Serum Fetuin-A levels in obese children with biopsy proven nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Fetuin-A has been proposed as a marker of liver damage in adults with obesity-related NAFLD. The aim of this study was to test serum fetuin-A concentrations in obese children with NAFLD diagnosed either by ultrasonography or by liver biopsy and to determine its applicability as predictive tool in pediatric NAFLD. METHODS AND RESULTS: Metabolic parameters and fetuin-A levels were investigated in 81 obese children with NAFLD diagnosed by biopsy, 79 obese children with NAFLD defined by liver ultrasonography and 23 lean subjects. Serum fetuin-A correlated significantly with age, waist circumference, systolic blood pressure, fasting insulin and 2-h postload insulin during OGTT, HOMA-IR, ISI, CRP, and apo B levels. Obese children with NAFLD detected by ultrasonography had significantly higher fetuin-A levels compared to those with normal liver. In obese children who underwent liver biopsy, no significant differences were detected in fetuin-A levels between subject with nonalcoholic steatohepatitis and those with simple steatosis. Fetuin-A was not different between obese and lean children. CONCLUSION: Fetuin-A is not related with the degree of liver damage in obese children with NAFLD and its routine measurement as marker of liver disease severity is therefore not recommended.

Evaluation of the relationship between obesity, dental caries and periodontal disease in adolescents.

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 ±± 1.12; normal-weight: 1.00 ± 1.90; P<0.001) and less compromised dental surfaces (dmfs obese: 0.51 ± 2.14; normal-weight: 1.61 ± 3.10; P<0.001). Furthermore obese patients showed minor gingival inflammation with less bleeding on probing (GBI) (obese: 23.95 ± 21.43; normal-weight: 38.17± 24.37; P<0.001), and less probing depth in a greater number of sites (PPD ≤ 3) (obese: 101.92 ± 9.27; normal-weight: 97.28 ± 12.13; P<0.001). Moreover, the obese group showed a better oral hygiene (VPI) (obese: 25.69 ±25.83; normal-weight: 37.72 ±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.

Urinary (1)H-NMR-based metabolic profiling of children with NAFLD undergoing VSL#3 treatment.

BACKGROUND: Nowadays, non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in children. Our recent clinical trial demonstrated that dietary and VSL#3-based interventions may improve fatty liver by ultrasound and body mass index (BMI) after 4 months. OBJECTIVES: As in this short-term trial, as in others, it is impracticable to monitor response to therapy or treatment by liver biopsy, we aimed to identify a panel of potential non-invasive metabolic biomarkers by a urinary metabolic profiling. METHODS: Urine samples from a group of 31 pediatric NAFLD patients, enrolled in a VSL#3 clinical trial, were analyzed by high-resolution proton nuclear magnetic resonance spectroscopy in combination with analysis of variance-Simultaneous Component Analysis model and multivariate data analyses. Urinary metabolic profiles were interpreted in terms of clinical patient feature, treatment and chronology pattern correlations. RESULTS: VSL#3 treatment induced changes in NAFLD urinary metabolic phenotype mainly at level of host amino-acid metabolism (that is, valine, tyrosine, 3-amino-isobutyrate or ß-aminoisobutyric acid (BAIBA)), nucleic acid degradation (pseudouridine), creatinine metabolism (methylguanidine) and secondarily at the level of gut microbial amino-acid metabolism (that is, 2-hydroxyisobutyrate from valine degradation). Furthermore, some of these metabolites correlated with clinical primary and secondary trial end points after VSL#3 treatment: tyrosine and the organic acid U4 positively with alanine aminotransferase (R=0.399, P=0.026) and BMI (R=0.36, P=0.045); BAIBA and tyrosine negatively with active glucagon-like-peptide 1 (R=-0.51, P=0.003; R=-0.41, P=0.021, respectively). CONCLUSIONS: VSL#3 treatment-dependent urinary metabotypes of NAFLD children may be considered as non-invasive effective biomarkers to evaluate the response to treatment.

Nonalcoholic fatty pancreas disease and Nonalcoholic fatty liver disease: more than ectopic fat.

