Significant Subset of Children With NAFLD Progress to Definite NASH, Fibrosis, and Diabetes

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A team of investigators studied the relationship between changes in liver histology and changes in body mass index, dyslipidemia, and measures of glucose homeostasis in children.

Approximately one-third of children with nonalcoholic fatty liver disease (NAFLD) who received placebo and standard-of-care lifestyle advice in the setting of clinical trials experienced progression to definite nonalcoholic steatohepatitis (NASH) or fibrosis as well as worsening glycemic control and weight gain within 2 years, according to the results of a study published in Gastroenterology.

The Treatment of NASH in Children (TONIC; Identifier:  NCT00063635) and the Cysteamine Bitartrate Delayed Release for the Treatment of NAFLD in Children (CyNCh; Identifier: NCT01529268) trials enrolled children between 8 and 17 years of age (mean age, 13±3 years) who had biopsy-confirmed NAFLD. A total of 139 participants with NAFLD who received placebo and standard-of-care lifestyle advice were included in the study. Using regression analysis, the investigators compared histologic changes in clinical variables between baseline and up to 2 years.

Approximately 31% of children in the TONIC and CyNCh trials had definite NASH at time of enrollment. Borderline zone 1 NASH, borderline zone 3 NASH, and fatty liver without NASH were reported in 34%, 13%, and 21% of children, respectively. Borderline or definite NASH resolved in 29% of participants over a mean follow-up period of 1.6±0.4 years. In contrast, definite NASH developed in 18% of children with fatty liver or borderline NASH. Additionally, approximately 34% of children had improved fibrosis, whereas fibrosis worsened in 23% of children.

Progression to definite NASH or fibrosis was reported in 36% of children with baseline NAFL or borderline NASH. Approximately 11% of patients developed composite progression to definite NASH and progression to fibrosis. Improvement in fibrosis or NASH was noted in 52% of participants, whereas improvement in both conditions was reported in 20% of participants. Approximately 5% of the overall sample developed type 2 diabetes over the mean 1.6±0.4-year follow-up from baseline to end-of-treatment biopsy.

Factors associated with any progression to definite NASH and/or fibrosis included adolescent age (13-17 years vs 8-12 years: relative odds [RO], 2.86; 95% CI, 1.20-6.81; P =.02), higher waist circumference (RO, 1.48; 95% CI, 1.08-2.01; P =.01), levels of alanine aminotransferase (RO, 2.28; 95% CI, 1.10-4.70; P =.03) or aspartate aminotransferase (RO, 4.15; 95% CI, 1.08-16.02; P =.04), baseline total cholesterol (RO, 3.63; 95% CI, 1.11-11.91; P =.03) and low-density lipoprotein cholesterol (RO, 4.08; 95% CI, 1.00-16.68; P =.05), increasing level of alanine aminotransferase (RO, 2.31; 95% CI, 1.13-4.75; P =.02), and change in glycated hemoglobin (RO, 2.58; 95% CI, 1.05-6.30; P =.04).

Additionally, progression to definite NASH and/or fibrosis was associated with increasing level of gamma-glutamyl transferase (RO, 45.4; 95% CI, 2.59-797; P =.009) and development of type 2 diabetes (RO, 9.08; 95% CI, 1.80-45.72; P =.007). Increasing levels of gamma-glutamyl transferase were associated with reduced odds of any improvement (RO, 0.03; 95% CI, 0.002-0.29; P =.003).

A limitation of this study is the enrollment of children who received only placebo and standard-of-care lifestyle advice in the setting of clinical trials, which the investigators suggest limits their understanding as to whether the findings are applicable to the real-world setting.

Despite this limitation, the researchers believe this study indicates that “more effective interventions are needed for children who fail to respond to standard lifestyle advice.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

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Xanthakos SA, Lavine JE, Yates KP, et al; for the NASH Clinical Research Network. Progression of fatty liver disease in children receiving standard of care lifestyle advice. Gastroenterology. Published online July 23, 2020. doi:10.1053/j.gastro.2020.07.034