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

• ClinicalTrials.gov Identifier: NCT00677183
• Recruitment Status: Withdrawn
• First Posted: May 14, 2008
• Last Update Posted: August 25, 2015
• Sponsor: Medical College of Wisconsin
• Information provided by (Responsible Party): Medical College of Wisconsin

Study Description

Brief Summary:

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.

Condition or disease
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 Design

• Study Type: Observational
• Actual Enrollment: 0 participants
• Observational Model: Family-Based
• Time Perspective: Prospective
• Official Title: Development of a Biomarker for Development of Non-Alcoholic Steatohepatitis (NASH) in Children
• Study Start Date: May 2008
• Estimated Primary Completion Date: May 2016
• Estimated Study Completion Date: May 2016

Groups and Cohorts

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.

Outcome Measures

Primary Outcome Measures :

1. 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 ]
2. 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 ]

Biospecimen Retention:   Samples With DNA

10mL of blood will be retained from each participant and their parents. 5mL of this blood will undergo DNA extraction and genotyping for several known NASH related genes. The other 5mL of blood will be saved as serum for future analysis.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

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

Criteria

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

Contacts and Locations

Locations

United States, Wisconsin

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Medical College of Wisconsin

Investigators

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

More Information

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.

• Responsible Party: Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT00677183
• Other Study ID Numbers: CHW 08/36; GC 618
• First Posted: May 14, 2008
• Last Update Posted: August 25, 2015
• Last Verified: August 2015

Keywords provided by Medical College of Wisconsin:

NASH; Biomarker

Additional relevant MeSH terms:

Fatty Liver; Non-alcoholic Fatty Liver Disease; Liver Diseases; Digestive System Diseases