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

Non-Alcoholic Steatohepatitis Clinical Trial

— NASH  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00677183
• Other study ID #: CHW 08/36
• Secondary ID: GC 618
• Status: Withdrawn
• Phase: N/A
• First received: May 9, 2008
• Last updated: August 21, 2015
• Start date: May 2008
• Est. completion date: May 2016

Study information

• Verified date: August 2015
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: May 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 18 Years

Eligibility

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 Design

Observational Model: Family-Based, Time Perspective: Prospective

Related Conditions & MeSH terms

• Fatty Liver
• Non-Alcoholic Steatohepatitis

Locations

Country	Name	City	State
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin

Sponsors (1)

Lead Sponsor	Collaborator
Medical College of Wisconsin

Country where clinical trial is conducted

United States, 

References & Publications (9)

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. — View Citation

B.E. Huang, C.I. Amos, and D.Y. Lin. Detecting Haplotype Effects in Genome wide Association Studies. Genet. Epidemiol. 31:1-10, 2007.

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.

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. — View Citation

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. — View Citation

Marra F. NASH: are genes blowing the hits? J Hepatol. 2004 May;40(5):853-6. Review. — View Citation

Marshall RJ. Partitioning methods for classification and decision making in medicine. Stat Med. 1986 Sep-Oct;5(5):517-26. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	We will compare the proportions of those with NASH to those without NASH and those with fibrosis compared to those without fibrosis.		Three years	No