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Establishing a metabolomic model for the prognosis of hepatitis B virus-induced acute-on-chronic liver failure treated with different liver support systems

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Abstract

Liver failure induced by hepatitis B virus (HBV) is a severe disease with a high mortality rate. Liver support treatment is a powerful method for treating liver failure and is a bridge to liver transplantation. Patients with similar liver function indices, however, have different outcomes following treatment, and no satisfying prediction parameters exist. In this study, we used ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) to investigate plasma metabolites in groups of acute-on-chronic liver failure patients with different prognosis. An orthogonal partial least squares (OPLS) model, with satisfactory explanatory and predictive ability (R 2 Y = 0.943, Q 2 = 0.913) was established using SIMCA-P + 12.0. The model was based on samples collected just before the first artificial treatment for comparable model efficacy. The concordance statistics of our model was 0.968 (95% CI [0.951, 0.985]) which is superior to that of the MELD (the Model for End-stage Liver Diseases) score (0.737, 95% CI [0.578, 0.896]). Three groups of markers were identified: lysophosphatidylcholine, primary fatty acid amides and conjugated bile acids. Lysophosphatidylcholine and conjugated bile acids were protection factors for survival and primary fatty acid amides were risk factors. The cut-off point for the predictive value of our model was greater than or equal to 0.196, at which the model showed the best discrimination between the recovery and non-recovery groups, with a sensitivity of 95% and a specificity of 87%. This metabolomic model, based on plasma UPLC-MS profiles, provides not only excellent discrimination and prognostic ability for HBV-induced acute-on-chronic liver failure but also early and precise warning of possible liver transplantation.

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References

  • Antoniades, C. G., Berry, P. A., Wendon, J. A., & Vergani, D. (2008). The importance of immune dysfunction in determining outcome in acute liver failure. Journal of Hepatology, 49, 845–861.

    Article  PubMed  CAS  Google Scholar 

  • Bernal, W. (2010). Lactate is important in determining prognosis in acute liver failure. Journal of Hepatology, 53, 209–210.

    Article  PubMed  CAS  Google Scholar 

  • Bernal, W., Donaldson, N., Wyncoll, D., & Wendon, J. (2002). Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: A cohort study. Lancet, 359, 558–563.

    Article  PubMed  CAS  Google Scholar 

  • Boger, D. L., Fecik, R. A., Patterson, J. E., Miyauchi, H., Patricelli, M. P., & Cravatt, B. F. (2000). Fatty acid amide hydrolase substrate specificity. Bioorganic & Medicinal Chemistry Letters, 10, 2613–2616.

    Article  CAS  Google Scholar 

  • Chen, Y. S., Wu, Z. W., He, J. Q., Yu, J., Yang, S. G., Zhang, Y. M., et al. (2007). The curative effect of ALSS on 1-month mortality in AoCLF patients after 72 to 120 hours. The International Journal of Artificial Organs, 30, 906–914.

    PubMed  CAS  Google Scholar 

  • Cravatt, B. F., Giang, D. K., Mayfield, S. P., Boger, D. L., Lerner, R. A., & Gilula, N. B. (1996). Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature, 384, 83–87.

    Article  PubMed  CAS  Google Scholar 

  • Cravatt, B. F., Saghatelian, A., Hawkins, E. G., Clement, A. B., Bracey, M. H., & Lichtman, A. H. (2004). Functional disassociation of the central and peripheral fatty acid amide signaling systems. Proceedings of the National Academy of Sciences of the United States of America, 101, 10821–10826.

    Article  PubMed  CAS  Google Scholar 

  • Dhiman, R. K., Jain, S., Maheshwari, U., Bhalla, A., Sharma, N., Ahluwalia, J., et al. (2007). Early indicators of prognosis in fulminant hepatic failure: An assessment of the Model for End-Stage Liver Disease (MELD) and King’s College Hospital criteria. Liver Transplantation, 13, 814–821.

    Article  PubMed  Google Scholar 

  • DI Campli, C., Zocco, M. A., Gaspari, R., Novi, M., Candelli, M., Santoliquido, A., et al. (2005). The decrease in cytokine concentration during albumin dialysis correlates with the prognosis of patients with acute on chronic liver failure. Transplantation Proceedings, 37, 2551–2553.

