Serum and urinary metabolomics and outcomes in cirrhosis

English version

Autoři: Jasmohan S. Bajaj ^aff001; Sili Fan ^aff002; Leroy R. Thacker ^aff003; Andrew Fagan ^aff001; Edith Gavis ^aff001; Melanie B. White ^aff001; Douglas M. Heuman ^aff001; Michael Fuchs ^aff001; Oliver Fiehn ^aff002
Působiště autorů: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, United States of America ^aff001; West Coast Metabolomics Center, University of California, Davis, California, United States of America ^aff002; Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, United States of America ^aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0223061

Souhrn

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.

Klíčová slova:

Drug metabolism – Cirrhosis – Permutation – Urine – Liver transplantation – Metabolites – Metabolomics – Amino acid metabolism

Zdroje

1. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371(9615):838–51. doi: 10.1016/S0140-6736(08)60383-9 18328931.

2. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715–35. doi: 10.1002/hep.27210 25042402.

3. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217–31. doi: 10.1016/j.jhep.2005.10.013 16298014.

4. Claria J, Stauber RE, Coenraad MJ, Moreau R, Jalan R, Pavesi M, et al. Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure. Hepatology. 2016;64(4):1249–64. doi: 10.1002/hep.28740 27483394.

5. Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, et al. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol. 2011;54(4):640–9. doi: 10.1016/j.jhep.2010.07.045 21163546.

6. Bajaj JS, Vargas HE, Reddy KR, Lai JC, O’Leary JG, Tandon P, et al. Association Between Intestinal Microbiota Collected at Hospital Admission and Outcomes of Patients With Cirrhosis. Clin Gastroenterol Hepatol. 2019;17(4):756–65 e3. doi: 10.1016/j.cgh.2018.07.022 30036646.

7. Bajaj JS, Thacker LR, Fagan A, White MB, Gavis E, Hylemon PB, et al. Gut microbial RNA and DNA analysis predicts hospitalizations in cirrhosis. JCI Insight. 2018;3(5).

8. McPhail MJ, Montagnese S, Villanova M, El Hadi H, Amodio P, Crossey MM, et al. Urinary metabolic profiling by (1)H NMR spectroscopy in patients with cirrhosis may discriminate overt but not covert hepatic encephalopathy. Metab Brain Dis. 2017;32(2):331–41. doi: 10.1007/s11011-016-9904-0 27638475.

9. McPhail MJW, Shawcross DL, Lewis MR, Coltart I, Want EJ, Antoniades CG, et al. Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis. J Hepatol. 2016;64(5):1058–67. doi: 10.1016/j.jhep.2016.01.003 26795831.

10. Bajaj JS, Gillevet PM, Patel NR, Ahluwalia V, Ridlon JM, Kettenmann B, et al. A longitudinal systems biology analysis of lactulose withdrawal in hepatic encephalopathy. Metab Brain Dis. 2012;27(2):205–15. doi: 10.1007/s11011-012-9303-0 22527995.

11. Khan V, Putluri N, Sreekumar A, Mindikoglu AL. Current Applications of Metabolomics in Cirrhosis. Metabolites. 2018;8(4). doi: 10.3390/metabo8040067 30360420.

12. Fiehn O, Barupal DK, Kind T. Extending biochemical databases by metabolomic surveys. J Biol Chem. 2011;286(27):23637–43. Epub 2011/05/14. doi: 10.1074/jbc.R110.173617 21566124.

13. Durbin BP, Hardin JS, Hawkins DM, Rocke DM. A variance-stabilizing transformation for gene-expression microarray data. Bioinformatics. 2002;18 Suppl 1:S105–10. doi: 10.1093/bioinformatics/18.suppl_1.s105 12169537.

14. Wanichthanarak K, Fan S, Grapov D, Barupal DK, Fiehn O. Metabox: A Toolbox for Metabolomic Data Analysis, Interpretation and Integrative Exploration. PLoS One. 2017;12(1):e0171046. doi: 10.1371/journal.pone.0171046 28141874 Dmitry Grapov’s contribution to the manuscript occurred while he was not part of CDS and instead the Principal Statistician at the University of California Davis. We have changed his affiliation to reflect this fact and he maintains his stated no conflict of interest.

15. Barupal DK, Fiehn O. Chemical Similarity Enrichment Analysis (ChemRICH) as alternative to biochemical pathway mapping for metabolomic datasets. Sci Rep. 2017;7(1):14567. doi: 10.1038/s41598-017-15231-w 29109515.

16. Barupal DK, Haldiya PK, Wohlgemuth G, Kind T, Kothari SL, Pinkerton KE, et al. MetaMapp: mapping and visualizing metabolomic data by integrating information from biochemical pathways and chemical and mass spectral similarity. BMC Bioinformatics. 2012;13:99. doi: 10.1186/1471-2105-13-99 22591066.

17. Tapper EB, Halbert B, Mellinger J. Rates of and Reasons for Hospital Readmissions in Patients With Cirrhosis: A Multistate Population-based Cohort Study. Clin Gastroenterol Hepatol. 2016;14(8):1181–8 e2. doi: 10.1016/j.cgh.2016.04.009 27085758.

18. Bajaj JS, Reddy KR, Tandon P, Wong F, Kamath PS, Garcia-Tsao G, et al. The 3-month readmission rate remains unacceptably high in a large North American cohort of patients with cirrhosis. Hepatology. 2016;64(1):200–8. doi: 10.1002/hep.28414 26690389.

19. Bajaj JS, Heuman DM, Sanyal AJ, Hylemon PB, Sterling RK, Stravitz RT, et al. Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLoS One. 2013;8(4):e60042. doi: 10.1371/journal.pone.0060042 23565181.