OBJECTIVE: The aim of this study was to evaluate the metabolic effects of fatty pancreas (nonalcoholic fatty pancreas disease - NAFPD) in a group of obese paediatric patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We included 121 consecutive children with echographic evidence of hepatic steatosis. All patients underwent to abdominal ultrasound to evaluate pancreatic echogenic pattern. We divided the patients into two groups on the basis of the presence of fatty pancreas. In all patients liver function tests, lipid and gluco-insulinemic profile were evaluated. A selected subset of patients (67) underwent to liver biopsy. RESULTS: Of these 121 patients, 58 showed NAFPD and 63 patients exhibited a normal pancreatic echogenic pattern. No differences were found in age, transaminases serum levels, lipid profile and pancreatic enzymes between the two groups. The patients with NAFPD had a significantly higher z-BMI, fasting insulin, insulin resistance (HOMA-IR) and lower ISI respect to the group without fatty pancreas. The patients with fatty pancreas showed a more advanced form of liver disease, with higher values of fibrosis, ballooning and NAS score with respect to the group without NAFPD. CONCLUSIONS: Our study demonstrated that NAFPD is a frequent condition in obese paediatric patients affected by NAFLD. Our data suggest that pancreatic fat should not be considered an inert accumulation of fat, but as an additional factor able to affect glucose metabolism and severity of liver disease, increasing the risk of develop metabolic syndrome.

Early left ventricular abnormality/dysfunction in obese children affected by NAFLD.

BACKGROUND AND AIMS: Although it is generally accepted that non alcoholic fatty liver disease (NAFLD) is linked to increased risk of cardiovascular disease, the presence of abnormalities in cardiac function among NAFLD children is limited and controversial. Aim of the study was to detect cardiac abnormalities/dysfunction in a paediatric population of NAFLD. METHODS AND RESULTS: Anthropometric, laboratory, cardiovascular fitness, 24 h blood pressure monitoring and Doppler echocardiography parameters were obtained in 50 untreated children (37 males; mean age 12.2 + 2.5) with biopsy-proven NAFLD. Abnormalities in both cardiac function and geometry could be identified in the whole study population: prevalence of about 35% in left ventricular hypertrophy, 14% of concentric remodelling and 16% of left atrial dilatation. Furthermore children with NAFLD (NAS score <5) showed lower cardiac alterations compared to NASH patients (NAS score >5). After adjusting for age, sex and BMI, a positive correlation was found only between LV mass and NAS score (p < 0.001). CONCLUSION: Our results suggest that cardiac dysfunction can be detectable early in NAFLD children and this is not linked to cardiovascular and metabolic alteration, other than to liver damage. Although as a preliminary stage, we can speculate a possible direct relationship between liver and heart steatosis, already occurring during childhood.

Docosahexaenoic acid for the treatment of fatty liver: randomised controlled trial in children.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children. We tested whether dietary supplementation with docosahexaenoic acid (DHA) can decrease liver fat content in children with NAFLD. METHODS AND RESULTS: We performed a randomized controlled trial of DHA supplementation (250 mg/day and 500 mg/day) vs. placebo in 60 children with NAFLD (20 children per group). The main outcome was the change in liver fat as detected by ultrasonography after 6, 12, 18 and 24 months of treatment. Secondary outcomes were changes in triglycerides, alanine transaminase (ALT), body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA). The odds of more severe versus less severe liver steatosis decreased to the same degree at 6 months in children treated with DHA 250 mg/day and DHA 500 mg/day vs. placebo and persisted virtually unmodified for 24 months (OR ≤ 0.02, p ≤ 0.05 for all time points). Triglycerides were lower in the DHA groups than in the placebo group at any time point and ALT was lower in these groups from month 12 onwards. HOMA was lower in the DHA 250 mg group vs. placebo at months 6 and 12. CONCLUSION: DHA supplementation improves liver steatosis in children with NAFLD. Doses of 250 mg/day and 500 mg/day of DHA appear to be equally effective in reducing liver fat content.

Effect of intrauterine growth retardation on liver and long-term metabolic risk.

