Patients with chronic fatigue syndrome (CFS) have a broad and variable spectrum of signs and symptoms with variable onsets. This report outlines the results of a single-blind, cross-sectional research project that extensively investigated a large cohort of 100 CFS patients and 82 nonfatigued control subjects with the aim of performing a case-control evaluation of alterations in standard blood parameters and urinary amino and organic acid excretion profiles. Blood biochemistry and full blood counts were unremarkable and fell within normal laboratory ranges. However, the case-control comparison of the blood cell data revealed that CFS patients had a significant decrease in red cell distribution width and increases in mean platelet volume, neutrophil counts, and the neutrophil-lymphocyte ratio. Evaluation of the urine excretion parameters also revealed a number of anomalies. The overnight urine output and rate of amino acid excretion were both reduced in the CFS group (P < 0.01). Significant decreases in the urinary excretion of asparagine (P < 0.0001), phenylalanine (P < 0.003), the branch chain amino acids (P < 0.005), and succinic acid (P < 0.0001), as well as increases in 3-methylhistidine (P < 0.05) and tyrosine (P < 0.05) were observed. It was concluded that the urinary excretion and blood parameters data supported the hypothesis that alterations in physiologic homeostasis exist in CFS patients.
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References
1.
Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, Jones JF, Dubois RE, Cunningham-Rundles C, Pahwa S, Tosato G, Zegans LS, Purtilo DT, Brown N, Schooley RT, Brus I. Chronic fatigue syndrome: a working case definition. Ann Intern Med108:387–389, 1988.
2.
Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med121:953–959, 1994.
3.
Lloyd AR, Hickie I, Boughton CR, Spencer O, Wakefield D. Prevalence of chronic fatigue syndrome in an Australian population. Med J Aust153:522–528, 1990.
4.
Gunn WJ, Connell DB, Randall B. Epidemiology of chronic fatigue syndrome: the Centers for Disease Control study. Ciba Found Symp173:83–93, 1993.
5.
Buchwald D, Umali P, Umali J, Kith P, Pearlman T, Komaroff AL. Chronic fatigue and the chronic fatigue syndrome: prevalence in a Pacific Northwest health care system. Ann Intern Med123:81–88, 1995.
6.
Jason LA, Taylor R, Wagner L, Holden J, Ferrari JR, Plioplys AV, Plioplys S, Lipkin D, Papernik M. Estimating rates of chronic fatigue syndrome from a community-based sample: a pilot study. Am J Community Psychol23:557–568, 1995.
7.
Lawrie SM, Manders DN, Geddes JR, Pelosi AJ. A population-based incidence study of chronic fatigue. Psych Med27:343–353, 1997.
8.
Wessely S, Chalder T, Hirsch S, Wallace P, Wright D. The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. Am J Public Health87:1449–1455, 1997.
DeLuca J, Johnson SK, Ellis SP, Natelson BH. Sudden vs gradual onset of chronic fatigue syndrome differentiates individuals on cognitive and psychiatric measures. J Psychiatr Res31:83–90, 1997.
11.
Komaroff AL. Clinical presentation of chronic fatigue syndrome. Ciba Found Symp173:43–54, 1993.
12.
MacDonald KL, Osterholm MT, LeDell KH, White KE, Schenck CH, Chao CC, Persing DH, Johnson RC, Barker JM, Peterson PK. A case-control study to assess possible triggers and cofactors in chronic fatigue syndrome. Am J Med100:548–554, 1996.
13.
Eaton KK, Hunnisett A. Abnormalities in essential amino acids in patients with chronic fatigue syndrome. J Nutr Med2:369–375, 1991.
14.
McGregor NR, Dunstan RH, Zerbes M, Butt HL, Roberts TK, Klineberg IJ. Preliminary determination of a molecular basis to Chronic Fatigue Syndrome. Biochem Mol Med57:73–80, 1996.
15.
McGregor NR, Dunstan RH, Zerbes M, Butt HL, Roberts TK, & Klineberg IJ. Preliminary determination of the association between symptom expression and urinary metabolites in subjects with chronic fatigue syndrome. Biochem Mol Med58:85–92, 1996.
16.
