Paolo Ciampalini

NAFLD in children: A prospective clinical‐pathological study and effect of lifestyle advice

Nonalcoholic fatty liver disease (NAFLD), a common cause of chronic liver disease in adults, is incompletely characterized in children. We conducted a prospective study to better characterize the clinical presentation of NAFLD in children and to determine the effect of lifestyle advice in the management of pediatric NAFLD. From June 2001 to April 2003, 84 children (age 3‐18.8 yr) who had elevated aminotransferases and the diagnosis of NAFLD confirmed via liver biopsy underwent a 2‐hour oral glucose tolerance test and a 12‐month program of lifestyle advice consisting of diet and physical exercise. Thirty‐four (40.5%) patients were obese (body mass index [BMI] >97th percentile), and 43 (51.2%) were overweight (BMI 85th‐97th percentile). Ten (12%) had abnormal glucose tolerance; 10 (12%) had elevated triglycerides, cholesterol, or both; and all had normal blood pressure. Most children (67/84, 80%) were insulin‐resistant, including the 7 children with normal BMI (<85th percentile). Increased liver fibrosis was present in 49 (58.1%) patients and was independently associated with obesity (OR 2.7, 95% CI 1.2‐6.2) and age (1‐year increase; OR 1.2, 95% CI 1.04‐1.5). A 12‐month program with diet and physical exercise resulted in a significant decrease in BMI, and levels of fasting glucose, insulin, lipids, and liver enzymes, as well as liver echogenicity on ultrasonography. In conclusion, children with NAFLD are almost always insulin‐resistant regardless of BMI. Obesity and older age are independently associated with increased liver fibrosis. A simple lifestyle advice program significantly improves insulin resistance, and the liver disease in pediatric NAFLD. (HEPATOLOGY 2006;44:458–465.)

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 ⩾85th percentile and 84% had a waist ⩾90th 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.

Metformin Use in Children with Nonalcoholic Fatty Liver Disease : An Open-Label, 24-Month, Observational Pilot Study

BACKGROUND There is no consensus on the treatment of pediatric nonalcoholic fatty liver disease (NAFLD). However, in a small pilot study conducted in 10 children, metformin has been proposed to be effective. OBJECTIVE We aimed to determine the effect of metformin in addition to lifestyle intervention/modification in children with NAFLD. METHODS Overweight or obese children aged 9 to 18 years with biopsy-proven NAFLD or nonalcoholic steatohepatitis were enrolled in an observational pilot study, initially planned for 12 months, which aimed to estimate the effect of metformin on liver enzymes. The study was extended to 24 months to estimate outcomes on liver histology. All subjects received lifestyle intervention (nutritional counseling and a physical exercise regimen) and metformin 1.5 g/d (MET group). To serve as the control in this study, we selected a control group from a separate but parallel study (N=30) that had identical inclusion criteria on the use of antioxidants in NAFLD. End points were changes in liver enzymes and histology. Insulin resistance (IR) was estimated by the Homeostasis Model Assessment of IR (HOMA-IR) and liver biopsy was determined by the NAFLD activity score (NAS). RESULTS Sixty patients were assessed for inclusion in this study. However, 2 patients in the MET group dropped out of the study during the first year because they relocated abroad, and 1 patient in the control group refused follow-up after 12 months. Thus, study data is based on the findings in the 57 remaining patients. Alanine aminotransferase significantly improved from baseline with decreasing body weight in both groups (MET: 35 [range, 21-43] to 32 [20-46] U/L; control: 66 [28-121] to 33 [14-45] U/L; P<or=0.01). HOMA-IR significantly improved in both groups from baseline with decreasing body weight as well (MET: 1.4 [range, 0.5-5.11] to 1.3 [0.13-4.21]; control: 2.29 [0.86-5.76] to 1.5 [0.70-4.23]; P<or=0.01). Steatosis was reduced in both the MET (P=0.02) and control (P=0.02) groups as well as ballooning (both, P=0.008). Lobular inflammation improved from baseline in the MET group (P=0.003). The NAS score decreased from baseline (both, P=0.001), but no significant changes in fibrosis were detected. CONCLUSION In this small, 24-month observational study, metformin did not appear more effective than lifestyle intervention in ameliorating levels of aminotransferases, steatosis, and liver histology in these children with NAFLD.

The Continuous Glucose Monitoring System (CGMS) in type 1 diabetic children is the way to reduce hypoglycemic risk

Diabetic children treated with intensive insulin therapy are showing a dangerous increase in severe hypoglycemic episodes. The Continuous Glucose Monitoring System (CGMS) allows glycemic profiles to be monitored over a 72‐h period. The aim of the present study was to evaluate whether this system is sufficiently sensitive to detect asymptomatic hypoglycemia, and to determine if its periodic application would help to minimize the hypoglycemic risk in children with type 1 diabetes mellitus (T1DM).

Glucose tolerance status in 510 children and adolescents attending an obesity clinic in Central Italy

Brufani C, Ciampalini P, Grossi A, Fiori R, Fintini D, Tozzi A, Cappa M, Barbetti F. Glucose tolerance status in 510 children and adolescents attending an obesity clinic in Central Italy.

