Association between Serum Atypical Fibroblast Growth Factors 21 and 19 and Pediatric Nonalcoholic Fatty Liver Disease

Atypical fibroblast growth factors (FGF) 21 and 19 play a central role in energy metabolism through the mediation of Klotho coreceptor. Contradictory findings are available about the association of FGF21 and FGF19 with nonalcoholic fatty liver disease (NAFLD) in humans. We investigated the association of serum FGF21, FGF19 and liver Klotho coreceptor with non-alcoholic steatohepatitis (NASH) and fibrosis in children with NAFLD. Serum FGF21 and FGF19 were measured in 84 children with biopsy-proven NAFLD and 23 controls (CTRL). The hepatic expression of Klotho coreceptor was measured in 7 CTRL, 9 patients with NASH (NASH+) and 11 patients without NASH (NASH-). FGF21 and FGF19 showed a tendency to decrease from CTRL (median FGF21 = 196 pg/mL; median FGF19 = 201 pg/mL) to NASH- (FGF21 = 89 pg/mL; FGF19 = 81 pg/mL) to NASH+ patients (FGF21 = 54 pg/mL; FGF19 = 41 pg/mL) (p<0.001 for all comparisons) and were inversely associated with the probability of NASH and fibrosis in children with NAFLD. The hepatic expression of Klotho coreceptor was inversely associated with NASH (R2 = 0.87, p<0.0001) and directly associated with serum FGF21 (R2 = 0.57, p<0.0001) and FGF19 (R2 = 0.67, p<0.0001). In conclusion, serum FGF19 and FGF21 and hepatic Klotho expression are inversely associated with hepatic damage in children with NAFLD and these findings may have important implications for understanding the mechanisms of NAFLD progression. © 2013 Alisi et al

The Role of Vitamin D in Sleep Disorders of Children and Adolescents: A Systematic Review

This review investigates the association between vitamin D and sleep disorders. Vitamin D is an essential nutrient known to play an important role in the growth and bone health of the human body, but it also appears to play a role in sleep. The goal of our review is to examine the association between vitamin D and sleep disorders in children and adolescents. We summarize the evidence about the role and the mechanism of action of vitamin D in children and adolescents with sleep disorders such as insomnia, obstructive sleep apnea (OSA), restless legs syndrome (RLS), and other sleep disorders. Systematic electronic database searches were conducted using Pubmed and Cochrane Library. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. The studies that met the established inclusion criteria were analyzed and compared. Results suggest a strict relationship between vitamin D deficiency in children and sleep disorders. There is evidence that vitamin D is implicated in the different neurochemical mechanisms involved in sleep regulation and mainly in the serotonergic and dopaminergic pathways. This might be responsible for the association of vitamin D deficiency and restless sleep, sleep hyperhidrosis, OSA, and RLS

Association between Serum Atypical Fibroblast Growth Factors 21 and 19 and Pediatric Nonalcoholic Fatty Liver Disease

<div><p>Atypical fibroblast growth factors (FGF) 21 and 19 play a central role in energy metabolism through the mediation of Klotho coreceptor. Contradictory findings are available about the association of FGF21 and FGF19 with nonalcoholic fatty liver disease (NAFLD) in humans. We investigated the association of serum FGF21, FGF19 and liver Klotho coreceptor with non-alcoholic steatohepatitis (NASH) and fibrosis in children with NAFLD. Serum FGF21 and FGF19 were measured in 84 children with biopsy-proven NAFLD and 23 controls (CTRL). The hepatic expression of Klotho coreceptor was measured in 7 CTRL, 9 patients with NASH (NASH+) and 11 patients without NASH (NASH−). FGF21 and FGF19 showed a tendency to decrease from CTRL (median FGF21 = 196 pg/mL; median FGF19 = 201 pg/mL) to NASH− (FGF21 = 89 pg/mL; FGF19 = 81 pg/mL) to NASH+ patients (FGF21 = 54 pg/mL; FGF19 = 41 pg/mL) (<i>p</i><0.001 for all comparisons) and were inversely associated with the probability of NASH and fibrosis in children with NAFLD. The hepatic expression of Klotho coreceptor was inversely associated with NASH (R² = 0.87, p<0.0001) and directly associated with serum FGF21 (R² = 0.57, p<0.0001) and FGF19 (R² = 0.67, p<0.0001). In conclusion, serum FGF19 and FGF21 and hepatic Klotho expression are inversely associated with hepatic damage in children with NAFLD and these findings may have important implications for understanding the mechanisms of NAFLD progression.</p></div

