Association of homoarginine and methylarginines with liver dysfunction and mortality in chronic liver disease

Previous studies on arginine metabolites reported an association of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) with liver dysfunction and an inverse relation of homoarginine (hArg) with cardiovascular risk. The aim of the present study was to investigate the relationships between hArg, ADMA, SDMA, and the dimethylarginine score (DAS, i.e., ADMA + SDMA) and liver dysfunction and survival in chronic liver disease. In 94 consecutive cirrhotic patients admitted to our outpatient liver clinic, serum levels of hArg, ADMA, and SDMA were measured by HPLC at baseline. Patients were followed with respect to mortality. In the entire study cohort (age 58.5 +/- A 11.2 years; 31 % females), the serum concentrations were 1.94 +/- A 0.90 A mu M for homoarginine, 0.90 +/- A 0.22 A mu M for ADMA, and 0.70 (0.60-0.93) A mu M for SDMA. ADMA correlated with both Child-Pugh and MELD scores, while SDMA, DAS, and hArg correlated with MELD score only. Thirty patients (32 %) died during a median follow-up of 3.5 years. Age- and sex-adjusted Cox proportional hazard ratios (HR) per A mu M (with 95 % confidence intervals) showed that hArg was associated with decreased mortality [HR 0.59 (0.37-0.96)], whereas mortality was increased in patients with higher ADMA [HR 3.78 (0.98-14.60)], SDMA [HR 6.54 (3.15-13.59)] and DAS [HR 4.13 (2.26-7.56)]. Only SDMA and DAS remained significantly associated with mortality after additional adjustments for either Child-Pugh stage or MELD score. In conclusion, in cirrhotic patients seen in an outpatient liver clinic, hArg as well as the dimethylarginines ADMA and SDMA was related to long-term mortality. In particular, SDMA predicts mortality independently of both Child-Pugh stage and MELD score.