Metabolic analysis of amino acids and vitamin B6 pathways in lymphoma survivors with cancer related chronic fatigue


Autoři: Alexander Fosså aff001;  Knut Halvor Smeland aff001;  Øystein Fluge aff004;  Karl Johan Tronstad aff005;  Jon Håvard Loge aff006;  Øivind Midttun aff007;  Per Magne Ueland aff007;  Cecilie Essholt Kiserud aff001
Působiště autorů: Department of Oncology, National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital, Oslo, Norway aff001;  Department of Oncology, Oslo University Hospital, Oslo, Norway aff002;  KG Jebsen Center for B-cell malignancies, Oslo University, Oslo, Norway aff003;  Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway aff004;  Department of Biomedicine, University of Bergen, Bergen, Norway aff005;  Regional Centre for Excellence in Palliative Care, Oslo University Hospital, Oslo, Norway aff006;  Bevital AS, Bergen, Norway aff007;  Department of Clinical Science, University of Bergen, Bergen, Norway aff008
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227384

Souhrn

Chronic cancer-related fatigue (CF) is a common and distressing condition in a subset of cancer survivors and common also after successful treatment of malignant lymphoma. The etiology and pathogenesis of CF is unknown, and lack of biomarkers hampers development of diagnostic tests and successful therapy. Recent studies on the changes of amino acid levels and other metabolites in patients with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) have pointed to possible central defects in energy metabolism. Here we report a comprehensive analysis of serum concentrations of amino acids, including metabolites of tryptophan, the kynurenine pathway and vitamin B6 in a well characterized national Norwegian cohort of lymphoma survivors after high-dose therapy and autologous stem cell transplantation. Among the 20 standard amino acids in humans, only tryptophan levels were significantly lower in both males and females with CF compared to non-fatigued survivors, a strikingly different pattern than seen in CFS/ME. Markers of tryptophan degradation by the kynurenine pathway (kynurenine/tryptophan ratio) and activation of vitamin B6 catabolism (pyridoxic acid/(pyridoxal + pyridoxal 5'-phosphate), PAr index) differed in survivors with or without CF and correlated with known markers of immune activation and inflammation, such as neopterin, C-reactive protein and Interleukin-6. Among personal traits and clinical findings assessed simultaneously in participating survivors, higher neuroticism score, obesity and higher PAr index were significantly associated with increased risk of CF. Collectively, these data point to low grade immune activation and inflammation as a basis for CF in lymphoma survivors.

Klíčová slova:

Amino acid analysis – Amino acid metabolism – Cancer treatment – Fatigue – Inflammation – Lymphomas – Metabolic pathways – Pyridoxine


Zdroje

1. Servaes P, Verhagen C, Bleijenberg G. Fatigue in cancer patients during and after treatment: prevalence, correlates and interventions. Eur J Cancer. 2002;38(1):27–43. doi: 10.1016/s0959-8049(01)00332-x 11750837

2. Wolfe F, Hawley DJ, Wilson K. The prevalence and meaning of fatigue in rheumatic disease. J Rheumatol. 1996;23(8):1407–17. 8856621

3. Fava M, Ball S, Nelson JC, Sparks J, Konechnik T, Classi P, et al. Clinical relevance of fatigue as a residual symptom in major depressive disorder. Depress Anxiety. 2014;31(3):250–7. doi: 10.1002/da.22199 24115209

4. Jason LA, Sunnquist M, Brown A, Reed J. Defining Essential Features of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. J Hum Behav Soc Environ. 2015;25(6):657–74. doi: 10.1080/10911359.2015.1011256 27047234

5. Reinertsen KV, Loge JH, Brekke M, Kiserud CE. Chronic fatigue in adult cancer survivors. Tidsskr Nor Laegeforen. 2017;137(21): doi: 10.4045/tidsskr.17.0040 29135175

6. Stone PC, Minton O. Cancer-related fatigue. Eur J Cancer. 2008;44(8):1097–104. doi: 10.1016/j.ejca.2008.02.037 18381237

