Elsevier

The Journal of Pediatrics

Volume 164, Issue 4, April 2014, Pages 707-713.e3
The Journal of Pediatrics

Original Article
Histological Abnormalities in Children with Nonalcoholic Fatty Liver Disease and Normal or Mildly Elevated Alanine Aminotransferase Levels

https://doi.org/10.1016/j.jpeds.2013.10.071Get rights and content

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.

Study design

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.

Conclusion

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.

Section snippets

Methods

The pediatric NAFLD studies were designed by subcommittees of the NASH CRN Steering Committee, composed of principal investigators from each clinical site, the 2 co-chairs of the Pathology Committee, the principal investigator from the Data Coordinating Center, and the NIDDK scientific officer. After approval by the Steering Committee, the study was approved by the Institutional Review Board at each site. Enrolled patients and their guardians provided written informed assent and consent. The

Results

Among the 483 children aged 5-18 enrolled in the 2 NASH CRN database studies between October 2004 and January 2013, 91 children had a normal or mildly elevated ALT level with a centrally reviewed liver biopsy specimen obtained within 180 days of baseline ALT measurement. Thirty-two of these 91 children (35%) were enrolled in the NAFLD Database Study, and 59 (65%) were enrolled in the NAFLD Pediatric Database 2 Study. Among the comparison group of 392 children, 11% were enrolled in the NAFLD

Discussion

NAFLD is the most common chronic liver disease in the pediatric population, occurring in 9.6% of children overall and in up to 38% of obese children.3, 11 Liver disease can range from isolated hepatic steatosis to steatohepatitis with active inflammation to cirrhosis.9 Ultrasonography is a commonly used noninvasive technique in steatosis screening, but has only a moderate positive predictive value, does not detect all cases, and reflects fat and sometimes fibrosis, but not inflammation or

References (21)

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Supported by the NIDDK (U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713) and the National Institute of Child Health and Human Development. Several clinical centers use support from General Clinical Research Centers or Clinical and Translational Science Awards in conduct of NASH CRN Studies (UL1RR024989, UL1RR025761, M01RR00188, UL1RR024131, UL1RR025014, UL1RR031990, UL1RR025741, UL1RR029887, UL1RR24156, UL1RR025055, and UL1RR031980). The authors declare no conflicts of interest.

Registered with ClinicalTrials.gov: NCT01061684

List of members of the NASH CRN is available at www.jpeds.com (Appendix).

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