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

• We will compare known frequencies from the Hapmap and specifically compare the proportions for those with NASH in adults to see if there is a difference in the child incidence of NASH. [ Time Frame: three years ] [ Designated as safety issue: No ]
• We will compare the proportions of those with NASH to those without NASH and those with fibrosis compared to those without fibrosis. [ Time Frame: Three years ] [ Designated as safety issue: No ]

The purpose of this study is to document how often specific genotypes known to be associated with adult-onset NASH (Non-Alcoholic Steatohepatitis) occur in a pediatric cohort and investigate whether these genotypes are associated with increased susceptibility to NASH.

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.

The child subjects will be recruited from the Hepatology Clinic at Children's Hospital of Wisconsin.

• SN###.#1
  All children in this cohort will have biopsy-proven NASH.
• SN###.#2
  This cohort will be parents (mother and father when possible) of child subjects with biopsy-proven NASH.

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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