Pediatric liver diseases: current challenges and future perspectives

Chronic liver diseases in children represent a rising problem with significant effects on public health. In fact, several pediatric liver diseases are precursors of adult chronic hepatopathies, cirrhosis and hepatocellular carcinoma. The prevalence of liver diseases in children is unknown. In the USA, every year, 15,000 children are hospitalized for liver diseases, but these disorders continue to be under-recognized or diagnosed late. The main reason is due to the frequent absence of symptoms in the vast majority of liver diseases, especially in the early stages. In the last few decades several advances have been made in understanding the pathogenesis of liver diseases, permitting the discovery of new therapeutic targets to treat liver diseases, thus improving the natural history of these disorders. In this article we discuss the most recent advances in the understanding of the pathogenesis, diagnosis and treatment of the most frequent pediatric liver diseases

Variations in exhaled nitric oxide in children with asthma during a 1-week stay in a mountain village sanatorium

Knowing about spontaneous variations in the fractional concentration of exhaled nitric oxide (FE(NO)) could improve monitoring of airway inflammation in asthmatic children. We aimed to assess FE(NO) variations (expiratory flow 50 mL/sec) in subjects maintained in similar environmental conditions. We tested spirometry and FE(NO) in symptom-free asthmatic children (9 corticosteroid-naive, 8 corticosteroid-treated) during a 1-week stay in a countryside sanatorium and in their healthy relatives (n = 12) staying in the immediate neighborhood on summer holiday (total 29 children, M/F: 14/15, 5.8-16.8 yrs). Testing sessions were repeated every 12 hours (8: 00 AM, 8: 00 PM) for 2 days and again on day 7. Measurements were defined as reproducible when they agreed with an intraclass correlation coefficient (ICC) above 0.60; deviation from mean differences was assessed by the coefficient of repeatability (CR = 2 SD). Lung function remained constant throughout the week in all groups. Baseline FE(NO) levels in corticosteroid-naive asthmatic children tended to decrease at the end of the week (from 13.9 ppb, 95% CI 12.2-19.1 to 9.2 ppb, 95% CI 5.8-15.9, p = 0.057). No differences were found between nocturnal and diurnal FE(NO). Within-session reproducibility for two FE(NO) measurements was high (ICC 0.99 in all groups and CR, 0.9 to 1.3 ppb). Between-session FE(NO) reproducibility at 12 hours and 24 hours was still high for each group but decreased markedly after 6 days in corticosteroid-naive asthmatic children (ICC 0.79 and CR 9.6 ppb at 24 hours vs. ICC 0.13 and CR 20.8 ppb after 6 days), whereas it decreased slightly in corticosteroid-treated asthmatics (from ICC 0.89 and CR 3.1 ppb to ICC 0.88 and CR 3.0 ppb) and healthy children (from ICC 0.79 and CR 4.8 ppb to ICC 0.65 and CR 5.7 ppb). In conclusion, in healthy subjects and in asthmatic children receiving therapy with inhaled corticosteroids (but not in corticosteroid-naive subjects), FE(NO) measurements are reproducible across a week

Elevated Hemoglobin Level Is Associated With Advanced Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease

OBJECTIVES: Hemoglobin (Hb) and red blood cell distribution width (RDW) have been reported to be a risk marker of metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). No study exists on pediatric populations. We aimed to determine the association between hematological parameters, and the severity of disease in children with biopsy-proven NAFLD. METHODS: A total of 117 children (85 boys, mean age 12 years) with ultrasound evidence of NAFLD undergoing liver biopsy for diagnosis of nonalcoholic steatohepatitis (NASH), were prospectively enrolled between January 2011 and May 2013 in the setting of a tertiary care center. Children were screened for routine hematological and metabolic parameters, and causes of liver steatosis other than nonalcoholic were excluded, before liver biopsy was performed. RESULTS: A total of 41 NAFLD (boys 29, mean age 11.2 years) and 76 NASH (boys 56, mean age 12.8 years) children were studied. Alanine transaminase levels were significantly higher in NASH group compared with NAFLD group (P\u200a=\u200a0.05), and homeostatic model assessment of insulin resistance and triglycerides levels (P\u200a=\u200a0.03 and 0.02, respectively). Regarding hematological components: red cell count, Hb, hematocrit, and RDW values were all significantly higher in NASH group compared with NAFLD group (P\u200a<\u200a0.05 for each parameter). CONCLUSIONS: Children with NASH were more likely to have high levels of RDW compared to those with steatosis only. Moreover, NASH was associated with higher red cell count, Hb, and hematocrit. If confirmed in future follow-up studies, hematological parameters may be introduced in algorithms for NASH risk prediction

Cannabinoid Receptor <em>Type 2</em> Functional Variant Influences Liver Damage in Children with Non-Alcoholic Fatty Liver Disease

<div><p>Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor <em>type 2</em> (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis.</p> <p>Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically-proven NAFLD.</p> <p>CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage.</p> <p>We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (<em>p</em> = 0.002) and the presence of NASH (<em>p</em> = 0.02).</p> <p>Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage.</p> </div

Clinical and Laboratory Characteristics of the 118 Italian Pediatric Patients with biopsy-proven NAFLD.

<p>Values are expressed as means ± standard deviations. Abbreviations: BMI: Body Mass Index; HOMA-IR: homeostatic model of assessment of insulin resistance; ISI: insulin sensitivity index; IGT: Impaired Glucose Tolerance; ALT: alanine transaminase; AST: aspartate transaminase; Gamma-GT: Gamma-Glutamyl transferase; NASH: nonalcoholic steatohepatitis; G = grading.</p

Clinical and laboratory characteristics of the 118 Italian children with NAFLD stratified by the rs35761398 <i>CNR2</i> SNP encoding for the Q63R CB2 protein variant.

<p>Values are expressed as means ± standard deviations or as numbers and percentages. Mean values are compared by analysis of ANOVA. GLM analysis including gender, age, waist circumference and HOMA-IR as covariates has been used to compare continuous variables. Abbreviations: BMI: Body Mass Index; HOMA-IR: homeostatic model of assessment of insulin resistance; ISI: insulin sensitivity index; IGT: Impaired Glucose Tolerance; ALT: alanine transaminase; AST: aspartate transaminase; Gamma-GT: Gamma-Glutamyl transferase.</p

<i>CNR2</i> rs35761398 genotype and susceptibility to NASH.

<p><b>A</b>) Relationship between the <i>CNR2</i> rs35761398 genotype and the presence of NASH in 118 children with NAFLD (<i>p</i> = 0.02). Fifty-three out of 118 patients show definitive NASH. Among these NASH subjects 2 were homozygous for the CB2 Q63 allele, 23 were CB2 Q63R heterozygous and 28 homozygous for the CB2 R63. <b>B</b>) Relationship between the <i>CNR2</i> rs35761398 genotype and the presence of NASH in 55 I148M PNPLA3 heterozygous children with NAFLD (<i>p</i> = 0.001). Among I148M PNPLA3 subjects 38 out of 55 show definitive NASH and were all QR or RR for the CB2 Q63R variant. Age, sex, waist circumference and HOMA-IR index have been used as covariates.</p