Advertisement

Metabolomics

, 15:43 | Cite as

Metabolomics profiles of patients with Wilson disease reveal a distinct metabolic signature

  • Gaurav V. Sarode
  • Kyoungmi Kim
  • Dorothy A. Kieffer
  • Noreene M. Shibata
  • Tomas Litwin
  • Anna Czlonkowska
  • Valentina MediciEmail author
Original Article

Abstract

Introduction

Wilson disease (WD) is characterized by excessive intracellular copper accumulation in liver and brain due to defective copper biliary excretion. With highly varied phenotypes and a lack of biomarkers for the different clinical manifestations, diagnosis and treatment can be difficult.

Objective

The aim of the present study was to analyze serum metabolomics profiles of patients with Wilson disease compared to healthy subjects, with the goal of identifying differentially abundant metabolites as potential biomarkers for this condition.

Methods

Hydrophilic interaction liquid chromatography-quadrupole time of flight mass spectrometry was used to evaluate the untargeted serum metabolome of 61 patients with WD (26 hepatic and 25 neurologic subtypes, 10 preclinical) compared to 15 healthy subjects. We conducted analysis of covariance with potential confounders (body mass index, age, sex) as covariates and partial least-squares analysis.

Results

After adjusting for clinical covariates and multiple testing, we identified 99 significantly different metabolites (FDR < 0.05) between WD and healthy subjects. Subtype comparisons also revealed significantly different metabolites compared to healthy subjects: WD hepatic subtype (67), WD neurologic subtype (57), WD hepatic-neurologic combined (77), and preclinical (36). Pathway analysis revealed these metabolites are involved in amino acid metabolism, the tricarboxylic acid cycle, choline metabolism, and oxidative stress.

Conclusions

Patients with WD are characterized by a distinct metabolomics profile providing new insights into WD pathogenesis and identifying new potential diagnostic biomarkers.

Keywords

Copper Metabolomics Biomarkers Phenotype 

Abbreviations

WD

Wilson disease

HILIC-QTOF MS

Hydrophilic interaction liquid chromatography-quadrupole time of flight mass spectrometry

PLS-LDA

Partial least-squares regression with linear discriminant analysis

FDR

False discovery rate

TCA

Tricarboxylic acid

HN

Hepatic-neurologic manifestations combined

GSH

Glutathione

GR

Glucocorticoid receptor

PDH

Pyruvate dehydrogenase

ROS

Reactive oxygen species

2-HBA

2-Hydroxybutanoic acid

AA

Ascorbic acid

IPA

Indole-3-proprionic acid

Notes

Acknowledgements

We would like to acknowledge Triston Mosbacher (Department of Public Health Sciences, Division of Biostatistics, University of California, Davis) for his contribution to the analysis.

Author contributions

All authors took part in the study design and contributed to the final draft of the paper. In addition, VM conceived and designed the study, and wrote the paper. GS analyzed and interpreted the data, and wrote the paper. AC and TL provided the samples for the studies. NS proofread, contributed to the discussion, and assisted with arranging the final draft. KK performed the data analysis. DK managed the human subject samples and database, and contributed to data interpretation. All authors read and approved the final manuscript.

Funding

This research was supported by the National Institutes of Health/NIDDK through grant number R01DK104770 (to V.M.).

Compliance with ethical standards

Conflict of interest

Conflict of Interest: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors who participated in this study declared they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Ethical approval

This study was conducted according to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Institutional Review Board at the University of California, Davis.

Informed consent

Written informed consent was obtained from each patient and healthy subject in this study.