Intrauterine growth retardation predisposes toward long-term morbidity from type 2 diabetes and cardiovascular disease. To explain this association, the concept of programming was introduced to indicate a process whereby a stimulus or insult at a critical period of development has lasting or lifelong consequences on key endocrine and metabolic pathways. Subtle changes in cell composition of tissues, induced by suboptimal conditions in utero, can influence postnatal physiological functions. There is increasing evidence, suggesting that liver may represent one of the candidate organs targeted by programming, undergoing structural, functional and epigenetic changes following exposure to an unfavorable intrauterine environment. The aim of this review is to provide insights into the molecular mechanisms underlying liver programming that contribute to increase the cardiometabolic risk in subjects with intrauterine growth restriction.

Liver transplantation for refractory severe pruritus related to widespread multifocal hepatic focal nodular hyperplasia (FNH) in a child: case report and review of literature.

FNH is a rare and benign tumor of the liver. It is not a conventional indication for liver transplantation, and no transplant for FNH in a child has been reported to date. Multifocal FNH growing in adolescent age to a widespread tumor invading the whole liver and associated with severe refractory pruritus was an unusual indication for transplantation in a 13-yr-old girl. The operation and the follow-up were uneventful, allowing full recovery and disappearance of pruritus.

Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease.

BACKGROUND/AIMS: The aim of this study was to assess the effect of functional ENPP1(ectoenzyme nucleotide pyrophosphate phosphodiesterase 1)/PC-1 (plasma cell antigen-1) and IRS-1 (insulin receptor substrate-1) polymorphisms influencing insulin receptor activity on liver damage in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, whose progression is associated with the severity of insulin resistance. PATIENTS AND METHODS: 702 patients with biopsy-proven NAFLD from Italy and the UK, and 310 healthy controls. The Lys121Gln ENPP1/PC-1 and the Gly972Arg IRS-1 polymorphisms were evaluated by restriction analysis. Fibrosis was evaluated according to Kleiner. Insulin signalling activity was evaluated by measuring phosphoAKT levels by western blotting in a subset of obese non-diabetic patients. RESULTS: The ENPP1 121Gln and IRS-1 972Arg polymorphisms were detected in 28.7% and 18.1% of patients and associated with increased body weight/dyslipidaemia and diabetes risk, respectively. The ENPP1 121Gln allele was significantly associated with increased prevalence of fibrosis stage >1 and >2, which was higher in subjects also positive for the 972Arg IRS-1 polymorphism. At multivariate analysis, the presence of the ENPP1 121Gln and IRS-1 972Arg polymorphisms was independently associated with fibrosis >1 (OR 1.55, 95% CI 1.24 to 1.97; and OR 1.57, 95% CI 1.12 to 2.23, respectively). Both polymorphisms were associated with a marked reduction of approximately 70% of AKT activation status, reflecting insulin resistance and disease severity, in obese patients with NAFLD. CONCLUSIONS: The ENPP1 121Gln and IRS-1 972Arg polymorphisms affecting insulin receptor activity predispose to liver damage and decrease hepatic insulin signalling in patients with NAFLD. Defective insulin signalling may play a causal role in the progression of liver damage in NAFLD.

Waist circumference correlates with liver fibrosis in children with non-alcoholic steatohepatitis.

