic steatohepatitis.
        Eur J Gastroenterol Hepatol. 2007; 19: 827-834
        • Rubinstein E.
        • Lavine J.E.
        • Schwimmer J.B.
        Hepatic, cardiovascular, and endocrine outcomes of the histological subphenotypes of nonalcoholic fatty liver disease.
        Semin Liver Dis. 2008; 28: 380-385
        • Sanyal A.J.
        • Banas C.
        • Sargeant C.
        • et al.
        Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.
        Hepatology. 2006; 43: 682-689
        • Bullock R.E.
        • Zaitoun A.M.
        • Aithal G.P.
        • et al.
        Association of non-alcoholic steatohepatitis without significant fibrosis with hepatocellular carcinoma.
        J Hepatol. 2004; 41: 685-686
        • Zen Y.
        • Katayanagi K.
        • Tsuneyama K.
        • et al.
        Hepatocellular carcinoma arising in non-alcoholic steatohepatitis.
        Pathol Int. 2001; 51: 127-131
        • Koebnick C.
        • Getahun D.
        • Reynolds K.
        • et al.
        Trends in nonalcoholic fatty liver disease-related hospitalizations in US children, adolescents, and young adults.
        J Pediatr Gastroenterol Nutr. 2009; 48: 597-603
        • Feldstein A.E.
        • Charatcharoenwitthaya P.
        • Treeprasertsuk S.
        • et al.
        The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years.
        Gut. 2009; 58: 1538-1544
        • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
        Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
        Circulation. 2002; 106: 3143-3421
        • Ekstedt M.
        • Franzen L.E.
        • Mathiesen U.L.
        • et al.
        Long-term follow-up of patients with NAFLD and elevated liver enzymes.
        Hepatology. 2006; 44: 865-873
        • Demircioglu F.
        • Kocyigit A.
        • Arslan N.
        • et al.
        Intima-media thickness of carotid artery and susceptibility to atherosclerosis in obese children with nonalcoholic fatty liver disease.
        J Pediatr Gastroenterol Nutr. 2008; 47: 68-75
        • Pacifico L.
        • Cantisani V.
        • Ricci P.
        • et al.
        Nonalcoholic fatty liver disease and carotid atherosclerosis in children.
        Pediatr Res. 2008; 63: 423-427
        • Aygun C.
        • Kocaman O.
        • Sahin T.
        • et al.
        Evaluation of metabolic syndrome frequency and carotid artery intima-media thickness as risk factors for atherosclerosis in patients with nonalcoholic fatty liver disease.
        Dig Dis Sci. 2008; 53: 1352-1357
        • Nadeau K.J.
        • Klingensmith G.
        • Zeitler P.
        Type 2 diabetes in children is frequently associated with elevated alanine aminotransferase.
        J Pediatr Gastroenterol Nutr. 2005; 41: 94-98
        • Adams L.A.
        • Lymp J.F.
        • St Sauver J.
        • et al.
        The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
        Gastroenterology. 2005; 129: 113-121
        • Fan J.G.
        • Li F.
        • Cai X.B.
        • et al.
        Effects of nonalcoholic fatty liver disease on the development of metabolic disorders.
        J Gastroenterol Hepatol. 2007; 22: 1086-1091
        • de Piano A.
        • Prado W.L.
        • Caranti D.A.
        • et al.
        Metabolic and nutritional profile of obese adolescents with nonalcoholic fatty liver disease.
        J Pediatr Gastroenterol Nutr. 2007; 44: 446-452
        • Reinehr T.
        • Schmidt C.
        • Toschke A.M.
        • et al.
        Lifestyle intervention in obese children with nonalcoholic fatty liver disease: 2-year follow-up study.
        Arch Dis Child. 2009; 94: 437-442
        • Tock L.
        • Prado W.L.
        • Caranti D.A.
        • et al.
        Nonalcoholic fatty liver disease decrease in obese adolescents after multidisciplinary therapy.
        Eur J Gastroenterol Hepatol. 2006; 18: 1241-1245
        • Wang C.L.
        • Liang L.
        • Fu J.F.
        • et al.
        Effect of lifestyle intervention on non-alcoholic fatty liver disease in Chinese obese children.
