Introduction

Eating habits of western countries have considerably changed in the last decades, with an increased consumption of foods and beverages high in saturated fats and carbohydrates and low intake of fibres, often coupled with sedentary lifestyle. These conditions lead to the development of metabolic disorders (obesity, type 2 diabetes mellitus (T2DM), cardiovascular diseases and non-alcoholic fatty liver disease (NAFLD) also in children [1].

NAFLD represents the most common cause of chronic liver disease in children and adolescents, mainly related to the increased worldwide incidence of obesity in the paediatric population. The exact prevalence of paediatric NAFLD is actually unknown, but available data report a prevalence ranging from 3 to 12 % in the general paediatric group, with peaks of as much as 70 % in obese children [2]. NAFLD is characterised by accumulation of fat in the hepatocytes (>5 %) in the absence of other causes of liver steatosis, such as Wilson’s disease, deficiency of alfa-1-antitripsin, celiac disease, autoimmune hepatitis, HCV infection, metabolic disorders, and alcohol or drug consumption. The simple hepatic steatosis is usually a benign condition, but in some cases it progresses to more advanced forms of liver damage, characterised by the presence of inflammation and various degrees of fibrosis [non-alcoholic steato-hepatitis (NASH)] up to cirrhosis, predisposing to liver failure and/or hepatocellular carcinoma (HCC) [3].

Several evidences have clearly demonstrated that many components of the diet are strictly involved in the development of visceral obesity and insulin resistance since they play an important role in the pathogenesis of T2DM, NAFLD and metabolic syndrome (MetS) [4]. As a matter of fact, to date, many studies show that NAFLD should be considered as one of the diagnostic criteria for MetS. Atabek et al. found that the prevalence of MetS in children with NAFLD, diagnosed after both IDF and WHO criteria, was 25.5 and 20.8 %, respectively. In addition, the hazard ratio for NAFLD was 7.06 (CI 1.29–5.50) in the MetS group (diagnosed in accordance with IDF criteria) [5].

In the last decades, the consumption of soft drinks, energy drinks and alcohol has been increasing exponentially in the paediatric age [6].

In 2010, the European Food Safety Authority (EFSA) conducted a study to evaluate the consumption of energy drinks in 52,000 participants—14,500 adults, 32,000 adolescents and 5,500 children—coming from 16 different European countries. The study confirmed the relevant increase of energy drink consumption in Europe, mainly in adolescents. In fact, the 68 % of enrolled adolescents referred to habitually consume sugary energy drinks, while this prevalence decreased to 30 % in adults and to 18 % in children. Moreover, this study showed that consumption of alcohol is as frequent among adults (56 %) as it is among adolescents (53 %). Additionally, EFSA estimated that the intake of caffeine and taurine was higher in children (48 %) than in adolescents (16 %) and adults (13 %), since children were regular consumers of beverages containing caffeine [7]. A recent Italian study on 870 adolescents (aged 15–19 years) confirmed the European percentages, showing that 55 % of Italian adolescents regularly consume energy and soft drinks, and that in the 63 % of cases these beverages are mixed with alcohol. Finally, it was reported that only 13 % of adolescents know the composition of such beverages, while the others consider them similar to rehydration drinks [8].

In this review, we discuss the role of these beverages and their components in the pathogenesis and progression of NAFLD/NASH in paediatric patients.

NAFLD

In the United States, the prevalence of overweight/obesity in children has tripled over the past 30–40 years. It was recently reported that in America, 32 % of adolescents are affected by overweight and 16.9 % by obesity [9]. In Europe, almost everywhere, the prevalence of paediatric obesity is increasing and, in some countries, it almost reaches the American percentages. In fact, childhood obesity is one of the primary public health emergencies in highly developed countries. The epidemic of childhood obesity in the recent years is responsible for the appearance—also in the paediatric population—of diseases previously observed exclusively in adulthood, such as MetS, T2DM and NAFLD [10].

