The relationship between excessive dietary fructose consumption and paediatric fatty liver disease

Abstract

The global prevalence of non-alcoholic fatty liver disease (NAFLD) in children and adolescents is escalating and currently represents the most common chronic liver disease in the paediatric population. NAFLD is associated with high daily caloric intake and sedentary behaviour, with excessive consumption of added sugar emerging as an important contributor to NAFLD risk in children. This is a particularly important factor for adolescents with obesity, who are the heaviest consumers of added sugar. Table sugar, or sucrose, is a disaccharide comprised of fructose and glucose, yet only fructose has been strongly linked to NAFLD pathogenesis largely due to the unique characteristics of its metabolism and detrimental effects on key metabolic pathways. To date, the relationship between excessive fructose intake and risk of NAFLD in children and adolescents remains incompletely understood, and it is not yet known whether fructose actually causes NAFLD or instead exacerbates hepatic fat accumulation and possible hepatocellular injury only within the context of cardiometabolic factors. The purpose of this review is to summarize recent studies linking fructose consumption with NAFLD in the paediatric population and integrate results from interventional studies of fructose restriction in children and adolescents on NAFLD and related metabolic markers. Given the overall positive impact of lifestyle modifications in the management of paediatric NAFLD, reduction of added sugar consumption may represent an important, early opportunity to mitigate or prevent NAFLD in high-risk children and adolescents.

Keywords: fructose; hepatic steatosis; liver fibrosis; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; uric acid.

Fig 1.. Hepatic metabolism of fructose.

Following transport into liver cells, fructose is first rapidly metabolized by ketohexokinase to fructose-1-phosphate, which is then broken down by adolase B to dihydroxyacetone phosphate and glyceraldehyde. Fructose phosphorylation utilizes adenosine triphosphate (ATP); excessive amounts of incoming fructose result in ATP depletion from hepatic stores and generation of adenosine monophosphate (AMP), a precursor to uric acid. Both dihydroxyacetone and glyceraldehyde contribute to the synthesis of glyceraldehyde-3-phosphate, via the actions of glycerol-3-phosphate dehydrogenase and triokinase, respectively. Glycerol-3-phosphate serves as a precursor substrate for de novo lipogenesis (DNL). The large blue hashed arrows represent several enzymatic steps that have not been included in the figure. Increased rates of uric acid synthesis and DNL are known to contribute directly or indirectly to insulin resistance, hepatic and systemic inflammation, NAFLD, and other cardiometabolic diseases.

Fig 2.. Effects of excessive fructose consumption on biological pathways that contribute to increased risk of NAFLD development and progression in children and adolescents.

As discussed in the text, high intake of added sugar or fructose has been associated with increased DNL, hepatic insulin resistance (IR), hyperuricemia, hepatic inflammation, oxidative stress, and visceral adiposity. High fructose intake has also been associated with gut dysbiosis.