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Serum and urinary metabolomics and outcomes in cirrhosis.

ABSTRACT: BACKGROUND:Cirrhosis can alter several metabolic pathways. Metabolomics could prognosticate outcomes like hepatic encephalopathy (HE), transplant, hospitalization and death. AIM:Determine changes in serum and urine metabolomics in cirrhotics who develop outcomes. METHODS:Cirrhotic outpatients underwent data, serum/urine collection and were followed for 90 days. Demographics, cirrhosis details and medications were collected. Metabolomics was performed on urine/serum using GC/MS with subsequent bioinformatics analyses (ChemRICH, MetaMAPP and PLS-DA). Logistic regression adjusting for covariates (demographics, alcohol etiology, prior HE, PPI, SBP prophylaxis, rifaximin/lactulose) were performed and ROC curves comparing MELD to adjusted serum & urine metabolites were created. RESULTS:211 patients gave serum, of which 64 were hospitalized, 19 developed HE, 13 were transplanted and 11 died. 164 patients gave urine of which 56 were hospitalized, 18 developed HE, 12 were transplanted and 11 died. Metabolomics: Saturated fatty acids, amino acids and bioenergetics-related metabolites differentiated patients with/without outcomes. After regression, 232, 228, 284 and 229 serum metabolites were significant for hospitalization, HE, death and transplant. In urine 290, 284, 227 & 285 metabolites were significant for hospitalization, HE, death and transplant respectively. AUC was higher for serum metabolites vs MELD for HE (0.85 vs.0.76), death (0.99 vs.0.88), transplant (0.975 vs.0.94) and hospitalizations (0.84 vs.0.83). Similarly, urinary metabolite AUC was also higher than MELD for HE (0.87 vs.0.72), death (0.92 vs 0.86), transplant (0.99 vs.0.90) and hospitalizations (0.89 vs.0.84). CONCLUSIONS:In this exploratory study, serum and metabolites focused on lipid, bioenergetics and amino acid metabolism are altered in cirrhotics who develop negative outcomes.

SUBMITTER: Bajaj JS

PROVIDER: S-EPMC6764675 | biostudies-other | 2019

REPOSITORIES: biostudies-other

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Serum and urinary metabolomics and outcomes in cirrhosis.

Bajaj Jasmohan S JS Fan Sili S Thacker Leroy R LR Fagan Andrew A Gavis Edith E White Melanie B MB Heuman Douglas M DM Fuchs Michael M Fiehn Oliver O

PloS one 20190927 9

<h4>Background</h4>Cirrhosis can alter several metabolic pathways. Metabolomics could prognosticate outcomes like hepatic encephalopathy (HE), transplant, hospitalization and death.<h4>Aim</h4>Determine changes in serum and urine metabolomics in cirrhotics who develop outcomes.<h4>Methods</h4>Cirrhotic outpatients underwent data, serum/urine collection and were followed for 90 days. Demographics, cirrhosis details and medications were collected. Metabolomics was performed on urine/serum using GC ...[more]

PMID: 31560724

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Project description:Background and aimsAcute kidney injury (AKI) has a poor prognosis in cirrhosis. Given the variability of creatinine, the prediction of AKI and dialysis by other markers is needed. The aim of this study is to determine the role of serum and urine metabolomics in the prediction of AKI and dialysis in an inpatient cirrhosis cohort.Approach and resultsInpatients with cirrhosis from 11 North American Consortium of End-stage Liver Disease centers who provided admission serum/urine when they were AKI and dialysis-free were included. Analysis of covariance adjusted for demographics, infection, and cirrhosis severity was performed to identify metabolites that differed among patients (1) who developed AKI or not; (2) required dialysis or not; and/pr (3) within AKI subgroups who needed dialysis or not. We performed random forest and AUC analyses to identify specific metabolite(s) associated with outcomes. Logistic regression with clinical variables with/without metabolites was performed. A total of 602 patients gave serum (218 developed AKI, 80 needed dialysis) and 435 gave urine (164 developed AKI, 61 needed dialysis). For AKI prediction, clinical factor-adjusted AUC was 0.91 for serum and 0.88 for urine. Major metabolites such as uremic toxins (2,3-dihydroxy-5-methylthio-4-pentenoic acid [DMTPA], N2N2dimethylguanosine, uridine/pseudouridine) and tryptophan/tyrosine metabolites (kynunerate, 8-methoxykyunerate, quinolinate) were higher in patients who developed AKI. For dialysis prediction, clinical factor-adjusted AUC was 0.93 for serum and 0.91 for urine. Similar metabolites as AKI were altered here. For dialysis prediction in those with AKI, the AUC was 0.81 and 0.79 for serum/urine. Lower branched-chain amino-acid (BCAA) metabolites but higher cysteine, tryptophan, glutamate, and DMTPA were seen in patients with AKI needing dialysis. Serum/urine metabolites were additive to clinical variables for all outcomes.ConclusionsSpecific admission urinary and serum metabolites were significantly additive to clinical variables to predict AKI development and dialysis initiation in inpatients with cirrhosis. These observations can potentially facilitate earlier initiation of renoprotective measures.

