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 dimethylargininedimethylamino-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-dimethylaminohydrolase 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. Conclusion: 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. (HEPATOLOGY 2007;45:62-71.)A lcoholic hepatitis (AH) is a severe presentation of alcoholic liver disease associated with high mortality. 1 Patients present with acute hepatic decompensation on the background of cirrhosis, related to complications associated with portal hypertension. A potential link between changes in portal blood flow and poor outcome in severe AH has been suggested. 2 Furthermore, elevated portal pressures in patients with decompensated cirrhosis independently predicts survival 3 although the pathophysiological mechanisms behind these haemodynamic disturbances are incompletely defined.Factors modulating intrahepatic resistance, an important component in the severity of portal hypertension include liver ultrastructural changes secondary to cirrhosis, in addition to variable components such as myofibroblastic stellate cell activity and vaso-active mediators such as nitric oxide (NO). 4 Data from animal studies strongly support the notion that in portal hypertension, there is a deficiency of intrahepatic NO resulting from a reduction in the activity of endothelial NO synthase (eNOS). 5,6 Hepatic NO delivery in these models reduces the severity of portal hypertension through a reduction in intrahepatic resistance. 7 .

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

“…Renal dysfunction, particularly in the context of reno-vascular hypertension, has been described as being associated with higher than normal range values of ADMA (40). Plasma ADMA levels have been shown to be markedly increased in ALF, and its levels correlate with severity of liver failure and the presence of added inflammation and are significantly higher than the levels described in renal disease, which would support the assertion that the ADMA levels in these models are primarily impacted on by hepatic impairment (15,27). As ADMA is a competitive inhibitor of the NOS-arginine binding site, lowering the arginine to ADMA ratio may directly result in a reduction in NOS activity.…”

“…In a previous study, we have shown that ADMA levels were higher in patients with ALF and that the increase was associated with worse outcome (27). Similarly, an increase in the level of plasma arginase, released during hepatic stresses (8), can reduce the amount of available arginine, preventing eNOS-mediated NO synthesis.…”

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

“…This identifies the liver as an important organ for ADMA elimination in humans (157). An increase in plasma ADMA in patients with alcoholic hepatitis is accompanied by decreased hepatic DDAH protein expression and increased hepatic protein expression of PRMT-1 (113).…”

The Rise of Glutaminase in End-Stage Liver Diseases

“…Splanchnic vasodilatation leads to vasoconstriction of numerous vascular beds, including the liver, kidneys, and has significant effects on the brain. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of eNOS (endothelial nitric oxide synthase), the levels of which are increased in liver failure (Leiper, Nandi et al 2007;Mookerjee, Malaki et al 2007). It has been shown that treatment of cirrhotic rats with OP resulted in restoration of the NOS pathways which may have a direct effect on cerebral perfusion (Balasubramaniyan, Wright et al 2011).…”