        World J Gastroenterol. 2008; 14: 1598-1602
        • Ouyang X.
        • Cirillo P.
        • Sautin Y.
        • et al.
        Fructose consumption as a risk factor for non-alcoholic fatty liver disease.
        J Hepatol. 2008; 48: 993-999
        • Vos M.B.
        • Weber M.B.
        • Welsh J.
        • et al.
        Fructose and oxidized low-density lipoprotein in pediatric nonalcoholic fatty liver disease: a pilot study.
        Arch Pediatr Adolesc Med. 2009; 163: 674-675
        • Nobili V.
        • Manco M.
        • Ciampalini P.
        • et al.
        Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study.
        Clin Ther. 2008; 30: 1168-1176
        • Lavine J.E.
        • Schwimmer J.B.
        • Molleston J.P.
        • et al.
        Treatment of nonalcoholic fatty liver disease in children: TONIC trial design.
        Contemp Clin Trials. 2010; 31: 62-70
        • Aithal G.P.
        • Thomas J.A.
        • Kaye P.V.
        • et al.
        Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.
        Gastroenterology. 2008; 135: 1176-1184
        • Belfort R.
        • Harrison S.A.
        • Brown K.
        • et al.
        A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
        N Engl J Med. 2006; 355: 2297-2307
        • Ratziu V.
        • Giral P.
        • Jacqueminet S.
        • et al.
        Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.
        Gastroenterology. 2008; 135: 100-110
        • Chalasani N.P.
        • Sanyal A.J.
        • Kowdley K.V.
        • et al.
        Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design.
        Contemp Clin Trials. 2009; 30: 88-96
        • Sanjay A.
        A randomized controlled trial of pioglitazone or vitamin E for nonalcoholic steatohepatitis (PIVENS).
        Hepatology. 2009; 50: 90A
        • Lavine J.E.
        Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study.
        J Pediatr. 2000; 136: 734-738
        • Nobili V.
        • Manco M.
        • Devito R.
        • et al.
        Effect of vitamin E on aminotransferase levels and insulin resistance in children with non-alcoholic fatty liver disease.
        Aliment Pharmacol Ther. 2006; 24: 1553-1561
        • 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: 119-128
        • Obinata K.
        • Maruyama T.
        • Hayashi M.
        • et al.
        Effect of taurine on the fatty liver of children with simple obesity.
        Adv Exp Med Biol. 1996; 403: 607-613
        • Dufour J.F.
        • Oneta C.M.
        • Gonvers J.J.
        • et al.
        Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis.
        Clin Gastroenterol Hepatol. 2006; 4: 1537-1543
        • Ersoz G.
        • Gunsar F.
        • Karasu Z.
        • et al.
        Management of fatty liver disease with vitamin E and C compared to ursodeoxycholic acid treatment.
        Turk J Gastroenterol. 2005; 16: 124-128
        • ClinicalTrials.gov
        Pilot Study of Ursodeoxycholic Acid in Non-Alcoholic Steatohepatitis (URSONASH).
        (Identifier: NCT00470171. Available at:) (Accessed February 2, 2009)
        • Sanyal A.
        • Mudaliar S.
        • Henry R.
        A new therapy for nonalcoholic fatty liver disease and diabetes? INT-747—the first FXR hepatic therapeutic study.
        Hepatology. 2009; 50: 389A
        • ClinicalTrials.gov
        Effects of FXR activation on hepatic lipid and glucose metabolism.
        (Identifier: NCT00465751. Available at:) (Accessed October 31, 2007)
        • Merat S.
        • Malekzadeh R.
        • Sohrabi M.R.
        • et al.
        Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study.
        J Hepatol. 2003; 38: 414-418
        • Pamuk G.E.
        • Sonsuz A.
        N-acetylcysteine in the treatment of non-alcoholic steatohepatitis.
        J Gastroenterol Hepatol. 2003; 18: 1220-1221
        • Uygun A.
        • Kadayıfcı A.
        • Bağcı S.
        • et al.
        L-Carnitine therapy in non-alcoholic steatohepatitis.
        Turk J Gastroenterol. 2000; 11: 196-201
        • Hyogo H.
        • Tazuma S.
        • Arihiro K.
        • et al.
        Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia.