Supplementary material

11306_2019_1505_MOESM1_ESM.docx (1.1 mb)
Supplementary material 1 (DOCX 1110 KB)

References

  1. Ala, A., Walker, A. P., Ashkan, K., Dooley, J. S., & Schilsky, M. L. (2007). Wilson’s disease. The Lancet, 369, 397–408.CrossRefGoogle Scholar
  2. Aliasgharpour, M. (2015). A review on copper, ceruloplasmin and Wilson’s disease. International Journal of Medical Investigation, 4(4), 344–347.Google Scholar
  3. Alonso, C., Fernandez-Ramos, D., Varela-Rey, M., Martinez-Arranz, I., Navasa, N., Van Liempd, S. M., Lavin Trueba, J. L., Mayo, R., Ilisso, C. P., de Juan, V. G., Iruarrizaga-Lejarreta, M., delaCruz-Villar, L., Minchole, I., Robinson, A., Crespo, J., Martin-Duce, A., Romero-Gomez, M., Sann, H., Platon, J., Van Eyk, J., Aspichueta, P., Noureddin, M., Falcon-Perez, J. M., Anguita, J., Aransay, A. M., Martinez-Chantar, M. L., Lu, S. C., & Mato, J. M. (2017) Metabolomic identification of subtypes of nonalcoholic steatohepatitis. Gastroenterology, 152, 1449–1461.e7.CrossRefGoogle Scholar
  4. Ames, B. N., Cathcart, R., Schwiers, E., & Hochstein, P. (1981). Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: A hypothesis. Proceedings of National Academy of Sciences of United States of America, 78, 6858–6862.CrossRefGoogle Scholar
  5. Attri, S., Sharma, N., Jahagirdar, S., Thapa, B. R., & Prasad, R. (2006). Erythrocyte metabolism and antioxidant status of patients with Wilson disease with hemolytic anemia. Pediatric Research, 59, 593–597.CrossRefGoogle Scholar
  6. Baker, D. H., & Czarnecki-Maulden, G. L. (1987). Pharmacologic role of cysteine in ameliorating or exacerbating mineral toxicities. Journal of Nutrition, 117, 1003–1010.CrossRefGoogle Scholar
  7. Banasch, M., Goetze, O., Knyhala, K., Potthoff, A., Schlottmann, R., Kwiatek, M. A., Bulut, K., Schmitz, F., Schmidt, W. E., & Brockmeyer, N. H. (2006). Uridine supplementation enhances hepatic mitochondrial function in thymidine-analogue treated HIV-infected patients. AIDS, 20, 1554–1556.CrossRefGoogle Scholar
  8. Brancaccio, D., Gallo, A., Piccioli, M., Novellino, E., Ciofi-Baffoni, S., & Banci, L. (2017). [4Fe-4S] Cluster assembly in mitochondria and its impairment by copper. Journal of the American Chemical Society, 139, 719–730.CrossRefGoogle Scholar
  9. Braymer, J. J., & Lill, R. (2017). Iron-sulfur cluster biogenesis and trafficking in mitochondria. Journal of Biological Chemistry, 292, 12754–12763.CrossRefGoogle Scholar
  10. Briggs, J., Finch, P., Matulewicz, M. C., & Weigel, H. (1981). Complexes of copper(II), calcium, and other metal ions with carbohydrates: Thin-layer ligand-exchange chromatography and determination of relative stabilities of complexes. Carbohydrate Research, 97, 181–188.CrossRefGoogle Scholar
  11. Bull, P. C., Thomas, G. R., Rommens, J. M., Forbes, J. R., & Cox, D. W. (1993). The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nature Genetics, 5, 327–337.CrossRefGoogle Scholar
  12. Cabras, T., Sanna, M., Manconi, B., Fanni, D., Demelia, L., Sorbello, O., Iavarone, F., Castagnola, M., Faa, G., & Messana, I. (2015). Proteomic investigation of whole saliva in Wilson’s disease. Journal of Proteomics, 128, 154–163.CrossRefGoogle Scholar
