Maria Rita Sartorelli

Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: A randomized, controlled trial†

No proven treatment exists for nonalcoholic fatty liver disease (NAFLD) in children and adolescents. We sought to determine the efficacy of lifestyle intervention with or without antioxidant therapy in pediatric NAFLD. A total of 53 patients (age 5.7‐18.8 years, 37 boys) were included. Lifestyle intervention consisting of a diet tailored to the patients calorie needs, and increased physical activity was prescribed in all. Patients were concomitantly randomized to alpha‐tocopherol 600 IU/day plus ascorbic acid 500 mg/day (n = 25) or placebo (n = 28), and treated for 24 months. The study was an extension of a previous study aimed at evaluating the effect of 12‐month lifestyle intervention and antioxidant therapy on serum levels of aminotransferases. The primary end point of the present study was change in liver histology on repeated biopsy at 24 months. Secondary end points were changes in body weight, liver enzymes, and insulin sensitivity indices on 2‐hour oral glucose tolerance test. The amount of weight lost at 24 months was similar in the placebo and antioxidant groups (−4.75 [range, −16‐4.0] versus −5.5 [range, −12.2‐0.4] kg, respectively, P = 0.9). A significant improvement occurred in the grade of steatosis, lobular inflammation, and hepatocyte ballooning, and in the NAFLD activity score in both groups. Levels of aminotransferases, triglycerides, cholesterol, fasting glucose, and insulin, and insulin sensitivity indices improved significantly as well. The improvement in all these parameters was not significantly different between the two groups. Conclusion: Lifestyle intervention with diet and increased physical activity induces weight loss and is associated with a significant improvement in liver histology and laboratory abnormalities in pediatric NAFLD. Alpha‐tocopherol plus ascorbic acid does not seem to increase the efficacy of lifestyle intervention alone. (HEPATOLOGY 2008.)

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.)

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-β 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⩽0.05). Prevalence of a grade of steatosis ⩾2 (P=0.05) and fibrosis (P⩽0.01) was higher in subjects with MS. Histology was associated significantly with higher values of a number of clinical and biochemical parameters (steatosis ⩾2 with BMI z-score (P=0.04), fasting insulin (P=0.02), HOMA-IR (P=0.03), β-cell secretion (P=0.04); necroinflammation with BMI z-score (P=0.007), glucose (P⩽0.0001), cholesterol (P⩽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⩽0.0001) and mean values of the hormone at the OGTT (P=0.03), HOMA-IR (P⩽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.

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.

Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.

In this study, we report further results of mutation analysis of the ATP7B gene in Wilson disease (WD) patients of Mediterranean origin. A total of 136 WD chromosomes, 73 of which were of Italian, 43 of Turkish, 18 of Sardinian, and two of Spanish origin, were analysed and the mutation characterised in 84.5% of them. We found 50 different mutations of which 19 are novel, including three nonsense, one frameshift, and 15 missense mutations. The mutations detected were rare and mostly found in the compound heterozygous state together with other mutations and only rarely in homozygosity. Most of these mutations lie in the transmembrane and ATP binding loop regions. These data expand our knowledge of both the structure-function relationships of the WD protein and the molecular pathology of WD, thus improving our capability of prevention and genetic counselling.

High dosage alpha-interferon for treatment of children and young adults with chronic hepatitis C disease.

BACKGROUND There are limited data on the use of high interferon (IFN) dosage for treatment of children and young adults with hepatitis C virus infection and in those affected by thalassemia major (TM). OBJECTIVES To assess the response of children and young adults with chronic hepatitis C disease, including those affected by TM, to high dose natural alpha-interferon (IFN-alpha). To evaluate the effect of iron overload in response to high dose IFN-alpha in young chronic hepatitis C virus thalassemia patients. METHODS We conducted a therapeutic trial of natural IFN-alpha, using 10 million units/m2 three times a week for 6 months in 14 chronic hepatitis C patients ages 5 to 28 years; 7 also had TM. The follow-up period lasted 12 months. RESULTS Ten patients (73%) showed normal or nearly normal alanine aminotransferase values at the end of follow-up (biochemical response), but only five (35%) were negative for serum hepatitis C virus-RNA (complete responders). Four of the patients (57%) with TM were sustained complete responders. No correlation was found between the initial serum concentration of ferritin and response to IFN therapy. Patients infected with genotype 1b showed a poor response although high dose of natural IFN was used. CONCLUSIONS These results indicate that IFN-alpha can be used in children and young patients with chronic hepatitis C disease as well as in those affected by TM. Treatment with high dosage natural IFN-alpha in children and young adults with hepatitis C infection does not appear to be more effective than dosages previously used.

