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Summary: Objectives: The liver‐specific miR‐122 was proposed as biomarker for NAFLD in adults. Here, we investigated the relationship between miR‐122 levels, parameters of liver metabolism and NAFLD in pre‐pubertal obese children. Methods: Parameters of liver metabolism (ALT, AST and GGT) of three European cohorts were included (German cohort [n = 71; age: 11.53 ± 1.29 years; BMI z‐score: 2.96 ± 0.64], Italian cohort [n = 45; age: 9.60 ± 2.11 years; BMI z‐score: 3.57 ± 1.16], Slovenian cohort [n = 31; age: 7.53 ± 1.47 years; BMI z‐score: 3.66 ± 0.88]). MiR‐122 levels and CK18 concentrations were measured in fasting blood samples. In the German and Italian cohort, the diagnosis of NAFLD and grading of NAFLD was assessed by ultrasound. Results: NAFLD was diagnosed in n = 50 patients of the German cohort (29.6%) and in n = 29 patients (72.5%) of the Italian cohort. In all three cohorts, miR‐122 was positively correlated with ALT and AST as well as with CK18 concentrations. MiR‐122 levels were higher in children with NAFLD compared with healthy controls. Conclusions: MiR‐122 levels in pre‐pubertal obese children could be a potential biomarker for paediatric NAFLD. [ABSTRACT FROM AUTHOR]

Lysosomal storage diseases (LSDs) are a heterogeneous group of inherited disorders caused by loss-of-function mutations in genes encoding for lysosomal enzymes/proteins. The consequence is a progressive accumulation of substrates in these intracellular organelles, resulting in cellular and tissue damage. The overall incidence is about 1/8000 live births, but is likely underestimated. LSDs are chronic progressive multi-systemic disorders, generally presenting with visceromegaly, and involvement of the central nervous system, eyes, the skeleton, and the respiratory and cardiovascular systems. The age at onset and phenotypic expression are highly variable, according to the specific enzymatic defect and tissues involved, the residual activity, and the disease-causing genotype. Enzyme-replacement therapies and substrate-reduction therapies have recently become available, leading to the improvement in symptoms, disease progression and quality of life of affected individuals. Liver involvement and hepatosplenomegaly are frequent features of LSDs and a hallmark of adult-onset forms, frequently leading to medical attention. LSDs should therefore be considered in the differential diagnosis of liver disease with organomegaly. The present document will provide a short overview of adult-onset LSDs with hepatic involvement, highlighting the specificities and systemic manifestations of the ones most frequently encountered in clinical practice, which may hint at the correct diagnosis and the appropriate treatment., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis., Methods: We analyzed data from 1738 subjects (44.9% with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also collected data on demographic features, metabolic comorbidities, and genetic factors, and performed logistic regression analyses. Findings were validated using data from 118 consecutive patients with NAFLD who underwent sequential liver biopsies at tertiary referral centers in Italy., Results: In the cross-sectional cohort, 132 of 389 patients (33.9%) with significant fibrosis had no NASH and 39 patients (10.0%) had no inflammation. The dissociation between NASH and fibrosis was significantly greater in patients with severe obesity (P < .005). Steatosis, ballooning, and lobular inflammation each were associated independently with significant fibrosis (P < .001); age, adiposity, fasting hyperglycemia, and the PNPLA3 I148M variant also were associated with fibrosis. In patients without, but not in those with NASH, significant fibrosis was associated with steatosis grade and the PNPLA3 I148M variant. In patients without NASH, age, fasting hyperglycemia, ballooning, and inflammation were associated with fibrosis. In the validation cohort, 16 of 47 patients (34.0%) with clinically significant fibrosis did not have NASH at baseline. In patients with fibrosis without baseline NASH, worsening of fibrosis (based on later biopsies) was associated with fasting hyperglycemia and more severe steatosis (P = .016)., Conclusions: In an analysis of biopsy specimens collected from patients with NAFLD at a single time point, one third of patients with significant fibrosis did not have NASH. We validated this finding in a separate cohort. In patients without NASH, fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and the PNPLA3 I148M variant identified those at risk of significant fibrosis., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to evaluate long-term nutritional outcomes and clinical characteristics in a cohort of children with pediatric intestinal pseudo-obstruction (PIPO) at neonatal-onset (NO-PIPO) and at later-onset (LO-PIPO)., Methods: All children fulfilling new PIPO criteria over a 30-year period were reviewed. Baseline demographic and clinical features as well as nutritional outcomes were collected. Nutritional outcomes included overall survival, prevalence of enteral autonomy and parenteral nutrition (PN) dependency, rate of major PN complications, and growth course., Results: Forty-four patients were still alive at the end of the follow-up. Twenty-five patients (57%) achieved enteral autonomy, whilst 18 remained on PN. Among the patients requiring PN at the beginning of the study period, we found that 55% (CI 34-70) has the probability of remaining on PN at the latest follow-up. Prevalence of gastrointestinal obstruction symptoms (P < 0.01), urinary involvement (P < 0.05), stoma placements [gastrostomy (P < 0.01), ileostomy P < 0.05)] and complex gastrointestinal surgery (P < 0.05) were significantly higher in NO-PIPO than in LO-PIPO. The number of patients requiring long-term PN (P < 0.001) and the number of PN days (P < 0.05) were significantly higher in NO-PIPO, whilst the number of patients achieving enteral autonomy was significantly higher in LO-PIPO (P < 0.05)., Conclusions: In our study, we have reported the nutritional outcome of a cohort of children with PIPO over a 30-year period showing that about 20% of patients develop irreversible intestinal failure requiring life-long PN. Nutritional and clinical outcomes seem to be influenced by the time of onset of the disease.