Bralley JA, Lord RS. Chronic fatigue and amino acids. J Appl Nutr46:74–78, 1994.
17.
Bralley JA, Lord RS. Treatment of chronic fatigue syndrome with specific amino acid supplementation. J Appl Nutr46:74–78, 1997.
18.
Jones MG, Cooper E, Amjad S, Goodwin CS, Barron JL, Chalmers RA, Jones MG, Cooper E, Amjad S, Goodwin CS, Barron JL, Chalmers RA. Urinary and plasma organic acids and amino acids in chronic fatigue syndrome. Clin Chim Acta361:150–158, 2005.
19.
Truss CO. Metabolic abnormalities in patients with chronic candidiasis. The acetaldehyde hypothesis. J Orthomol Psychiatr13:66–93, 1984.
20.
Moldofsky H, Warsh JJ. Plasma tryptophan and musculoskeletal pain in non-articular rheumatism ("fibrositis syndrome"). Pain5:65–71, 1978.
21.
Russell IJ, Michalek JE, Vipraio GA, Fletcher EM, Wall K. Serum amino acids in fibrositis/fibromyalgia syndrome. J Rheumatol16:158–163, 1989.
22.
Russell IJ, Michalek JE, Vipraio GA, Fletcher EM, Javors MA, Bowden CA. Platelet 3H-imipramine uptake receptor density and serum serotonin levels in patients with fibromyalgia/fibrositis syndrome. J Rheumatol19:104–109, 1992.
23.
Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ. A report -chronic fatigue syndrome: guidelines for research. J Royal Soc Med84:118–121, 1991.
24.
MacKenzie SL, Tenaschuk D. Gas-liquid chromatography of N-heptafluorobutyryl isobutyl esters of amino acids. J Chromatogr97:19–24, 1974.
25.
Westgard JO, Barry PL, Hunt MR, Groth T. A multi-rule Shewart chart for quality control in clinical chemistry. Clin Chem27:493–501, 1981.
26.
Buchwald D. Laboratory findings in CFS. In: Jenkins R, Mowbray JF, Eds. Post-Viral Fatigue Syndrome (Myalgic Encephalomyelitis). Chichester, UK: John Wiley & Sons Ltd., pp123–136, 1991.
Dacie JV, Lewis SM. Practical Haematology (7th ed). Edinburgh, UK: Churchill Livingstone, 1991.
29.
Richards RS, Roberts TK, Mathers D, Dunstan RH, McGregor NR, Butt HL. Investigation of erythrocyte oxidative damage in rheumatoid arthritis and chronic fatigue syndrome. J Chronic Fatigue Syndrome6:37–46, 2000.
30.
Richards RS, Roberts TK, Mathers D, Dunstan RH, McGregor NR, Butt HL. Erythrocyte morphology in rheumatoid arthritis and chronic fatigue syndrome: a preliminary study. J Chronic Fatigue Syndrome6:23–35, 2000.
31.
Simpson LO (1992) The role of nondiscocytic erythrocytes in the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome. In: Hyde BM, Goldstein J, Levine P, Eds. The Clinical and Scientific Basis of the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Ottawa: The Nightingale Research Foundation, pp597–605, 1992.
32.
Simpson LO, Murdoch JC, Herbison GP. Red cell shape changes following trigger finger fatigue in subjects with chronic tiredness and healthy controls. N Z Med J106:104–107, 1993.
33.
Mukherjee TM, Smith K, Maros K. Abnormal red-blood-cell morphology in myalgic encephalomyelitis. Lancet2:328–329, 1987.
34.
Roberts TK, McGregor NR, Dunstan RH, Donohoe M, Murdoch RN, Hope D, Zhang S, Butt HL, Watkins JA, Taylor WG. Immunological and haematological parameters in patients with chronic fatigue syndrome. J Chronic Fatigue Syndrome4:51–65, 1998.
35.
Simpson LO, Shand BI, Olds RJ. Blood rheology and myalgic encephalomyelitis: a pilot study. Pathology18:190–192, 1986.
36.
Simpson LO. Nondiscocytic erythrocytes in myalgic encephalomyelitis. N Z Med J102:126–127, 1989.
