Paediatric Nonalcoholic Fatty Liver Disease

Anna Alisi; Guido Carpino; Valerio Nobili


Curr Opin Gastroenterol. 2013;29(3):279-284. 

In This Article

Risk Factors and Pathogenesis

Although paediatric NAFLD tends to track to adulthood form representing an early beginning of the pathological process, it is prevalently of primary origin making it more easy to identify risk factors and pathogenetic mechanisms. Specific genotypes, intrauterine environment and postnatal nutrition are widely recognized as the major risk factors for development and progression of NAFLD in children.


On the basis of the lower number of confounding factors (e.g. the duration of disease, comorbidities and drugs), genetic background represents a major component in paediatric NAFLD. In fact, during the last year, genetic studies have highlighted several single nucleotide polymorphisms (SNPs) that may characterize children with a high risk for NAFLD development and progression.[3,13,14,15,16,17]

Mutations in the gene encoding for the patatin-like phospholipase domain-containing protein-3 (PNLA3), and in particular the common rs738409 C>G SNP, are associated with increased liver enzyme serum levels and liver steatosis, and influence the NASH risk and histological severity of fibrosis in obese paediatric patients.[13]

More recently, several additional SNPs of genes implicated in NAFLD pathogenesis have been shown to influence disease severity and fibrosis progression in paediatric individuals. Among these SNPs, there are the rs2854116 SNP of glucokinase regulator that predisposes to steatosis and dyslipidemia in obese paediatric individuals independently of PNPLA3;[18] the C47T rs4880 SNP of manganese superoxide dismutase 2 that is involved in the regulation of hepatocyte metabolism and fibrogenesis;[19] rs13412852 SNP influencing the expression of lipin-1 protein that results significantly associated to lipid levels, NASH severity and hepatic fibrosis in children;[14] the rs35761398 SNP of cannabinoid receptor type 2 gene that is associated with inflammation, and NASH severity and presence;[15] the rs8192678 SNP of the gene encoding for the peroxisome proliferator activated receptor-[gamma] coactivator-1a that is associated with an increased risk of NAFLD, independently of PNPLA3.[16]

More recently, a major advance has come from the recognition first obtained by genome-wide association studies (GWAS) conducted in a population-based cohort (Raine Study) of 928 adolescents (17 years) assessed for NAFLD. The GWAS demonstrate that SNPs in two genes, one encoding for lymphocyte cytosolic protein-1 and the other for lipid phosphatise related protein type 4, expressed in liver are associated with NAFLD in adolescents. Interestingly, also SNPs in two genes expressed in neurons are associated with NAFLD in the same cohort.[17]

Intrauterine Environment

Several epidemiological studies have shown that impaired intrauterine environment is crucial for metabolism. Suboptimal intrauterine conditions, particularly malnutrition, may lead to foetus adaptive responses, permanently reprogramming tissue structure and functions.[20] Once the organism is programmed in response to an adverse uterine environment, the exposure to different postnatal environmental conditions, such as overnutrition, will determine a mismatch between intrauterine and extra-uterine environments eventually leading to the increased risk of metabolic syndrome features and paediatric NASH.[21,22] Susceptibility of both of these diseases is increased by formula feeding used to counteract intrauterine growth retardation, and interestingly, it has been reported that breastfeeding is protective for the development of NASH in children.[23,24] This evidence highlights that an early adequate peri-conceptional and prenatal nutrient intake should be ensured to avoid the negative effects of metabolic programming on paediatric livers.


Unhealthy diet and sedentary lifestyle, such as excessive television watching coupled with extremely reduced physical activity, are the major causes of energy imbalance between intake and consumption of calories that lead to obesity and related diseases, such as metabolic syndrome and NAFLD. Particularly, low-cost diets including those enriched in fat, sugar and salt, and energy-dense and micronutrient-poor foods increase the risk of obesity, metabolic syndrome and NAFLD in children and adolescents of industrialized countries.[3,25]

Accordingly, a recent study[26] demonstrates that dietary cholesterol is a strong risk factor for NAFLD development in Greek children with high levels of triglycerides and low-density lipoprotein cholesterol. The pro-steatotic effect of dietary cholesterol may be due to particular cholesterol metabolites (i.e. oxysterols), which are able to upregulate fatty acid synthesis and consequent intrahepatic fat accumulation.[27] Furthermore, in a recent 2-d, crossover feeding study, Jin et al.[28] report that dietary fructose induces a marked elevation of triglycerides and a decrease in high-density lipoprotein in children with NAFLD. Interestingly, this fructose-dependent dyslipidemic effect is more marked in children with NAFLD than in age-matched healthy individuals. Although, much is known about regulation of fructose metabolism in the liver, its multiple pathogenetic role in paediatric NAFLD is still unclear and requires further investigation.[29]

In summary, diet enriched in fat and fructose may act by favouring the occurrence of metabolic and cellular/molecular alterations that account for NAFLD pathogenesis.

Pathogenesis and Severe Organ Damage in Nonalcoholic Fatty Liver Disease Children

Mechanisms leading to paediatric NAFLD seem to be similar to those observed in adults, in which multiple factors are able to create a complex cross-talk between molecules and pathways contributing both to development and progression of the disease.

The 'multiple-hit theory' is to date adopted to explain the two steps of NAFLD: simple steatosis development and progression to NASH.[30] The insulin resistance and hepatic accumulation of fatty acids/triglycerides are crucial to make the liver more prone to secondary factors that lead to NASH. During this second phase of the disease, several secondary hits, including oxidative stress, mitochondrial dysfunction, immune system response and inflammation, cooperate to ultimately induce the liver damage that characterizes NAFLD. Importantly, a continuous organ cross-talk sustains all processes implied in NAFLD pathogenesis, and a crucial role of the gut has been suggested.[31] In fact, severe liver damage in NAFLD has been associated with gut dysbiosis and release of both pathogen and damage-associated molecular pattern molecules, which in turn activate pattern-recognition receptor signalling. Accordingly, lipopolysaccharide, one of the most studied pathogen-associated molecular pattern molecules, is associated with the severity of liver damage in paediatric NASH.[32] High-fat/fructose diet may disturb the gut microbiota configuration worsening hepatic steatosis, inflammation and fibrosis that in NAFLD children is characterized by the increase of intrahepatic CD45+ and CD163+ cells.[33]

The role of hepatic progenitor cells (HPCs) is another important piece of the puzzle of NAFLD. HPCs are located in the canals of Hering and are usually quiescent. The regenerative process, induced by partial hepatectomy or during fibrogenesis, promotes HPC proliferation and restores hepatocyte population, but the HPC compartment appears central also in the development of NAFLD-associated fibrosis via Hedgehog pathway.[34] Nobili et al.[35] have recently demonstrated that the HPC compartment is expanded in paediatric NASH and that this increase is significantly correlated with fibrosis degree. Swiderska-Syn et alet al.[36] provide the first evidence of the role of Hedgehog pathway in paediatric NAFLD. The authors demonstrated that the stage of liver fibrosis significantly correlated with the number of cells producing Hedgehog ligands and the number of Hedgehog responsive cells. Furthermore, the number of Gli2-positive cells was significantly associated with portal fibrosis justifying the histological pattern of paediatric NAFLD.