OBJECTIVE: Waist circumference is widely accepted as a risk factor for cardiovascular disease and metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) is a feature of the metabolic syndrome. A contribution of metabolic syndrome, and especially of waist circumference, to liver fibrosis in children with NAFLD is strongly suspected. DESIGN: Cross-sectional study. SETTING: Department of Hepatogastroenterology and Nutrition, Paediatric Hospital "Bambino Gesù", Rome, Italy. PATIENTS: 197 consecutive Caucasian children with NAFLD (136 males and 61 females) aged 3-19 years. MAIN OUTCOME MEASURES: Multivariable logistic regression models were used to examine the contribution of gender, age, body mass index (BMI) and metabolic syndrome components (waist circumference, high-density lipoprotein (HDL)-cholesterol, triglycerides, blood pressure and glucose) to the odds of liver fibrosis as detected by liver biopsy. RESULTS: 92% of the children had BMI > or = 85(th) percentile and 84% had a waist > or = 90(th) percentile for gender and age. Ten per cent of the children had metabolic syndrome and 67% had liver fibrosis, mostly of low degree. At multivariable analysis, waist was the only metabolic syndrome component to be associated with liver fibrosis. This was seen both when the components of the metabolic syndrome were coded as dichotomous (odds ratio (OR) = 2.40; 95% confidence interval (CI), 1.04 to 5.54) and continuous (OR = 2.07; 95% CI, 1.43 to 2.98 for a 5 cm increase). In the latter case, age was also associated with the outcome (OR = 0.70; 95% CI, 0.55 to 0.89 for a 1 year increase). CONCLUSIONS: Abdominal rather than generalised obesity contributes to liver fibrosis in children with NAFLD. Waist is also the only component of the metabolic syndrome to be associated with fibrosis in these children. Therefore, the presence of abdominal obesity is an additional criterion for the selection of children and adolescents who should undergo extensive investigation, including liver biopsy.

Metabolic syndrome and liver histology in paediatric non-alcoholic steatohepatitis.

OBJECTIVE: Our aim was to estimate prevalence of metabolic syndrome (MS), obesity and comorbidities in a cohort of 120 children (3-18 years) with biopsy-proven non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) and to evaluate correlations between clinical or biochemical variables and liver histology. RESEARCH METHODS AND PROCEDURES: MS was diagnosed according to the adapted National Cholesterol Education Program criteria. Homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin-sensitivity check index (QUICKI); and ISI composite, insulin secretion (insulin response at 30 min after a glucose load; HOMA-beta cell; insulinogenic index) were all estimated. BMI z-score and total body fat (dual-energy X-ray absorptiometry) were evaluated as indexes of obesity. RESULTS: MS was diagnosed in 66% of children. About 92% had weight above the 85th percentile, of which 42% were obese with weight above 97th percentile. Prevalence of hypertriglyceridaemia was 63%, low HDL cholesterol 45%, hypertension 40% and impaired glucose tolerance 10%. Levels of aminotransferases were higher as the number of comorbidities increased, the highest values being found in subjects with MS (P< or =0.05). Prevalence of a grade of steatosis > or =2 (P=0.05) and fibrosis (P< or =0.01) was higher in subjects with MS. Histology was associated significantly with higher values of a number of clinical and biochemical parameters (steatosis > or =2 with BMI z-score (P=0.04), fasting insulin (P=0.02), HOMA-IR (P=0.03), beta-cell secretion (P=0.04); necroinflammation with BMI z-score (P=0.007), glucose (P< or =0.0001), cholesterol (P< or =0.04) and white blood cells (P=0.025); fibrosis with body weight (P=0.05), BMI z-score (P=0.03), cholesterol (P=0.05), triglycerides (P=0.05), fasting insulin (P< or =0.0001) and mean values of the hormone at the OGTT (P=0.03), HOMA-IR (P< or =0.0001)). CONCLUSION: Presence of MS or clinical and biochemical variables associated with the syndrome seems to be strictly related to histological features of NASH in paediatric fatty liver disease. Thus, routinely liver biopsy should be encouraged in these children.

Circulating levels of miR-122 and nonalcoholic fatty liver disease in pre-pubertal obese children.

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.

Screening for non-alcoholic fatty liver disease in children: do guidelines provide enough guidance?

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the industrialized world in children. Its high prevalence and important health risks make NAFLD highly suitable for screening. In practice, screening is widely, albeit not consistently, performed. AIM: To review the recommendations on screening for NAFLD in children. METHOD: Recommendations on screening were reviewed from major paediatric obesity guidelines and NAFLD guidelines. A literature overview is provided on open questions and controversies. RESULTS: Screening for NAFLD is advocated in all obesity and most NAFLD guidelines. Guidelines are not uniform in whom to screen, and most guidelines do not specify how screening should be performed in practice. Screening for NAFLD remains controversial, due to lack of a highly accurate screening tool, limited knowledge to predict the natural course of NAFLD and limited data on its cost effectiveness. CONCLUSIONS: Guidelines provide little guidance on how screening should be performed. Screening for NAFLD remains controversial because not all conditions for screening are fully met. Consensus is needed on the optimal use of currently available screening tools. Research should focus on new accurate screening tool, the natural history of NAFLD and the cost effectiveness of different screening strategies in children.