Association between the hepatic expression of Klotho, liver histopathology and serum FGF21 and FGF19.

<p>Association of Klotho with histopathology, FGF21 and FGF19 (see text for further details on statistical analysis). Abbreviations: log_e = natural logarithm; RMSE = root mean squared error of the estimate; R² = coefficient of determination; AIC = Akaike information criterion. Circles are means and bars 95% confidence intervals.</p

Measurements of children evaluated in the Klotho substudy.

<p>Medians not sharing the same superscript are significantly different at a level of <i>p</i><0.05 (quantile regression with Bonferroni’s correction).</p><p>Abbreviations: P = percentile; BMI = body mass index; ALT = alanine transaminase; AST = aspartate transaminase; GTT = gamma-glutamyl-transferase; FGF = fibroblast growth factor; FI = fluorescence intensity.</p

NASH and serum levels of FGF21 and FGF19.

<p>Distribution of serum FGF21 (panel <b>A</b>) and FGF19 (panel <b>B</b>) in controls, NAFLD children without NASH (NASH−) and NASH children with NASH (NASH+). Lines superimposed to dot-plots are medians.</p

Probability of NASH and fibrosis as a function of serum FGF21 and FGF19.

<p>Probability of NASH and fibrosis of any degree as a function of log_e-transformed values of FGF21 and FGF19 (see text for further details on statistical analysis). Abbreviations: NASH = non-alcoholic steatohepatitis; log_e = natural logarithm; AIC = Akaike information criterion. Circles are means and bars 95% confidence intervals.</p

Representative confocal immunofluorescence for expression and intracellular distribution of Klotho co-receptor.

<p>The representative confocal immunofluorescence was performed on liver tissue cryostat sections OCT-embedded. The staining of Klotho co-receptor in the overweight-obese children without NAFLD (<b>A</b>), in the NAFLD overweight-obese children without NASH (<b>B</b>), and in the overweight-obese children with NASH (C) is shown in green. The nuclei are revealed by specific DAPI staining, displayed in blue. The white bar represents a 30 µm length.</p

Liver histopathology of the 84 children with NAFLD.

<p>Abbreviations: NAS = NAFLD Activity Score.</p

Representative confocal immunofluorescence of Klotho co-receptor localization in liver tissues.

<p>The representative confocal immunofluorescence was performed on liver tissue cryostat sections OCT-embedded. (<b>A–C</b>) Co-staining of Klotho co-receptor (green) and CD163 (red) in children without NAFLD (<b>A</b>), with NAFLD NASH− (<b>B</b>) and with NASH+ (<b>C</b>). (<b>D–F</b>) Co-staining of Klotho co-receptor (green) and cytokeratin 8/18 (red) in children without NAFLD (<b>D</b>), with NAFLD NASH− (<b>E</b>) and with NASH+ (<b>F</b>). (<b>G–I</b>) Co-staining of Klotho co-receptor (green) and alpha-SMA (red) in children without NAFLD (<b>G</b>), with NAFLD NASH− (<b>H</b>) and with NASH+ (<b>I</b>). Yellow arrows indicate hepatic stellate cells. The white bar represents a 30 µm length. (<b>J</b>) Histological scores for panels from A to I.</p