Unique metabolomic signature associated with hepatorenal dysfunction and mortality in cirrhosis

Abstract

The application of nontargeted metabolomic profiling has recently become a powerful noninvasive tool to discover new clinical biomarkers. This study aimed to identify metabolic pathways that could be exploited for prognostic and therapeutic purposes in hepatorenal dysfunction in cirrhosis. One hundred three subjects with cirrhosis had glomerular filtration rate (GFR) measured using iothalamate plasma clearance, and were followed until death, transplantation, or the last encounter. Concomitantly, plasma metabolomic profiling was performed using ultrahigh performance liquid chromatography-tandem mass spectrometry to identify preliminary metabolomic biomarker candidates. Among the 1028 metabolites identified, 34 were significantly increased in subjects with high liver and kidney disease severity compared with those with low liver and kidney disease severity. The highest average fold-change (2.39) was for 4-acetamidobutanoate. Metabolite-based enriched pathways were significantly associated with the identified metabolomic signature (P values ranged from 2.07E-06 to 0.02919). Ascorbate and aldarate metabolism, methylation, and glucuronidation were among the most significant protein-based enriched pathways associated with this metabolomic signature (P values ranged from 1.09E-18 to 7.61E-05). Erythronate had the highest association with measured GFR (R-square = 0.571, P <0.0001). Erythronate (R = 0.594, P <0.0001) and N6-carbamoylthreonyladenosine (R = 0.591, P <0.0001) showed stronger associations with measured GFR compared with creatinine (R = 0.588, P <0.0001) even after controlling for age, gender, and race. The 5 most significant metabolites that predicted mortality independent of kidney disease and demographics were S-adenosylhomocysteine (P = 0.0003), glucuronate (P = 0.0006), trans-aconitate (P = 0.0018), 3-ureidopropionate (P = 0.0021), and 3-(4-hydroxyphenyl)lactate (P = 0.0047). A unique metabolomic signature associated with hepatorenal dysfunction in cirrhosis was identified for further investigations that provide potentially important mechanistic insights into cirrhosis-altered metabolism.

Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy

“…The greatest change (2.39) was for 4-acetamidobutanoate, the acetylated metabolite of GABA and a product of arginine and proline metabolism (http://www.hmdb.ca/metabolites/HMDB0003681). Pathway enrichment analysis identified glucuronidation and methylation, together with ascorbate and aldarate metabolism, that were linked to hepatorenal dysfunction [138]. Another study in China used both NMR and UPLC-ESI-QTOFMS to analyze serum from LC (42), HCC (43) and HV (18).…”

Current Applications of Metabolomics in Cirrhosis

“…A unique metabolomic signature consisting of 34 metabolites that significantly increased in patients with high liver and kidney disease severity has recently been described in patients with cirrhosis [18]. Among these metabolites, 4-acetamidobutanoate, trans-aconitate, 1-methylhistidine, glucuronate, N4-acetylcytidine, 3-ureidopropionate, 3-methoxytyramine sulfate, cytidine, S -adenosylhomocysteine (SAH) and myo-inositol were the 10 most significantly increased ones when patients with high liver and kidney liver disease severity were compared with those with low liver and kidney disease severity [18].…”

“…A unique metabolomic signature consisting of 34 metabolites that significantly increased in patients with high liver and kidney disease severity has recently been described in patients with cirrhosis [18]. Among these metabolites, 4-acetamidobutanoate, trans-aconitate, 1-methylhistidine, glucuronate, N4-acetylcytidine, 3-ureidopropionate, 3-methoxytyramine sulfate, cytidine, S -adenosylhomocysteine (SAH) and myo-inositol were the 10 most significantly increased ones when patients with high liver and kidney liver disease severity were compared with those with low liver and kidney disease severity [18]. This study that used ultrahigh performance liquid chromatography/tandem mass spectrometry to detect plasma metabolites, also showed that all signature metabolites were independent predictors of glomerular filtration rate measured by non-radiolabeled iothalamate plasma clearance in patients with cirrhosis; and erythronate had the highest significant association with measured glomerular filtration rate [18].…”

When Should We Stop Treatment With Terlipressin and Albumin for Patients With Hepatorenal Syndrome?

“…The latter hypothesis was recently reinforced by the discovery of a biosignature of plasma metabolites that correlated with hepatorenal dysfunction in patients with cirrhosis. 6 Patients with ACLF-3 and HRS had a considerable risk of 90-day mortality of up to 80% in this study. Does this mean that we should not treat HRS in patients with ACLF-3 at all?…”