    Article  PubMed  Google Scholar 

  • Driscoll, W. J., Chaturvedi, S., & Mueller, G. P. (2007). Oleamide synthesizing activity from rat kidney: Identification as cytochrome c. The Journal of Biological Chemistry, 282, 22353–22363.

    Article  PubMed  CAS  Google Scholar 

  • Du, W. B., Li, L. J., Huang, J. R., Yang, Q., Liu, X. L., Li, J., et al. (2005). Effects of artificial liver support system on patients with acute or chronic liver failure. Transplantation Proceedings, 37, 4359–4364.

    Article  PubMed  CAS  Google Scholar 

  • Giang, D. K., & Cravatt, B. F. (1997). Molecular characterization of human and mouse fatty acid amide hydrolases. Proceedings of the National Academy of Sciences of the United States of America, 94, 2238–2242.

    Article  PubMed  CAS  Google Scholar 

  • Huang, Y. H., Schafer-Elinder, L., Wu, R., Claesson, H. E., & Frostegard, J. (1999). Lysophosphatidylcholine (LPC) induces proinflammatory cytokines by a platelet-activating factor (PAF) receptor-dependent mechanism. Clinical and Experimental Immunology, 116, 326–331.

    Article  PubMed  CAS  Google Scholar 

  • Kamath, P. S., Wiesner, R. H., Malinchoc, M., Kremers, W., Therneau, T. M., Kosberg, C. L., et al. (2001). A model to predict survival in patients with end-stage liver disease. Hepatology, 33, 464–470.

    Article  PubMed  CAS  Google Scholar 

  • Kim, W. R., Biggins, S. W., Kremers, W. K., Wiesner, R. H., Kamath, P. S., Benson, J. T., et al. (2008). Hyponatremia and mortality among patients on the liver-transplant waiting list. New England Journal of Medicine, 359, 1018–1026.

    Article  PubMed  CAS  Google Scholar 

  • Kjaergard, L. L., Liu, J., Als-Nielsen, B., & Gluud, C. (2003). Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: A systematic review. JAMA, 289, 217–222.

    Article  PubMed  Google Scholar 

  • Li, N., Li, Q., Qian, Z., Zhang, Y., Chen, M., & Shi, G. (2009). Impaired TLR3/IFN-beta signaling in monocyte-derived dendritic cells from patients with acute-on-chronic hepatitis B liver failure: Relevance to the severity of liver damage. Biochemical and Biophysical Research Communications, 390, 630–635.

    Article  PubMed  CAS  Google Scholar 

  • Lin, S. D., Kawakami, T., Ushio, A., Sato, A., Sato, S., Iwai, M., et al. (2006). Ratio of circulating follistatin and activin A reflects the severity of acute liver injury and prognosis in patients with acute liver failure. Journal of Gastroenterology and Hepatology, 21, 374–380.

    Article  PubMed  CAS  Google Scholar 

  • Lindon, J. C., Nicholson, J. K., & Holmes, E. (Eds.). (2008). The handbook of metabonomics and metabolomics. Beijing: Science Press.

    Google Scholar 

  • Liver Failure and Artificial Liver Group, C. S. O. I. D., Chinese Medical Association & Severe Liver Diseases and Artificial Liver Group, C. S. O. H., Chinese Medical Association. (2006). Diagnostic and treatment guidelines for liver failure. Zhonghua Gan Zang Bing Za Zhi, 14, 643–646.

    Google Scholar 

  • Macquillan, G. C., Seyam, M. S., Nightingale, P., Neuberger, J. M., & Murphy, N. (2005). Blood lactate but not serum phosphate levels can predict patient outcome in fulminant hepatic failure. Liver Transplantation, 11, 1073–1079.

    Article  PubMed  Google Scholar 

  • Montejo Gonzalez, J. C., Catalan Gonzalez, M., Meneu Diaz, J. C., Moreno Elola-Olaso, A., De La Cruz, J., & Moreno Gonzalez, E. (2009). Artificial liver support system in acute liver failure patients waiting liver transplantation. Hepato-Gastroenterology, 56, 456–461.

