Fatty Acids Lipidome and Oxidative Stress in Liver Transplantation

Liver Cirrhosis Clinical Trial

Official title:

Fatty Acids Lipidome and Oxidative Stress Markers as Indicators of Liver Transplant Outcome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01389115
• Other study ID #: Iul_LC
• Status: Recruiting
• Phase: N/A
• First received: May 6, 2011
• Last updated: December 10, 2015
• Start date: July 2001
• Est. completion date: September 2016

Study information

• Verified date: December 2015
• Source: University of Roma La Sapienza
• Contact: Stefano Corradini, M.D., Ph.D.
• Phone: +390649972086
• Email: stefano.corradini[@]uniroma1.it
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Observational

Clinical Trial Summary

The purpose of this study is to determine lipid metabolism in chronic liver disease in the attempt to find a useful biomarker of liver function and of prognostic value of graft function in those patients who undergo liver transplant. The present study enrolls subjects with liver cirrhosis (with different ethiology), including subjects eligible for a full-size liver transplantation, and healthy controls.

Description:

Liver has a central role in fatty acids metabolism that is impaired in chronic liver diseases. Polyunsaturated fatty acids are reportedly reduced in liver cirrhosis, which is considered a condition of essential fatty acids deficiency. However, there is a paucity of data concerning the level of the multitude of circulating fatty acids in liver cirrhosis. Oxidative stress is involved in the pathogenesis of chronic liver disease and fibrosis. Increased oxidative stress with impaired antioxidant status at the systemic level has been described in different chronic liver diseases and negatively influences graft function after liver transplantation (Poli G. 2000, Loguercio C 2003). 7-Ketocholesterol and 7beta-hydroxycholesterol, prototype molecules of free radical-mediated cholesterol oxidation, are very important oxysterols currently accepted as in vivo reliable markers of oxidative stress. High oxysterols plasma levels are associated with an alteration of normal plasma fatty acid pattern in cystic fibrosis (Iuliano 2009). The Model for End-Stage Liver Disease (MELD) score is a common score used routinely to stage liver function in patients with liver cirrhosis (Al Sibae 2010). After ischemia-reperfusion injury at liver transplantation oxidative stress, hepatic endoplasmic reticulum (ER) stress and cholesterol metabolism are interrelated key processes to preserve graft regeneration and function. A blood sample is obtained in each subject to measure MELD score at the first visit and at liver transplantation. Further blood samples are collected at days seven and 30 post transplantation. Blood samples are also obtained from healthy subjects. Liver biopsy samples are obtained from liver transplant donors. Oxidative stress and fatty acids lipidomics are measured to evaluate the actual plasma concentration in liver cirrhosis patients to be compared with healthy controls. Oxidative stress and fatty acids are also analyzed as a function of disease status, and for its influence on transplant outcomes. Lipid metabolism gene and endoplasmic stress reticulum gene expression are evaluated in liver biopsy specimen to study the influence on graft function.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 320
• Est. completion date: September 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 15 Years to 69 Years

Eligibility

Liver cirrhosis inclusion criteria:

• subjects with liver cirrhosis eligible for liver transplant, and one MELD score determination performed at least 3 months before liver transplantation

Liver cirrhosis exclusion criteria:

• liver transplant contraindication and re-transplantation

• current use of antioxidants and fatty acids supplements

Healthy controls are recruited recruited among the University personnel, after a review of their medical history.

Exclusion criteria for control participants included the use of drugs that affect fatty acids (systemic corticosteroids, isotretinoin, and ursodiol) and/or oxidative stress (antioxidants and hypolipemic drugs).

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Liver Cirrhosis

Locations

Country	Name	City	State
Italy	Laboratory of Vascular Medicine, Department of Medical Sciences and Biotechnology, Sapienza University of Rome	Latina
Italy	Department of Clinical Medicine Division of Gastroenterology, Sapienza University of Rome	Rome	RM
Italy	Liver Transplant Center Paride Stefanini, Sapienza University of Rome	Rome	RM

Sponsors (1)

Lead Sponsor	Collaborator
University of Roma La Sapienza

Country where clinical trial is conducted

Italy, 

References & Publications (7)

Al Sibae MR, Cappell MS. Accuracy of MELD scores in predicting mortality in decompensated cirrhosis from variceal bleeding, hepatorenal syndrome, alcoholic hepatitis, or acute liver failure as well as mortality after non-transplant surgery or TIPS. Dig Dis Sci. 2011 Apr;56(4):977-87. doi: 10.1007/s10620-010-1390-3. Epub 2010 Sep 16. Review. — View Citation

Corradini SG, Elisei W, De Marco R, Siciliano M, Iappelli M, Pugliese F, Ruberto F, Nudo F, Pretagostini R, Bussotti A, Mennini G, Eramo A, Liguori F, Merli M, Attili AF, Muda AO, Natalizi S, Berloco P, Rossi M. Preharvest donor hyperoxia predicts good ea — View Citation

Corradini SG, Micheletta F, Natoli S, Iappelli M, Di Angelantonio E, De Marco R, Elisei W, Siciliano M, Rossi M, Berloco P, Attili AF, Diczfalusy U, Iuliano L. High preoperative recipient plasma 7beta-hydroxycholesterol is associated with initial poor gra — View Citation

Iuliano L, Micheletta F, Natoli S, Ginanni Corradini S, Iappelli M, Elisei W, Giovannelli L, Violi F, Diczfalusy U. Measurement of oxysterols and alpha-tocopherol in plasma and tissue samples as indices of oxidant stress status. Anal Biochem. 2003 Jan 15; — View Citation

Iuliano L, Monticolo R, Straface G, Zullo S, Galli F, Boaz M, Quattrucci S. Association of cholesterol oxidation and abnormalities in fatty acid metabolism in cystic fibrosis. Am J Clin Nutr. 2009 Sep;90(3):477-84. doi: 10.3945/ajcn.2009.27757. Epub 2009 Jul 8. — View Citation

Loguercio C, Federico A. Oxidative stress in viral and alcoholic hepatitis. Free Radic Biol Med. 2003 Jan 1;34(1):1-10. Review. — View Citation

Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med. 2000 Jun;21(3):49-98. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Post operative graft function after liver transplantation	• Multiple lipid metabolism biomarkers (fatty acids, cholesterol and oxysterols) are evaluated in the plasma of liver cirrhosis patients before liver transplantation. A logistic regression model is used to evaluate which of these biomarkers is an independent predictor of graft function	Change in graft function after 7 and 30 days after liver transplantation	No
Secondary	Early gene expression in the liver graft	Assessment of lipid metabolism-, oxidative stress-, and ER stress-gene expression in graft tissue liver tissue specimens of patients undergoing organ transplantation and their impact on graft function. Lipid metabolism and ER gene expression (genes: LDL-R, HMGCR, CD81, SREBP2, NPC1L1, XBP-1, XBP2, ATF6, GRP78, GRP94, LXR, INSIG1, INSIG2) in liver graft specimens at transplantation before and after ischemia-reperfusion injury; downregulated and upregulated genes are related to early graft function.	30 days	No