Asymmetric dimethylarginine is strongly associated with cognitive dysfunction and brain MR spectroscopic abnormalities in cirrhosis.
OBJECTIVE
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 (mI), 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 mI compared to cirrhotics. Prior HE patients had worse cognition, higher ADMA and Glx and lower mI 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 mI. 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.
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA 23249, USA. jsbajaj@vcu.edu
Jasmohan S
JS
Bajaj
Vishwadeep
V
Ahluwalia
James B
JB
Wade
Arun J
AJ
Sanyal
Melanie B
MB
White
Nicole A
NA
Noble
Pamela
P
Monteith
Michael
M
Fuchs
Richard K
RK
Sterling
Velimir
V
Luketic
Iliana
I
Bouneva
Richard T
RT
Stravitz
Puneet
P
Puri
Kenneth A
KA
Kraft
Hochong
H
Gilles
Douglas M
DM
Heuman
D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism; D003430:Cross-Sectional Studies; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000209:etiology* / Q000378:metabolism*; D006801:Humans; D007294:Inositol / Q000378:metabolism; D008103:Liver Cirrhosis / Q000150:complications* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
D015415:Biomarkers; D005973:Glutamine; D001224:Aspartic Acid; D018698:Glutamic Acid; D007294:Inositol; C018524:N,N-dimethylarginine; D001120:Arginine; C000179:N-acetylaspartate