  13. Chen, Y., Yang, Y., Miller, M. L., Shen, D., Shertzer, H. G., Stringer, K. F., Wang, B., Schneider, S. N., Nebert, D. W., & Dalton, T. P. (2007). Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Hepatology, 45, 1118–1128.CrossRefGoogle Scholar
  14. Chinnasamy, T., Sharma, Y., Gupta, P., & Gupta, S. (2016) Arsenic (As) and Copper (Cu) serve as cofactors to produce hepatotoxicity with mitochondrial damage, double strand DNA breaks and disruption of ATM signaling. The FASEB Journal, 30, 1026.3.Google Scholar
  15. Chong, A. S., Huang, W., Liu, W., Luo, J., Shen, J., Xu, W., Ma, L., Blinder, L., Xiao, F., Xu, X., Clardy, C., Foster, P., & Williams, J. A. (1999). In vivo activity of leflunomide: Pharmacokinetic analyses and mechanism of immunosuppression. Transplantation, 68, 100–109.CrossRefGoogle Scholar
  16. Czlonkowska, A., Litwin, T., Dusek, P., Ferenci, P., Lutsenko, S., Medici, V., Rybakowski, J. K., Weiss, K. H., & Schilsky, M. L. (2018). Wilson disease. Nature Review Disease Primers, 4, 21.CrossRefGoogle Scholar
  17. Droge, W. (2005). Oxidative stress and ageing: Is ageing a cysteine deficiency syndrome? Philosophical Transactions of Royal Society London. Series B, Biological Sciences, 360, 2355–2372.CrossRefGoogle Scholar
  18. Eriksson, U. J., Naeser, P., & Brolin, S. E. (1986). Increased accumulation of sorbitol in offspring of manifest diabetic rats. Diabetes, 35, 1356–1363.CrossRefGoogle Scholar
  19. Ferenci, P., Caca, K., Loudianos, G., Mieli-Vergani, G., Tanner, S., Sternlieb, I., Schilsky, M., Cox, D., & Berr, F. (2003). Diagnosis and phenotypic classification of Wilson disease. Liver International, 23, 139–142.CrossRefGoogle Scholar
  20. Ferenci, P., Stremmel, W., Czlonkowska, A., Szalay, F., Viveiros, A., Stattermayer, A. F., Bruha, R., Houwen, R., Pop, T., Stauber, R., Gschwantler, M., Pfeiffenberger, J., Yurdaydin, C., Aigner, E., Steindl-Munda, P., Dienes, H. P., Zoller, H., & Weiss, K. H. (2018) Age, sex, but not ATP7B genotype effectively influences the clinical phenotype of Wilson disease. Hepatology.  https://doi.org/10.1002/hep.30280.CrossRefPubMedGoogle Scholar
  21. Gall, W. E., Beebe, K., Lawton, K. A., Adam, K. P., Mitchell, M. W., Nakhle, P. J., Ryals, J. A., Milburn, M. V., Nannipieri, M., Camastra, S., Natali, A., Ferrannini, E., & RISC Study Group. (2010). alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE, 5, e10883.CrossRefGoogle Scholar
  22. Gao, X., Chen, W., Li, R., Wang, M., Chen, C., Zeng, R., & Deng, Y. (2012). Systematic variations associated with renal disease uncovered by parallel metabolomics of urine and serum. BMC Systems Biology, 6(Suppl 1), S14.CrossRefGoogle Scholar
  23. Gasser, T., Moyer, J. D., & Handschumacher, R. E. (1981). Novel single-pass exchange of circulating uridine in rat liver. Science, 213, 777–778.CrossRefGoogle Scholar
  24. Gaynes, B. I., & Watkins, J. B. III (1989). Comparison of glucose, sorbitol and fructose accumulation in lens and liver of diabetic and insulin-treated rats and mice. Comparative Biochemistry and Physiology, Part B, 92, 685–690.CrossRefGoogle Scholar
  25. Huster, D., Kuhne, A., Bhattacharjee, A., Raines, L., Jantsch, V., Noe, J., Schirrmeister, W., Sommerer, I., Sabri, O., Berr, F., Mossner, J., Stieger, B., Caca, K., & Lutsenko, S. (2012). Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology, 142, 947–956 e5.CrossRefGoogle Scholar
