Development of Biomarker for Development of Non-Alcoholic Steatohepatitis (NASH) in Children

NASH is a clinico-pathological entity characterized by the development of histological
changes of inflammation and fibrosis in the liver that are nearly identical to those induced
by excessive alcohol intake, but in the absence of alcohol abuse. Nonalcoholic
steatohepatitis occurs commonly children with additional comorbidities such as obesity and
diabetes mellitus. Paralleling the increasing prevalence of obesity and type 2 diabetes in
the pediatric population, nonalcoholic fatty liver disease (NAFLD) and especially its more
severe histological form NASH, is expected to become one of the most common causes of
end-stage liver disease in both children and young adults.

Although no genome wide association studies have been conducted in association with NASH to
date, individual candidate gene investigations have identified several genes associated with
increase susceptibility to NASH in adults including the microsomal triglyceride transfer
protein (MTP) which regulates the incorporation of triglycerides into apolipoprotein B and a
key enzyme for the assembly and secretion of VLDL from hepatocytes, the manganese superoxide
dismutase (MnSOD) gene which catalyzes the conversion of two molecules of superoxide anion,
a highly unstable ROS, into hydrogen peroxide and oxygen more stable ROS, and lastly,
phosphatidylethanolamine N-methyltransferase (PEMT) which is required for hepatic secretion
of triacylglycerol in very low density lipoproteins (VLDL).

We propose the following aim:

Aim 1: To document the frequency of specific genotypes, previously identified to be
associated with adult-onset NASH, in a purely pediatric cohort.

Aim 2: To investigate whether these genotypes are associated with increased susceptibility
to NASH and increased occurrence of fibrosis in the cohort of pediatric subjects. Our
hypothesis would be:

A significantly higher proportion of the polymorphisms would exist in those subjects with
NASH compared to controls.

Aim 3: To investigate the presence of other polymorphisms or other biomarker that are
indicative of pediatric NASH. Such that our secondary hypothesis would be:

Specific polymorphisms or biomarkers will be identified that will indicate a higher
probability of NASH.

Inclusion Criteria:

- All subjects aged 2-18 with biopsy proven NAFLD and/or NASH undergoing a blood draw
and willing to consent to this study will qualify for inclusion in this protocol.

Exclusion Criteria:

- other causes of chronic liver disease or other chronic diseases, specifically
autoimmune disorders, immunodeficiencies, or individuals with congenital/genetic
disorders

- chronic viral hepatitis, Wilson's disease, or alpha -1- antitrypsin deficiency

- acute life threatening illness or conditions