7. Loge JH, Abrahamsen AF, Ekeberg O, Kaasa S. Hodgkin's disease survivors more fatigued than the general population. J Clin Oncol. 1999;17(1):253–61. doi: 10.1200/JCO.1999.17.1.253 10458240

8. Reinertsen KV, Engebraaten O, Loge JH, Cvancarova M, Naume B, Wist E, et al. Fatigue During and After Breast Cancer Therapy-A Prospective Study. J Pain Symptom Manage. 2017;53(3):551–60. doi: 10.1016/j.jpainsymman.2016.09.011 28042070

9. Loge JH, Ekeberg O, Kaasa S. Fatigue in the general Norwegian population: normative data and associations. J Psychosom Res. 1998;45(1):53–65. doi: 10.1016/s0022-3999(97)00291-2 9720855

10. Sprauten M, Haugnes HS, Brydoy M, Kiserud C, Tandstad T, Bjoro T, et al. Chronic fatigue in 812 testicular cancer survivors during long-term follow-up: increasing prevalence and risk factors. Ann Oncol. 2015;26(10):2133–40. doi: 10.1093/annonc/mdv328 26265167

11. Bower JE. Cancer-related fatigue—mechanisms, risk factors, and treatments. Nat Rev Clin Oncol. 2014;11(10):597–609. doi: 10.1038/nrclinonc.2014.127 25113839

12. Seland M, Holte H, Bjoro T, Schreiner T, Bollerslev J, Loge JH, et al. Chronic fatigue is prevalent and associated with hormonal dysfunction in long-term non-Hodgkin lymphoma survivors treated with radiotherapy to the head and neck region. Leuk Lymphoma. 2015;56(12):3306–14. doi: 10.3109/10428194.2015.1036258 25827172

13. Knobel H, Havard Loge J, Lund MB, Forfang K, Nome O, Kaasa S. Late medical complications and fatigue in Hodgkin's disease survivors. J Clin Oncol. 2001;19(13):3226–33. doi: 10.1200/JCO.2001.19.13.3226 11432890

14. Ng AK, Li S, Recklitis C, Neuberg D, Chakrabarti S, Silver B, et al. A comparison between long-term survivors of Hodgkin's disease and their siblings on fatigue level and factors predicting for increased fatigue. Ann Oncol. 2005;16(12):1949–55. doi: 10.1093/annonc/mdi407 16227316

15. Bower JE, Ganz PA, Irwin MR, Arevalo JM, Cole SW. Fatigue and gene expression in human leukocytes: increased NF-kappaB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. Brain Behav Immun. 2011;25(1):147–50. doi: 10.1016/j.bbi.2010.09.010 20854893

16. Orre IJ, Reinertsen KV, Aukrust P, Dahl AA, Fossa SD, Ueland T, et al. Higher levels of fatigue are associated with higher CRP levels in disease-free breast cancer survivors. J Psychosom Res. 2011;71(3):136–41. doi: 10.1016/j.jpsychores.2011.04.003 21843747

17. Hamre H, Zeller B, Kanellopoulos A, Ruud E, Fossa SD, Loge JH, et al. Serum cytokines and chronic fatigue in adults surviving after childhood leukemia and lymphoma. Brain Behav Immun. 2013;30:80–7. doi: 10.1016/j.bbi.2013.01.006 23333795

18. Yamano E, Sugimoto M, Hirayama A, Kume S, Yamato M, Jin G, et al. Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Scientific Reports. 2016;6:34990. doi: 10.1038/srep34990 27725700

19. Fluge Ø, Mella O, Bruland O, Risa K, Dyrstad SE, Alme K, et al. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. 2017;1(21): doi: 10.1172/jci.insight.89376 28018972

20. Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016;113(37):E5472–E80. doi: 10.1073/pnas.1607571113 27573827

21. Tomas C, Brown A, Strassheim V, Elson J, Newton J, Manning P. Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLOS ONE. 2017;12(10):e0186802. doi: 10.1371/journal.pone.0186802 29065167