  26. Kalita, J., Kumar, V., Misra, U. K., Ranjan, A., Khan, H., & Konwar, R. (2014). A study of oxidative stress, cytokines and glutamate in Wilson disease and their asymptomatic siblings. Journal of Neuroimmunology, 274, 141–148.CrossRefGoogle Scholar
  27. Karbownik, M., Reiter, R. J., Garcia, J. J., Cabrera, J., Burkhardt, S., Osuna, C., & Lewinski, A. (2001). Indole-3-propionic acid, a melatonin-related molecule, protects hepatic microsomal membranes from iron-induced oxidative damage: Relevance to cancer reduction. Journal of Cell Biochemistry, 81, 507–513.CrossRefGoogle Scholar
  28. Kieffer, D. A., & Medici, V. (2017). Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence. Liver Research, 1, 121–130.CrossRefGoogle Scholar
  29. Kim, S. J., Kim, S. H., Kim, J. H., Hwang, S., & Yoo, H. J. (2016). Understanding metabolomics in biomedical research. Endocrinology and Metabolism (Seoul), 31, 7–16.CrossRefGoogle Scholar
  30. Lai, J. C., & Blass, J. P. (1984). Neurotoxic effects of copper: Inhibition of glycolysis and glycolytic enzymes. Neurochemical Research, 9, 1699–1710.CrossRefGoogle Scholar
  31. Le, T. T., Ziemba, A., Urasaki, Y., Hayes, E., Brotman, S., & Pizzorno, G. (2013). Disruption of uridine homeostasis links liver pyrimidine metabolism to lipid accumulation. Journal of Lipid Research, 54, 1044–1057.CrossRefGoogle Scholar
  32. Lee, B. H., Kim, J. M., Heo, S. H., Mun, J. H., Kim, J., Kim, J. H., Jin, H. Y., Kim, G. H., Choi, J. H., & Yoo, H. W. (2011) Proteomic analysis of the hepatic tissue of Long-Evans Cinnamon (LEC) rats according to the natural course of Wilson disease. Proteomics, 11, 3698–3705.CrossRefGoogle Scholar
  33. Li, M., Li, Y., Chen, J., Wei, W., Pan, X., Liu, J., Liu, Q., Leu, W., Zhang, L., Yang, X., Lu, J., & Wang, K. (2007). Copper ions inhibit S-adenosylhomocysteine hydrolase by causing dissociation of NAD+ cofactor. Biochemistry, 46, 11451–11458.CrossRefGoogle Scholar
  34. Lichtmannegger, J., Leitzinger, C., Wimmer, R., Schmitt, S., Schulz, S., Kabiri, Y., Eberhagen, C., Rieder, T., Janik, D., Neff, F., Straub, B. K., Schirmacher, P., DiSpirito, A. A., Bandow, N., Baral, B. S., Flatley, A., Kremmer, E., Denk, G., Reiter, F. P., Hohenester, S., Eckardt-Schupp, F., Dencher, N. A., Adamski, J., Sauer, V., Niemietz, C., Schmidt, H. H., Merle, U., Gotthardt, D. N., Kroemer, G., Weiss, K. H., & Zischka, H. (2016). Methanobactin reverses acute liver failure in a rat model of Wilson disease. Journal of Clinical Investigation, 126, 2721–2735.CrossRefGoogle Scholar
  35. Macomber, L., & Imlay, J. A. (2009). The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity. Proceedings of National Academy of Sciences of United States of America, 106, 8344–8349.CrossRefGoogle Scholar
  36. Mandal, N., Bhattacharjee, D., Rout, J. K., Dasgupta, A., Bhattacharya, G., Sarkar, C., & Gangopadhyaya, P. K. (2016). Effect of copper on l-cysteine/l-cystine influx in normal human erythrocytes and erythrocytes of Wilson’s disease. Indian Journal of Clinical Biochemistry, 31, 468–472.CrossRefGoogle Scholar
  37. Maus, A., & Peters, G. J. (2017). Glutamate and alpha-ketoglutarate: Key players in glioma metabolism. Amino Acids, 49, 21–32.CrossRefGoogle Scholar
