Fish Oil and Nonalcoholic Fatty Liver Disease (NAFLD) Study

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
eicasanoid 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.

We 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 - 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, GGT, plasma phospholipids, plasma
lipids, insulin levels and estimation of HOMA-R.

Inclusion Criteria:

- Body Mass Index (BMI i.e. wt(Kg)/ht(m)2) above the 95th % as defined by the NHANES
tables.

- Elevated liver enzymes (ALT and/or AST) to at least 1.5 times the upper limit on at
least 2 examinations, (ALT, the upper limit of normal values in our laboratory is 41
U/L; AST, upper limit of normal values in our laboratory is 38 U/L).

- Subjects must demonstrate ability to swallow capsules.

Exclusion Criteria:

- Overt Diabetes

- Viral or autoimmune hepatitis, Wilson's disease, Alpha-1 antitrypsin deficiency,
hemochromatosis or any other form of chronic liver disease not related to NAFLD

- Exposure to drugs or hepatotoxins less than 14 days prior to recruitment

- Alcohol consumption > 20 grams/day

- Evidence of cirrhosis on liver biopsy.