Effect of vitamin E on aminotransferase levels and insulin resistance in children with non-alcoholic fatty liver disease.

BACKGROUND: Few data are available on the effect of antioxidants in paediatric non-alcoholic fatty liver disease (NAFLD). AIM: To compare the effect of a nutritional programme alone or combined with alpha-tocopherol and ascorbic acid on alanine aminotransferase (ALT) levels, and insulin resistance (IR) in biopsy-proven NAFLD children. METHODS: IN a 12-month double-blind placebo study, 90 patients were prescribed a balanced calorie diet (25-30 cal/kg/d), physical exercise, and placebo (group A) or alpha-tocopherol 600 IU/day plus ascorbic acid 500 mg/day (group B). IR was estimated by the homeostasis model assessment (HOMA-IR). RESULTS: At month 12, ALT (32.67 +/- 8.09 vs. 32.18 +/- 11.39 IU/L; P = NS), HOMA-IR (1.52 +/- 0.66 vs. 1.84 +/- 0.95 IU/L; P = NS), and weight loss (32% vs. 35% of excessive body weight; P = NS) did not differ between the two arms. Among subjects who lost >or=20% of their excessive weight, ALT and body weight percentage changes were significantly related (r(o) = 0.260; P = 0.03). In subjects, who lost more than 1.0 kg, HOMA-IR significantly decreased (2.20 +/- 0.21 to 1.57 +/- 0.13 in group A (P

Non-Alcoholic Fatty Liver Disease (NAFLD) in children and adolescents with Prader-Willi Syndrome (PWS).

We tested the hypothesis that patients with Prader-Willi syndrome (PWS) may be at lower risk of developing non-alcoholic fatty liver disease (NAFLD) because of a higher insulin sensitivity. Twenty-one PWS patients and 42 control subjects closely similar for age, gender, pubertal stage and body mass index (CNT), were studied. Metabolic profile and body composition were assessed. NAFLD was established by a validated method of US grading (range from G0 to G3). PWS patients showed a significantly better metabolic profile (lower waist circumference, fasting glucose levels, HOMA-IR, cholesterol, transaminase levels and trunk fat mass/fat mass ratio). Furthermore, NAFLD G1stage was significantly more frequent in PWS subjects (P < 0.05), whereas G2 stage was significantly more frequent in control patients (P < 0.05). NAFLD grading seems to correlate with body composition in PWS, also after adjustment for sex and GH treatment. To our knowledge, this is the first report suggesting a reduced risk of NAFLD in PWS children.

Obalon intragastric balloon in the treatment of paediatric obesity: a pilot study.

BACKGROUND: Lifestyle interventions are often ineffective in the treatment of pediatric obesity. Weight loss devices have been introduced for the temporary nonsurgical treatment of morbid obesity. OBJECTIVE: The aim of the study is to evaluate the efficacy of Obalon Intragastric Balloon on weight loss and on metabolic and cardiovascular parameters in a pediatric population with severe obesity. METHODS: We enrolled 10 children with severe obesity. In all patients anthropometric parameters, biochemical tests, ultrasound liver examination and blood pressure monitoring were evaluated at the time of insertion and after removal of device. RESULTS: The Obalon had a positive effect on decrease of weight, body mass index and percentage of excess body weight within 3 months from placement. Moreover, this safe minimally invasive device improves the cardio-metabolic profiles of obese children. CONCLUSIONS: The Obalon could be a useful tool in the difficult management of pediatric patients with morbid obesity, inducing in short-term a meaningful weight loss.

[Orbital cellulitis in pediatric age. Report of a case and review of the literature]. / Cellulite orbitaria in età pediatrica. Descrizione di un caso e rassegna della letteratura.

The authors report about 2-year-old female affected by orbital cellulitis. The most recent advances about physiopathology, diagnosis and therapy of orbital cellulitis are described.