Non-alcoholic fatty liver disease in children and adolescents

Obesity and the metabolic syndrome

Obesity is increasing in prevalence throughout the world and with this change there is a major increase in associated cardiac, metabolic and other diseases [1]. In fact, according to the definition that the World Health Organization proposed in 2000, overweight and obesity are seen as a social hindrance and it is known that both these conditions are associated with cardiovascular and metabolic diseases [2]. In particular, since 1980, the prevalence of childhood obesity has almost tripled in USA and in some European countries. In particular, it has been estimated that 200 million school-aged children were overweight or obese in 2010 worldwide, with a prevalence of >20% in European states and >30% in regions of North America [3]. The prevalence of obesity both in childhood and adulthood remains very high. Recently, several authors have suggested that in some Western countries such as the United States, Western Europe, Australia, and Japan, the levels of childhood obesity may have reached a plateau in the last decade and do not increase further while the number of obese adolescents is still increasing [4]. In addition, overweight and obesity during childhood and adolescence leads to adult obesity and the progression of the metabolic syndrome [5]. Definitions of the metabolic syndrome are wide-ranged but most often a cluster of different metabolic disorders leading to e.g. cardiovascular diseases, abdominal obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).

NAFLD – cause or consequence of the metabolic syndrome

During the last years, NAFLD has become the most common pediatric hepatic chronic disease in industrialized countries, mainly as a result of the epidemic of obesity [4, 6]. In fact, a prevalence of 3%–10% in the general pediatric population has been reported and this number increases in young patients with obesity or overweight [6, 7]. It has been reported that lipid accumulation in the liver and subsequent inflammation in this organ are closely associated with the metabolic syndrome and other obesity-related complications, like cardiovascular disorders, type 2 diabetes, hypertension and chronic kidney diseases.

NAFLD covers a wide range of diseases, ranging from simple steatosis to steatohepatitis (NASH), advanced fibrosis and cirrhosis. Despite recent advances in the understanding of pediatric NAFLD, the natural history and the consequences of this condition are still unclear. In particular, hyperinsulinemia and hyperglycemia, which occur with the development of insulin resistance, seem to be the main actors in the initiation and in the progression of NAFLD. In fact, in the presence of an insulin resistance status, insulin is no more able to suppress the hormone-sensitive lipase in the visceral adipose tissue (VAT) leading to an efflux of free fatty acids into the portal vein to the liver. In addition, high serum insulin levels inhibit the hepatic β-oxidation and increases the expression of transcription factors for the de novo lipogenesis, as sterol-regulatory binding protein 1c (SREBP-1c). In parallel, the excess blood glucose is absorbed by the liver and metabolized to acetyl-CoA, which is important for the de novo lipogenesis. Lipolysis in VAT as well as decreased hepatic β-oxidation and increased de novo lipogenesis are the major drivers for the genesis of hepatic steatosis and for the progression in NASH and cirrhosis [8].

During the last years, several studies described the role of sugar-sweetened beverages and fructose as central factors involved in NAFLD. However, this topic is still a matter of debate [9]. In this issue Hamza et al. assess the relationship between the fructose intake and NAFLD in obese and normal-weight children. In particular, the authors demonstrate that a higher fructose intake is associated with an increased grade of NAFLD [10]. However, also a high consumption of saturated fat and cholesterol and a low intake of polyunsaturated fatty acids, fiber, vitamin C and vitamin E have been found as risk factors in children and adolescents to develop NAFLD [6]:

One major problem regarding the diagnosis of NAFLD is a lack of non-invasive methods and surrogate markers for the progression of the disease. Liver biopsy represents the gold standard to define the grade of non-alcoholic fatty liver. However, this method is invasive and painful and thus not suitable for early diagnosis and prevention of severe liver injury within a routine checkup. Therefore, it is challenging and important to find surrogate markers for NAFLD. A recent study has shown that many of the normally used markers of NAFLD such as increases in liver enzymes (ALT) or uric acids present a low sensitivity [11], therefore new and more specific markers are needed. In this issue Kan et al. propose two markers of NAFLD: vascular endothelial cadherin (VE-Cad) and thrombomodulin (TM), both normally expressed by vascular endothelial cells. The authors consider three different groups: lean children and overweight/obese children with and without NAFLD. In all study participants, VE-Cad and TM in the serum were measured. One of the main results of this study shows that both these markers are significantly increased in the overweight/obese children with NAFLD compared to non-NAFLD, while ALT levels were not significantly different between the two groups. Furthermore, VE-Cad and TM were positively correlated with BMI and ALT, therefore they could play a new role in the diagnosis of NAFLD [12]. Another study proposes high procollagen type III N-terminal peptide (P3NP) as a potential marker of NAFLD with a cutoff value of 8.5 ng/mL [10]. One of the new proposed markers for metabolic diseases and NAFLD is represented by ferritin. In fact, it is known that serum ferritin predicts metabolic syndrome and NAFLD in adults. However, no consistent data are available for the pediatric population. Yi et al. investigate the association of ferritin levels with metabolic syndrome and elevated ALT levels in 4855 children and adolescents who participated in the Korea National Health and Nutrition Examination Survey from 2007 to 2012). This study demonstrates that elevated serum ferritin levels are independently associated with the metabolic syndrome or elevated ALT levels already in children and adolescents [13].

Thereby, it is very important to identify the NAFLD in a very early stage of disease in order to prevent further side effects, considering that NAFLD, at the early stage, is reversible only by life style intervention. These studies underline the importance of finding more surrogate markers for the early diagnosis of NAFLD.