Association of homoarginine and methylarginines with liver dysfunction and mortality in chronic liver disease
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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 ± 11.2 years; 31 % females), the serum concentrations were 1.94 ± 0.90 µM for homoarginine, 0.90 ± 0.22 µM for ADMA, and 0.70 (0.60–0.93) µM 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 µM (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.
KeywordsADMA SDMA Dimethylarginine score Homoarginine Amino acids Cirrhosis
Analysis of variance
Coefficient of variation
Dimethylarginine score (i.e., ADMA + SDMA)
High-performance liquid chromatography
Model for end-stage liver disease
Protein arginine N-methyltransferase 1
Receiver operating characteristic
This work was supported by BioPersMed (COMET K-project 825329), which is funded by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT), the Austrian Federal Ministry of Economics and Labour/the Federal Ministry of Economy, Family and Youth (BMWA/BMWFJ), and the Styrian Business Promotion Agency (SFG). Katharina Kienreich was supported by funding from the Austrian National Bank (Jubilaeumsfonds: project number: 13905). The authors thank Hannelore Pock and Sabine Paulitsch for assistance with storage and measurements of blood samples.
Conflict of interest
The authors declare that they have no conflict of interest.
The study was approved by the local ethics committee.
- Becker T, Mevius I, de Vries DK, Schaapherder AF, zu Vilsendorf AM, Klempnauer J, Frölich JC, Tsikas D (2009) The l-arginine/NO pathway in end-stage liver disease and during orthotopic liver and kidney transplantation: biological and analytical ramifications. Nitric Oxide 20:61–67CrossRefPubMedGoogle Scholar
- Cullen ME, Yuen AH, Felkin LE, Smolenski RT, Hall JL, Grindle S, Miller LW, Birks EJ, Yacoub MH, Barton PJ (2006) Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis. Circulation 114(1 Suppl):I16–I20PubMedGoogle Scholar
- Karakurt F, Carlioglu A, Koktener A, Ozbek M, Kaya A, Uyar ME, Kasapoglu B, Ilhan A (2009) Relationship between cerebral arterial pulsatility and carotid intima media thickness in diabetic and non-diabetic patients with non-alcoholic fatty liver disease. J Endocrinol Invest 32:63–68CrossRefPubMedGoogle Scholar
- Laleman W, Omasta A, Van de Casteele M, Zeegers M, Vander Elst I, Van Landeghem L, Severi T, van Pelt J, Roskams T, Fevery J, Nevens F (2005) A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis. Hepatology 42:1382–1390CrossRefPubMedGoogle Scholar
- Li J, Wilson A, Gao X, Liu Y, Poloyac S, Pitt B, Xie W, Li S (2009) Coordinated regulation of dimethylarginine dimethylaminohydrolase-1 and cationic amino acid transporter-1 by farnesoid X receptor in mouse liver and kidney and its implication in the control of blood levels of asymmetric dimethylarginine. J Pharmacol Exp Ther 331:234–243PubMedCentralCrossRefPubMedGoogle Scholar
- Lluch P, Mauricio MD, Vila JM, Segarra G, Medina P, Del Olmo JA, Rodrigo JM, Serra MA (2006) Accumulation of symmetric dimethylarginine in hepatorenal syndrome. Exp Biol Med (Maywood) 231:70–75Google Scholar
- Meinitzer A, Puchinger M, Winklhofer-Roob BM, Rock E, Ribalta J, Roob JM, Sundl I, Halwachs-Baumann G, März W (2007) Reference values for plasma concentrations of asymmetrical dimethylarginine (ADMA) and other arginine metabolites in men after validation of a chromatographic method. Clin Chim Acta 384:141–148CrossRefPubMedGoogle Scholar
- Meinitzer A, Drechsler C, Tomaschitz A, Pilz S, Krane V, Wanner C, März W (2011a) Homoarginine: a new cardiovascular risk marker in hemodialysis patients. Lab Med 35:153–159Google Scholar
- Meinitzer A, Kielstein JT, Pilz S, Drechsler C, Ritz E, Boehm BO, Winkelmann BR, März W (2011b) Symmetrical and asymmetrical dimethylarginine as predictors for mortality in patients referred for coronary angiography: the Ludwigshafen Risk and Cardiovascular Health study. Clin Chem 57:112–121CrossRefPubMedGoogle Scholar
- Nijveldt RJ, Teerlink T, Siroen MP, van der Hoven B, Prins HA, Wiezer MJ, Meijer C, van der Sijp JR, Cuesta MA, Meijer S, van Leeuwen PA (2004) Elevation of asymmetric dimethylarginine (ADMA) in patients developing hepatic failure after major hepatectomy. JPEN J Parenter Enteral Nutr 28:382–387CrossRefPubMedGoogle Scholar
- Pilz S, Meinitzer A, Tomaschitz A, Kienreich K, Dobnig H, Schwarz M, Wagner D, Drechsler C, Piswanger-Sölkner C, März W, Fahrleitner-Pammer A (2013) Associations of homoarginine with bone metabolism and density, muscle strength and mortality: cross-sectional and prospective data from 506 female nursing home patients. Osteoporos Int 24:377–381CrossRefPubMedGoogle Scholar
- Tsikas D, Thum T, Becker T, Pham VV, Chobanyan K, Mitschke A, Beckmann B, Gutzki FM, Bauersachs J, Stichtenoth DO (2007) Accurate quantification of dimethylamine (DMA) in human urine by gas chromatography-mass spectrometry as pentafluorobenzamide derivative: evaluation of the relationship between DMA and its precursor asymmetric dimethylarginine (ADMA) in health and disease. J Chromatogr B 851:229–239CrossRefGoogle Scholar
- Valtonen P, Laitinen T, Lyyra-Laitinen T, Raitakari OT, Juonala M, Viikari JS, Heiskanen N, Vanninen E, Punnonen K, Heinonen S (2008) Serum l-homoarginine concentration is elevated during normal pregnancy and is related to flow-mediated vasodilatation. Circ J 72:1879–1884CrossRefPubMedGoogle Scholar