37.
Pacy PJ, Read M, Peters TJ, Halliday D. Post-absorptive whole body leucine kinetics and quadriceps muscle protein synthetic rate (MPSR) in the post-viral syndrome. Clin Sci75:36P–37P, 1988.
38.
Halliday D, Pacy PJ. Whole body and muscle protein synthesis in Myalgic Encephalomyelitis. In: Hyde BM, Goldstein J, Levine P, Eds. The Clinical and Scientific Basis of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome. Ottawa, Canada: The Nightingale Research Foundation, pp357–363, 1992.
39.
Byrne E, Trounce I, Dennett X. Chronic relapsing myalgia (post-viral): clinical, histological, and biochemical studies. Aust N Z J Med15:305–308, 1985.
40.
Wong R, Lopaschuk G, Zhu G, Walker D, Catellier D, Burton D, Teo K, Collinsnakai R, Montague T. Skeletal muscle metabolism in the chronic fatigue syndrome - in vivo assessment by 31P nuclear magnetic resonance spectroscopy. Chest102:1716–1722, 1992.
Adibi SA. Roles of branched-chain amino acids in metabolic regulation. J Lab Clin Med95:475–484, 1980.
43.
Odessey R, Goldberg AL. Oxidation of leucine by rat skeletal muscle. Am J Physiol223:1376–1383, 1972.
44.
Costa DC, Tannock C, Brostoff J. Brainstem perfusion is impaired in chronic fatigue syndrome. Q J Med88:767–773, 1995.
45.
Felig P, Wahren J, Ahlborg G. Uptake of individual amino acids by the human brain. Proc Soc Exp Biol Med142:230–231, 1973.
46.
Smith QR, Momma S, Aoyagi M, Rapoport SI. Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem49:1651–1658, 1987.
47.
Yudkoff M, Daikhin Y, Lin ZP, Nissim I, Stern J. Interrelationships of leucine and glutamate metabolism in cultured astrocytes. J Neurochem62:1192–1202, 1994.
48.
Yudkoff M, Daikhin Y, Grunstein L, Nissim I, Stern J, Pleasure D, Nissim I. Astrocyte leucine metabolism: significance of branched-chain amino acid transamination. J Neurochem66:378–385, 1996.
49.
Yudkoff M, Daikhin Y, Nelson D, Nissim I, Erecinska M. Neuronal metabolism of branched-chain amino acids: flux through the amino-transferase pathway in synaptosomes. J Neurochem66:2136–2145, 1996.
50.
Yudkoff M, Nissim I, Hertz L. Precursors of glutamic acid nitrogen in primary neuronal cultures: studies with 15N. Neurochem Res15:1191–1196, 1990.
51.
Kanamori K, Ross BD, Kondrat RW. Rate of glutamate synthesis from leucine in rat brain measured in vivo by 15N NMR. J Neurochem70:1304–1315, 1998.
52.
Daikhin Y, Yudkoff M. Compartmentation of brain glutamate metabolism in neurons and glia. J Nutr130:1026S–1031S, 2000.
53.
McEntee WJ, Crook TH. Glutamate: its role in learning, memory, and the aging brain. Psychopharmacology111:391–401, 1993.
54.
Cangiano C, Cardelli-Cangiano P, James JH, Rossi-Fanelli F, Patrizi MA, Brackett KA, Strom R, Fischer JE. Brain microvessels take up large neutral amino acids in exchange for glutamine. Cooperative role of Na+-dependent and Na+-independent systems. J Biol Chem258:8949–8954, 1983.
55.
Brooks N. Interaction between the glutamine cycle and the uptake of large neutral amino acids in astrocytes. J Neurochem60:1923–1928, 1993.
56.
Mortimore GE, Poso AR. Intracellular protein catabolism and its control during nutrient deprivation and supply. Annu Rev Nutr7:539–564, 1987.
57.
Teahon K, Preedy VR, Smith DG, Peters TJ. Clinical studies of the post-viral fatigue syndrome (PVFS) with special reference to skeletal muscle function. Clin Sci75:45P, 1988.
58.
