Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis.
Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylarginine-dimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P = 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylamino-hydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function.


CONCLUSIONS
Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis.
Mookerjee
Rajeshwar P
RP
Liver Failure Group, The UCL Institute of Hepatology, Division of Medicine, University College London, UK.
Malaki
Mohammed
M
Davies
Nathan A
NA
Hodges
Stephen J
SJ
Dalton
R Neil
RN
Turner
Charles
C
Sen
Sambit
S
Williams
Roger
R
Leiper
James
J
Vallance
Patrick
P
Jalan
Rajiv
R
D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D006519:Hepatitis, Alcoholic / Q000097:blood* / Q000150:complications / Q000401:mortality; D006801:Humans; D006975:Hypertension, Portal / Q000097:blood / Q000209:etiology; D008104:Liver Cirrhosis, Alcoholic / Q000097:blood; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity; D015996:Survival Rate
D015415:Biomarkers; D012097:Repressor Proteins; C487735:dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D000581:Amidohydrolases; C059999:dimethylargininase