Childhood Fructoholism and Fructoholic Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is an emerging entity, becoming the most prevalent pediatric chronic liver disease. Its broad spectrum of histological findings, comorbidities, and complications, including cirrhosis and liver failure, can occur in childhood, emphasizing the severity of pediatric NAFLD. Current lifestyle and diet modifications have been linked to the increasing prevalence of NAFLD, including the rise of fructose consumption, a monosaccharide present in foods that contain added sugar, such as sugar-sweetened beverages. Excessive fructose consumption is believed to cause addiction like alcohol and other drugs. As such, the new term "fructoholism" refers to the consumption of a substance (fructose) that can cause psychological and physical damage and become a major public health concern, highlighting the seriousness of the excessive consumption of fructose in the pediatric age. Hepatic fructose metabolization leads to hepatic steatosis and progression to fibrosis through mechanisms comparable to alcoholic liver disease, hence the term "fructoholic liver disease." Conclusion: The importance of implementing reliable global strategies, such as education campaigns to promote healthy diet, increasing taxes on foods that contain added sugars, subsidies to promote accessibility to fruit and vegetables, and strict food industry regulation to reduce sugar intake in children and adolescents, cannot be overemphasized.

Figure 1

In hepatic fructose metabolism, the major part of fructose is metabolized directly to pyruvate. Due to the liver mitochondria cannot metabolizing the substrate excess, there is an overproduction of DNL and VLDL (very‐low‐density lipoprotein), which is exported out of the liver to contribute to fructose‐induced hypertriglyceridemia. Fructose induces substrate‐dependent phosphate depletion, which increases uric acid contributing to the decrease of FA ß‐oxidation, leading to intrahepatic lipid accumulation, and it is also primarily responsible for the oxidative stress. Fructose also stimulates the overexpression of key transcription factors, which lead to up‐regulation of DNL as ChREBP (carbohydrate response element binding protein) and PGC‐1ß (peroxisomal proliferator‐activated receptor‐γ coactivator‐1ß). PGC‐1ß is a transcriptional coactivator for SREBP‐1c (sterol regulatory element binding protein‐1c), which accentuates DNL enzymatic activity, and JNK‐1 (c‐jun N‐terminal kinase), which, once is induced, begins the inflammation cascade. As part of its inflammatory action, JNK‐1 activation induces IRS‐1 (insulin receptor substrate‐1), which promotes hepatic insulin resistance. In hepatic alcohol metabolism, ethanol is metabolized to acetaldehyde, which, because of its free aldehyde, can generate ROS (reactive oxygen species) formation and toxic damage. Furthermore, acetaldehyde stimulates SREBP‐1c, activating the enzymes of DNL and JNK‐1, promoting the inflammation process and hepatic insulin resistance by inducing IRS‐1. In the ethanol metabolization process there is an excess of the product intermediaries, which stimulates an overproduction of DNL, resulting in further intrahepatic lipid build‐up. By suppressing the activity of the protein that mediates the VLDL production, ethanol intake contributes to hypertriglyceridemia.