        Metabolism. 2008; 57: 1711-1718
        • Nelson A.
        • Torres D.M.
        • Morgan A.E.
        • et al.
        A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial.
        J Clin Gastroenterol. 2009; 43: 990-994
        • Daniels S.R.
        • Greer F.R.
        Lipid screening and cardiovascular health in childhood.
        Pediatrics. 2008; 122: 198-208
        • O’Gorman C.S.
        • Higgins M.F.
        • O’Neill M.B.
        Systematic review and metaanalysis of statins for heterozygous familial hypercholesterolemia in children: evaluation of cholesterol changes and side effects.
        Pediatr Cardiol. 2009; 30: 482-489
        • de Ferranti S.
        • Ludwig D.S.
        Storm over statins—the controversy surrounding pharmacologic treatment of children.
        N Engl J Med. 2008; 359: 1309-1312
        • Zelber-Sagi S.
        • Kessler A.
        • Brazowsky E.
        • et al.
        A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease.
        Clin Gastroenterol Hepatol. 2006; 4: 639-644
        • Klein S.
        • Mittendorfer B.
        • Eagon J.C.
        • et al.
        Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease.
        Gastroenterology. 2006; 130: 1564-1572
        • Barker K.B.
        • Palekar N.A.
        • Bowers S.P.
        • et al.
        Non-alcoholic steatohepatitis: effect of Roux-en-Y gastric bypass surgery.
        Am J Gastroenterol. 2006; 101: 368-373
        • Dixon J.B.
        • Bhathal P.S.
        • O’Brien P.E.
        Weight loss and non-alcoholic fatty liver disease: falls in gamma-glutamyl transferase concentrations are associated with histologic improvement.
        Obes Surg. 2006; 16: 1278-1286
        • Mathurin P.
        • Hollebecque A.
        • Arnalsteen L.
        • et al.
        Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease.
        Gastroenterology. 2009; 137: 532-540
        • Mattar S.G.
        • Velcu L.M.
        • Rabinovitz M.
        • et al.
        Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic syndrome.
        Ann Surg. 2005; 242 ([discussion: 618–20]): 610-617
        • Holterman A.X.
        • Browne A.
        • Dillard 3rd, B.E.
        • et al.
        Short-term outcome in the first 10 morbidly obese adolescent patients in the FDA-approved trial for laparoscopic adjustable gastric banding.
        J Pediatr Gastroenterol Nutr. 2007; 45: 465-473
        • Nadler E.P.
        • Reddy S.
        • Isenalumhe A.
        • et al.
        Laparoscopic adjustable gastric banding for morbidly obese adolescents affects android fat loss, resolution of comorbidities, and improved metabolic status.
        J Am Coll Surg. 2009; 209: 638-644
        • Nadler E.P.
        • Youn H.A.
        • Ren C.J.
        • et al.
        An update on 73 US obese pediatric patients treated with laparoscopic adjustable gastric banding: comorbidity resolution and compliance data.
        J Pediatr Surg. 2008; 43: 141-146
        • Pratt J.S.
        • Lenders C.M.
        • Dionne E.A.
        • et al.
        Best practice updates for pediatric/adolescent weight loss surgery.
        Obesity (Silver Spring). 2009; 17: 901-910
        • Park H.S.
        • Han J.H.
        • Choi K.M.
        • et al.
        Relation between elevated serum alanine aminotransferase and metabolic syndrome in Korean adolescents.
        Am J Clin Nutr. 2005; 82: 1046-1051
        • Imhof A.
        • Kratzer W.
        • Boehm B.
        • et al.
        Prevalence of non-alcoholic fatty liver and characteristics in overweight adolescents in the general population.
        Eur J Epidemiol. 2007; 22: 889-897
        • Zhou Y.J.
        • Li Y.Y.
        • Nie Y.Q.
        • et al.
        Prevalence of fatty liver disease and its risk factors in the population of South China.
        World J Gastroenterol. 2007; 13: 6419-6424
        • Tominaga K.
        • Fujimoto E.
        • Suzuki K.
        • et al.
        Prevalence of non-alcoholic fatty liver disease in children and relationship to metabolic syndrome, insulin resistance, and waist circumference.
        Environ Health Prev Med. 2009; 14: 142-149