Fish Oil and Nonalcoholic Fatty Liver Disease (NAFLD) Study
Condition: Non-Alcoholic Fatty Liver Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional

Summary: 
      Over the past 30 years, the prevalence of childhood obesity in the United States has tripled
      from 5% to 15%. Major consequences of obesity include insulin resistance, type- 2 diabetes,
      cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). The liver pathology
      encompasses a range from isolated fatty liver to advanced fibrosis, cirrhosis and end-stage
      liver disease. Weight loss, particularly if gradual, may lead to improvement in liver
      histology. Unfortunately, few patients in the pediatric population are willing to follow
      these recommendations and achieve weight loss. Medical treatment directed specifically at the
      liver disease has only recently been investigated and approved in patients with NAFLD. The
      beneficial effects of fish oil are attributed to its high concentrations of n - 3 fatty
      acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are major regulators
      of pathways that participate in decreased production and break down of triglycerides and
      fatty acids in the liver. The investigators hypothesize that children with obesity related
      NAFLD will normalize elevated liver enzymes, plasma lipid levels, and attenuate insulin
      resistance with supplements of n-3 fatty acids. If this hypothesis is proven true, then fish
      oil could be used to treat NAFLD and to prevent the deterioration of fatty liver into
      end-stage liver disease.
    

Detailed description: 
      Scientific Abstract:

      Over the past 30 years, the prevalence of childhood obesity in the United States has tripled
      from 5% to 15%. Overweight is defined as a body mass index (BMI) above the 95%centile for age
      and gender. The recent estimates of obesity prevalence based on the National Health and
      Nutrition Examination Study (NHANES) 1999-2000 suggest that 15.3% to 15.5% of 6-19 year old
      children have a BMI above the 95% centile for age. Major consequences of obesity include
      insulin resistance, type 2 diabetes mellitus, cardiovascular disease and nonalcoholic fatty
      liver disease (NAFLD). NAFLD represents a spectrum of conditions characterized by
      macrovesicular hepatic steatosis. The liver pathology encompasses a range from isolated fatty
      liver to steatohepatitis, advanced fibrosis, cirrhosis and end-stage liver disease.
      Nonalcoholic steatohepatitis (NASH) may progress to cirrhosis even in children. Weight loss,
      particularly if gradual, may lead to improvement in liver histology. Unfortunately, few
      patients in the pediatric population are willing to follow these recommendations and achieve
      weight loss. Pharmacological therapy directed specifically at the liver disease has only
      recently been investigated in patients with NAFLD. Most of these studies have been
      uncontrolled pilot studies, lasting one year or less and have produced equivocal results.
      Thus, there is currently no effective treatment for this disorder. The beneficial effects of
      fish oil are attributed to its high concentrations of n - 3 fatty acids: eicosapentaenoic
      acid (EPA) and docosahexaenoic acid (DHA). Long-chain polyunsaturated n-3 FA (LCPUFA) are
      major regulators of molecular pathways altering many areas of cellular and organ function,
      metabolism and gene expression, and are active in reducing inflammation through the
      eicosanoid pathway. N-3 LCPUFA are well established negative regulators of hepatic
      lipogenesis. Recently it has been shown that the suppressive effects of n-3 LCPUFA on
      lipogenic enzymes are mediated by the reduction of mature SREBP-1c protein in the liver, a
      key transcription factor that activates transcription of genes involved in fatty acid
      synthesis. It is also well established today that the n-3 LCPUFA act as PPAR-alpha and gamma
      modulators, important in triglyceride (TG) and fatty acid catabolism. N-3 LCPUFA produce a
      dramatic increase in the size and number of hepatic peroxisomes and increase the capacity of
      the hepatocyte to metabolize fatty acids by inducing peroxisomal beta-oxidation enzymes, such
      as acyl CoA oxidase . We hypothesize that children with obesity related NAFLD will normalize
      elevated liver enzymes, plasma lipid levels, and attenuate insulin resistance with
      supplements of n-3 LCPUFA. If this hypothesis is proven true, then fish oil could be used to
      treat NAFLD and to prevent the deterioration of fatty liver into end-stage liver disease.

      The investigators will study 20 patients with NAFLD and hypertriglyceridemia, age 12y and
      above. Excluded from the study will be those with evidence of chronic infectious hepatitis,
      metabolic liver disease, autoimmune and chronic cholestatic liver diseases, insulin dependent
      diabetes and those with history of alcohol consumption, or exposure to drugs or hepatotoxins.
      Those qualifying for this study will be age 12 and above obese individuals (BMI > 95% for
      age), who have hyperlipidemia, but will have normal fasting glucose levels. For inclusion all
      will have elevation of serum aminotransferases to at least 1.5 times the upper limit of
      normal for a minimum of 3 months and evidence of fatty liver by abdominal ultrasound and
      liver biopsy. Patients will be randomized to placebo dummy capsules (controls) or n-3 LCPUFA
      supplements (Lovaza - GlaxoSmithKline (GSK) Pharmaceuticals, provided free of charge) at a
      dose of 4gr/day. They will be followed up at 3 and 6 months; monitoring height, weight, BMI,
      liver enzyme levels (ALT, AST, ALP), bilirubin total and direct, Gamma-glutamyl transferase
      (GGT), plasma phospholipids, plasma lipids, insulin levels and estimation of HOMA-R.
    

Intervention name(s): Fish Oil Supplementation; Placebo Supplementation
Intervention type(s): Drug; Drug
Intervention description(s): Group A will receive fish oil capsules, containing n3-Fatty Acids, at a dose of 4g/day. Each 1g capsule will contain 465mg of EPA and 375 mg of DHA.; Group B will receive corn oil in the capsules at the same dose as Group A. The corn oil capsules will appear identical in size and color to the fish oil capsules.
Other intervention name(s): Fish Oil Pills; Placebo Pills
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Fatty Liver Disease; Hepatic Steatosis; Docosahexaenoic Acid; Eicosapentanoic Acid; Omega-3 Fatty Acids; Elevated Transaminases; Fish oil supplements