The Italian Consensus Position Statement on Diagnosis, Treatment and Prevention of Obesity in Children and Adolescents integrates and updates the previous guidelines to deliver an evidence based approach to the disease. The following areas were reviewed: (1) obesity definition and causes of secondary obesity; (2) physical and psychosocial comorbidities; (3) treatment and care settings; (4) prevention.The main novelties deriving from the Italian experience lie in the definition, screening of the cardiometabolic and hepatic risk factors and the endorsement of a staged approach to treatment. The evidence based efficacy of behavioral intervention versus pharmacological or surgical treatments is reported. Lastly, the prevention by promoting healthful diet, physical activity, sleep pattern, and environment is strongly recommended since the intrauterine phase.

Aim: To assess the prevalence of caries, oral hygiene quality and periodontal disease in a cohort of obese adolescents compared to a control group., Materials and Methods: Study Design: cross-sectional study conducted on 204 subjects (age range 10-16 years). Ninety obese subjects (BMI >90) and 114 normal-weight subjects (BMI <75) were visited at the Bambino Gesù Children's Hospital and in a junior high school in Rome, respectively. An ad hoc questionnaire (investigating demographic and oral health behaviour data) was filled in by patients and their caregivers. Accurate oral examinations were conducted. The Decayed-Missing-Filled Teeth/Surfaces Index in both permanent (DMFT/DMFS) and primary dentition (dmft/dmfs), Gingival Bleeding Index (GBI), Visible Plaque Index (VPI), and Probing Depth (PD) were recorded., Statistics: data analysis was carried out using the Statistical Package for the Social Sciences (SPSS 21.0; SPSS IBM, New York, NY). The data of the two groups were compared by means of Student's t Test or the Mann-Whitney test for numerical data and the Chi-square test for categorical data., Results: Patients affected by obesity, compared with controls, presented less compromised teeth in the primary dentition (dmft obese: 0.30 &#177;± 1.12; normal-weight: 1.00 &#177; 1.90; P<0.001) and less compromised dental surfaces (dmfs obese: 0.51 &#177; 2.14; normal-weight: 1.61 &#177; 3.10; P<0.001). Furthermore obese patients showed minor gingival inflammation with less bleeding on probing (GBI) (obese: 23.95 &#177; 21.43; normal-weight: 38.17&#177; 24.37; P<0.001), and less probing depth in a greater number of sites (PPD &#8804; 3) (obese: 101.92 &#177; 9.27; normal-weight: 97.28 &#177; 12.13; P<0.001). Moreover, the obese group showed a better oral hygiene (VPI) (obese: 25.69 &#177;25.83; normal-weight: 37.72 &#177;24.34; P<0.001)., Conclusion: In our study, obese adolescents showed a better oral hygiene, fewer compromised teeth and better periodontal health when compared with normal-weight patients.