    PubMed  Google Scholar 

  • O’grady, J. G., Alexander, G. J., Hayllar, K. M., & Williams, R. (1989). Early indicators of prognosis in fulminant hepatic failure. Gastroenterology, 97, 439–445.

    PubMed  Google Scholar 

  • Olofsson, K. E., Andersson, L., Nilsson, J., & Bjorkbacka, H. (2008). Nanomolar concentrations of lysophosphatidylcholine recruit monocytes and induce pro-inflammatory cytokine production in macrophages. Biochemical and Biophysical Research Communications, 370, 348–352.

    Article  PubMed  CAS  Google Scholar 

  • Piotto, M., Moussallieh, F. M., Dillmann, B., Imperiale, A., Neuville, A., Brigand, C., et al. (2009). Metabolic characterization of primary human colorectal cancers using high resolution magic angle spinning 1H magnetic resonance spectroscopy. Metabolomics, 5, 292–301.

    Article  CAS  Google Scholar 

  • Polson, J., & Lee, W. M. (2005). AASLD position paper: The management of acute liver failure. Hepatology, 41, 1179–1197.

    Article  PubMed  Google Scholar 

  • Quinn, M. T., Parthasarathy, S., & Steinberg, D. (1988). Lysophosphatidylcholine: A chemotactic factor for human monocytes and its potential role in atherogenesis. Proceedings of the National Academy of Sciences of the United States of America, 85, 2805–2809.

    Article  PubMed  CAS  Google Scholar 

  • Radu, C. G., Yang, L. V., Riedinger, M., Au, M., & Witte, O. N. (2004). T cell chemotaxis to lysophosphatidylcholine through the G2A receptor. Proceedings of the National Academy of Sciences of the United States of America, 101, 245–250.

    Article  PubMed  CAS  Google Scholar 

  • Ren, F., Chen, Y., Wang, Y., Yan, Y., Zhao, J., Ding, M., et al. (2010). Comparative serum proteomic analysis of patients with acute-on-chronic liver failure: Alpha-1-acid glycoprotein maybe a candidate marker for prognosis of hepatitis B virus infection. Journal of Viral Hepatitis, 17, 816–824.

    Article  Google Scholar 

  • Schiodt, F. V., Ostapowicz, G., Murray, N., Satyanarana, R., Zaman, A., Munoz, S., et al. (2006). Alpha-fetoprotein and prognosis in acute liver failure. Liver Transplantation, 12, 1776–1781.

    Article  PubMed  Google Scholar 

  • Schiodt, F. V., Rossaro, L., Stravitz, R. T., Shakil, A. O., Chung, R. T., & Lee, W. M. (2005). Gc-globulin and prognosis in acute liver failure. Liver Transplantation, 11, 1223–1227.

    Article  PubMed  Google Scholar 

  • Schmidt, L. E., & Dalhoff, K. (2002). Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology, 36, 659–665.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt, L. E., & Larsen, F. S. (2010). Is lactate concentration of major value in determining the prognosis in patients with acute liver failure? Hardly. Journal of Hepatology, 53, 211–212.

    Article  PubMed  CAS  Google Scholar 

  • Shepherd, L., Alexander, C., Sungurtas, J., Mcnicol, J., Stewart, D., & Davies, H. (2010). Metabolomic analysis of the potato tuber life cycle. Metabolomics, 6, 274–291.

    Article  CAS  Google Scholar 

  • Sun, Q. F., Ding, J. G., Xu, D. Z., Chen, Y. P., Hong, L., Ye, Z. Y., et al. (2009). Prediction of the prognosis of patients with acute-on-chronic hepatitis B liver failure using the model for end-stage liver disease scoring system and a novel logistic regression model. Journal of Viral Hepatitis, 16, 464–470.

    Article  PubMed  Google Scholar 

  • Wei, B. Q., Mikkelsen, T. S., Mckinney, M. K., Lander, E. S., & Cravatt, B. F. (2006). A second fatty acid amide hydrolase with variable distribution among placental mammals. The Journal of Biological Chemistry, 281, 36569–36578.

