title: Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis.
abstract: 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.
authors.affiliation: Liver Failure Group, The UCL Institute of Hepatology, Division of Medicine, University College London, UK.
authors.forename: Rajeshwar P
authors.initials: RP
authors.lastname: Mookerjee
authors.forename: Mohammed
authors.initials: M
authors.lastname: Malaki
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Davies
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hodges
authors.forename: R Neil
authors.initials: RN
authors.lastname: Dalton
authors.forename: Charles
authors.initials: C
authors.lastname: Turner
authors.forename: Sambit
authors.initials: S
authors.lastname: Sen
authors.forename: Roger
authors.initials: R
authors.lastname: Williams
authors.forename: James
authors.initials: J
authors.lastname: Leiper
authors.forename: Patrick
authors.initials: P
authors.lastname: Vallance
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
mesh_terms: 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
chemical_list: 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