Sexual dimorphism of body composition and insulin sensitivity across pubertal development in obese Caucasian subjects

Background Puberty is a period of rapid growth associated with metabolic, hormonal, and body composition changes that can influence risk factors for chronic diseases such as type 2 diabetes. Objective To evaluate body composition and insulin sensitivity (IS) modifications throughout puberty in a large group of obese Caucasian subjects. Methods Five hundred and nineteen obese subjects (4-19 years), grouped according to gender and Tanner stage (T), underwent oral glucose tolerance test. Quantitative insulin check index (QUICKI) and ISI were calculated as indexes of IS. In 309 subjects, body composition by dual-energy X-ray absorptiometry, IGF1, adiponectin, and leptin were also evaluated. Results Body composition modifications were sexually dimorphic, with girls not modifying fat and lean percentage and fat distribution (P>0.15), and boys decreasing fat percentage and increasing lean percentage and central fat depot (P<0.001) across Ts. IS decreased during mid-puberty and returned to prepubertal levels by the end of puberty. Girls showed lower IS than boys (P<0.01 and =0.03 for QUICKI and ISI respectively). In multivariate analysis factors that negatively influenced IS, independently from T or age, were total fat mass and central fat depot in girls (P<0.05 and <0.01, respectively), total fat and lean mass in boys (P<0.01). IGF1, adiponectin, and leptin were not related to pubertal IS. Conclusions In obese Caucasian subjects, further decrease of IS observed during puberty is a transient phenomenon. Factors that independently from T or age influence IS are central fat depot in girls, lean amount in boys, and total fat mass in both sexes.

An observational study comparing continuous subcutaneous insulin infusion (CSII) and insulin glargine in children with type 1 diabetes.

The advantages of continuous subcutaneous insulin infusion (CSII) or insulin glargine have been demonstrated both in adult and paediatric diabetic patients; however, as no data comparing these two approaches during childhood are available, we have examined the efficacy of these two intensive approaches.

Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene

Glucokinase is essential for glucose-stimulated insulin release from the pancreatic beta-cell, serving as glucose sensor in humans. Inactivating or activating mutations of glucokinase lead to different forms of glucokinase disease, i.e. GCK-monogenic diabetes of youth, permanent neonatal diabetes (inactivating mutations), and congenital hyperinsulinism, respectively. Here we present a novel glucokinase gene (GCK)-activating mutation (p.E442K) found in an infant with neonatal hypoglycemia (1.5 mmol/liter) and in two other family members suffering from recurrent hypoglycemic episodes in their childhood and adult life. In contrast to the severe clinical presentation in the index case, functional studies showed only a slight activation of the protein (relative activity index of 3.3). We also report on functional studies of two inactivating mutations of the GCK (p.E440G and p.S441W), contiguous to the activating one, that lead to monogenic diabetes of youth. Interestingly, adult family members carrying the GCK pE440G mutation show an unusually heterogeneous and progressive diabetic phenotype, a feature not typical of GCK-monogenic diabetes of youth. In summary, we identified a novel activating GCK mutation that although being associated with severe neonatal hypoglycemia is characterized by the mildest activation of the glucokinase enzyme of all previously reported.

All glutathione forms are depleted in blood of obese and type 1 diabetic children.

Pastore A, Ciampalini P, Tozzi G, Pecorelli L, Passarelli C, Bertini E, Piemonte F. All glutathione forms are depleted in blood of obese and type 1 diabetic children.

Basal insulin supplementation in Type 1 diabetic children: A long-term comparative observational study between continuous subcutaneous insulin infusion and glargine insulin

No long-term data are available on the efficacy of glargine insulin in comparison with continuous sc insulin infusion (CSII) in children and adolescents affected by Type 1 diabetes (T1D). Our aim was to compare the 2-yr efficacy of the 2 insulin approaches, in order to know how to best supply basal insulin in these patients. Thirty-six 9 to 18-yr-old consecutive children with at least 3 yr previous T1D diagnosis were enrolled. As part of routine clinical care, the patients consecutively changed their previous insulin scheme (isophane insulin at bedtime and human regular insulin at meals) and were randomly selected in order to receive either multiple daily injections (MDI) treatment with once-daily glargine and human regular insulin at meals, or CSII with aspart or lispro insulin. Both groups showed a significant decrease in glycosylated hemoglobin (HbA1c) values during the 1st year of therapy, though only in the CSII treated children was the decrease also observed during the 2nd year. The overall insulin requirement significantly decreased only in the CSII group and exclusively during the 1st year, while no significant differences were observed concerning body mass index SD score, severe hypoglycémic episodes and basal insulin supplementation. The work illustrates the first long-term study comparing the efficacy of CSII to MDI using glargine as basal insulin in children. Only with CSII were better HbA1c values obtained for prolonged periods of time, so that CSII might be considered the gold standard of intensive insulin therapy also for long-term follow-ups.