Asymmetric dimethylarginine is strongly associated with cognitive dysfunction and brain MR spectroscopic abnormalities in cirrhosis

Background & Aims: Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide synthase that accumulates in liver disease and may contribute to hepatic encephalopathy (HE). We aimed at evaluating the association of ADMA with cognition and brain MR spectroscopy (MRS) in cirrhosis. Methods: Cirrhotic patients with/without prior HE and non-cirrhotic controls underwent cognitive testing and ADMA determination. A subgroup underwent brain MRS [glutamine/glutamate (Glx), myoinositol (ml), N-acetyl-aspartate (NAA) in parietal white, occipital gray, and anterior cingulated (ACC)]. Cognition and ADMA in a cirrhotic subgroup before and one month after transjugular intrahepatic portosystemic shunting (TIPS) were also tested. Cognition and MRS values were correlated with ADMA and compared between groups using multivariable regression. ADMA levels were compared between those who did/did not develop post-TIPS HE. Results: Ninety cirrhotics (MELD 13, 54 prior HE) and 16 controls were included. Controls had better cognition and lower ADMA, Glx, and higher ml compared to cirrhotics. Prior HE patients had worse cognition, higher ADMA and Glx and lower ml compared to non-HE cirrhotics. ADMA was positively correlated with MELD (r = 0.58, p<0.0001), abnormal cognitive test number (r = 0.66, p<0.0001), and Glx and NAAA (white matter, ACC) and negatively with ml. On regression, ADMA predicted number of abnormal tests and mean Z-score independent of prior HE and MELD. Twelve patients underwent TIPS; 7 developed HE post-TIPS. ADMA increased post-TIPS in patients who developed HE (p = 0.019) but not in others (p = 0.89). Conclusions: A strong association of ADMA with cognition and prior HE was found independent of the MELD score in cirrhosis. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.