  38. Mazagova, M., Wang, L., Anfora, A. T., Wissmueller, M., Lesley, S. A., Miyamoto, Y., Eckmann, L., Dhungana, S., Pathmasiri, W., Sumner, S., Westwater, C., Brenner, D. A., & Schnabl, B. (2015). Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB Journal, 29, 1043–1055.CrossRefGoogle Scholar
  39. Medici, V., Kieffer, D. A., Shibata, N. M., Chima, H., Kim, K., Canovas, A., Medrano, J. F., Islas-Trejo, A. D., Kharbanda, K. K., Olson, K., Su, R. J., Islam, M. S., Syed, R., Keen, C. L., Miller, A. Y., Rutledge, J. C., Halsted, C. H., & LaSalle, J. M. (2016) Wilson disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model. Epigenetics, 11, 804–818.CrossRefGoogle Scholar
  40. Medici, V., Shibata, N. M., Kharbanda, K. K., Islam, M. S., Keen, C. L., Kim, K., Tillman, B., French, S. W., Halsted, C. H., & LaSalle, J. M. (2014) Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease. Epigenetics, 9, 286–296.CrossRefGoogle Scholar
  41. Medici, V., Shibata, N. M., Kharbanda, K. K., LaSalle, J. M., Woods, R., Liu, S., Engelberg, J. A., Devaraj, S., Torok, N. J., Jiang, J. X., Havel, P. J., Lonnerdal, B., Kim, K., & Halsted, C. H. (2013) Wilson’s disease: Changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease. Hepatology, 57, 555–565.CrossRefGoogle Scholar
  42. Metges, C. C. (2000). Contribution of microbial amino acids to amino acid homeostasis of the host. The Journal of Nutrition, 130, 1857S–1864S.CrossRefGoogle Scholar
  43. Nagasaka, H., Inoue, I., Inui, A., Komatsu, H., Sogo, T., Murayama, K., Murakami, T., Yorifuji, T., Asayama, K., Katayama, S., Uemoto, S., Kobayashi, K., Takayanagi, M., Fujisawa, T., & Tsukahara, H. (2006). Relationship between oxidative stress and antioxidant systems in the liver of patients with Wilson disease: Hepatic manifestation in Wilson disease as a consequence of augmented oxidative stress. Pediatric Research, 60, 472–477.CrossRefGoogle Scholar
  44. Naik, S. R., & Kokil, G. R. (2013) Development and discovery avenues in bioactive natural products for glycemic novel therapeutics. In Atta-ur-Rahman (Ed.), Studies in natural products chemistry (pp. 431–466). Amsterdam: Elsevier.Google Scholar
  45. Nussinson, E., Shahbari, A., Shibli, F., Chervinsky, E., Trougouboff, P., & Markel, A. (2013). Diagnostic challenges of Wilson’s disease presenting as acute pancreatitis, cholangitis, and jaundice. World Journal of Hepatology, 5, 649–653.CrossRefGoogle Scholar
  46. Obrosova, I. G. (2005). Increased sorbitol pathway activity generates oxidative stress in tissue sites for diabetic complications. Antioxidants & Redox Signaling, 7, 1543–1552.CrossRefGoogle Scholar
  47. Ogihara, H., Ogihara, T., Miki, M., Yasuda, H., & Mino, M. (1995). Plasma copper and antioxidant status in Wilson’s disease. Pediatric Research, 37, 219–226.CrossRefGoogle Scholar
  48. Park, J. Y., Mun, J. H., Lee, B. H., Heo, S. H., Kim, G. H., & Yoo, H. W. (2009). Proteomic analysis of sera of asymptomatic, early-stage patients with Wilson’s disease. Proteomics Clinical Applications, 3, 1185–1190.CrossRefGoogle Scholar
  49. Pierson, H., Muchenditsi, A., Kim, B.-E., Ralle, M., Zachos, N., Huster, D., & Lutsenko, S. (2018). The function of ATPase copper transporter ATP7B in intestine. Gastroenterology, 154, 168–180.e5.CrossRefGoogle Scholar
  50. Poulsom, R., & Heath, H. (1983). Inhibition of aldose reductase in five tissues of the streptozotocin-diabetic rat. Biochemical Pharmacology, 32, 1495–1499.CrossRefGoogle Scholar