20. Kirpich IA, Miller ME, Cave MC, Joshi-Barve S, McClain CJ. Alcoholic Liver Disease: Update on the Role of Dietary Fat. Biomolecules. 2016;6(1):1. doi: 10.3390/biom6010001 26751488.

21. Gluud LL, Dam G, Les I, Marchesini G, Borre M, Aagaard NK, et al. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017;5:CD001939. doi: 10.1002/14651858.CD001939.pub4 28518283.

22. Dam G, Sorensen M, Buhl M, Sandahl TD, Moller N, Ott P, et al. Muscle metabolism and whole blood amino acid profile in patients with liver disease. Scandinavian journal of clinical and laboratory investigation. 2015;75(8):674–80. 26243157.

23. Williams HR, Cox IJ, Walker DG, Cobbold JF, Taylor-Robinson SD, Marshall SE, et al. Differences in gut microbial metabolism are responsible for reduced hippurate synthesis in Crohn’s disease. BMC Gastroenterol. 2010;10:108. doi: 10.1186/1471-230X-10-108 20849615.

24. Sarma MK, Huda A, Nagarajan R, Hinkin CH, Wilson N, Gupta RK, et al. Multi-dimensional MR spectroscopy: towards a better understanding of hepatic encephalopathy. Metab Brain Dis. 2011;26(3):173–84. doi: 10.1007/s11011-011-9250-1 21698453.

25. Riggio O, Mannaioni G, Ridola L, Angeloni S, Merli M, Carla V, et al. Peripheral and splanchnic indole and oxindole levels in cirrhotic patients: a study on the pathophysiology of hepatic encephalopathy. Am J Gastroenterol. 2010;105(6):1374–81. doi: 10.1038/ajg.2009.738 20125128.

26. Jimenez B, Montoliu C, MacIntyre DA, Serra MA, Wassel A, Jover M, et al. Serum metabolic signature of minimal hepatic encephalopathy by (1)H-nuclear magnetic resonance. J Proteome Res. 2010;9(10):5180–7. doi: 10.1021/pr100486e 20690770.

27. Lu SC. Glutathione synthesis. Biochim Biophys Acta. 2013;1830(5):3143–53. Epub 2012/09/22. doi: 10.1016/j.bbagen.2012.09.008 22995213.

28. Juanola O, Ferrusquia-Acosta J, Garcia-Villalba R, Zapater P, Magaz M, Marin A, et al. Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis. FASEB J. 2019:fj201901327R. Epub 2019/07/28. doi: 10.1096/fj.201901327R 31345057.

29. Tapper EB. Challenge accepted: Confronting readmissions for our patients with cirrhosis. Hepatology. 2016;64(1):26–8. doi: 10.1002/hep.28471 26806609.

30. McPhail MJ, Shawcross DL, Lewis MR, Coltart I, Want EJ, Antoniades CG, et al. Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis. J Hepatol. 2016;64(5):1058–67. doi: 10.1016/j.jhep.2016.01.003 26795831.

31. Mindikoglu AL, Opekun AR, Putluri N, Devaraj S, Sheikh-Hamad D, Vierling JM, et al. Unique metabolomic signature associated with hepatorenal dysfunction and mortality in cirrhosis. Transl Res. 2018;195:25–47. doi: 10.1016/j.trsl.2017.12.002 29291380.

32. Kamath PS, Kim WR, Advanced Liver Disease Study G. The model for end-stage liver disease (MELD). Hepatology. 2007;45(3):797–805. doi: 10.1002/hep.21563 17326206.

33. Patidar KR, Thacker LR, Wade JB, Sterling RK, Sanyal AJ, Siddiqui MS, et al. Covert hepatic encephalopathy is independently associated with poor survival and increased risk of hospitalization. Am J Gastroenterol. 2014;109(11):1757–63. doi: 10.1038/ajg.2014.264 25178701.

34. Bajaj JS, Betrapally NS, Hylemon PB, Heuman DM, Daita K, White MB, et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology. 2015;62(4):1260–71. doi: 10.1002/hep.27819 25820757.

35. Bajaj JS, Betrapally NS, Hylemon PB, Thacker LR, Daita K, Kang DJ, et al. Gut Microbiota Alterations can predict Hospitalizations in Cirrhosis Independent of Diabetes Mellitus. Sci Rep. 2015;5:18559. doi: 10.1038/srep18559 26692421.

36. Lai JC, Rahimi RS, Verna EC, Kappus MR, Dunn MA, McAdams-DeMarco M, et al. Frailty Associated With Waitlist Mortality Independent of Ascites and Hepatic Encephalopathy in a Multicenter Study. Gastroenterology. 2019;156(6):1675–82. doi: 10.1053/j.gastro.2019.01.028 30668935.

37. Ney M, Tangri N, Dobbs B, Bajaj J, Rolfson D, Ma M, et al. Predicting Hepatic Encephalopathy-Related Hospitalizations Using a Composite Assessment of Cognitive Impairment and Frailty in 355 Patients With Cirrhosis. Am J Gastroenterol. 2018;113(10):1506–15. doi: 10.1038/s41395-018-0243-0 30267028.

38. Bajaj JS, Moreau R, Kamath PS, Vargas HE, Arroyo V, Reddy KR, et al. Acute-on-Chronic Liver Failure: Getting Ready for Prime Time? Hepatology. 2018;68(4):1621–32. doi: 10.1002/hep.30056 29689120.

39. Bajaj JS, Wong F, Kamath PS. Defining Acute on Chronic Liver Failure: More Elusive Than Ever. Hepatology. 2019. Epub 2019/02/26. doi: 10.1002/hep.30589 30805952.