NAFLD now represents the most common liver disease in adults and children, usually related to the presence of other metabolic impairments, such as visceral obesity, insulin resistance/T2DM, dyslipidemia and MetS [11]. As previously stated, the histological hallmark of NAFLD is the accumulation of lipids in hepatocytes, with involvement of at least 5 % of hepatic cells (simple steatosis). The accumulation of lipids in the hepatocytes is caused by an imbalance between input and output of free fatty acids (FFAs) in the hepatic cells. When the amount of FFAs in hepatocytes exceeds the capacity of storage and use for energy purposes, the FFAs are redirected to different metabolic pathways, with intracellular accumulation of toxic metabolites, causing damage of mitochondrial structures and activation of inflammatory response. When intracellular anti-oxidant mechanisms are saturated by oxygen free radicals (ROS) and other oxidant species, lipid peroxidation is activated with production of several cytokines and adipokines (TNF-α, IL-6, leptin and adiponectin), which contribute to inflammation, hepatocyte apoptosis and collagen deposition, leading to fibrosis. Another important role in the development of hepatic injury is played by the intestinal microbiota that, following imbalanced diet and altered intestinal permeability related to obesity, produces endotoxins which activate the innate immune response in the liver [12]. Although the mechanisms of progression of liver damage in NAFLD/NASH remain unclear, the “multiple hits” theory is now accepted. According to this theory, several genetic and epigenetic factors, as well as metabolic agents (insulin resistance, inflammation, oxidative stress and intestinal dysbiosis), interact in the complex mechanism of disease progression [12, 13].

The first diagnostic step in obese children (BMI >95th and WC >95th percentile), with chronically elevated aminotransferase values, should be abdominal ultrasound scan and liver function tests, also to exclude other liver diseases. Children with normal ultrasound and normal liver function tests should be monitored and re-tested, due to the low sensitivity of these tests in a single assessment. Several studies have suggested other anthropometric parameters (waist circumference and sagittal abdominal diameter [SAD]), the abdominal bioelectrical impedance analysis (BIA), and several abdominal ultrasonographic measurements for the diagnosis of NAFLD and NASH, without useful results [14, 15]. In fact, to date, liver biopsy remains the gold standard for the diagnosis and the detection of liver damage progression, especially when it is necessary to exclude other treatable diseases in case of clinical suspected advanced liver disease.

NAFLD and diet

It is currently known that the consumption of diet high in carbohydrates, mainly simple sugars, and saturated fats are associated with hepatic steatosis and NASH, especially in the adult population [16]. Studies on obese adolescents have demonstrated that fatty liver, assessed by abdominal ultrasound, is associated with the intake of sugar [17].

In 2014, the World Health Organization (WHO) and the Scientific Committee of the United Kingdom on Nutrition (SACN) tried to define the first guidelines for daily dietary sugar consumption. More than 1.700 papers on this topic were evaluated, in this meta-analysis, concluding that sugar intake is a close determinant of body weight [18]. At the same time, SACN recommended that sugars should provide no more than 10 % of the daily food energy intake [19].

Therefore, it is recommended that about 5 % of dietary energy should be obtained from the consumption of plain sugar to get no more than 10 % of total energy intake and that the consumption of sweetened beverages should be minimised [20]. These new recommendations are much stricter than those from the United States, which suggest a maximum consumption of sugar of 25 % of total energy [21].

Given the marked increase in consumption of sugary beverages observed in the last decades in paediatric age, this aspect should be carefully considered in the evaluation of metabolic disorders, such as NAFLD, in paediatric patients.

Soft drinks (SDs) and NAFLD

Soft Drinks (SDs) are carbonated beverages, including soda, tonic, Coke™, and Pepsi™. The “SDs classics” are sweetened with monosaccharides, in particular fructose and glucose, or their progenitor sucrose (the common sugar), while the “SDs light” contains non-caloric sweeteners, the most common and widely used of which is aspartame.

The SDs should be presently considered as an important component of the diet in western countries. They can account for as much as 15 % of daily calories, considering that a common serving of any SD (330 ml) contains an average of 125 kcal, distributed as follows: 1.0 g of protein, 28.4 g of carbohydrates and 0.3 g of lipids [22]. Several studies have demonstrated that the consumption of SDs in adults is associated with a higher risk of MetS, obesity, NAFLD, and insulin resistance. Recently, the Framingham Heart Study reported a cohort of 6039 participants (mean age 52.9 years) who, at enrolment, had MetS. After 4 years, 717 (17.8 %) out of 4033 participants who consumed SDs <1/day developed MetS, vs. 433 (21.6 %) in the group of 2006 participants consuming SDs ≥1/day. Moreover, this study demonstrated that patients who consumed SDs ≥1/day had a higher risk of MetS (odds ratio [OR] 1.48; 95 % CI 1.30–1.69), obesity (OR 1.31; 95 % CI 1.02–1.68), increased waist circumference (OR 1.30; 95 % CI 1.09–1.56) and impaired fasting glucose (OR 1.25; 95 % CI 1.05–1.48), compared to those consuming <1 drink/day [23].