  51. Robbins, K. R., & Baker, D. H. (1980). Effect of high-level copper feeding on the sulfur amino acid need of chicks fed corn-soybean meal and purified crystalline amino acid diets. Poultry Science, 59, 1099–1108.CrossRefGoogle Scholar
  52. Roberts, E. A., & Schilsky, M. L. and American Association for Study of Liver, D. (2008) Diagnosis and treatment of Wilson disease: An update. Hepatology 47, 2089–2111.CrossRefGoogle Scholar
  53. Rocha, A. G., & Dancis, A. (2016). Life without Fe–S clusters. Molecular Microbiology, 99, 821–826.CrossRefGoogle Scholar
  54. Roelofsen, H., Balgobind, R., & Vonk, R. J. (2004). Proteomic analyzes of copper metabolism in an in vitro model of Wilson disease using surface enhanced laser desorption/ionization-time of flight-mass spectrometry. Journal of Cell Biochemistry, 93, 732–740.CrossRefGoogle Scholar
  55. Rossi, L., Lombardo, M. F., Ciriolo, M. R., & Rotilio, G. (2004). Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance. Neurochemical Research, 29, 493–504.CrossRefGoogle Scholar
  56. Rouault, T. A. (2012). Biogenesis of iron-sulfur clusters in mammalian cells: New insights and relevance to human disease. Disease Models & Mechanisms, 5, 155–164.CrossRefGoogle Scholar
  57. Sheline, C. T., & Choi, D. W. (2004). Cu2+ toxicity inhibition of mitochondrial dehydrogenases in vitro and in vivo. Annals of Neurology, 55, 645–653.CrossRefGoogle Scholar
  58. Simpson, D. M., Beynon, R. J., Robertson, D. H., Loughran, M. J., & Haywood, S. (2004). Copper-associated liver disease: A proteomics study of copper challenge in a sheep model. Proteomics, 4, 524–536.CrossRefGoogle Scholar
  59. Sipos, K., Lange, H., Fekete, Z., Ullmann, P., Lill, R., & Kispal, G. (2002). Maturation of cytosolic iron-sulfur proteins requires glutathione. Journal of Biological Chemistry, 277, 26944–26949.CrossRefGoogle Scholar
  60. Song, M., Li, X., Zhang, X., Shi, H., Vos, M. B., Wei, X., Wang, Y., Gao, H., Rouchka, E. C., Yin, X., Zhou, Z., Prough, R. A., Cave, M. C., & McClain, C. J. (2018). Dietary copper–fructose interactions alter gut microbial activity in male rats. American Journal of Physiology-Gastrointestinal and Liver Physiology, 314, G119–G130.CrossRefGoogle Scholar
  61. Summer, K. H., & Eisenburg, J. (1985). Low content of hepatic reduced glutathione in patients with Wilson’s disease. Biochemical Medicine, 34, 107–111.CrossRefGoogle Scholar
  62. Thomas, M., & Hughes, R. E. (1983). A relationship between ascorbic acid and threonic acid in guinea-pigs. Food and Chemical Toxicology, 21, 449–452.CrossRefGoogle Scholar
  63. Umeki, S., Ohga, R., Konishi, Y., Yasuda, T., Morimoto, K., & Terao, A. (1986). Oral zinc therapy normalizes serum uric acid level in Wilson’s disease patients. American Journal of Medical Sciences, 292, 289–292.CrossRefGoogle Scholar
  64. Vallieres, C., Holland, S. L., & Avery, S. V. (2017). Mitochondrial ferredoxin determines vulnerability of cells to copper excess. Cell Chemical Biology, 24, 1228–1237.e3.CrossRefGoogle Scholar
  65. Vernis, L., El Banna, N., Baille, D., Hatem, E., Heneman, A., & Huang, M. E. (2017) Fe–S clusters emerging as targets of therapeutic drugs. Oxidative Medicine and Cellular Longevity, 2017, 3647657.CrossRefGoogle Scholar