22. Smeland KB, Loge JH, Aass HCD, Aspelin T, Bersvendsen H, Bolstad N, et al. Chronic fatigue is highly prevalent in survivors of autologous stem cell transplantation and associated with IL-6, neuroticism, cardiorespiratory fitness, and obesity. Bone Marrow Transplant. 2019;54(4):607–10. doi: 10.1038/s41409-018-0342-y 30262906

23. Murbraech K, Smeland KB, Holte H, Loge JH, Lund MB, Wethal T, et al. Heart Failure and Asymptomatic Left Ventricular Systolic Dysfunction in Lymphoma Survivors Treated With Autologous Stem-Cell Transplantation: A National Cross-Sectional Study. J Clin Oncol. 2015;33(24):2683–91. doi: 10.1200/JCO.2015.60.8125 26169610

24. Stenehjem JS, Smeland KB, Murbraech K, Holte H, Kvaløy S, Wethal T, et al. Diffusing capacity impairment is prevalent in long-term lymphoma survivors after high-dose therapy with autologous stem cell transplantation. Bone Marrow Transplant. 2016;52: doi: 10.1038/bmt.2016.338 27991891

25. Smeland KB, Kiserud CE, Lauritzsen GF, Fossa A, Hammerstrom J, Jetne V, et al. High-dose therapy with autologous stem cell support for lymphoma—from experimental to standard treatment. Tidsskr Nor Laegeforen. 2013;133(16):1735–9. doi: 10.4045/tidsskr.13.0319 24005713

26. Grov EK, Fossa SD, Bremnes RM, Dahl O, Klepp O, Wist E, et al. The personality trait of neuroticism is strongly associated with long-term morbidity in testicular cancer survivors. Acta Oncol. 2009;48(6):842–9. doi: 10.1080/02841860902795232 19412812

27. Horowitz M, Wilner N, Alvarez W. Impact of Event Scale: a measure of subjective stress. Psychosom Med. 1979;41(3):209–18. doi: 10.1097/00006842-197905000-00004 472086

28. Mykletun A, Stordal E, Dahl AA. Hospital Anxiety and Depression (HAD) scale: factor structure, item analyses and internal consistency in a large population. Br J Psychiatry. 2001;179:540–4. doi: 10.1192/bjp.179.6.540 11731359

29. Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, et al. Development of a fatigue scale. J Psychosom Res. 1993;37(2):147–53. doi: 10.1016/0022-3999(93)90081-p 8463991

30. Midttun O, McCann A, Aarseth O, Krokeide M, Kvalheim G, Meyer K, et al. Combined Measurement of 6 Fat-Soluble Vitamins and 26 Water-Soluble Functional Vitamin Markers and Amino Acids in 50 muL of Serum or Plasma by High-Throughput Mass Spectrometry. Anal Chem. 2016;88(21):10427–36. doi: 10.1021/acs.analchem.6b02325 27715010

31. Midttun O, Kvalheim G, Ueland PM. High-throughput, low-volume, multianalyte quantification of plasma metabolites related to one-carbon metabolism using HPLC-MS/MS. Anal Bioanal Chem. 2013;405(6):2009–17. doi: 10.1007/s00216-012-6602-6 23232958

32. Midttun O, Hustad S, Ueland PM. Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2009;23(9):1371–9. doi: 10.1002/rcm.4013 19337982

33. Werner ER, Fuchs D, Hausen A, Reibnegger G, Wachter H. Simultaneous determination of neopterin and creatinine in serum with solid-phase extraction and on-line elution liquid chromatography. Clin Chem. 1987;33(11):2028–33. 3119253

34. Zuo H, Tell GS, Ueland PM, Nygård O, Vollset SE, Midttun Ø, et al. The PAr index, an indicator reflecting altered vitamin B-6 homeostasis, is associated with long-term risk of stroke in the general population: the Hordaland Health Study (HUSK). Am J Clin Nutr. 2018;107(1):105–12. doi: 10.1093/ajcn/nqx012 29381795

35. Ueland PM, Ulvik A, Rios-Avila L, Midttun Ø, Gregory JF. Direct and Functional Biomarkers of Vitamin B6 Status. Annu Rev Nutr. 2015;35(1):33–70.

