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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Non-Alcoholic Steatohepatitis

Detailed Description

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.

• Study Type: Observational

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

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

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.	three years
We will compare the proportions of those with NASH to those without NASH and those with fibrosis compared to those without fibrosis.	Three years

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Investigators: Principal Investigator: Vincent F Biank, MD, Medical College of Wisconsin

Publications and helpful links

General Publications

• Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999 Dec;30(6):1356-62. doi: 10.1002/hep.510300604.
• Huang BE, Amos CI, Lin DY. Detecting haplotype effects in genomewide association studies. Genet Epidemiol. 2007 Dec;31(8):803-12. doi: 10.1002/gepi.20242.
• Benjamini, Y. and Hochberg, Y. 1995. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. Royal Stat. Soc. B (57): 289-300.
• Breiman L, Friedman JH, Olshen RA, Stone CJ. Classification and Regression Trees. Classification and Regression Trees. 1984.
• Lin DY, Zeng D, Millikan R. Maximum likelihood estimation of haplotype effects and haplotype-environment interactions in association studies. Genet Epidemiol. 2005 Dec;29(4):299-312. doi: 10.1002/gepi.20098.
• Iacobellis A, Marcellini M, Andriulli A, Perri F, Leandro G, Devito R, Nobili V. Non invasive evaluation of liver fibrosis in paediatric patients with nonalcoholic steatohepatitis. World J Gastroenterol. 2006 Dec 28;12(48):7821-5. doi: 10.3748/wjg.v12.i48.7821.
• Marra F. NASH: are genes blowing the hits? J Hepatol. 2004 May;40(5):853-6. doi: 10.1016/j.jhep.2004.03.005. No abstract available.
• Song J, da Costa KA, Fischer LM, Kohlmeier M, Kwock L, Wang S, Zeisel SH. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J. 2005 Aug;19(10):1266-71. doi: 10.1096/fj.04-3580com.
• Marshall RJ. Partitioning methods for classification and decision making in medicine. Stat Med. 1986 Sep-Oct;5(5):517-26. doi: 10.1002/sim.4780050516.

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Anticipated): May 1, 2016
• Study Completion (Anticipated): May 1, 2016

Study Registration Dates

• First Submitted: May 9, 2008
• First Submitted That Met QC Criteria: May 9, 2008
• First Posted (Estimate): May 14, 2008

Study Record Updates

• Last Update Posted (Estimate): August 25, 2015
• Last Update Submitted That Met QC Criteria: August 21, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: Biomarker; NASH
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: CHW 08/36; GC 618