Abstract
AimSerum high mobility group box 1 protein (HMGB1) is a proinflammatory molecule that could potentially serve as a biomarker for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) due to its correlation with degree of liver fibrosis. The aim of the current study was to examine the cross-sectional and longitudinal relationships between serum HMGB1 levels and liver histology in adults and children with NAFLD participating in two large randomized controlled trials.MethodsSerum HMGB1 levels were measured at various time points in adults and children with NAFLD, who participated in PIVENS and TONIC clinical trials respectively. PIVENS trial compared vitamin E or pioglitazone to placebo in adults whereas TONIC trial compared vitamin E or metformin to placebo in children. Participants had liver biopsies at baseline and the end of treatment (96 weeks), and liver histology was reviewed by a central committee of study pathologists.ResultsIn the cross-sectional analyses (n = 205 for PIVENS and 109 for TONIC), there was no significant relationship between serum HMGB1 levels and histological features such as steatosis, ballooning, inflammation, fibrosis, or presence of steatohepatitis in either adults or children. Serum HMGB1 levels did not change significantly during treatment either with placebo, vitamin E therapy (P = 0.81) or pioglitazone (P = 0.09) in the PIVENS trial. Similarly, serum HMGB1 levels did not change significantly during treatment either with placebo, metformin (P = 0.15) or vitamin E (P = 0.23) in the TONIC trial. In the longitudinal analyses (n = 105 for PIVENS and 109 for TONIC), changes in serum HMGB1 levels did not correlate with histologic improvement or resolution of NASH in either adults or children. There was no relationship between serum HMGB1 and ALT levels in either adults or children with NAFLD.ConclusionSerum HMGB1 levels were not associated with histological severity or treatment response in either children or adults with NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a common liver condition and is estimated to affect one in three adults in the United States.[1]
Serum high mobility group box 1 protein (HMGB1) levels were measured at various time points in adults and children with NAFLD, who participated in PIVENS and TONIC clinical trials respectively
In the cross-sectional analyses (n = 205 for PIVENS and 109 for TONIC), there was no significant relationship between serum HMGB1 levels and histological features such as steatosis, ballooning, inflammation, fibrosis, or presence of steatohepatitis in either adults or children
Summary
Non-alcoholic fatty liver disease (NAFLD) is a common liver condition and is estimated to affect one in three adults in the United States.[1] Its prevalence in children is increasing in parallel with childhood obesity.[2,3,4] The severity of NAFLD is varied and could range from simple hepatic steatosis or non-alcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), a progressive condition that could lead to cirrhosis, hepatocellular cancer or liver failure.[5] Since NASH is a histologic diagnosis, a definitive diagnosis requires the patient to undergo a liver biopsy.[5] Currently, the therapeutic end point in clinical trials for NASH requires a liver biopsy at enrollment and after completion of the study in order to show resolution of NASH with therapeutic intervention.[6] A non-invasive biomarker for the diagnosis and severity of NAFLD that can change dynamically with histological improvement in a treatment trial is very desirable and currently an unmet need
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