Effect of Vitamin E on Pediatric Nonalcoholic Fatty Liver Disease (NAFLD)

Study Overview
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Brief Summary
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No proven treatment exists for nonalcoholic fatty liver disease (NAFLD) in children and adolescents. We aim to determine the efficacy of lifestyle intervention with or without antioxidant therapy in pediatric NAFLD.

Detailed Description
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InChildren or adolescents with well-characterized and liver biopsy confirmed NAFLD will be enrolled. They will be randomized to treatment with alpha tocopherol 600 IU/d plus ascorbic acid 500 mg/d (n=45) or an identical placebo (n=45) given orally. All patients will be included in a lifestyle intervention program consisting of a diet tailored on the individual requirements and physical exercise. The body mass index (BMI) and BMI Z-score will be calculated . Obesity was defined for a percentile of BMI ≥ 95th percentile for age and gender . Patients will undergo a medical evaluation every three months during the 24-month study period. Laboratory tests including liver enzymes and lipids will be repeated at 3-month intervals during the 24-month study duration. Ultrasonography of the liver will be repeated at the end of the study period. Evaluation of Glucose Metabolism and Insulin Sensitivity A 2-hour oral glucose tolerance test (OGTT) will be performed at baseline and repeated at 24 mo. of treatment with the standard 1.75 g of glucose per kg, or maximum of 75 g. Glucose tolerance status will be determined according to the classification of the American Diabetes Association in which fasting plasma glucose (FPG) levels up to 99 mg/dl are considered normal; impaired fasting glucose (IFG) is defined by a FPG of 100-125 mg/dl; impaired glucose tolerance (IGT) is defined by a 2-hour plasma glucose of 140-199 mg/dl; diabetes mellitus is defined by a FPG ≥126 mg/dl, or a 2-hour plasma glucose ≥200 mg/dl . The degrees of insulin resistance and sensitivity will be determined, respectively, by the homeostatic model assessment (HOMA-IR) using the formula: IR = (insulin*glucose)/22.5; and by the insulin sensitivity index (ISI) derived from OGTT using the formula: ISI = (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]). Liver biopsy Liver biopsy will be performed at baseline and repeated at 24 mo. of treatment. Biopsies will be routinely processed and analyzed as described previously. Pre- and post-treatment liver biopsies will be reviewed and scored by a single pathologist who will be unaware of the assigned treatment, patients' clinical and laboratory data, and liver biopsy sequence. The main histological features of NAFLD including steatosis (macro and microvesicular), inflammation (portal and lobular), hepatocyte ballooning, and fibrosis will be scored using the scoring system for NAFLD recently proposed by the NIH-sponsored NASH Clinical Research Network.

Official Title
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Lifestyle Intervention and Antioxidants in Children With Nonalcoholic Fatty Liver Disease: A Randomized, Controlled Trial

Conditions
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Inflammation, Fibrosis, Insulin Resistance

Intervention / Treatment
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* Dietary Supplement: Vitamin treatment (alpha tocopherol plus ascorbic acid)
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: persistently elevated serum aminotransferase levels, diffusely echogenic liver on imaging studies suggestive of fatty liver, and biopsy consistent with the diagnosis of NAFLD. Exclusion Criteria: hepatic virus infections (HCV RNA-PCR negative), Hepatitis A, B, C, D, E and G, cytomegalovirus and Epstein-Barr virus, alcohol consumption, history of parenteral nutrition, and use of drugs known to induce steatosis (e.g. valproate, amiodarone or prednisone) or to affect body weight and carbohydrate metabolism. Autoimmune liver disease, metabolic liver disease, Wilson's disease, and a-1-antitrypsin-associated liver disease were ruled out using standard clinical, laboratory and histological criteria.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin group<br>alpha tocopherol 600 IU/d plus ascorbic acid 500 mg/d and lifestyle intervention [hypocaloric Diet(25-30 cal/kg/d) or isocaloric (40-45 cal/kg/d) and physical activity]. | Dietary Supplement: Vitamin treatment (alpha tocopherol plus ascorbic acid)<br>* alpha tocopherol 600 IU/d plus ascorbic acid 500 mg/d and lifestyle intervention [hypocaloric Diet(25-30 cal/kg/d) or isocaloric (40-45 cal/kg/d) and physical activity].<br>* Other names: alpha-tocoferol;|
| Placebo Comparator: 2<br>placebo and lifestyle intervention [hypocaloric Diet(25-30 cal/kg/d) or isocaloric (40-45 cal/kg/d) and physical activity]. | Dietary Supplement: Placebo<br>* placebo and lifestyle intervention [hypocaloric Diet(25-30 cal/kg/d) or isocaloric (40-45 cal/kg/d) and physical activity].<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| serum levels of aminotransferases |  | months 12 and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver histology (inflammation and fibrosis) |  | month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Alcoholic Fatty Liver Disease (NAFLD), Non-Alcoholic Steatohepatitis (NASH), Liver histology, Insulin Resistance, Weight loss, Alpha-tocopherol, ascorbic acid