Clinical trial NCT01389115: Fatty Acids Lipidome and Oxidative Stress in Liver Transplantation
Official title: Fatty Acids Lipidome and Oxidative Stress Markers as Indicators of Liver Transplant Outcome
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Liver Cirrhosis
Keywords: liver cirrhosis
oxidative stress
liver transplant
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
First posted: 2011-07-07
Enrollment: 320
Sex: ALL
Minimum age (years): 15
Maximum age (years): 69
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 1. 150 cirrhotic patients, including Hepatocellular Carcinoma (HCC), Hepatitis C Virus (HCV) positive patients
2. 80 healthy controls
3. 100 liver donors

Brief 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Post operative graft function after liver transplantation
timeFrame: Change in graft function after 7 and 30 days after liver transplantation
Secondary outcomes:
measure: Early gene expression in the liver graft
timeFrame: 30 days
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Department of Clinical Medicine Division of Gastroenterology, Sapienza University of Rome
state: RM
city: Rome
country: Italy
facility: Liver Transplant Center Paride Stefanini, Sapienza University of Rome
state: RM
city: Latina
country: Italy
facility: Laboratory of Vascular Medicine, Department of Medical Sciences and Biotechnology, Sapienza University of Rome
Study officials:
affiliation: University of Roma La Sapienza
name: Stefano Corradini, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med. 2000 Jun;21(3):49-98. doi: 10.1016/s0098-2997(00)00004-2.
citation: Loguercio C, Federico A. Oxidative stress in viral and alcoholic hepatitis. Free Radic Biol Med. 2003 Jan 1;34(1):1-10. doi: 10.1016/s0891-5849(02)01167-x.
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.
citation: 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.
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 graft function after liver transplantation. Liver Transpl. 2005 Dec;11(12):1494-504. doi: 10.1002/lt.20524.
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;312(2):217-23. doi: 10.1016/s0003-2697(02)00467-0.
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 early graft function and longer graft survival after liver transplantation. Liver Transpl. 2005 Feb;11(2):140-51. doi: 10.1002/lt.20339.
citation: Ginanni Corradini S, Zerbinati C, Maldarelli F, Palmaccio G, Parlati L, Bottaccioli AG, Molinaro A, Poli E, Boaz M, Serviddio G, Mennini G, Corsi A, Bianco P, Rossi M, Iuliano L. Plasma fatty acid lipidome is associated with cirrhosis prognosis and graft damage in liver transplantation. Am J Clin Nutr. 2014 Aug;100(2):600-8. doi: 10.3945/ajcn.113.074427. Epub 2014 Jun 25.