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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 7, 2015; 21(17): 5131-5137
Published online May 7, 2015. doi: 10.3748/wjg.v21.i17.5131
Liver plays a central role in asymmetric dimethylarginine-mediated organ injury
Andrea Ferrigno, Laura G Di Pasqua, Clarissa Berardo, Plinio Richelmi, Mariapia Vairetti
Andrea Ferrigno, Laura G Di Pasqua, Clarissa Berardo, Plinio Richelmi, Mariapia Vairetti, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
Author contributions: Ferrigno A and Vairetti M wrote the draft and final versions; Di Pasqua LG and Berardo C contributed to data acquisition; Richelmi P revised and edited the draft versions; all authors approved the final version of the paper.
Supported by Fondazione Cariplo, Grant No. 2011-0439.
Conflict-of-interest: Authors declare no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Mariapia Vairetti, PhD, Department of Internal Medicine and Therapeutics, University of Pavia, Via Ferrata 9A, 27100 Pavia, Italy. mariapia.vairetti@unipv.it
Telephone: +39-382-986398 Fax: +39-382-986347
Received: January 27, 2015
Peer-review started: January 28, 2015
First decision: February 10, 2015
Revised: February 24, 2015
Accepted: March 31, 2015
Article in press: March 31, 2015
Published online: May 7, 2015
Processing time: 105 Days and 11.2 Hours
Abstract

Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is synthesized by protein methyltransferases followed by proteolytic degradation. ADMA is metabolized to citrulline and dimethylamine, by dimethylarginine dimethylaminohydrolase (DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver. The liver plays a crucial role in ADMA metabolism by DDAH-1 and, as has been recently demonstrated, it is also responsible for ADMA biliary excretion. A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies: plasma ADMA levels are increased in patients with liver cirrhosis, alcoholic hepatitis and acute liver failure. The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation, oxidative stress, and direct damage to DDAH. High plasma ADMA levels are also relevant as they are associated with the onset of multi-organ failure (MOF). Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality: a significant reduction in nitric oxide synthesis, leading to malperfusion in various organs, eventually culminating in multi organs dysfunction.

Keywords: Liver; Asymmetric dimethylarginine; Nitric oxide; Nitric oxide-synthase; Multiple organ failure

Core tip: Nitric oxide (NO) synthesis is blocked by asymmetric dimethylarginine (ADMA) which competes with L-arginine for NO-synthase. ADMA is metabolized principally in the liver, by dimethylarginine dimethylaminohydrolase. The kidney and the liver are involved in ADMA excretion. A correlation exists between plasma ADMA levels and degree of hepatic dysfunction in patients suffering from liver cirrhosis, alcoholic hepatitis and acute liver failure. High plasma ADMA levels are relevant because they are associated with the development of multi-organ failure (MOF): increased plasma ADMA concentration was identified as a risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality.