Plasma high mobility group box 1 protein reflects fibrosis in pediatric nonalcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) affects 3–12% of the general pediatric population. HMGB1 protein is presently considered a potent inflammatory mediator in several liver diseases, even if its role in NAFLD is still unknown in clinical studies. Here we investigated the relationships between circulating HMGB1, TGF-β and MCP-1 and liver damage in pediatric NAFLD. HMGB1, TGF-β and MCP-1 plasma levels were measured in 110 obese children with biopsy-proven NAFLD and 40 age-matched obese controls. HMGB1, TGF-β and MCP-1, ALT, AST and cholesterol plasma levels were significantly higher in NAFLD than in control children. A significant association between increased levels of HMGB1, TGF-β and MCP-1 and high degrees of fibrosis was found. In this study, we showed for the first time that circulating levels of HMGB1 were raised in children with NAFLD and strongly correlated with fibrosis and systemic inflammation.

Keywords::

• high mobility group box 1
• liver fibrosis
• monocyte chemoattractant protein-1
• non-alcoholic fatty liver disease
• TGF β

Financial & competing interests disclosure

This study was supported by the Italian Ministry of Health (fondi di Ricerca Corrente and 5X1000) to A Alisi and V Nobili and by Nicolò Valenti Onlus. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the pediatric population.

• Pathogen-associated molecular patterns, such as lipopolysaccharide, and damage-associated molecular patterns, such as high-mobility group box 1 (HMGB1), are suspected to induce low-grade inflammation and liver damage occurring in NAFLD.

• Increased plasma levels of HMGB1, were recently reported in adults with acute liver failure or acetaminophen-induced acute liver injury and with chronic hepatitis.

• We demonstrated that plasma levels of HMGB, lipopolysaccharide and hyaluronic acid are higher in overweight/obese children with NAFLD patients than in controls.

• We showed that HMGB1 plasma levels were strongly associated with the presence of fibrosis and were able to discriminate mild versus severe fibrosis in pediatric NAFLD.

• In children with NAFLD, HMGB1 plasma levels also associate with those of other noninvasive biomarkers of liver damage, including hyaluronic acid and cytokeratin-18 fragment.

• The results of this study suggest the use of HMGB1 inhibitors as potential treatments to reduce hepatic fibrosis.

• Our findings open the view to a possible future use of HMGB1 as a noninvasive biomarker of liver fibrosis in children with NAFLD.

Notes