36. Ulvik A, Theofylaktopoulou D, Midttun O, Nygard O, Eussen SJ, Ueland PM. Substrate product ratios of enzymes in the kynurenine pathway measured in plasma as indicators of functional vitamin B-6 status. Am J Clin Nutr. 2013;98(4):934–40. doi: 10.3945/ajcn.113.064998 24004893

37. Ueland PM, McCann A, Midttun Ø, Ulvik A. Inflammation, vitamin B6 and related pathways. Mol Aspects Med. 2017;53:10–27. doi: 10.1016/j.mam.2016.08.001 27593095

38. Gieseg SP, Baxter-Parker G, Lindsay A. Neopterin, Inflammation, and Oxidative Stress: What Could We Be Missing? Antioxidants (Basel). 2018;7(7).

39. Cowen MP-B P.J., Newsholme E.A. Decreased plasma tryptophan levels in major depression. J Affect Disord. 1989;16:27–31. doi: 10.1016/0165-0327(89)90051-7 2521647

40. Doolin K, Allers KA, Pleiner S, Liesener A, Farrell C, Tozzi L, et al. Altered tryptophan catabolite concentrations in major depressive disorder and associated changes in hippocampal subfield volumes. Psychoneuroendocrinology. 2018;95:8–17. doi: 10.1016/j.psyneuen.2018.05.019 29787958

41. Badawy AA, Guillemin G. The Plasma [Kynurenine]/[Tryptophan] Ratio and Indoleamine 2,3-Dioxygenase: Time for Appraisal. Int J Tryptophan Res. 2019;12: doi: 1178646919868978 31488951

42. Ye Z, Yue L, Shi J, Shao M, Wu T. Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications. J Cancer. 2019;10(12):2771–82. doi: 10.7150/jca.31727 31258785

43. Wang Q, Liu D, Song P, Zou MH. Tryptophan-kynurenine pathway is dysregulated in inflammation, and immune activation. Front Biosci (Landmark Ed). 2015;20:1116–43.

44. Platten M, Nollen EAA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019;18:379–401. doi: 10.1038/s41573-019-0016-5 30760888

45. Pedersen ER, Tuseth N, Eussen SJ, Ueland PM, Strand E, Svingen GF, et al. Associations of plasma kynurenines with risk of acute myocardial infarction in patients with stable angina pectoris. Arterioscler Thromb Vasc Biol. 2015;35(2):455–62. doi: 10.1161/ATVBAHA.114.304674 25524770

46. Christensen MHE, Fadnes DJ, Røst TH, Pedersen ER, Andersen JR, Våge V, et al. Inflammatory markers, the tryptophan-kynurenine pathway, and vitamin B status after bariatric surgery. PLOS ONE. 2018;13(2):e0192169. doi: 10.1371/journal.pone.0192169 29401505

47. Clarke G, Fitzgerald P, Cryan JF, Cassidy EM, Quigley EM, Dinan TG. Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort. BMC Gastroenterol. 2009;9: doi: 10.1186/471-230X-9-6

48. Strasser B, Becker K, Fuchs D, Gostner JM. Kynurenine pathway metabolism and immune activation: Peripheral measurements in psychiatric and co-morbid conditions. Neuropharmacology. 2017;112(Pt B):286–96. doi: 10.1016/j.neuropharm.2016.02.030 26924709

49. Ulvik A, Midttun O, Pedersen ER, Eussen SJ, Nygard O, Ueland PM. Evidence for increased catabolism of vitamin B-6 during systemic inflammation. Am J Clin Nutr. 2014;100(1):250–5. doi: 10.3945/ajcn.114.083196 24808485

50. Myte R, Gylling B, Haggstrom J, Schneede J, Magne Ueland P, Hallmans G, et al. Untangling the role of one-carbon metabolism in colorectal cancer risk: a comprehensive Bayesian network analysis. Sci Rep. 2017;7:43434. doi: 10.1038/srep43434 28233834


Článek vyšel v časopise

PLOS One


2020 Číslo 1