Background: Non-alcoholic fatty liver disease encompasses a spectrum of diseases that range from simple steatosis to the aggressive form of non-alcoholic steatohepatitis. Non-alcoholic steatohepatitis is currently diagnosed through liver biopsy., Aim: To develop a non-invasive predictive model of non-alcoholic steatohepatitis in children with non-alcoholic fatty liver disease., Methods: Anthropometric, laboratory, and histologic data were obtained in a cohort of children with biopsy-proven non-alcoholic fatty liver disease. Multivariable logistic regression analysis was employed to create a nomogram predicting the risk of non-alcoholic steatohepatitis. Internal validation was performed by bootstrapping., Results: Three hundred and two children were included in this analysis with a mean age of 12.3 ± 3.1 years, a mean body mass index percentile of 94.3 ± 6.9, and non-alcoholic steatohepatitis was present in 67%. Following stepwise variable selection, total cholesterol, waist circumference percentile, and total bilirubin were included as variables in the model, with good discrimination with an area under the receiver operating characteristic curve of 0.737., Conclusions: A nomogram was constructed with reasonable accuracy that can predict the risk of non-alcoholic steatohepatitis in children with non-alcoholic fatty liver disease. If validated externally, this tool could be utilized as a non-invasive method to diagnose non-alcoholic steatohepatitis in children with non-alcoholic fatty liver disease., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: The aim of the present study was to evaluate whether the lipin1 rs13412852 C>T polymorphism is associated with nonalcoholic steatohepatitis and fibrosis in pediatric Italian patients with nonalcoholic fatty liver disease (NAFLD)., Methods: A total of 142 untreated, consecutive children and 115 adults with biopsy-proven NAFLD and 337 healthy controls without steatosis were studied. Liver histology was assessed by the NAFLD activity score and the rs13412852 polymorphism by a 5' nuclease Taqman assay., Results: Homozygosity for the rs13412852 T allele was underrepresented in pediatric, but not adult, patients with NAFLD compared with healthy controls (7% vs 14%; odds ratio [OR] 0.58, 95% confidence interval [CI] 0.35-0.91), and it was associated with lower triglycerides both in pediatric patients and healthy controls (P ≤ 0.01). Affected children carrying the rs13412852 TT genotype had a trend for a lower prevalence of nonalcoholic steatohepatitis, and significantly less severe liver damage, as indicated by NAFLD activity score severity (P = 0.026) and a lower prevalence of liver fibrosis (P = 0.012). The negative association between rs13412852 TT genotype and fibrosis was independent of Patatin-like phospholipase domain-containing-3 genotype and other clinical risk factors, including age, waist circumference, the presence of hyperglycemia, and alanine transaminase levels (OR 0.29; 95% CI 0.11-0.66), and it was confirmed at multivariate analysis in adults (OR 0.15; 95% CI 0.02-0.67)., Conclusions: Lipin1 rs13412852 single nucleotide polymorphism is associated with the severity of liver damage and fibrosis progression in pediatric patients with histological NAFLD.

Background: The non-alcoholic steato-hepatitis Clinical Research Network has recently shown that portal chronic inflammation is associated with liver fibrosis in American children with non-alcoholic fatty liver disease., Aim: We tested whether the portal chronic inflammation-fibrosis association was present in a series of Italian children with non-alcoholic fatty liver disease., Methods: We re-assessed the liver biopsies of 144 consecutive Italian children with non-alcoholic fatty liver disease aged 3-18 years and followed at the "Bambino Gesù" Paediatric Hospital. Non-alcoholic fatty liver disease and portal chronic inflammation were diagnosed using the non-alcoholic steato-hepatitis Clinical Research Network criteria. Anthropometry, body composition, liver enzymes, metabolic parameters and blood pressure were measured in all children., Results: Two children had no portal chronic inflammation, 84 had mild and 58 more than mild portal chronic inflammation according to the non-alcoholic steato-hepatitis Clinical Research Network criteria. Children with no or mild portal chronic inflammation had the same clinical features of those with more than mild portal chronic inflammation except for insulin resistance, which was greater. There was no association between steatosis, lobular inflammation, ballooning, fibrosis and portal chronic inflammation., Conclusion: We were not able to confirm the existence of a clinico-pathological association between portal chronic inflammation and disease severity in a series of Italian children with non-alcoholic fatty liver disease. Some clinico-pathological correlates of paediatric non-alcoholic fatty liver disease may be population-specific., (Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. The aim of this study was to assess the relationship between severity of liver injury and atherogenic lipid profile in a large group of children with NAFLD. A total of 118 consecutive children with biopsy-proven NAFLD were included. Patients underwent extensive metabolic profiling. The NAFLD activity and fibrosis scores showed a significant positive correlation with triglyceride/HDL, total cholesterol/HDL, and LDL/HDL ratios (p<0.05) but not with apolipoprotein B/apolipoprotein A-1 ratio (p=0.58). After adjusting for BMI, homeostatic model assessment, impaired glucose tolerance, and presence of metabolic syndrome, both the NAFLD activity score and stage of fibrosis remained independent predictors of proatherogenic lipid profile. All lipid ratios, except for apolipoprotein B/apolipoprotein A-1, were found to be markedly higher in children with nonalcoholic steatohepatitis compared with those with simple steatosis or borderline disease (p<0.05). This study shows for the first time that in children with NAFLD, the severity of liver injury is strongly associated with the presence of a more atherogenic lipid profile, having potential significant diagnostic and therapeutic implications.