Celiac disease in pediatric patients with autoimmune hepatitis: etiology, diagnosis, and management.

Celiac disease (CD) is defined as a permanent intolerance to ingested wheat gliadins and other cereal prolamins, occurring in genetically susceptible people. Persistent elevation of serum aminotransferase activity is expression of liver damage related to CD, which occurs in two distinctive forms. The most frequent is a mild asymptomatic liver injury, with a moderate increase of serum aminotransferase activities and a mild inflammatory portal and lobular infiltrate on liver biopsy (celiac hepatitis), reversible on a gluten-free diet (GFD). More rarely, severe and progressive inflammatory liver damage, induced by an autoimmune process and identified as autoimmune hepatitis (AIH), can develop and it is generally unaffected by gluten withdrawal.Surveys that included only pediatric patients report a wide range of prevalence of CD in AIH of 11.5–46% (mean 21.5%). CD and AIH share selected combinations of genes coding for class II human leukocyte antigens, which could explain their coexistence. Increased intestinal permeability and circulation of anti-tissue transglutaminase (tTG) have also been considered as further potential causes of liver damage in CD patients. tTG in the liver and in other extraintestinal tissues could modify other external- or self-antigens and generate different neo-antigens, which are responsible for liver injury in patients with CD.Patients with AIH represent a population at high risk for developing CD; screening for CD should be integrated into the diagnostic routine of all patients with AIH, with or without gastrointestinal manifestations, before starting immunosuppressive treatments. The only currently available treatment for CD is the GFD and the supportive nutritional care for iron, calcium, and vitamin deficiencies. Due to the difficulties of a GFD, in the past decade researchers have become increasingly interested in therapeutic alternatives to continuous or intermittent use of a GFD in patients with CD. Interventions addressed to correct the defect in the intestinal barrier are currently at the most advanced stage of clinical trials. The impact of a GFD on the outcome of AIH is not clear but it seems to be ineffective in the treatment of AIH. The early detection and treatment of CD, however, may prevent progression to end-stage liver failure.

Autoimmune hepatitis in children: an overview of the disease focusing on current therapies.

Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory disease of the liver characterized by elevation of IgG, presence of characteristic autoantibodies, and histological features of interface hepatitis. Two types of juvenile AIH have been recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH type 1) or liver kidney microsomal antibody (AIH type 2). The exact pathogenesis of AIH is still unclear, but it is known that unidentified environmental factors, and occasionally drugs, might trigger disease in genetically susceptible individuals. The clinical spectrum of this disease is very wide, ranging from asymptomatic individuals with abnormal liver function to those with fulminant liver failure. The diagnosis is based on a combination of biochemical and histological parameters and on exclusion of other liver diseases. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. Alternative therapies are increasingly being explored in patients who do not respond to standard treatment and/or have intolerable side-effects. The purpose of this paper is to review our current knowledge about AIH in children, evaluating mainly the therapeutic options for its treatment, considering also the newer immunosuppressant agents used in difficult-to-treat cases.

Beverage consumption and paediatric NAFLD

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents, due to the increased worldwide incidence of obesity among children. It is now clear enough that of diet high in carbohydrates and simple sugars are associated with hepatic steatosis and non-alcoholic steatohepatitis (NASH). Several studies have shown that an increased consumption of simple sugars is also positively associated with overweight and obesity, and related co-morbidities, such as type 2 diabetes, metabolic syndrome and NAFLD. It is difficult to define the role of the various components of soft drinks and energy drinks in the pathogenesis of NAFLD and its progression in NASH, but the major role is played by high calorie and high sugar consumption, mainly fructose. In addition, other components of these beverages (e.g. xanthine) seem to have an important role in the pathogenesis of metabolic disorders, crucial pathways involved in NAFLD/NASH. The drastic reduction in the consumption of energy drinks and soft drinks is an appropriate intervention for the prevention of obesity and NAFLD in young people.

Successful tenofovir treatment for fulminant hepatitis B infection in an infant

Fulminant hepatic failure is defined by the presence of severe impairment of liver function, with or without encephalopathy, in patients with no underlying chronic liver disease. We report the case of a 4-month-old infant who developed fulminant hepatitis B infection and recovered concomitant with tenofovir therapy without liver transplantation.