title: Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels.
abstract: OBJECTIVE
  To investigate the histological spectrum of nonalcoholic fatty liver disease (NAFLD) in children with normal, mildly elevated (26-50 U/L boys, 23-44 U/L girls), or elevated (>50 U/L in boys, >44 U/L in girls) serum alanine aminotransferase (ALT) levels.
  
  
  METHODS
  The Nonalcoholic Steatohepatitis Clinical Research Network enrolls children aged 5-18 years with NAFLD. We analyzed baseline clinical and histological data from 91 children with suspected NAFLD and normal or mildly elevated ALT and liver biopsy analysis within 180 days of ALT measurement, and compared them with data from 392 children with elevated ALT.
  
  
  RESULTS
  Seventeen of the 91 children with suspected NAFLD (19%) had a normal ALT level, and 74 (81%) had a mildly elevated ALT level. Overall, 45% of the biopsy specimens analyzed had steatosis ≥33%, 22% had grade ≥2 lobular inflammation, 81% had portal inflammation, 29% had ballooned hepatocytes, 35% had "suspicious/borderline" steatohepatitis, 8% had definite nonalcoholic steatohepatitis, 34% had an NAFLD activity score ≥4, and 46% had fibrosis (38% mild/moderate and 8% bridging/cirrhosis). Marked steatosis (50% vs 24%) and fibrosis (54% vs 12%) were significantly more common in the patients with mildly elevated ALT compared with those with normal ALT, with no difference in ballooning, inflammation, or NAFLD activity score ≥4 between the 2 groups. Fibrosis stage 3/4 was seen in none of the children with normal ALT, in 9% of those with mildly elevated ALT, and in 15% of those with elevated ALT.
  
  
  CONCLUSIONS
  Liver biopsy specimens from children with NAFLD with normal or mildly elevated ALT levels show significant histological abnormalities, including advanced fibrosis in children with mildly elevated ALT. Thus, measurement of ALT may underestimate liver injury in NAFLD. The use of appropriate ALT cutoff levels can help identify children at risk for more severe disease.
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Indiana University School of Medicine, Indianapolis, IN. Electronic address: jpmolles@iu.edu.
authors.forename: Jean P
authors.initials: JP
authors.lastname: Molleston
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, CA; Department of Gastroenterology, Rady Children's Hospital, San Diego, CA; Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, La Jolla, CA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Schwimmer
authors.affiliation: Data Coordinating Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Yates
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Seattle Children's Hospital, Seattle, WA.
authors.forename: Karen F
authors.initials: KF
authors.lastname: Murray
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Cummings
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia University, New York, NY.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Lavine
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.affiliation: Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins Children's Center, Baltimore, MD.
authors.forename: Ann O
authors.initials: AO
authors.lastname: Scheimann
authors.affiliation: Data Coordinating Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Aynur
authors.initials: A
authors.lastname: Unalp-Arida
mesh_terms: D000410:Alanine Transaminase / Q000097:blood*; D002648:Child; D005234:Fatty Liver / Q000097:blood* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D011446:Prospective Studies; D012016:Reference Values
chemical_list: D000410:Alanine Transaminase