Fructose

Fructose, a simple ketonic monosaccharide commonly found in fruits and honey, is added to many drinks for palatability and taste enhancement. Fructose is phosphorylated in the liver by the fructokinase enzyme, forming fructose-1-phosphate, which can be converted in three different molecules: glyceraldehydes, dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. These three molecules can be used for gluconeogenesis or to generate lipids, such as very low-density lipoprotein (VLDL). In addition, fructose can bypass the fructokinase enzyme, enter glycolysis, and through an esterification process synthesize triglycerides. It has also been shown that fructose can trigger the activation of pathways involved in the lipogenesis as well as in liver inflammation and insulin metabolism [24, 25]. Recently, it has been reported that increasing fructose consumption causes an increased intestinal permeability with translocation of endotoxins by the toll-like receptor-4 (TLR-4) pathway, thus contributing to the development of NAFLD/NASH [26]. Several subsequent clinical studies have demonstrated that an excessive consumption of fructose is associated with obesity, insulin resistance and NAFLD both in adults and children. Studies in healthy subjects have actually demonstrated that a 4-week moderate fructose supplementation (1.5 g/kg/daily) increases plasma triglycerides and fasting glucose, and a 7-day high-fructose diet (3.5 g/kg/daily) causes dyslipidemia and ectopic lipid accumulation (in liver and muscle) [27, 28]. As demonstrated by Ouyang and co-workers, fructose consumption is higher (two or three times) in subjects with NAFLD compared to healthy controls [29]. Furthermore, the phosphorylated derivatives of fructose cause a rapid depletion of high-energy phosphate compounds in the cells [adenosine triphosphate (ATP)] with production of uric acid. Several studies described the role of uric acid in the development and progression of fatty liver and endothelial damage, through release of pro-inflammatory cytokines [30, 31].

In summary, even if available data are not sufficient to demonstrate a causative role of fructose per se in the development of NAFLD, the evidence of inducing visceral obesity, insulin resistance, dyslipidemia and intestinal endotoxemia by high-fructose diet is sufficient to recommend a reduction in fructose consumption among patients at risk to develop fatty liver and/or affected by NAFLD/NASH [4].

Aspartame

The aspartame is used, alone or in combination with sugar and sugar-derivatives, as a sweetener for production of light beverages. The aspartame is an amino compound, 160 times sweeter than sugar. It is absorbed from the bowel and metabolized by the liver with production of phenylalanine, aspartic acid and methanol.

The role of aspartame is very complex and to date there are no studies in humans about its effect on the pathogenesis of liver damage in NAFLD. Preliminary animal data have shown that a long-term administration (approximately 9 weeks) of at least 35 mg/kg/day of aspartame induces lipid peroxidation in the liver due to the reduction of the antioxidant cellular systems (glutathione peroxidase, catalase, superoxide dismutase). Moreover, it caused an increase of serum aminotransferase levels and lipids (triglycerides and total cholesterol). This data seem to indicate that aspartame may induce hepatic damage by oxidative stress and alteration of glutathione-dependent system [32].

Energy drinks (EDs) and NAFLD

The EDs are non-alcoholic beverages containing stimulants which are supposed to have a positive effect on physical and mental energy with consequent improvement of sports and cognitive performance. Caffeine is the main stimulant substance contained in the EDs. Other ingredients frequently present are taurine, carnitine, vitamins B, ginseng and other plant derivatives (Table 1). The energy content in EDs is about 44 kcal/100 ml, all of them contributed by carbohydrates (11 g/ml). In the last decades a “boom” in consumption of EDs has been observed. In the US an increase of average annual sales amounted to 55 %, with a market volume of 5.4 billion dollars per year. Fifty-one percent of American college students declare to consume EDs more than once a month [33]. In Europe, the EFSA published in 2013 data regarding the consumption of EDs in European children and adolescents. This study revealed that 68 % of adolescents habitually consume EDs and that 12 % of them ingest an average of 7 l of EDs in a month. Among children aged 4–10 years, 18 % are regular consumers of EDs, while 16 % takes an average quantity of 0.95l, a week. In this study, the consumption of caffeine, contained in these drinks at a concentration of about 400 mg/l, resulted at the highest level in the paediatric population [34].

