The results of the present study indicate that higher BMI levels and moderate/severe liver steatosis are predictors for severe liver fibrosis in children and adolescents. Three months of nutritional intervention based on a low carbohydrate diet improved hepatic steatosis and fibrosis in a pediatric population with NAFLD.
Our data corroborate those of others [3, 7, 14, 15] by demonstrating a high rate of NAFLD with a significant percent of moderate to severe fibrosis in morbidly obese young individuals, reaching approximately 70% of our patients. Only few attempts have been made to stratify the risk for advanced fibrosis in this unique population [6–8]. Moreover, recent data have suggested that adult scores may not be accurate to predict advanced fibrosis in children [7, 16–17], thus establishing a clear need to evaluate noninvasive approaches in children as well. The pediatric NAFLD fibrosis index is based on age, waist circumference, and triglycerides, and it has been described by Nobili et al as a possible tool to predict liver fibrosis in children [4]. It is, however, limited by not including children with moderate/severe fibrosis. The recent pediatric NAFLD fibrosis score which included ALT, alkaline phosphatase, platelet counts, and gamma glutamyl transferase was reported to predict the presence of significant fibrosis, but it lacks external validation [6].
Our current results demonstrated that moderate/severe fibrosis correlated with higher BMI levels and moderate/severe steatosis. This reinforces previous findings which demonstrated that children and adolescent with severe obesity (BMI ≥ 120% of the 95th percentile or an absolute BMI ≥ 35 kg/m²) are more prone to severe complications, such as cardiovascular disease, dyslipidemia and inflammation [18, 19] compared to children and adolescents with obesity and lower BMI levels. This highlights the need for early dietary intervention, even among youngsters, before further complications develop and the severity increases.
The only metabolic parameter that was significantly related to moderate/severe fibrosis was lower LDL. Moreover, we found a trend for higher triglyceride levels among patients with lower fibrosis levels. These results may reflect the recent NASH Clinical Research Network data which demonstrated that zone 1 steatosis, while rare in adult populations, was highly prevalent in children with NAFLD, and that it represents a distinct sub-phenotype with unique metabolic and histologic parameters. Children with zone 1 steatosis had lower fasting triglyceride levels and lower fasting insulin according to the NASH report. However, zone 1 steatosis was found to have more fibrosis of any grade (81% vs 51) and more advanced fibrosis (13% vs 5%) compare to children with zone 3 steatosis [20]. Our findings did not include biopsy data, but these unique differences in metabolic parameters between subjects with moderate/severe fibrosis to patients with minimal or no fibrosis may also serve to emphasize the need for early intervention in NAFLD patients even if no other metabolic disorder is present.
Seventeen of our patients completed 3 months of follow-up with dietary interventions and repeated blood tests and elastography. There was a significant decrease in the BMI Z score with a significant decrease in liver fibrosis and steatosis scores at the end of follow-up. Moreover, ALT and triglycerides serum levels decreased significantly as well. There are several possible explanations for the significant restitution of liver fibrosis that was documented in our study after only 3 months. First, it may be due to the weight loss itself that was documented in our cohort. Reduction of visceral fat depots after weight loss protects against the overflow of fatty acids to the liver [21–22]. Increased availability of fatty acid, in turn, is pivotal to the pathogenesis of fatty liver, causing mitochondrial dysfunction and lipotoxicity [22]. Second, it may be due to the specific dietary intervention. The change in liver fat in our study occurred without major weight loss. This was also described in other studies of adults and children [21–23], suggesting the possibility of clinical benefit solely with low carbohydrate dietary modification, since a lower glycemic response causes less hepatic glucose absorption [24–26]. Several clinical trials demonstrated that a reduction of fructose or sugar consumption resulted in lower intrahepatic fat, lipogenesis, inflammation, and insulin resistance [24–26]. Moreover, because this diet does not restrict either fat or protein, it may also be more behaviorally sustainable and can therefore result in better adherence over time [28]. Lastly, it could be that the rapid and significant reversal in liver histology, compared to the adult population, stems from the differences in histologic distribution among the 2 populations in terms of inflammation and hepatocellular damage [16, 20, 29].
The main limitation of our study is the lack of liver biopsies for assessing NAFLD, which is still considered the gold standard for NAFLD diagnosis. However, the well-known limitations of liver biopsy and the fact that liver biopsy cannot be applied to all patients suspected of having NAFLD have led to the development of noninvasive methods for the assessment of liver fibrosis. Shear-wave elastography was recently shown to be an accurate and reproducible noninvasive technique that efficiently depicts the presence of liver fibrosis in the pediatric population with NAFLD [9, 17], with high levels of repeatability and reproducibility and a high intra-observer (ICC = 0.89–0.90) and inter-observer (ICC = 0.81–0.85) coefficients [30–31]. Other limitations of our study are the lack of a control group and the 3-month follow-up period that may not have been long enough to observe the full extent of influence of macronutrient contents on NAFLD and fibrosis. Nevertheless, the prospective nature of this study and the fact that each patient serves as his/her own control enables us to draw important conclusions about the need for early intervention in the obese pediatric population with NAFLD, and be encouraged by the results that testify to the ability of histological improvement if appropriate treatment is offered in time.