Background: Percutaneous needle biopsy of the liver is the most common procedure used in clinical hepatology for histopathological examination and assessment of liver disease, and remains the cornerstone in the evaluation and management of parenchymal liver diseases. Liver biopsy is generally regarded as a safe procedure, but mortality rates up to 1:10,000 have been reported. In 2003, our group showed that routine use of US as a guide to liver biopsy reduces the rate of complications and provides a higher diagnostic yield., Objective: To report our experience of US-guided liver biopsy in children., Materials and Methods: We retrospectively reviewed all 421 liver biopsies performed in our department from October 2003 to December 2008. All samples had been obtained by the US-guided technique. All patients had a liver US examination performed prior to the procedure by the same radiologist performing the biopsy., Results: US guidance allowed constant visualization of the needle leading to appropriate tissue sampling in all 421 children (including 221 obese children), and in 79% of children with only one pass. Pain in the right upper quadrant after liver biopsy was experienced by 36% of patients., Conclusion: US-guided percutaneous biopsy of the liver in children, performed in a specialized tertiary care paediatric centre by experienced and skilled physicians, can be considered safe and effective.

Objective: Prevalence of non-alcoholic fatty liver disease (NAFLD) among children is increasing dramatically. It is unclear why some patients develop steatohepatitis (NASH), fibrosis and cirrhosis from steatosis, and others do not. A role for leptin has been claimed. This study aims to evaluate the relationship between leptin, insulin resistance (IR) and NAFLD in children., Design and Methods: In 72 biopsy-proven NAFLD children (aged 9-18 years; 51M/21F), fasting leptin and its soluble receptor (sOB-R) were measured; free leptin index (FLI) was calculated as leptin/sOB-R; IR was estimated by homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISI-comp); glucose tolerance by oral glucose tolerance test (OGTT). Percentage of total body fat (TBF) by dual-energy X-ray absorptiometry (DXA) was available in 65 patients., Results: Prevalence of diabetes, impaired fasting and/or after load glucose tolerance was 11%. HOMA-IR and ISI-comp values were 2.55 +/- 1.39 and 4.4 +/- 2. NASH was diagnosed in 38 and simple steatosis in 25 children; diagnosis was indeterminate in 29 children. Increased fibrosis, mostly of mild severity, was observed in 41 patients. Median NAFLD activity (NAS) score was 3.42 +/- 1.60. According to histology, levels of leptin and FLI increased as steatosis (leptin from 11.9 +/- 6.3 in score 1 to 17.4 +/- 6.9 in score 2 (P = 0.01) and 22.2 +/- 6.8 ng/ml in score 3 (P < 0.001); FLI 2.56 +/- 1.40, 3.57 +/- 0.34, 4.45 +/- 0.64 respectively (P = 0.05)); ballooning (from 13.7 +/- 6.7 in score 1 to 17 +/- 7.5 in score 2 (P = 0.001) and 22.1 +/- 7.1 ng/ml in score 3 (P = 0.01); FLI 2.81 +/- 1.50, 3.40 +/- 1.65, 4.57 +/- 1.67 (P = 0.01 between 0 and 2)); fibrosis (from 14.3 +/- 7 to18.3 +/- 6.9; P = 0.03; FLI 3.03 +/- 1.57 vs 3.92 +/- 077; P < 0.05) and NAS score (score 1-2: 12.9 +/- 6.9; score 3-4: 17 +/- 6.9 (P = 0.01); score 5-7: 22.9 +/- 7.5 ng/ml (P = 0.03); FLI 2.70 +/- 1.53, 3.12 +/- 1.53, 4.58 +/- 1.57 P = 0.01 and P = 0.05 between 1-2 vs 3-4 and 3-4 vs 5-7 respectively) worsened. Higher leptin correlated with more severe steatosis, ballooning and NAS score (r(0) = 0.6, 0.4 and 0.6 respectively; for all P < 0.001); FLI with ballooning (r(0) = 0.4, P < 0.0001), steatosis (r(0) = 0.5, P < 0.0001) and NAS score (r(0) = 0.5, P < 0.0001)., Conclusions: Leptin and liver injury correlated independently of age, BMI and gender in the present study. Nevertheless, any causative role of leptin in NAFLD progression could be established. Thus, studies are needed to define whether the hormone plays a major role in the disease.

We report the case of a 9-year-old Senegalese girl with co-occurring wild-type (HBeAg-positive) chronic hepatitis B and antinuclear antibody-positive autoimmune hepatitis. Her HLA haplotype was A1, B8, DRB1*04, DQB1*02. Steriod and lamivudine therapy led to biochemical remission, and reactivation occurred when the patient stopped steroids. Persistent HBV infection due to wild-type virus (likely acquired vertically or early in life, as the mother was HBsAg positive) may have acted as a trigger for autoimmune hepatitis in this young girl.