Preedy VR, Smith DG, Salisbury JR, Peters TJ. Biochemical and muscle studies in patients with acute onset post-viral fatigue syndrome. J Clin Pathol46:722–726, 1993.
59.
Peters TJ, Preedy VR (1991) Pathological changes in skeletal muscle in ME: implications for management. In: Jenkins R, Mowbray JF, Eds. Post-Viral Fatigue Syndrome (Myalgic Encephalomyelitis). Chichester, UK: John Wiley & Sons Ltd., pp137–146, 1991.
60.
Straus SE, Tosato G, Armstrong G, Lawley T, Preble OT, Henle W, Davey R, Pearson G, Epstein J, Brus I. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med102:7–16, 1985.
61.
Morag A, Tobi M, Ravid Z, Revel M, Schattner A. Increased (2′–5′)-oligo-A synthetase activity in patients with prolonged illness associated with persistent Epstein-Barr virus infection. Lancet1:744, 1982.
62.
Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Muller WE, Schroder HC, Carter WA. Upregulation of the 2–5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Inf Dis18(Suppl 1):S96–S104, 1994.
63.
Suhadolnik RJ, Reichenbach NL, Hitzges P, Adelson ME, Peterson DL, Cheney PR, Salvato P, Thompson C, Loveless M, Muller WEG, Schroder HC, Strayer DR, Carter WA. Changes in the 2–5A synthetase/RNase L antiviral pathway in a controlled clinical trial with Poly (I)-Poly (C12U) in chronic fatigue syndrome. In Vivo8:599–604, 1994.
64.
Suhadolnik RJ, Peterson DL, O’Brien K, Cheney PR, Herst CV, Reichenbach NL, Kon N, Horvath SE, Iacono KT, Adelson ME, De Meirleir K, De Becker P, Charubala R, Pfleiderer W. Biochemical evidence for a novel low molecular weight 2–5A-dependent RNase L in chronic fatigue syndrome. J Interferon Cytokine Res17:377–385, 1997.
65.
Suhadolnik RJ, Peterson DL, Cheney PR, Horvath SE, Reichenbach NL, O’Brien K, Lombardi V, Welsch S, Furr EG, Charubala R, Pfleiderer W. Biochemical dysregulation of the 2–5/RNase L antiviral defense pathway in chronic fatigue syndrome. In: Fourth International Research, Clinical and Patient Conference. Chronic Fatigue Syndrome. Proceedings. Cambridge, MA: American Association for Chronic Fatigue Syndrome, pp39, 1998.
66.
Vojdani A, Ghoneum M, Choppa PC, Magtoto L, Lapp CW. Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. J Intern Med242:465–478, 1997.
67.
Linde A, Andersson B, Svenson SB, Ahrne A, Carlsson M, Forsberg P, Hugo H, Karstorp A, Lenkei R, Lindwall A, Loftenius A, Säll C, Andersson J. Serum levels of lymphokines and soluble cellular receptors in primary Epstein-Barr virus infection and in patients with chronic fatigue syndrome. J Infect Dis165:994–1000, 1992.
68.
Patarca R, Klimas NG, Lugtendorf S, Antoni M, Fletcher MA. Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome: interrelations with cellular sources and patterns of soluble immune mediator expression. Clin Inf Dis18:S147–S153, 1992.
69.
Swanink CM, Vercoulen JH, Galama JM, Roos MT, Meyaard L, van der Ven-Jongekrijg J, de NR, Bleijenberg G, Fennis JF, Miedema F, van der Meer JW. Lymphocyte subsets, apoptosis, and cytokines in patients with chronic fatigue syndrome. J Infect Dis173:460–463, 1996.
70.
Mawle AC, Nisenbaum R, Dobbins JG, Gary HE, Stewart JA, Reyes M, Steele L, Schmid DS, Reeves WC. Immune responses associated with chronic fatigue syndrome: a case-control study. J Infect Dis175:136–141, 1997.
71.
Chao CC, Janoff EN, Hu SX, Thomas K, Gallagher M, Tsang M, Peterson PK. Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine3:292–298, 1991.
72.
Lloyd A, Gandevia S, Brockman A, Hales J, Wakefield D. Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise. Clin Inf Dis18:S142–S146, 1994.