Table 1 Energy drinks: ingredients and effects
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Xanthine

The principal xanthine contained in EDs is caffeine, which is mainly found in coffee beans, but also, together with other xanthines, in cacao beans, tea leaves and cola nuts. Caffeine added to EDs comes mainly from the latter source.

The caffeine reaches the bloodstream within 30–40 min of ingestion. It is distributed throughout the body, and then metabolized and excreted in the urine. The half-life of caffeine in the body is 4 h. Increased alertness and sustained attention for a variable time, after caffeine assumption, is well documented, its primary action as a stimulant of the central nervous system being due to its action as an adenosine antagonist. Caffeine blocks adenosine receptors in the nerve tissue, particularly in the brain, maintaining a waking state [35].

Recent studies demonstrated a protective effect of caffeine in NAFLD, showing a decreased risk of fibrotic damage in caffeine consumers. In fact, the study of Catalano et al. had suggested a decrease in fatty liver ecographic severity in coffee drinkers compared to non-coffee drinkers (β = −2.58, p = 0.01; CI −0.13 to 0.018). Moreover, the coffee was inversely associated with obesity and insulin resistance [36].

Recently, Molloy et al. have evaluated the consumption of coffee in 306 patients with biopsy-proven NASH. Their data demonstrate that coffee consumption is significantly higher in patients with initial stage of NASH, when compared with patients with advanced forms of NASH (advanced fibrosis) [37].

Several studies have been conducted in the last years to elucidate the anti-fibrotic mechanisms sustained by caffeine. Available data suggest that caffeine reduces the production of transforming growth factor beta (TGF-β), by decreasing the activation of hepatic stellate cells and, consequently, reducing the production of collagens and inhibiting other mechanisms of fibrosis [38].

Taurine and Niacin

Although caffeine appears to have a protective role in the modulation of liver inflammation and fibrosis, it must be said that many EDs contain additives, such as taurine, vitamins B and other ingredients that have an important role in the development of obesity, insulin resistance and NAFLD. As a matter of fact, several cases of hypertransaminasemia and liver damage, even progressive up to cirrhosis and fulminant hepatitis, have been previously described following the consumption of EDs high in niacin (vitamin B3). It has been reported that doses of vitamin B3 > 2000 mg/day increase the risk of hepatotoxic events of about 50 times. In 2014, a case of fulminant hepatitis requiring liver transplantation was reported in a 36-year-old man, who consumed three cans daily of EDs for 1 year (about 120 mg/daily of niacin) [39]. Niacin is used at pharmacological doses for the treatment of hypertriglyceridemia. A recent study shown that niacin improved lipid profile with a 28 % decrease in triglycerides and an increase of 17 % in HDL-C; however, in patients with MetS, it induced insulin resistance also in the liver, with deterioration of the NAFLD, after 8 weeks of treatment. The mechanism may be associated with the action of niacin on the enzyme diacylglycerol acyltransferase 2 (DGAT2). Actually, the over expression of DGAT2, caused by high doses of niacin, induces significant hepatic steatosis through triglyceride accumulation in hepatocytes.

Moreover, it should be considered that EDs have a high caloric content, which increases the risk to develop T2DM, obesity and NAFLD [40].

Another worrisome aspect of EDs is represented by the practice, more and more frequent among adolescents in the last ten years, to consume then in combination with alcohol. This combined use is associated with a higher risk of adverse effects. Several studies demonstrated that this mix induces a lower perception of symptoms of alcohol intoxication, such as headache, fatigue and dry mouth. Moreover, the effect of mixture of coffee and alcohol increases the risk of alcohol dependence, accidents or violent behaviour [41]. To date, no studies have been performed, in vivo or in vitro, on the combined use of alcohol and EDs and its effect on the liver tissue. The FDA recommends in the EDs a maximum of 0.02 % of caffeine, which means 71 mg per (12 oz) 350 ml of beverage [42].

Alcohol and NAFLD

Alcohol use among adolescents is increasingly popular. In a study conducted in a population of European students (aged 15–16 years), 57 % affirmed that they had been consuming alcohol in the last month. More specifically, 25 % of adolescents used to drinking at least once a week, and 39 % declared to have consumed five or more drinks in the last 30 days [43]. Binge drinking is the most common pattern of alcohol consumption among young people, and is characterised by large assumption of alcohol in a short time. In the USA adolescents, 22.7 % of males and 7.2 % of females were reported as binge drinkers [44].

The consumption of alcohol has different effects, causing liver, heart and brain damage. Alcohol consumption during childhood and adolescence increases the risk in younger adults of pathologies like cancer, hepatic cirrhosis, respiratory and cardiovascular diseases [45].