  66. Wang, H., Zhou, Z., Hu, J., Han, Y., Wang, X., Cheng, N., Wu, Y., & Yang, R. (2015). Renal impairment in different phenotypes of Wilson disease. Neurological Sciences, 36, 2111–2115.CrossRefGoogle Scholar
  67. Wang, J. B., Pu, S. B., Sun, Y., Li, Z. F., Niu, M., Yan, X. Z., Zhao, Y. L., Wang, L. F., Qin, X. M., Ma, Z. J., Zhang, Y. M., Li, B. S., Luo, S. Q., Gong, M., Sun, Y. Q., Zou, Z. S., & Xiao, X. H. (2014) Metabolomic profiling of autoimmune hepatitis: The diagnostic utility of nuclear magnetic resonance spectroscopy. Journal of Proteome Research, 13(8), 3792–3801.CrossRefGoogle Scholar
  68. Whyte, I. M., Francis, B., & Dawson, A. H. (2007). Safety and efficacy of intravenous N-acetylcysteine for acetaminophen overdose: Analysis of the Hunter Area Toxicology Service (HATS) database. Current Medical Research and Opinion, 23, 2359–2368.CrossRefGoogle Scholar
  69. Wikoff, W. R., Anfora, A. T., Liu, J., Schultz, P. G., Lesley, S. A., Peters, E. C., & Siuzdak, G. (2009). Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proceedings of National Academy of Sciences of United States of America, 106, 3698–3703.CrossRefGoogle Scholar
  70. Wilmarth, P. A., Short, K. K., Fiehn, O., Lutsenko, S., David, L. L., & Burkhead, J. L. (2012). A systems approach implicates nuclear receptor targeting in the Atp7b(−/−) mouse model of Wilson’s disease. Metallomics, 4, 660–668.CrossRefGoogle Scholar
  71. Winquist, A., Steenland, K., & Shankar, A. (2010). Higher serum uric acid associated with decreased Parkinson’s disease prevalence in a large community-based survey. Movement Disorders, 25, 932–936.CrossRefGoogle Scholar
  72. Xu, J., Jiang, H., Li, J., Cheng, K. K., Dong, J., & Chen, Z. (2015). 1H NMR-based metabolomics investigation of copper-laden rat: A model of Wilson’s disease. PLoS ONE, 10, e0119654.CrossRefGoogle Scholar
  73. Yisireyili, M., Takeshita, K., Saito, S., Murohara, T., & Niwa, T. (2017). Indole-3-propionic acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory genes in proximal tubular cells. Nagoya Journal of Medical Science, 79, 477–486.PubMedPubMedCentralGoogle Scholar
  74. Zhang, H., Yan, C., Yang, Z., Zhang, W., Niu, Y., Li, X., Qin, L., & Su, Q. (2017). Alterations of serum trace elements in patients with type 2 diabetes. Journal of Trace Elements in Medicine and Biology, 40, 91–96.CrossRefGoogle Scholar
  75. Zheng, T., Liu, L., Shi, J., Yu, X., Xiao, W., Sun, R., Zhou, Y., Aa, J., & Wang, G. (2014). The metabolic impact of methamphetamine on the systemic metabolism of rats and potential markers of methamphetamine abuse. Molecular BioSystems, 10, 1968–1977.CrossRefGoogle Scholar
  76. Zhou, C., Jia, H. M., Liu, Y. T., Yu, M., Chang, X., Ba, Y. M., & Zou, Z. M. (2016). Metabolism of glycerophospholipid, bile acid and retinol is correlated with the early outcomes of autoimmune hepatitis. Molecular BioSystems, 12, 1574–1585.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Gastroenterology and Hepatology, Department of Internal MedicineUniversity of California DavisSacramentoUSA
  2. 2.Division of Biostatistics, Department of Public Health SciencesUniversity of California DavisDavisUSA
  3. 3.Department of NeurologyInstitute of Psychiatry and NeurologyWarsawPoland

Personalised recommendations