Donatella Comparcola

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.)

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.

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.

Management of chronic hepatitis B in children: An unresolved issue

Although a rather benign course of chronic hepatitis B virus (HBV) infection during childhood has been described, 3–5% and 0.01–0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9–24% and the incidence of cirrhosis to 2–3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer‐reviewed journals from January 1980 to February 2013. The search terms used included “Hepatitis B virus infection,” “children,” “HBV,” “interferon,” “lamivudine,” “adefovir,” “entecavir,” and “tenofovir.” Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune‐tolerant phase or in the inactive carrier state. For children in the immune‐active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies.

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.

An 8-year-old boy with autoimmune hepatitis and Candida onychosis as the first symptoms of autoimmune polyglandular syndrome (APS1): identification of a new homozygous mutation in the autoimmune regulator gene (aire)

An 8-year-old boy presented in 1995 with a 2-year history of hypertransaminasemia and hypergammaglobulinemia. Afterwards the patient displayed onychosis with a positive culture test for Candida albicans (CA). Because of the persistence of hypertransaminasemia, a percutaneous liver biopsy was performed showing ‘low grade chronic active autoimmune hepatitis’ (AIH), positive for liver-kidney microsomal autoantibodies and antibodies to the hepatic autoantigen cytochrome P450-1A2. Immunosuppressive treatment was initiated. In 2003 he developed Addison’s disease resulting in the diagnosis of autoimmune polyendocrinopathy candidiasis-ectodermal dysplasia (APECED) syndrome, also known as autoimmune polyendocrine syndrome type 1 (APS1). Anti-17OH hydroxylase antibodies tested negative, anti-21-OH hydroxylase autoantibodies were positive. Among the other relevant organ- and non organ- specific autoantibodies, aromatic L-amino acid decarboxylase (ADDC) autoantibodies and anti-tryptophan hydroxylase autoantibodies were positive. The patient also presented polyuria and polydypsia with diabetes insipidus. Because of the presence of two diagnostic criteria of APS1, mutations in the autoimmune regulator gene (AIRE) were performed, which revealed the presence of a novel mutation (c1314- 1326 del 13/insGT) in exon 11. In conclusion, the diagnosis of APECED should be suspected in any child with minimal hypertransaminasemia, anti-microsomal autoantibodies and Candida albicans onychosis.

Co-occurrence of chronic hepatitis B virus infection and autoimmune hepatitis in a young Senegalese girl.

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.

Treatment of chronic hepatitis C in children: Is it necessary and, if so, in whom?

Hepatitis C virus (HCV) infection continues to be an important global health problem. It is estimated that approximately 170 million people worldwide are infected with HCV [1], and although children are only a small portion of those infected and the incidence of new infections has decreased in recent years, HCV still contributes to chronic liver disease in childhood [2]. Currently, transmission occurs mainly during pregnancy or at delivery, and the transmission rate is low unless the mother is HIV-coinfected. Pre-natal screening, where done, allows identification of infected mothers and early detection of the infection in their children. Current guidelines recommend testing for HCVRNA after 18 months of age (the results being unreliable earlier in life) [3,4]. What is the natural history of hepatitis C in childhood? Several studies have tried to answer this question, but a low numbers of children in the majority of them, and the involvement in some studies of patients referred to tertiary care centres have made the results of many of these investigations questionable. Although only a very long-term prospective study on numerically valid, unselected cohorts of children infected during pregnancy or at delivery, can provide a proper estimate of the relative proportion of children who progress to end stage liver disease, studies thus far have clearly shown that children tend to have a much more benign HCV infection course than adults [5]. It is also clear that the development of severe liver disease can be accelerated by the co-occurrence of thalassemia [6], iron overload [6,7], chemotherapy [8–11], and HIV co-infection [12]. In adults, HCV therapeutic strategies have evolved frommonotherapywith interferon (IFN) alfa to combination therapywith IFN alfa and ribavirin (RBV);while in children, because of RBV-associated adverse effects (i.e. reversible hemolytic anemia, fetal abnor-

Hepatitis B virus infection in children

Hepatitis B can develop in less than 5% of neonates of infected mothers, despite neonatal serovaccination. Most children will develop a chronic hepatitis. Most children are in an immune-tolerant or in an inactive phase. Interferon is the treatment of choice, in the rare cases where it is necessary.