Considering the increasing use of alcohol between adolescents and the widespreading of NAFLD in paediatric patients, these factors could interact in the pathogenesis of liver damage, increasing the risk of chronic liver diseases, cirrhosis and liver cancer in young adults in the near future [46].

The mechanisms responsible for alcoholic steato-hepatitis (ASH) and NASH can have synergistic effects on the progression of liver damage. Both are supported by oxidative stress, derived from lipid peroxidation inducing the pro-inflammatory and pro-fibrogenic effects of reactive oxygen species [47, 48]. Therefore, coexistence of alcohol abuse with fatty liver tends to maximise the role of oxidative stress making liver tissue predisposed to inflammation and fibrosis. Moreover, the oxidation of ethanol, associated with the reduction of nicotinammide adenine dinucleotide (NAD to NADH), promotes the synthesis of FFAs causing the accumulation of triglycerides in hepatocytes [49]. In addition, several studies have demonstrated that alcohol abuse induces peripheral insulin resistance by itself.

It should always be kept in mind that, beside its toxicity, alcohol is a highly caloric beverage (7.1 cal/g) that can imbalance the energy intake and induce obesity. Recently, the American Medical Association (AMA) showed that many drinkers are overweight or obese, confirming the positive association between alcohol consumption and risk of obesity [50].

Another interesting common point between alcohol abuse and NAFLD is represented by the increased intestinal permeability. In the last years, the importance of the so-called “gut liver axis” in chronic hepatopathies, such as NAFLD, has been highlighted. Obesity induces a modification of the pattern of gut microbiome, which, in presence of increased intestinal permeability, permits the passage of damaging microbial products (endotoxin) into the portal circulation, causing the activation of pro-inflammatory and pro-fibrogenic hepatic pathways through TLR-4. Alcohol destroys cells in the intestinal epithelial tight junctions and impairs the function of the intestinal barrier, with greater entry of bacteria metabolites in the portal vein [51]. In fact, an increased intestinal permeability, due to the breakdown of tight junctions caused by ethanol and acetaldehyde, with a greater entrance of lipopolysaccharide (LPS), endotoxins and bacterial DNA in the liver, has been demonstrated in the bowel of habitual consumers of alcohol.

Discussion

Non-communicable diseases represent now a growing health burden and the leading cause of death globally. The global changes in dietary and behavioural habits have contributed to the onset of this new epidemic. In fact, in the last 20 years, the sedentary lifestyle associated to unhealthy hypercaloric diets and a widespread diffusion of sugary drinks has induced the onset of this new scenario in Western Countries. Several studies demonstrated that this rising trend in simple sugar consumption is positively associated with weight gain/obesity and related co-morbidities, such as T2DM, MetS and NAFLD. It is difficult to define the role of the various single components of SDs and EDs both in the pathogenesis of NAFLD and in its progression to NASH, but to date it seems that high caloric and high sugar, mainly fructose, contents play the major role. Not to be forgotten, though, that also other components of these beverages (e.g. xanthine) seem to have an important role in crucial pathogenetic pathways of metabolic disarray involved in NAFLD/NASH (Fig. 1).

Fig. 1
figure 1

The different hepatic mechanisms of sweetened drinks in the pathogenesis of NAFLD and progression of liver damage

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The drastic reduction of beverages, such as EDs and SDs, represents an appropriate intervention for the prevention of obesity and related metabolic co-morbidities, such as NAFLD, especially among young people.

At the present time, it seems that the intervention on lifestyles can be considered as the only established therapy for NAFLD in children. Nonetheless, in a very recent study (2016), the authors demonstrated that a lifestyle change applied for 6 months to 51 obese children with NAFLD led to a reduction of fatty liver in 43 % of those hospitalised vs. a reduction in 29 % of those followed as outpatients. This shows that the changes in lifestyles, even when closely monitored, are unable to obtain top results, at least in the paediatric population [52].

Effective interventions to address the problem should be performed either individually or at the household level, trying to help parents in regulating the consumption of unhealthy foods and beverages. On the other hand, paediatricians are not exempt from this multi-task issue: they should provide age- and development-appropriate anticipatory guidance to families, to avoid these unhealthy behaviours. At the same time, a better knowledge of the role of these substances in the pathogenetic mechanisms of metabolic disorder and in NAFLD should permit the identification of novel targets for the treatment of these diseases.