Project description:Characterizing the metabolic changes pertaining to hepatocellular carcinoma (HCC) in patients with liver cirrhosis is believed to contribute towards early detection, treatment, and understanding of the molecular mechanisms of HCC. In this study, we compare metabolite levels in sera of 78 HCC cases with 184 cirrhotic controls by using ultra performance liquid chromatography coupled with a hybrid quadrupole time-of-flight mass spectrometry (UPLC-QTOF MS). Following data preprocessing, the most relevant ions in distinguishing HCC cases from patients with cirrhosis are selected by parametric and non-parametric statistical methods. Putative metabolite identifications for these ions are obtained through mass-based database search. Verification of the identities of selected metabolites is conducted by comparing their MS/MS fragmentation patterns and retention time with those from authentic compounds. Quantitation of these metabolites is performed in a subset of the serum samples (10 HCC and 10 cirrhosis) using isotope dilution by selected reaction monitoring (SRM) on triple quadrupole linear ion trap (QqQLIT) and triple quadrupole (QqQ) mass spectrometers. The results of this analysis confirm that metabolites involved in sphingolipid metabolism and phospholipid catabolism such as sphingosine-1-phosphate (S-1-P) and lysophosphatidylcholine (lysoPC 17:0) are up-regulated in sera of HCC vs. those with liver cirrhosis. Down-regulated metabolites include those involved in bile acid biosynthesis (specifically cholesterol metabolism) such as glycochenodeoxycholic acid 3-sulfate (3-sulfo-GCDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), taurocholic acid (TCA), and taurochenodeoxycholate (TCDCA). These results provide useful insights into HCC biomarker discovery utilizing metabolomics as an efficient and cost-effective platform. Our work shows that metabolomic profiling is a promising tool to identify candidate metabolic biomarkers for early detection of HCC cases in high risk population of cirrhotic patients.

Project description:Background and aims: The serum metabolites changes in patients with hepatitis B virus (HBV)-related cirrhosis as progression. Peroxisome proliferator-activated receptor gamma (PPARγ) is closely related to lipid metabolism in cirrhotic liver. However, the relationship between fatty acids and the expression of hepatic PPARγ during cirrhosis regression remains unknown. In this study, we explored the serum metabolic characteristics and expression of PPARγ in patients with histological response to treatment with entecavir. Methods: Sixty patients with HBV-related cirrhosis were selected as the training cohort with thirty patients each in the regression (R) group and non-regression (NR) group based on their pathological changes after 48-week treatment with entecavir. Another 72 patients with HBV-related cirrhosis and treated with entecavir were collected as the validation cohort. All of the serum samples were tested using ultra-performance liquid chromatography coupled to tandem mass spectrometry. Data were processed through principal component analysis and orthogonal partial least square discriminant analysis. Hepatic PPARγ expression was observed using immunohistochemistry. The relationship between serum fatty acids and PPARγ was calculated using Pearson's or Spearman's correlation analysis. Results: A total of 189 metabolites were identified and 13 differential metabolites were screened. Compared to the non-regression group, the serum level of fatty acids was higher in the R group. At baseline, the expression of PPARγ in hepatic stellate cells was positively correlated with adrenic acid (r 2 = 0.451, p = 0.046). The expression of PPARγ in both groups increased after treatment, and the expression of PPARγ in the R group was restored in HSCs much more than that in the NR group (p = 0.042). The adrenic acid and arachidonic acid (AA) in the R group also upgraded more than the NR group after treatment (p = 0.037 and 0.014). Conclusion: Baseline serum differential metabolites, especially fatty acids, were identified in patients with HBV-related cirrhosis patients who achieved cirrhosis regression. Upregulation of adrenic acid and arachidonic acid in serum and re-expression of PPARγ in HSCs may play a crucial role in liver fibrosis improvement.

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Serum and urinary metabolomics and outcomes in cirrhosis.

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Serum and urinary metabolomics and outcomes in cirrhosis.

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