    Article  PubMed  CAS  Google Scholar 

  • Whitfield, P., Noble, P.-J., Major, H., Beynon, R., Burrow, R., Freeman, A., et al. (2005). Metabolomics as a diagnostic tool for hepatology: Validation in a naturally occurring canine model. Metabolomics, 1, 215–225.

    Article  CAS  Google Scholar 

  • Wiklund, S., Johansson, E., Sjostrom, L., Mellerowicz, E. J., Edlund, U., Shockcor, J. P., et al. (2008). Visualization of GC/TOF-MS-based metabolomics data for identification of biochemically interesting compounds using OPLS class models. Analytical Chemistry, 80, 115–122.

    Article  PubMed  CAS  Google Scholar 

  • Xing, T., Li, L., Cao, H., & Huang, J. (2007). Altered immune function of monocytes in different stages of patients with acute on chronic liver failure. Clinical and Experimental Immunology, 147, 184–188.

    PubMed  CAS  Google Scholar 

  • Yamagishi, Y., Saito, H., Ebinuma, H., Kikuchi, M., Ojiro, K., Kanamori, H., et al. (2009). A new prognostic formula for adult acute liver failure using computer tomography-derived hepatic volumetric analysis. Journal of Gastroenterology, 44, 615–623.

    Article  PubMed  Google Scholar 

  • Yamagishi, Y., Saito, H., Tada, S., Horie, Y., Kato, S., Ishii, H., et al. (2005). Value of computed tomography-derived estimated liver volume/standard liver volume ratio for predicting the prognosis of adult fulminant hepatic failure in Japan. Journal of Gastroenterology and Hepatology, 20, 1843–1849.

    Article  PubMed  Google Scholar 

  • Yang, J., Zhao, X., Liu, X., Wang, C., Gao, P., Wang, J., et al. (2006). High performance liquid chromatography-mass spectrometry for metabonomics: Potential biomarkers for acute deterioration of liver function in chronic hepatitis B. Journal of Proteome Research, 5, 554–561.

    Article  PubMed  CAS  Google Scholar 

  • Yantorno, S. E., Kremers, W. K., Ruf, A. E., Trentadue, J. J., Podesta, L. G., & Villamil, F. G. (2007). MELD is superior to King’s college and Clichy’s criteria to assess prognosis in fulminant hepatic failure. Liver Transplantation, 13, 822–828.

    Article  PubMed  Google Scholar 

  • Yasumi, Y., Takikawa, Y., Endo, R., & Suzuki, K. (2007). Interleukin-17 as a new marker of severity of acute hepatic injury. Hepatology Research, 37, 248–254.

    Article  PubMed  CAS  Google Scholar 

  • Zaman, M. B., Hoti, E., Qasim, A., Maguire, D., Mccormick, P. A., Hegarty, J. E., et al. (2006). MELD score as a prognostic model for listing acute liver failure patients for liver transplantation. Transplantation Proceedings, 38, 2097–2098.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Here I thank Dr. Zonghui Ding from the Second Affiliated Hospital, School of Medicine, Zhejiang University for his help in R statistics and thoughtful discussion. The work was supported by National S&T Major Project for Infectious Disease Control of China (2008ZX10002-05) and the National Natural Science Foundation of China (30630023).

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Authors and Affiliations

  1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China

    Shaorui Hao, Jiaojiao Xin, Jiangshan Lian, Qing Xie, Deying Chen, Yongzheng Guo, Yingfeng Lu, Guoping Sheng, Wei Xu, Jianrong Huang & Lanjuan Li

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  1. Shaorui Hao
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  2. Jiaojiao Xin
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  3. Jiangshan Lian
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  4. Qing Xie
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  6. Yongzheng Guo
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  7. Yingfeng Lu
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  9. Wei Xu
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  11. Lanjuan Li
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Correspondence to Lanjuan Li.

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Hao, S., Xin, J., Lian, J. et al. Establishing a metabolomic model for the prognosis of hepatitis B virus-induced acute-on-chronic liver failure treated with different liver support systems. Metabolomics 7, 400–412 (2011). https://doi.org/10.1007/s11306-010-0260-5

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